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Chronic Kidney
Disease
Diagnosis and Treatment
Junwei Yang
Weichun He
Editors
123
Chronic Kidney Disease
Junwei Yang • Weichun He
Editors

Diagnosis and Treatment
Editors
Junwei Yang Weichun He
Centre for Kidney Disease Centre for Kidney Disease
Second Affiliated Hospital Second Affiliated Hospital
Nanjing Medical University Nanjing Medical University
Nanjing Nanjing
Jiangsu Jiangsu
China China
ISBN 978-981-32-9130-0 ISBN 978-981-32-9131-7 (eBook)

https://doi.org/10.1007/978-981-32-9131-7
© Springer Nature Singapore Pte Ltd. 2020

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Preface
Chronic kidney disease (CKD) is a global health problem with an increasing

morbidity and mortality. The last decade has seen significant improvement in
perception of the epidemiology, etiology, pathogenesis, and complications of
CKD due in major part to the development of definitions of CKD by the
Kidney Disease Outcomes Quality Initiative (KDOQI) and the Kidney
Disease Improving Global Outcomes (KDIGO). The increased recognition of
CKD led to the awareness of the importance and urgency of familiarizing
clinicians with its diagnosis and treatment which are essential to the well-
being of the patients. The purpose of the work is to guide general practitio-
ners and residents, more than just nephrologists, and to provide them with a
comprehensive and systematic review of the latest available concept concern-
ing clinical diagnosis and therapeutics over a wide spectrum of clinically
important CKD.
Our goal of the work is to provide a concise, well-organized exposition
of the knowledge base of CKD to the readers. Thus, the book is designed
to consist of 19 chapters divided into three parts. As compared with the
previous books concerning kidney diseases and CKD, the number of
chapters in each part is limited, and the length of each chapter is stream-
lined. Chapters in Part I cover hot topics of particular concern, such as
diabetic kidney disease, hypertensive kidney disease, pregnancy in CKD,
CKD in the elderly, and the association between acute kidney injury and
CKD. It also contains pathophysiology of CKD and advanced image tech-
niques for diagnosis of CKD. Part II contains major complications of
CKD, e.g., cardiovascular disease, anemia, mineral bone disorder, vita-
min D deficiency and secondary hyperparathyroidism, immune deficiency
and infection, and nervous system disorders. Part III include several cru-
cial aspects of management of CKD, which is nutritional intervention,
medication, initiation timing and modality option for renal replacement
therapy, and three modalities of renal replacement therapy, i.e., hemodi-
alysis, peritoneal dialysis, and transplantation. Based on this framework,
the book is organized to be a practical guide to clinical management of
great majority of CKD, and it should prove useful and valuable to clini-
cians. It is our hope that the reader will become acquainted with the most
important topics in CKD from this book.
We wish to thank all authors of this book for taking considerable time and
effort to ensure that all chapters bring state-of-the-art knowledge. In the
course of compiling this book, each author has consulted the latest literatures
v
vi Preface
and textbooks with a rigorous attitude of scholarly study, thus ensuring the
scientificity and referential property of the book. We hope that the readers
achieve the same level of acquisition of new knowledge and enjoyment as we
have attained by editing the book.
Nanjing, China Junwei Yang

Nanjing, China Weichun He
Contents
Part I Chronic Kidney Disease
1 Chronic Kidney Disease: Overview�� 3

Yang Zhou and Junwei Yang
2 Pathophysiology of Chronic Kidney Disease �� 13
Jiafa Ren and Chunsun Dai
3 Diabetic Kidney Disease�� 33
Ting Cai and Junwei Yang
4 Hypertensive Kidney Disease�� 45
Xiaobing Ji
5 Pregnancy in Chronic Kidney Disease �� 57
Weichun He
6 Aging and Chronic Kidney Disease�� 71
Tao Zhang
7 Acute Kidney Injury and Chronic Kidney Disease�� 83
Yu Chen and Weichun He
8 Advanced Image Techniques in Chronic Kidney Disease�� 99
Zhuo Xu
Part II Complications of Chronic Kidney Disease
9 Cardiovascular Disease in Chronic Kidney Disease �� 111

Jining Wu, Wenjin Liu, and Hongdi Cao
10 Anemia in Chronic Kidney Disease�� 123
Yi Fang and Weichun He
11 Chronic Kidney Disease-Mineral and Bone Disorder,
Vitamin D Deficiency, and Secondary
Hyperparathyroidism�� 141
Mingxia Xiong
vii
viii Contents
12 Immune Deficiency and Infection in Chronic Kidney

Disease�� 153
Lei Jiang and Ping Wen
13 Nervous System Disorders in Chronic Kidney Disease:
Neurocognitive Dysfunction, Depression, and Sleep
Disorder�� 161
Wenjin Liu
Part III Management of Chronic Kidney Disease
14 Nutritional Management of Chronic Kidney Disease�� 173

Li Fang
15 Medication in Chronic Kidney Disease�� 187
Hongdi Cao
16 Initiation Timing and Modality Option for Renal
Replacement Therapy�� 199
Ping Wen
17 Hemodialysis�� 209
Hong Ye, Hao Ding, Wei Gan, Ping Wen, Yang Zhou,
Hongdi Cao, and Weichun He
18 Peritoneal Dialysis�� 233
Jia Di
19 Transplantation�� 241
Hao Ding and Junwei Yang
Contributors
Ting Cai, PhD Candidate Nanjing Medical University, Nanjing, Jiangsu,

China
Hongdi Cao, MD, PhD Centre for Kidney Disease, Second Affiliated
Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
Yu Chen, MD, PhD Division of Nephrology, Shanghai Fifth People’s
Hospital, Fudan University, Shanghai, China
Chunsun Dai, MD, PhD Centre for Kidney Disease, Second Affiliated
Jia Di, MD, PhD Division of Nephrology, Third Affiliated Hospital,
Soochow University, Changzhou, Jiangsu, China
Hao Ding, MD, PhD Centre for Kidney Disease, Second Affiliated Hospital,
Nanjing Medical University, Nanjing, Jiangsu, China
Li Fang, MD, PhD Department of Nephrology, Affiliated Hospital of
Nantong University, Nantong, Jiangsu, China
Yi Fang, MD Centre for Kidney Disease, Second Affiliated Hospital,
Wei Gan, MD Centre for Kidney Disease, Second Affiliated Hospital,
Weichun He, MD, PhD Centre for Kidney Disease, Second Affiliated
Xiaobing Ji, MD, PhD Division of Nephrology, Nanjing First Hospital,
Lei Jiang, MD, PhD Centre for Kidney Disease, Second Affiliated Hospital,
Wenjin Liu, MD, PhD Centre for Kidney Disease, Second Affiliated
Jiafa Ren, MD, PhD Division of Nephrology, Department of Medicine,
Duke University and Durham VA Medical Centers, Durham, NC, USA
Ping Wen, MD, PhD Centre for Kidney Disease, Second Affiliated Hospital,
ix
x Contributors
Jining Wu, MD, PhD Centre for Kidney Disease, Second Affiliated

Mingxia Xiong, MD, PhD Centre for Kidney Disease, Second Affiliated
Zhuo Xu, MD, PhD Centre for Kidney Disease, Second Affiliated Hospital,
Junwei Yang, MD, PhD Centre for Kidney Disease, Second Affiliated
Hong Ye, MD Centre for Kidney Disease, Second Affiliated Hospital,
Tao Zhang, MD, PhD Division of Nephrology, Department of Geriatrics,
First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu,
China
Yang Zhou, MD, PhD Centre for Kidney Disease, Second Affiliated
Part I
Chronic Kidney Disease: Overview
1
Yang Zhou and Junwei Yang
Abstract overview definition, epidemiology, cost, and

Chronic kidney disease (CKD) is a condition outcomes of CKD. The detailed diagnosis
characterized by gradual loss of kidney func- and treatment will be discussed in the follow-
tion over time. The major role of the kidney is ing chapters.
excretion of water-soluble waste products.
Meanwhile, the kidneys respond continually
to changes in blood volume as well as osmo-
lality, and adjust the levels of water, electro- 1.1 Introduction
lyte, and acid-base balance by selectively
excreting or reabsorbing them. In addition, Chronic kidney disease (CKD) has become a
the kidneys are main site of production for a global public health problem with an increasing
number of hormones, chiefly renin and eryth- prevalence and high mortality [1]. Owing to the
ropoietin. Millions of adults have CKD and growing elderly population and the increasing
others who have diabetes, hypertension, and prevalence of hypertension and diabetes as well
family history of renal failure are at high risk. as the improving treatment strategies, the preva-
Glomerular filtration rate is the best estimate lence of CKD will inevitably continue to increase
of kidney function, combining with protein- in the near future. Glomerular filtration rate
uria is used for staging of CKD. Patients with (GFR) and albuminuria are proposed as the best
CKD may develop complications like cardio- indicators of kidney function, with low GFR and
vascular disease, anemia, mineral and bone increased albuminuria being associated with a
disorders, and nervous system diseases. high risk of kidney failure requiring renal
Those who develop kidney failure require replacement therapy and of cardiovascular dis-
dialysis or kidney transplantation. The cost of ease, anemia, mineral and bone disorder, and
treatment for this growing epidemic repre- other complications. On account of the signifi-
sents an enormous burden on healthcare sys- cant development of CKD definitions by the
tems worldwide. In this chapter, we will Kidney Disease: Improving Global Outcomes
(KDIGO), the recognition of CKD has greatly
improved in the last few years [2]. Increased
Y. Zhou (*) · J. Yang (*) awareness of and uniform classification criteria
Centre for Kidney Disease, Second Affiliated for CKD have led to greater focus on the devel-
Hospital, Nanjing Medical University,
Nanjing, Jiangsu, China opment of methods to slow CKD progression,
e-mail: zhouyang@njmu.edu.cn; jwyang@njmu.edu.cn
© Springer Nature Singapore Pte Ltd. 2020 3

J. Yang, W. He (eds.), Chronic Kidney Disease, https://doi.org/10.1007/978-981-32-9131-7_1
4 Y. Zhou and J. Yang
increased emphasis on the early recognition and Assign causes based on observed or presumed
prevention of complications associated with pathological–anatomical findings within the kid-
CKD, and better understanding of the economic ney and presence or absence of systemic
burden of CKD and accompanying illnesses. disease.
Despite the progress, therapies and clinical trials Assign GFR categories as shown in Table 1.2.
on which to base recommendations remain Assign albuminuria categories as shown in
remarkably limited. Table 1.3.
Alternatively, protein or urinary reagent strip
results can be substituted (Table 1.4).
1.2 Definition
CKD is defined as abnormalities of kidney struc- 1.4 Causes and Risk Factors

ture or function, present for >3 months [3].
Table 1.1 summarizes the criteria for CKD, either Diabetes and hypertension are the leading causes
of which should be present for >3 months. of CKD in all industrialized countries and several
underdeveloped countries. However, glomerulo-
nephritis and unknown causes are more common
1.3 Staging in Asian and Sub-Saharan African countries.
Table 1.5 lists the risk factors for CKD [1–3].
The KDIGO 2012 Clinical Practice Guideline In China, the current leading causes of CKD
suggested that CKD could be classified accord- are glomerular disease, diabetic kidney disease,
ing to cause, GFR category, and albuminuria cat- and hypertension. IgA nephropathy is one of the
egory (CGA) [3]. most common glomerular diseases.
Table 1.1 Criteria for CKD (either of the following Table 1.2 GFR categories in CKD
should be present for >3 months)
GFR GFR (mL/
• Albuminuria (AER ≥30 mg/24 h; ACR ≥30 mg/g category min/1.73 m2) Terms
[≥3 mg/mmol]) G1 ≥90 Normal/high
• Urinary sediment abnormality G2 60–89 Mildly decreased (relative
• Electrolyte and other abnormalities due to tubular to young adult level)
disorders
G3a 45–59 Mildly to moderately
• Abnormalities detected by histology
decreased
• Structural abnormalities detected by imaging
G3b 30–44 Moderately to severely
• History of kidney transplantation
decreased
• GFR <60 mL/min/1.73 m2
G4 15–29 Severely decreased
CKD chronic kidney disease, AER albumin excretion
G5 <15 Kidney failure
rate, ACR albumin-to-creatinine ratio, GFR glomerular
filtration rate (Reproduced with permission from GFR glomerular filtration rate, CKD chronic kidney
Elsevier [3]) disease
Table 1.3 Albuminuria categories in CKD

ACR
Category AER (mg/24 h) (mg/mmol) (mg/g) Terms
A1 <30 <3 <30 Normal to mildly increased
A2 30–300 3–30 30–300 Moderately increased (relative to young adult level)
A3 >300 >30 >300 Severely increased (including nephrotic syndrome)
AER albumin excretion rate, ACR albumin-to-creatinine ratio
1 Chronic Kidney Disease: Overview 5
Table 1.4 Categories of proteinuria in CKD disease burden in Latin American and South
PCR Asian countries, with continued high prevalence
PER (mg/ Protein of infectious diseases and increasing prevalence
Category (mg/24 h) mmol) (mg/g) reagent strip and severity of lifestyle-related diseases, such as
A1 <150 <15 <150 Negative to diabetes, hypertension, and obesity.
trace
A2 150–500 15–50 150– Trace to
500 positive
A3 >500 >50 >500 Positive or 1.5 Prevalence
greater
CKD chronic kidney disease, PER protein excretion rate, Approximately 10% of the population is affected
PCR protein-to-creatinine ratio by CKD worldwide, with millions annually dying
because of lack of access to affordable treatment
Table 1.5 Risk factors for CKD [1]. In China, the adjusted prevalence rate of esti-
Clinical factors • Diabetes mated GFR (eGFR) <60 mL/min/1.73 m2 and
• Hypertension albuminuria is 1.7% and 9.4%, respectively. The
• Autoimmune disease overall prevalence rate of CKD is approximately
• Systemic infection
• Urinary tract infection 10.8%; therefore, 119.5 million patients are esti-
• Urinary stones mated to have CKD in China [4].
• Lower urinary tract CKD can affect individuals of any race. In
obstruction particular, African American, American Indians,
• Urolithiasis
• Family history of CKD Hispanics, and individuals of South Asian origin
• Recovery from acute (Bangladesh, India, Sri Lanka, or Pakistan) have
kidney injury a high risk of CKD. The prevalence of CKD is
• Kidney mass reduction high in the northern (16.9%) and southwest
• Exposure to certain drugs
• Low birth weight (18.3%) regions of China compared with that in
Sociodemographic • Older age other regions. In rural areas of China, the preva-
factors • Race lence of albuminuria positively correlates with
• Exposure to certain the level of local economic development.
chemical and
environmental conditions
Although CKD can occur at any age, it
• Low income/education becomes more common with increasing age and
CKD chronic kidney disease (Reproduced with permis- in the female gender. It has been known for
sion from Elsevier [3]) decades that eGFR declines in parallel with age.
The mean age of 9614 patients presenting with
These differences among countries are pri- stage 3 CKD in India and 1185 patients in China
marily related to disease burden shifting from is 51.0 and 63.6 years, respectively. It is esti-
infections toward chronic lifestyle-related dis- mated that one in five males and one in four
eases, increased life expectancy, and decreased females among individuals aged 65–74 years
birth rates in industrialized countries. In contrast, worldwide have CKD. The prevalence rate of
infectious diseases continue to be prevalent in CKD in the Chinese females population increases
less developed countries secondary to poor sani- from 7.4% among those aged 18–39 years to
tation, lack of safe water, and high concentrations 18.0% and 24.2% among those aged 60–69 and
of disease-transmitting vectors. Furthermore, 70 years, respectively. Relative increases in the
environmental pollution, pesticides, analgesic prevalence of CKD with age are equally striking
abuse, herbal medications, and use of unregu- in the USA, Canadian, and European populations
lated food additives contribute to the burden of despite between-country differences in the abso-
CKD in underdeveloped countries. lute prevalence. Moreover, it is estimated that the
Rapid urbanization and globalization have number of CKD cases will disproportionately
accelerated the transition and led to an overlap in increase in China, where the elderly population is
growing. This effect will be further magnified if hemodialysis in Beijing, China, was 76.8 per
the trends of increasing prevalence of diabetes 1000 patient-years in 2010, which was relatively
and hypertension persist, competing cardiovascu- low compared with 236.3 per 1000 patient-years
lar diseases- and stroke-caused deaths are reduced in 2009 in the USA. The three leading causes of
and access to treatment improves. death in patients on hemodialysis in China are
When CKD finally progresses to kidney fail- cardiovascular disease (31.0%), stroke (20.3%),
ure, renal replacement therapy becomes essen- and infection (19.9%).
tial for patients’ survival. However, the current Despite the high prevalence, screening indi-
treatment situation is appalling. Over two mil- viduals without risk factors or symptoms for
lion patients worldwide presently undergo dialy- CKD is not recommended. Current recommenda-
sis or transplantation, yet this number may only tions suggest screening those with structural dis-
represent 10% of those who actually require eases of the renal tract, hypertension,
treatment to live. The majority of these patients cardiovascular disease, diabetes, autoimmune
receiving therapy for kidney failure reside in diseases with potential for kidney involvement,
only five countries, namely the USA, Japan, family history of kidney disease, marked obesity,
Germany, Brazil, and Italy, which represent only and age >60 years during routine primary health
12% of the global population. More than 80% of encounters. Despite screening for CKD in indi-
all patients receiving therapy for kidney failure viduals with diabetes is cost-effective, it remains
are from affluent countries, with the remaining unclear whether screening for CKD in the gen-
20% being treated in approximately 100 devel- eral population is cost-effective.
oping countries, which constitute over 50% of
the global population. The point prevalence of
patients with kidney failure on maintenance dial- 1.6 Costs
ysis (including hemodialysis and peritoneal dial-
ysis) in 2008 was estimated to be 71.9 per million The cost of treatment for this dramatically grow-
population in mainland China, with an annual ing epidemic represents an enormous burden on
increase in the prevalence rate of 52.9%, and healthcare systems worldwide. Patients with kid-
reached 2584, 1106, and 1870 per million popu- ney failure require dialysis or transplantation,
lation in 2010 in Taiwan, Hong Kong, and the which are exceedingly costly and consume a
USA, respectively. Approximately 90% of sizeable portion of the health budget.
patients with kidney failure on dialysis in China In low- and middle-income countries, treat-
underwent hemodialysis at the end of 2012, ment with dialysis or transplantation imposes a
meaning that 270,000 patients underwent hemo- huge financial burden upon most patients who
dialysis compared with just 30,000 patients on require it. In another 112 countries, long-term
peritoneal dialysis [1, 4, 5–7]. dialysis is unaffordable for many patients, result-
CKD resulted in 956,000 deaths in 2013. ing in death due to untreated kidney failure in
According to the 2010 Global Burden of Disease over one million individuals.
Study, the rank of CKD in the list of causes of CKD was defined as a major chronic disease
total number of deaths worldwide rose from 27th by the Chinese government and enrolled in three
in 1990 to 18th in 2010, with such movement of basic medical insurance systems in China. The
ranking up the list being second only to that for economy will lose US$558 billion over the next
human immunodeficiency virus (HIV) infection decade owing to effects on death and disability
and acquired immune deficiency syndrome attributable to heart and kidney diseases [7, 8].
(AIDS). The overall increase in years of life lost An extreme example is in Uruguay, the annual
due to premature mortality caused by CKD is cost of dialysis is close to 30% of the National
82%, being only behind HIV infection and AIDS Resources Fund’s budget for specialized therapies.
(396%) and diabetes mellitus (93%). The raw The high cost of long-term dialysis for an
annual mortality in patients on maintenance increasing number of patients is also a problem
even in high-income countries. Kidney failure is Table 1.6 Sources of error in GFR estimation using
a major cost driver among patients and their fam- creatinine
ilies as well as taxpayers. Source of error Example
In the USA, the treatment for CKD is likely to Non-steady state AKI
exceed $48 billion per year. Less than 1% of the SCr difference
covered population consumes 6.7% of the total • Creatinine • Race/ethnicity
generation • Extremes of muscle mass
Medicare budget for treatment for kidney • Extremes of body size
failure. • Diet and nutritional status
CKD costs more than breast, lung, colon, and High-protein diet
skin cancers combined in England, recently Creatine supplements
• Muscle-wasting diseases
reported by NHS Kidney Care. • Ingestion of cooked meat
Treatment for all current and new cases of kid- • Tubular • Decrease by drug-induced
ney failure up to 2020 will cost about $12 billion secretion of inhibition
in Australia. creatinine Trimethoprim
Cimetidine
Fenofibrate
• Extrarenal • Dialysis
1.7 Diagnosis elimination • Inhibition of gut creatininase by
of creatinine antibiotics
The diagnosis of CKD includes the evaluation of • Large volume loss of
extracellular fluid
chronicity, causes, GFR, albuminuria, and pro-
Higher GFR Measurement error in SCr and GFR
gression [6].
Interference • Spectral interferences (bilirubin,
with creatinine some drugs)
assay • Chemical interferences (glucose,
1.7.1 Evaluation of Chronicity ketones)
AKI acute kidney injury, SCr serum creatinine, GFR glo-
For individuals with kidney damage or GFR merular filtration rate
<60 mL/min/1.73 m2 (Table 1.1), reviewing their
history and past measurements is necessary to Use SCr-based GFR-estimating equation
determine the course of kidney disease. (2009 Chronic Kidney Disease Epidemiology
CKD is confirmed if the course exceeds Collaboration [CKD-EPI] creatinine equation)
3 months; otherwise, not confirmed. Tests should instead of SCr concentration alone although
be accordingly repeated to differentiate CKD, eGFRcreat might be less accurate in some clinical
acute kidney disease, or both. settings (Table 1.6).
Furthermore, the performance of additional
tests (cystatin C) for confirmation is suggested
1.7.2 Evaluation of Causes when SCr-based eGFR is less accurate.
To confirm CKD, cystatin C should be mea-
Review family and personal history, environmen- sured in adults with eGFRcreat of 45–59 mL/
tal and social factors, and medications, and per- min/1.73 m2 but without kidney damage markers.
form physical examination, lab and imaging CKD is confirmed if eGFRcys or eGFRcreat–
measurements to determine the causes of CKD cys is also <60 mL/min/1.73 m2. Otherwise,
and establish a pathological diagnosis. CKD is not confirmed if eGFRcys or eGFRcreat–
cys is ≥60 mL/min/1.73 m2.
Similarly, use cystatin C-based GFR-
1.7.3 Evaluation of GFR estimating equations (2012 CKD-EPI cystatin C
and 2012 CKD-EPI creatinine–cystatin C equa-
It is recommended to use serum creatinine (SCr)- tions) rather than cystatin C concentration alone.
based GFR-estimating equation for initial Sometimes, eGFRcys and eGFRcreat–cys are
assessment. also less accurate in clinical settings (Table 1.7).
Table 1.7 Sources of error in GFR estimation using cys- surable albumin. Stored samples should be
tatin C allowed to attain room temperature and thor-
Source of error Example oughly mixed prior to analysis.
Non-steady state AKI Non-albumin proteinuria could be detected
Serum cystatin C difference using assays for specific urinary proteins, such as
• Cystatin C • Race/ethnicity monoclonal heavy or light chains (known as
generation • Thyroid function disorders
• Corticosteroid “Bence Jones” proteins) and α1-microglobulin.
administration
• Other hypothesized factors
(diabetes, adiposity) 1.7.5 Evaluation of Progression
• Tubular secretion None identified
of creatinine
• Extrarenal Severe decrease in GFR GFR and albuminuria should be assessed at least
elimination of annually in individuals with CKD. Moreover,
creatinine assess GFR and albuminuria more often in indi-
Higher GFR • Biological variability in viduals at a higher risk of progression and/or in
non-GFR determinants
relative to GFR
cases in which measurement will affect therapeu-
• Measurement error in tic decisions. However, GFR are commonly fluc-
serum cystatin C and GFR tuated slightly and not necessarily indicative of
Interference with Heterophilic antibodies progression.
cystatin C assay Accelerated CKD progression is defined as a
AKI acute kidney injury, GFR glomerular filtration rate drop in GFR ≥25% from baseline, a decline in
GFR category, and a sustained decrease in GFR
It is necessary to measure GFR using exoge- >5 mL/min/1.73 m2 per year.
nous filtration markers when more accurate Take the following steps to determine the rate
ascertainment of GFR will affect treatment of CKD progression: perform a minimum of
decisions. The strengths and limitations of clear- three GFR estimations over a period of not less
ance methods and filtration markers for clearance than 90 days; for individuals with a new finding
measurements are summarized in Table 1.8. of reduced GFR, review the current management,
repeat GFR estimation within 2 weeks to exclude
causes of acute deterioration in GFR (e.g., AKI
1.7.4 Evaluation of Albuminuria or initiation of renin–angiotensin system [RAS]
antagonist therapy), and consider referral to a
For initial proteinuria testing, the following mea- specialist.
surements are suggested using early morning urine CKD patients are at increased risk of progres-
sample (in descending order): urinary albumin-to- sion to end-stage kidney disease if posed with
creatinine ratio (ACR), urinary protein- to- either of accelerated progression conditions.
creatinine ratio, reagent strip urinalysis for total
protein with automated reading, and reagent strip
urinalysis for total protein with manual reading. 1.8 Management Principles
The high biological variation and other physi-
ological and pathological causes affect the accu- The management of CKD begins by providing
racy of albuminuria (Table 1.9), repeat testing is patient education and offering information tai-
required to confirm albuminuria. It is more accu- lored to the cause, severity, and associated com-
rate to measure the albumin excretion rate or total plications of CKD and the risk of progression [6].
protein excretion rate in a timed urine sample. Encourage patients to perform exercise, loss
Urinary albumin or protein may be analyzed weight, and stop smoking. Offer dietary advice
using fresh samples, stored at 4 °C within 1 week, about salt intake, potassium, calorie, and phos-
or stored at −70 °C for longer periods. However, phate appropriate to the severity of CKD
freezing at −20 °C may result in the loss of mea- (Table 1.10).
Table 1.8 Strengths and limitations of GFR measurement methods and markers
Approach Strengths Limitations
Methods
Urinary clearance
Bladder catheter and • Gold standard • Invasive
continuous intravenous method
infusion of marker
Spontaneous bladder • Patient comfort • Possibility of incomplete bladder emptying
emptying • Less invasive • Low flow rates in individuals with low GFR levels
Bolus administration • Shorter duration • Rapidly declining plasma levels at high GFR levels
of marker • Longer equilibration time in extracellular volume
expansion
24-h urine collection • Cumbersome
• Prone to error
Plasma clearance • No urine collection • Overestimation of GFR in extracellular volume expansion
required • Inaccurate values with one-sample technique, particularly
• With potential for at lower GFR levels
increased precision • Longer plasma sampling duration required at low GFR
levels
Nuclear imaging • No urine collection • Less accurate
or repeated blood
sampling required
Markers
Inulin • Gold standard • Expensive
• No side effects • Difficult to dissolve and maintain in solution
• Short supply
Creatinine • Endogenous marker, • Section can vary among and within individuals
no need for
administration
• Assay available in all
clinical laboratories
Iothalamate • Inexpensive • Probable tubular secretion
• Long half life • Requirement for storage, administration, and disposal of
radioactive substances when using 125I as tracer
• Requirement for expensive assay when using
nonradioactive iothalamate
• Cannot be used in patients with allergies to iodine
Iohexol • Nonradioactive • Possible tubular reabsorption or protein binding
• Inexpensive • Requirement for expensive assay when using low doses
• Sensitive assay • Cannot be used in patients with allergies to iodine
allows for low dose • Nephrotoxicity and risk of allergic reactions at high doses
EDTA • Widely available in • Probable tubular reabsorption
Europe • Requirement for storage, administration, and disposal of
radioactive substances when using 51Cr as tracer
DTPA • Widely available in • Requirement for storage, administration, and disposal of
the USA radioactive substances when using 99mTc as tracer
• New, sensitive, and • Requires standardization for 99mTc
easy-to-use assay for • Dissociation and protein binding of 99mTc
gadolinium • Concern for NSF when using gadolinium as tracer
GFR glomerular filtration rate, EDTA ethylenediaminetetraacetic acid, DPTA diethylenetriamine pentaacetic acid, NSF
nephrogenic systemic fibrosis
For individuals with CKD, aim to maintain the blood pressure below 130 mmHg (target range,
blood pressure below 140 (target range, 120– 120–129 mmHg)/80 mmHg.
139 mmHg)/90 mmHg. For those with diabetes RAS antagonist should be administered to indi-
and ACR ≥70 mg/mmol, aim to maintain the viduals with CKD under the following conditions:
Table 1.9 Factors affecting urinary albumin-to- Table 1.10 Dietary and lifestyle modification for
creatinine ratio patients with CKD
Factors Examples of effect Salt intake • Lower salt intake to <90 mmol
Preanalytical factors (<2 g) of sodium per day
Transient • Menstrual blood (corresponding to 5 g of sodium
elevation in contamination chloride) in adults, unless
albuminuria • Symptomatic urinary tract contraindicated
infection • Restrict sodium intake in
• Exercise children with CKD who have
• Upright posture (orthostatic hypertension (systolic and/or
proteinuria) diastolic blood pressure >95th
• Other conditions that increase percentile) or prehypertension
vascular permeability (e.g., (systolic and/or diastolic blood
septicemia) pressure >90th percentile and
Intraindividual • Intrinsic biological variability <95th percentile), following the
variability • Genetic variability age-based recommended daily
intake
Preanalytical Albumin degradation prior to
• Supply free water and sodium to
storage conditions analysis
children with CKD and polyuria
Nonrenal causes • Age (lower in children and to avoid chronic intravascular
of variability in older people) depletion and to promote
creatinine • Race optimal growth
excretion • Muscle mass
Protein intake • Lower protein intake to 0.8 g/kg/
• Gender (lower in women)
day in adults with or without
Change in Non-steady state creatinine diabetes and GFR <30 mL/
creatinine concentration (acute kidney min/1.73 m2 (G4–G5)
excretion injury) • Avoid high protein intake
Analytical factors (>1.3 g/kg/day) in adults with
Antigen excess Samples with very high albumin CKD at risk of progression
(prozone) effect concentrations may be falsely Hyperuricemia Despite the relationship between
reported as low or normal using hyperuricemia and incidence of
some assays CKD, there is insufficient evidence
Reproduced with permission from Elsevier [3] supporting or refuting the use of
agents to lower serum uric acid
(1) diabetes and an ACR ≥3 mg/mmol (ACR cat- concentrations in individuals with
CKD and either symptomatic or
egory A2 or A3) and (2) hypertension and an ACR asymptomatic hyperuricemia in
≥30 mg/mmol (ACR category A3) or ACR order to delay CKD
≥70 mg/mmol (irrespective of hypertension or Lifestyle • Encourage patients with CKD to
cardiovascular disease). However, the evidence perform physical activity
compatible with their
supporting these criteria in individuals aged cardiovascular health and
>70 years is limited. Do not administer a combina- tolerance (aiming for at least
tion of RAS antagonists to individuals with CKD. 30 min five times per week)
Serum potassium concentrations and estimate • Achieve a healthy weight (BMI
20–25, according to country-
GFR should be measured before starting RAS specific demographics)
antagonist therapy. Repeat tests between 1 and • Stop smoking
2 weeks after starting RAS antagonist therapy Additional Provide expert dietary advice and
and after each dose increase. Do not routinely dietary advice information in the context of an
administer RAS antagonist to individuals if pre- education program tailored to the
severity of CKD and the need to
treatment serum potassium concentration is intervene on salt, phosphate,
>5.0 mmol/L. When hyperkalemia precludes the potassium, and protein intake, when
use of RAS antagonists, assessment, and treat- indicated
ment of factors promoting hyperkalemia should CKD chronic kidney disease, GFR glomerular filtration
be undertaken, then recheck the serum potassium rate, BMI body mass index
concentration. Stop RAS antagonist therapy if Patients with features summarized in

the serum potassium concentration increases to Table 1.11 should normally be referred to a spe-
≥6.0 mmol/L and discontinue other drugs known cialist for assessment.
to promote hyperkalemia. Provide patients with stage 5 CKD with infor-
Following the introduction of RAS antagonists mation on treatment options for renal replace-
or an increase in their dose, do not modify the ment therapy. Treatment options include
dose if either the GFR decrease from pretreatment transplantation and dialysis (hemodialysis and
baseline is <25% or the SCr increase from base- peritoneal dialysis). Table 1.12 shows the timing
line is <30%. If there is a <25% decrease in eGFR for the initiation of renal replacement therapy.
or 30% increase in SCr from baseline after start-
ing RAS antagonist therapy or increasing the dose
of RAS antagonists, repeat the test in 1–2 weeks. Table 1.11 When to refer
Do not modify the dose of RAS antagonists if the GFR <30 mL/min/1.73 m2 (GFR category G4 or G5),
change in eGFR or SCr is <25% or <30%, respec- with or without diabetes
tively. If the change in eGFR or SCr is ≥25% or ACR ≥70 mg/mmol, unless known to be due to
diabetes and already appropriately treated
≥30%, respectively, investigate other causes of
ACR ≥30 mg/mmol (ACR category A3), together with
deterioration in renal function, such as concurrent hematuria
medication or volume depletion. If no other Sustained decrease in GFR ≥25%, and a change in
causes of deterioration in renal function are iden- GFR category or sustained decrease in GFR ≥15 mL/
tified, stop the RAS antagonist therapy or reduce min/1.73 m2 within 12 months
to previous tolerated dose and add an alternative Hypertension that remains poorly controlled despite
the use of at least four antihypertensive drugs at
antihypertensive medication, if required. therapeutic doses
For CKD patients with diabetes, the target Known or suspected rare or genetic causes of CKD
hemoglobin A1c (HbA1c) level is approximately Suspected renal artery stenosis
7.0% (53 mmol/mol) in order to prevent or delay GFR glomerular filtration rate, ACR albumin-to-creatinine
the progression of diabetic kidney disease. This ratio, CKD chronic kidney disease (Reproduced with per-
HbA1c target is not suitable for patients at risk of mission from Elsevier [3])
hypoglycemia. The target HbA1c level should be
extended above 7.0% in individuals with limited Table 1.12 Timing for the initiation of renal replacement
life expectancy, comorbidities or at risk of hypo- therapy
glycemia. For patients with CKD who have diabe- Initiation of • Symptoms or signs attributable to
tes, glycemic control should be accompanied by dialysis kidney failure (e.g., serositis,
acid-base or electrolyte
multifactorial intervention strategies including abnormalities, pruritus)
blood pressure control and cardiovascular risk care. • Inability to control volume status
Use of RAS antagonists, statins, and antiplatelet or blood pressure
therapy are recommended if clinically indicated. • Cognitive impairment or
progressive deterioration in
For the prevention and treatment of cardiovas- nutritional status refractory to
cular diseases and several complications including dietary intervention
anemia, bone conditions, and metabolic acidosis, • This often but not invariably
see Part II. occurs in the GFR range of
5–10 mL/min/1.73 m2
When assessing CKD progression, extrapo-
Initiation of GFR is <20 mL/min/1.73 m2 with
late the current rate of decline in GFR, and take transplantation evidence of progressive and
this into account when planning intervention with living irreversible CKD over the preceding
strategies, particularly if it suggests that patients donor 6–12 months
might require renal replacement therapy through- GFR glomerular filtration rate, CKD chronic kidney
out their lifetime. disease
References
Key Messages
• KDIGO defined CKD as kidney abnor- 1. World Kidney Day: chronic kidney disease. 2016.
malities or GFR <60 mL/min/1.73 m2 http://www.worldkidneyday.org/faqs/chronic-
kidney-disease/.
for 3 months or longer and classified 2. Inker LA, Astor BC, Fox CH, et al. KDOQI US com-
CKD based on CGA. mentary on the 2012 KDIGO clinical practice guide-
• Lifestyle-related diseases, including line for the evaluation and management of CKD. Am
diabetes, hypertension, and obesity, and J Kidney Dis. 2014;63(5):713–35.
3. Kidney Disease: Improving Global Outcomes
glomerular disease are the major causes (KDIGO) CKD Work Group. KDIGO 2012 clinical
of and risk factors for CKD. practice guideline for the evaluation and manage-
• The incidence and prevalence of CKD ment of chronic kidney disease. Kidney Int Suppl.
substantially differ across countries and 2013;3(1):1–150.
4. Liu Z-H. Nephrology in China. Nat Rev Nephrol.
regions. The number of patients with 2013;9(9):523–8.
CKD is expected to continuously 5. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney
increase worldwide. Low levels of eco- disease: global dimension and perspectives. Lancet.
nomic development have been strongly 2013;382(9888):260–72.
6. Qaseem A, Hopkins RH, Sweet DE, et al. Screening,
associated with reduced availability of monitoring, and treatment of stage 1 to 3 chronic
renal replacement therapy. kidney disease: a clinical practice guideline from the
• The cost of treatment with dialysis or American College of Physicians. Ann Intern Med.
kidney transplantation for kidney failure 2013;159(12):835–47.
7. Zhang LX, Wang F, Wang L, et al. Prevalence of
represents an enormous burden on chronic kidney disease in China: a cross-sectional
healthcare systems in both developed survey. Lancet. 2012;379(9818):815–22.
and developing countries. 8. Couser WG, Remuzzi G, Mendis S, Tonelli M. The
• Evaluate chronicity, causes, GFR, and contribution of chronic kidney disease to the global
burden of major noncommunicable diseases. Kidney
albuminuria to confirm the diagnosis of Int. 2011;80(12):1258–70.
CKD.
• General approaches to CKD manage-
ment include patient education (e.g., life-
style modification), treatment of primary
diseases (e.g., hypertension, diabetes),
prevention and treatment of complica-
tions (e.g., cardiovascular diseases, ane-
mia), and renal replacement therapy.
Pathophysiology of Chronic
Kidney Disease 2
Jiafa Ren and Chunsun Dai
Abstract
2.1 Introduction
Chronic kidney disease (CKD), a general
term for heterogeneous disorders, frequently Chronic kidney disease (CKD) is defined as
occurs in association with a variety of factors decreased kidney function reflected in glomeru-
including diabetes, nephritis, hypertension, lar filtration rate (GFR) of less than 60 mL/min
and immune system disorder. As the etiologi- per 1.73 m2, markers of kidney damage, or
cally distinct cause progresses, a common both, of at least 3 months’ duration, regardless
renal pathological manifestation including of specific causes [1]. The prevalence of CKD
glomerulosclerosis and/or interstitial fibrosis is consistently reported to be ~10% in many
develops regardless of the cause. Over the countries [2], and patients with advanced CKD
past several years, rapid progress in decipher- have a high burden of physical and psychoso-
ing the cellular and molecular mechanisms cial symptoms, poor outcomes, and high costs
have led to better understanding of patho- of care.
physiology of CKD and would make it pos- The pathological manifestation of CKD is
sible to develop clinically effective anti-CKD the loss of renal cells and deposition of the
therapies. This chapter summarizes and extracellular matrix (ECM). Regardless of the
updates the pathophysiological knowledge of initial insults, the progressive renal disease is
CKD from animal models and human studies, characterized by morphological changes that
providing new insights into the complicated comprise renal inflammation, glomerulosclero-
process of CKD. sis, tubular atrophy, tubulointerstitial fibrosis,
and capillary rarefaction (Fig. 2.1). The patho-
genesis of renal fibrosis including glomerulo-
sclerosis and interstitial fibrosis is a progressive
process that ultimately leads to end-stage renal
J. Ren (*)
Division of Nephrology, Department of Medicine, failure, a devastating condition that requires
Duke University and Durham VA Medical Centers, renal replacement therapy (e.g., dialysis or
Durham, NC, USA transplantation). Current therapies for CKD
e-mail: jiafa.ren@duke.edu mainly involve blockade of the renin–angioten-
C. Dai (*) sin–aldosterone system (RAAS) [3]. Therefore,
Centre for Kidney Disease, Second Affiliated this chapter outlines the current understanding
Nanjing, Jiangsu, China of the cellular and molecular mechanisms of
e-mail: daichunsun@njmu.edu.cn renal fibrosis including glomerulosclerosis and

14 J. Ren and C. Dai
Injury/stress stimuli
Inflammatory factors
(IFN, TNF)
Renal parenchymal cells Chemokines Infiltrating immune cells

(MCP-1, RANTES)
Ang-II, TGF-β, CTGF, FGF, ROS. . .
Podocytes Mesangial cells Fibroblasts and pericytes Tubular cells Circulating fibrocytes
Podocytes injury Mesangial expansion

Proteinuria Myofibroblasts
and/or detachment and proliferation
Glomerosclerosis Interstitial fibrosis
Chronic kidney disease
Fig. 2.1 Schematic presentation for cellular events involved in the progression of chronic kidney disease
interstitial fibrosis. Thorough knowledge of the Glomerulosclerosis is characterized by an

pathophysiology of kidney fibrosis is crucial for increase in mesangial matrix accumulation and
developing newer therapeutic strategies. obliteration of glomerular capillaries. The under-
lying pathogenic mechanism of glomerulosclero-
sis is even more complicated and can be divided
2.2 Glomerulosclerosis into several distinctive phases. First, under the
influence of various risk factors such as hyperten-
Each normal glomerulus is a tuft of small blood sion, dyslipidemia, and/or deposition of immune
vessels called capillaries situated within complexes, glomerulus-resident cells are injured
Bowman’s capsule with the kidney. The tufts are and activated, followed by a release of multiple
structurally supported by mesangial cells, which cytokines and chemokines, which attract mono-
facilitate structural organization and integrity of cytes, lymphocytes, neutrophils, and other types
capillaries of glomerulus. Endothelial cells lining of inflammatory cells to immigrate and accumu-
capillaries uniquely have numerous pores also late at the injury site. Second, these infiltrating
named fenestrated endothelial cells. The glomer- cells accompanied with intrinsic cells further
ular base membrane (GBM) separating fenes- produce multiple cytokines and growth factors
trated endothelial cells from podocytes is the including angiotensin, transforming growth fac-
basal lamina layer of the glomerulus. The podo- tor β1 (TGF-β1), platelet-derived growth factor
cyte foot processes, GBM and endothelial cells (PDGF), fibroblast growth factor (FGF), tumor
constitute the glomerular filtration barrier, a necrosis factor (TNF), and interferon gamma
highly specialized blood filtration interface. (IFN-γ) to induce the capillary collapse and oblit-
Dysfunction of the glomerular filtration barrier eration, loss of podocytes, and activation of pari-
and expansion or proliferation of mesangial cells etal epithelium cells. The final process is
are thought to contribute to the development of fibrogenesis, featuring production of new ECM
glomerulosclerosis. components to replace damaged tissue, thereby
2 Pathophysiology of Chronic Kidney Disease 15
providing a scaffold for wound closure, remodel- structure of the glomerular filtration barrier.
ing, and repair. Thus, glomerulosclerosis mainly Podocytes stabilize the filtration barrier of glo-
reflects podocyte injury, proliferation, and matrix merular through production of GBM molecules,
production by mesangial cells as well as endothe- maintenance of the structure of slit diaphragm,
lial damage and dysfunction. and keeping viability of endothelial cell.
Podocyte injury is a key manifestation of pro- Podocytes injured by various risk factors undergo
teinuric glomerulopathies, including focal seg- detachment or apoptosis, which is an irreversible
mental glomerulosclerosis (FSGS), minimal loss that permanently causes inefficiency of
change disease (MCD), membranous-proliferative podocytes. Because podocytes are terminally dif-
glomerulonephritis (MPGN), amyloid nephropa- ferentiated cells and can’t proliferate, the area of
thy (AN), and diabetic nephropathy (DN). Four the GBM initially covered by podocyte becomes
major mechanisms cause injury to podocytes: exposed. To the areas of the exposed GBM, pari-
alteration of the GBM or its interactions with the etal epithelial cells may get attached. This sce-
podocyte, molecular change in the slit diaphragm nario leads to form adhesions or synechiae
or interference with its structure, dysfunction of between GBM and parietal cells, which are rec-
podocyte actin cytoskeleton, and changes in nega- ognized as some of the earliest signs of segmen-
tive surface charge on podocytes. In response to tal glomerulosclerosis. Maladaptive interactions
insults, podocytes appear different adaptive develop between the GBM and parietal epithelial
changes, such as hypertrophy, transdifferentia- cells. Extension of the synechiae leads to the
tion, dedifferentiation, detachment, and apopto- leakage of protein into Bowman’s space, collapse
sis. These adaptive responses of podocytes mainly and sclerosis of the associated capillary tuft, and
depend on the insult severity and duration. the loss of endothelial cells, which is suggestive
Mesangial cells constitute the central stalk of of the formation of crescents and sclerosis. Tracer
the glomerulus and represent continuation of the studies have been performed to disclose that fil-
extraglomerular mesangium and the juxtaglomer- tration of the tracer mainly accumulates extracel-
ular apparatus. Proliferation of mesangial cells is a lularly at the sites within tuft adhesions to
prominent feature of glomerular disease including Bowman’s capsule and related paraglomerular
IgA nephropathy (IgAN), membranous-spaces. The accumulation of protein debris is
proliferative glomerulonephritis (MPNG) lupus obligatory for capillary collapse. More than that,
nephritis (LN), and DN. Mesangial-cell prolifera- proteinaceous fluid derived from misdirected fil-
tion and matrix accumulation promoted by many tration is trapped within the space between pari-
kinds of profibrotic factors including TGF- β, etal epithelium and GBM, ultimately causing the
PDGF, and FGF2 are believed to contribute to the progression to global sclerosis and
development of glomerulosclerosis. In response to obsolescence.
initial injury factors, mesangial cells undergo
transformation to mesangioblasts. The latter are 2.2.1.1 Slit-Diaphragm Destruction
capable of producing an excessive ECM, leading The slit diaphragm is the main barrier that limits
to mesangial expansion: an early sign of glomeru- protein leakage. The slit-diaphragm system
losclerosis. The relative contribution of podocytes, destruction can lead to foot process effacement
mesangial cells, and other resident glomerular (FPE). The slit diaphragm can be subdivided into
cells to matrix accumulation and glomerulosclero- two parts structurally. ZO-1, α-actinin-4, podocin,
sis may depend on the disease in question. and CD2AP have been recognized as intracellu-
lar parts of the slit diaphragm; NEPH family
members, Nephrin, FAT, and P-cadherin are
2.2.1 Podocyte Injury known to constitute the extracellular components
of the slit diaphragm. Proteinuria is an early con-
The podocyte is one of the most important cell sequence of podocyte injury and is a typical sign
types for the glomerular filtration barrier. The of kidney disease [4]. Podocyte-specific ablation
podocyte and its slit diaphragm are the main of slit-diaphragm-related proteins in mice may
result in severe proteinuria and sclerosis. their polarity, which causes proteins normally
Clinically, proteinuria is a strong independent situated on the podocyte slit diaphragm to spread
risk factor of progressive CKD. Although podo- to abnormal locations. Arrangement of these pro-
cyte injury directly results in proteinuria, it is teins may interrupt the communications between
possible that proteinuria further worsens podo- podocytes and lead to disorganization of the
cyte injury. Electron-microscopic studies have architecture and to FPE shown in proteinuric
shown that a large number of protein droplets in renal diseases. The slit diaphragm may also have
the podocyte may be related to proteinuria. After signal transduction functions. For example, tyro-
proteinuria develops, tubular cells also take in sine phosphorylation of nephrin correlates with
large amounts of albumin, which can cause inter- the activation of signaling pathways in vivo and
stitial inflammation and fibrosis. in vitro [8]. After nephrin phosphorylation, mul-
In congenital nephrosis, it is known that neu- tiple downstream molecules perform critical
tralization of nephrin by a specific antibody and a functions to maintain podocyte polarity and regu-
podocyte-specific conditional knockout of a slit- late cell survival.
diaphragm gene such as nephrin, CD2AP, or
α-actinin-4 each results in severe proteinuria and 2.2.1.2 Changes in the Actin
sclerosis [5]. In response to injurious stimuli, Cytoskeleton of Podocytes
podocytes undergo phenotypic alteration charac- It is known that podocytes function to support
terized by downregulation of slit-diaphragm- and maintain the structural of the glomerular tuft.
associated proteins including P-cadherin, ZO-1, Podocyte foot processes with highly dynamic
and nephrin and their own molecular signatures performance partly depend on a rich actin cyto-
such as Wilms tumor protein 1 (WT1), synapto- skeleton, which eventually establishes the podo-
podin, and initiation of expression of mesenchy- cyte’s shape. A study conducted by Ichimura
mal markers, including desmin, fibroblast-specific et al. [9] have shown that using electron micros-
protein 1 (FSP1), and matrix metallopeptidase 9 copy, two populations of actin cytoskeletons are
(MMP-9), producing interstitial matrix compo- included in matured podocytes. One is actin bun-
nents, such as fibronectin and type I collagen. dle running above the level of slit diaphragms
This phenotypic alteration also involves upregu- and the other is the cortical actin network situated
lation of the transcription factor Snail and beneath the plasmalemma. FPE often has close
integrin-linked kinase. Liu et al. have named this relations with an increase in the number of micro-
process “podocyte epithelial–mesenchymal tran- filaments. Meanwhile, the podocyte actin system
sition (EMT),” which is similar to kidney tubular is regulated by the Rho family of guanosine tri-
epithelial cells undergoing mesenchymal transi- phosphatases, whose member Cdc42 mediates
tion during kidney interstitial fibrosis [6, 7]. A filopodia formation [10]. Mice with a podocyte-
number of important intracellular signal path- specific Cdc42 knockout have severe proteinuria
ways, such as ILK, Wnt–β-catenin, Jagged- and extensive nephrosclerosis associated with a
Notch, and Snail, often specially drive podocyte reduction in the expression of slit-diaphragm
into “EMT” program in the pathogenesis of vari- components. Guanosine triphosphatase dynamin
ous proteinuric renal diseases. These data are plays a basic role in regulating actin cytoskeleton
suggestive of podocyte undergoing “EMT” pro- of podocytes [11], and interference with oligo-
gram in response to various injuries. Eventually, merization of actin-dependent dynamin with
impairment of podocyte filtration barrier is con- inhibitor effectively attenuates proteinuria and
sequence for podocyte phenotype changes, lead- progress of renal diseases [12]. The actin cyto-
ing to proteinuria and glomerulosclerosis. skeleton system is necessary not only for sup-
Furthermore, slit diaphragm, the only structure porting foot processes but also for podocytes to
participating in cell–cell junctions and communi- confront the filtrate pressure. Thus, these findings
cations, have important implications for stabiliz- suggest that protein molecules maintaining or
ing cellular polarity. Damaged podocytes lose regulating podocyte actin cytoskeleton system
are extremely important to podocyte functions, talin-1 in podocytes leads to severe nephrosis
and any changes in the actin or actin-related pro- with FPE [15]. Clinically, podocytes and certain
teins may cause podocyte shape alterations and podocyte-specific protein products can be
podocyte dysfunctions [13]. detected in the urine of patients with proteinuric
renal disease, but not in healthy subjects or in
2.2.1.3 Loss of Podocytes nonpodocyte glomerular disease [13]. A study by
Ye et al. has shown that podocyte present in urine
Podocyte Detachment is thought to be a more sensitive marker than pro-
As mentioned above, podocyte detachment from teinuria. The major underlying mechanism of
the GBM resulting in the formation of adhesions podocyte loss is detachment of podocytes from
or synechiae is the main pathophysiological the GBM, which contributes to the progression of
mechanism of glomerulosclerosis. Podocytes are CKD [16].
normally tethered to the GBM by integrins and
dystroglycans. Integrins and dystroglycans Podocyte Apoptosis
expressed on the podocyte plasma membrane A second cause of the loss of podocytes is aug-
specifically bind to ligands in the GBM matrix to mented apoptosis. Podocyte apoptosis leads to
maintain tight cell attachment. Several mecha- proteinuria and/or glomerulosclerosis. Bottinger
nisms of podocyte detachment, including is among the first to report augmented apoptosis
mechanical distension, shear forces, and/or of podocytes responding to TGF-β in a transgenic
impaired adhesion to the GBM, have been sug- mouse model. The cytokine TGF-β and its recep-
gested. In response to mechanical forces, includ- tors are upregulated in a variety of podocyto-
ing intraglomerular hypertension, hyperfiltration, pathic diseases, including membranous
hypertrophy, and podocytes may undergo detach- nephropathy (MN), DN, and FSGS. Proteinuria
ment from the GBM. Intraglomerular hyperten- in turn accelerates podocyte loss or death. One
sion will contribute to (1) not only increased study has revealed that upregulation of podocyte
axial capillary wall and circumferential stress but Notch1 in models of DN and FSGS is associated
also increased filtrate flow, causing (2) an increase with proteinuria and glomerulosclerosis by
in fluid shear stress on the podocytes. (3) In this Notch1-driven podocyte apoptosis via a
setting of circumstances, podocytes are chal- p53-mediated pathway [17]. In vitro study, a
lenged by the hypertrophy of glomerular to Notch2 knockdown increases podocyte apopto-
obtain more motility and cover more areas of the sis. Inhibition of Notch2 by its specific antibody
GBM. (4) In the progressive phase of the disease, alleviates proteinuria in a FSGS mouse model
podocytes will be challenged by increased [18]. Nevertheless, research indicates that podo-
expansile forces and then undergo detachment. cyte apoptosis may not be the main cause of the
Studies also show integrin outside-in signals loss of podocytes [19]. Many findings about
regulate podocyte-GBM adhesion; inside-out podocyte apoptosis are obtained in in vitro stud-
signals from the podocyte cytoskeleton are also ies; thus, whether these studies are reliable—
critical for podocyte adhesion to the from the point of view of proving that apoptosis
GBM. Research suggests that there is decreased is the common mechanism of podocyte loss in
expression of integrin α3β1 on podocytes of situ—needs further investigation.
humans and rats during diabetes; this phenome-
non causes detachment of podocytes from the
GBM [14]. Talin-1, a large cytoskeletal protein in 2.2.2 Mesangial Expansion
the podocyte, favors inside-out signal transduc- and/or Proliferation
tion through the activating β1 integrin and medi-
ating integrin–actin binding. Suppression of The role of mesangial cells can be investigated by
calpain-induced talin-1 cleavage with inhibitor the injurious consequences of accumulation of
compound alleviates proteinuria, and ablation of mesangial immune complexes with subsequent
complement activation and production of media- initiation and progression of diabetic glomeru-
tors of inflammation, such as prostanoids; lopathy. Besides, changes in mesangial cell bio-
platelet-activating factor (PAF); reactive oxygen logical functions can also be noted in other
species (ROS); cytokines such as IL-6, TNF-α, glomerular diseases, such as amyloidosis and
CSF-1; and chemokines. Immune complexes light chain deposition diseases.
such as those involving IgA get deposited in the
mesangium with simultaneous complement acti-
vation. In response to these aberrant immune 2.3 Renal Interstitial Fibrosis
complexes, mesangial cells are activated and pro-
duce several mediators of inflammation, such as The process of renal interstitial fibrosis, a fail-
chemokines, cytokines, and growth factors, such ure of wound healing that takes place after the
as mesangial cells bFGF, PDGF, and TGF-β. initial various damages, is characterized by
These may result in mesangial-cell proliferation excessive deposition of the ECM in the intersti-
and matrix expansion. The production of proin- tial compartment. Almost all cell types (either
flammatory mediators by mesangial cells may resident or nonresident kidneys cells) are in
also cause a deleterious circle between these some way responsible for the pathogenesis of
mediators, altering the endothelial barrier, allow- kidney interstitial fibrosis. Major cellular and
ing more macromolecules to enter the mesan- molecular events are comprised of inflamma-
gium, and further accelerating the production of tory cell infiltration, fibroblast activation and
inflammatory mediators, ultimately leading to myofibroblast development from various cell
local leukocyte adhesion, activation, and extrava- types, generation and deposition of ECM mole-
sation. Finally, a number of inflammatory media- cules, and tubular atrophy with microvascular
tors produced by mesangial cells (in response to rarefaction. The process of renal interstitial
immune complex deposition) and by the infiltrat- fibrosis may be artificially subdivided into four
ing leukocytes may also change glomerular distinguishable (but sometimes overlapping)
permselectivity by affecting podocyte function, phages:
eventually leading to proteinuria.
Besides being activated by the immune com- 1. After a sustained injury (e.g., proteinuria, high
plex, mesangial cells can be activated by concentration of glucose, or hypoxemia),
advanced glycation end products via binding to kidney-resident cells are damaged and release
their receptor on mesangial cells in diabetes. chemotactic factors providing a signal that
Furthermore, production of various growth fac- attracts inflammatory cells to infiltrate into the
tors, matrix components, and alteration of matrix injury site.
metabolism by mesangial cells can also be caused 2. The infiltrating inflammatory cells producing
by glomerular hypertension in the early phage of various compounds including ROS and
diabetes, even in the absence of systemic hyper- multiple protein factors, such as MCP-1,

tension. The resulting appearance is early TNF-α, IL-1, TGF-β1, CTGF, and angiotensin
mesangial- cell hypertrophy, proliferation, and II (Ang II), aggravate renal-cell injury. This
deposition of mesangial matrix. The pathological series of events induces fibroblasts and other
manifestation of DN is characterized by the for- cell types, including tubular epithelial cells,
mation of nodular glomerulosclerosis first pericytes, and endothelial cells, to undergo
described by Kimmelstiel and Wilson. Finally, phenotypic activation or transition and to pro-
activation of mesangial cells by hyperglycemia duce a great amount of ECM components.
and the sequelae mentioned above also produce 3.
Activated myofibroblasts from different
chemokines that involve in the leukocytes infil- sources generate ECM, as well as promoting
tration, thereby provoking destructive proapop- excessive ECM deposition in renal intersti-
totic and profibrotic responses. Consequently, tium that results in renal tubular apoptosis and
mesangial cells significantly participate in the atrophy.

4. Over-generation of extracellular matrix and Research suggests that vascular pericytes are
their degradation defects are accountable for also a major source of myofibroblasts in fibrotic
excessive matrix accumulation in the renal kidneys [24, 25]. Pericytes are defined anatomi-
interstitium. In the early stage of kidney intersti- cally as cells of mesenchymal origin attached to
tial fibrosis, the fibrosis may be reversible due to capillaries that share a common basement mem-
the extracellular matrix prone to proteolysis. brane and form junctions with endothelial cells
Nonetheless, as injuries are sustained and fibro- [23]. Following kidney injury, pericytes get
sis progresses, cross-linking with tissue trans- detached from the endothelium, undergo migra-
glutaminase and lysyl oxidase is thought to tion and proliferation, and differentiate into myo-
modify matrix in late stage of renal fibrosis, fibroblasts [26]. The detachment of pericytes and
eventually leading to make the matrix stiff and their differentiation into myofibroblasts not only
highly resistant to proteolysis [20]. Excessive lead to instability of the microvasculature, but
deposition of the ECM results in the ultimate also contribute to activation of myofibroblasts,
destruction of renal parenchyma, microvascular which results in interstitial fibrosis. In addition,
rarefaction, and loss of kidney function. pericytes play pivotal roles in sensing of injury,
the regulation of recruitment of leukocytes, and
Due to the limitations of space, we are going perpetuation of inflammation.
to focus on the principal cell types that are
responsible for the process of interstitial fibrosis.
2.3.2 Epithelial–Mesenchymal
Transition (EMT)
2.3.1 Activation of Fibroblasts
and Pericytes Another origin of cells producing matrix may be
the tubular epithelium that involves in EMT: a
In healthy adult kidneys, fibroblasts are located in phenotypic transformation program is that is
the interstitial space between capillaries and epi- characterized by the loss of epithelial markers
thelia, and interact with each other throughout the and a gain of mesenchymal features. Similarly,
entire kidney, therefore stabilizing tissue architec- capillary endothelium via endothelial–mesen-
ture and matrix homeostasis via production of a chymal transition (EndoMT) may be another
basal amount of ECM molecules under physio- source of fibroblasts and/or myofibroblasts.
logical conditions [21]. In a resting quiescent EndoMT is recognized as a special form of
state, interstitial fibroblasts express some rela- EMT as endothelial cells are thought as a spe-
tively specific markers, including CD73 (also cialized type of epithelia. That tubular epithelial
known as ecto-5′-nucleotidase), PDGF-β, and cells undergo EMT in vitro is not debated.
fibroblast-specific protein 1 (FSP1; also known as Whether this transition occurs in vivo is at the
S100A4). None of these markers, however, is spe- center of a controversy. An early study has
cific for fibroblasts. Profibrotic factors and revealed that tubular epithelium contributes to
mechanical stress trigger fibroblast differentiation over one-third of FSP1+ interstitial fibroblasts
into αSMA-expressing myofibroblasts. A study by using bone marrow chimeras and transgenic
by LeBleu et al. shows that 50% of the total pool reporter mice in a UUO model [27]. Meanwhile,
of myofibroblasts arises from local resident fibro- two studies also have revealed that EndoMT
blasts through proliferation during the process of occurring in various fibrotic kidney diseases
unilateral ureteral obstruction (UUO) [22]. As in significantly participates in the formation of
resident fibroblasts, there are no universal peri- fibroblast and/or myofibroblasts. Nonetheless,
cyte markers, whereas kidney pericytes express a some studies question the above experimental
number of typical pericyte markers, including results and find that no or only a small number
PDGFR-β, PDGFR-α, CD248, CD146, desmin, of epithelial or endothelial cells participate in
and others [23]. EMT [26, 28].
In 2015, however, two important studies process, suggesting that an inflamed milieu that
readdressed this debate and shed light on the contains a complex mixture of cytokines is a
potential impacts of tubular EMT in the initia- major determinant of fibrocytic differentiation.
tion and development of kidney interstitial The relative contribution of fibrocytes to renal
fibrosis [29, 30]. These studies clarify the issue fibrogenesis is another field full of controversy.
via several new models of genetically modified Studies by different labs have led to different
mice, in which Snail or Twist1, two key tran- conclusions. It is a great challenge to clearly dis-
scription factors regulating the EMT program, criminate fibrocytes from monocytes/macro-
are specifically deleted in tubules. Consequently, phages, fibroblasts, and myofibroblasts due to the
the EMT program is suppressed significantly in fact that there is no specific marker for fibrocytes.
the renal tubular cells in vivo. Both studies show In addition, subpopulations of fibrocytes seem to
that suppression of the EMT program by exist [31]. Until now, results of studies on the
tubular-specific deletion of Snail or Twist1 contribution of fibrocytes in the pathogenesis
attenuates interstitial fibrosis in several CKD of kidney interstitial fibrosis are controversial
models, including UUO, nephrotoxic-serum- [27, 32, 33].
induced nephritis, and folic-acid-induced Over the years, board agreement has been
nephropathy. Thus, the EMT program is pivotal reached that myofibroblasts in renal interstitial
and required for provoking tubular dysfunction fibrosis have a variety of origins. They accomplish
and promoting fibrosis progression under patho- tissue repair and remodeling through synthesis and
logical conditions. organization of the ECM that causes scarring.
Myofibroblasts form from fibroblastic cells (via
differentiation) that have distinct biological fea-
2.3.3 Recruitment of Circulating tures, thus supporting the concept of phenotypic
Fibrocytes heterogeneity of fibroblasts. A better understand-
ing of what cell types generate a larger amount of
Fibrocytes are recognized as bone marrow- ECM components and how they are regulated
derived cells that circulate in the peripheral blood under pathological conditions may shed new light
and generate matrix components such as colla- on designing effective therapeutic strategies.
gens and vimentin. Fibrocytes may be identified
by dual positivity for CD34 or CD45 and type I
collagen or procollagen 1. A study suggests that 2.4 Key Molecules or Events
three markers, CD45RO, 25F9, and S100A8/A9, in CKD
can distinguish monocyte-derived fibrocytes from
monocytes, macrophages, and fibroblasts [31]. 2.4.1 RAAS
Nevertheless, specific markers of fibrocytes have
yet to be identified. It is noteworthy that fibrocytes The kidney has all the components of the RAAS,
isolated from humans and mice also express cer- and Ang II formation in kidney does not depend
tain chemokine receptors, such as CCR2, CCR3, on the circulating RAAS. Ang II acting through
CCR5, CCR7, and CXCR4, thereby regulating AT1 receptors activates local components of the
the recruitment to sites of fibrosis. Fibrocytes RAAS inside the kidney. Meanwhile, Ang II act-
migrate, infiltrate into renal tissue, and involve in ing as contracting factor mediates intraglomerular
the pathogenesis of kidney fibrosis following ini- hypertension that contributes to impairment of
tial renal injury. Other immune cells like CD4+ T glomerular endothelial, podocytes, and mesangial
cells can modulate the Gr1+ monocytes differen- cells. Moreover, aldosterone and Ang II perform a
tiation into fibrocytes via secretion of cytokines number of nonhemodynamic functions that are
[32]. Profibrotic cytokines IL-4 and IL-13 pro- critical for the pathogenesis of CKD, including
mote fibrocytic differentiation, whereas antifi- effects on inflammation, ECM production, endo-
brotic cytokines IFN-γ and IL-12 inhibit this thelial dysfunction, and ROS generation.
Ang II as a main vasoconstrictor of RAAS conducted by Zhang et al. indicates that activa-
predominantly effects on postglomerular arteri- tion of AT1 receptors on macrophages can ame-
oles, which leads to intraglomerular hyperten- liorate kidney fibrosis by inhibiting macrophage
sion, an increase in filtration, and impairment of M1 polarization and by reducing the inflamma-
the size-selective function of glomerular barrier tory response. This study may remind us that the
toward macromolecules, such as plasma protein. RAAS acting on different cell lineages plays
Glomerular hypertension and outflow of plasma various roles during interstitial fibrogenesis, and
protein may be responsible for the initiation and angiotensin receptor blockade is related not only
progression of chronic kidney diseases. The non- to previously recognized side effects but also to
hemodynamic effects of Ang II, such as upregu- patently detrimental effects of blocking angioten-
lation of cytokines, increased generation of ROS, sin receptors on hematopoietic cells [36].
and cell adhesion molecules, play important roles Sustained activation of the intrarenal RAAS
in driving progression of kidney disease. In addi- results in renal injury and plays a pivotal part in
tion, Ang II is thought to impair the integrity of the pathogenesis of CKD. This fascinating sys-
glomerular filtration barrier by decreasing nega- tem is found to be increasingly complex as it is
tive charged proteoglycans synthesis and inhibit- characterized, and research into new members
ing nephrin expression [34]. Consequently, Ang continues. Identification and characterization of
II via hemodynamic and nonhemodynamic the RAAS together with novel pharmacological
effects—leads to proteinuria. approaches that target its components—we hope
The RAAS participates in interstitial fibrosis will provide methods to sufficiently retard the
mainly by promoting the proliferation of fibro- progression and to induce regression of kidney
blasts, enhancing EMT, increasing production of disease.
TGF-β, and by promoting the imbalance between
ECM synthesis and degradation. Studies have
uncovered a close link between the RAAS and 2.4.2 TGF-β
profibrotic cytokine TGF-β. Ang II not only pro-
motes TGF-β expression through several path- TGF-β is a key mediator of implicating in the
ways, but also stimulates expression of receptors regulation of fibrogenesis, cell proliferation,
for TGF-β. Furthermore, SMADs phosphoryla- apoptosis, and hypertrophy, contributing to
tion can be directly regulated by Ang II without kidney fibrosis and progressive CKD. The TGF-β
induction of TGF-β. In addition, other molecules superfamily consists of TGF-β1, -β2, and, -β3;
of the RAAS, such as renin, Ang III, and aldoste- activins; and bone morphogenic proteins (BMPs).
rone also promote activation of TGF-β system. Canonical and noncanonical signaling cascades
Given that therapeutic strategies for directly tar- can be provoked by TGF-β to exert various bio-
geting TGF-β system in human diseases have not logical functions. SMAD signaling is thought to
been feasible, angiotensin-converting enzyme be a major pathway among TGF-β-driven signal-
(ACE) inhibitors and AT1 receptor blockers are ings in progressive renal fibrosis. TGF-β signal-
currently the most promising drugs for interfering is initiated when ligand-bound type II TGF-β
ing with this Ang-II-induced TGF-β system acti- receptor (TβRII) binds to (and phosphorylates)
vation. Additionally, Ang II can induce PAI-1 and type I TGF-β receptor (TβRI) in the TβRI cyto-
tissue inhibitor of matrix metalloproteinases 1 plasmic glycine and serine (GS) region. Then,
(TIMP-1) via AT1 receptors. Meanwhile, the SMAD2 and/or -3 are highly activated along with
RAAS participates in EMT too. Aside from the a common SMAD: SMAD4. These SMAD pro-
mechanism mentioned above, Ang II activates teins form an oligomeric complex and then are
(through AT1 and AT2 receptors) the proinflam- translocated into the nucleus to regulate the tran-
matory transcription factor NF-κB [35], enhanc- scription of target genes in collaboration with
ing an inflammatory response and contributing to various coactivators and corepressors. Activation
renal interstitial fibrosis. In contrast, one study of SMAD3 is associated with the downregulation
of inhibitory SMAD7 via an ubiquitin E3 ligase- of αSMA into stress fibers in mesangial cells
dependent degradation mechanism. Additionally, [40].
TGF-β can function via SMAD-independent TGF-β exhibits profibrotic effects during kid-
pathways, including p38, ERK, MAPK, Rho ney interstitial fibrosis potentially via several
GTPases, Rac, Cdc42, ILK, β-catenin, and PI3K– mechanisms below: (1) As mentioned above,
Akt–mTOR cascades. kidney-resident and -nonresident cells can trans-
The cytokine TGF-β is closely associated with differentiate into myofibroblasts under the action
glomerular disease. This cytokine and its recep- of TGF-β. TGF-β treatment drives transdifferen-
tors are upregulated in a variety of podocyte dis- tiation of endothelial and epithelial cells in
eases, including MN, DN, and FSGS. Increased myofibroblast- like cells, whereas inhibiting
urinary concentration of TGF-β is detected in TGF-β–SMAD signaling with antagonists or
patients with some forms of nephrotic syndrome, blockers ameliorates or reverses the development
IgAN, and FSGS. Of note, detection of TGF-β in of EndMT or EMT [6, 41]. (2) TGF-β1 directly
urine can differentiate between FSGS and the promotes generation of the ECM, including
nonfibrotic process of minimal change disease fibronectin and type I collagen, via dependent or
(MCD). In addition to its profibrotic effects, independent of SMAD3 pathways. (3) TGF-β1
TGF-β signaling induces apoptosis. As described inhibits ECM degradation via MMPs inhibition
above, glomerulosclerosis in animal models and but TIMPs induction. (4) TGF-β1 directly exerts
humans is characterized in part by depletion of effects on various kidney-resident cells to per-
podocytes. TGF-β1 and SMAD7 synergize to form different functions; for instance, it induces
induce apoptosis in podocytes in vitro. A study fibroblast proliferation to generate more matrix
by Shankland’s group suggests that CDK inhibi- or may promote tubular epithelial cells apoptosis,
tor p21 is necessary for TGF-β-induced podocyte and this effect may cause more severe renal inter-
apoptosis [37]. In a TGF-β1 transgenic model of stitial fibrosis and incur more damage to kidney
progressive glomerulosclerosis, the time point of diseases.
peak podocyte apoptosis coincides with expres- Not surprisingly, due to the importance of
sion of TGF-β1 and SMAD7, and with the onset TGF-β signaling, therapeutic agents that inhibit
of albuminuria, but precedes mesangial expan- TGF-β signaling have been shown to reduce
sion [38]. In addition, podocyte depletion may matrix accumulation in animal models of diabe-
cause decreased expression of VEGF, which acts tes, puromycin nephropathy, and UUO. Many
on endothelial cells and promotes their survival potential therapeutic approaches based on
[39]. These pathogenic events mediated by inhibition of TGF-β have been tested in experi-
TGF-β signaling may represent the pathological mental models of CKD, such as the administra-
mechanism behind podocyte depletion and pro- tion of neutralizing anti-TGF-β antibodies, a
gressive glomerulosclerosis. soluble TGF-β receptor, or small interfering
Additionally, TGF-β signaling mediates RNAs that target TGF-β type II receptor. These
mesangial-cell-induced glomerulosclerosis. therapies reduce structural renal injury and
TGF-β1 stimulates production of type I and IV decrease renal fibrosis. In 2011, the results of a
collagens and fibronectin in mesangial cells, phase I clinical trial of fresolimumab, an anti-
leading to glomerular-matrix accumulation in TGF-β antibody, revealed that this agent is well
the pathogenesis of glomerulosclerosis. In addi- tolerated by patients with FSGS [42]. Phase II tri-
tion, TGF-β1 inhibits plasminogen activator pro- als of another anti-TGF-β antibody, LY2382770,
duction, and this effect stimulates PAI synthesis have been stopped early because of futility.
by normal glomeruli. Moreover, TGF-β can rap- Although TGF-β is generally considered a cen-
idly stimulate Ca2+ influx, without promoting a tral mediator of fibrotic diseases, inhibition of
Ca2+ release, thereby further promoting cytoskel- TGF-β and of its downstream targets has a long
etal rearrangement and increasing incorporation way to go before adoption in the clinic.
2.4.3 Wnt Signaling Pathway signaling events, active β-catenin is translocated

into the nucleus, binds to TCF and/or LEF tran-
Wnt signaling has been recognized for its impor- scription factors, and recruits coactivators—
tant functions not only in carcinogenesis but also including CREB-binding protein (CBP) or its
in embryonic development and in the stem cell closely related protein p300—to form a tran-
compartment. To date, 19 Wnt ligands and 15 scriptionally active complex. The latter promotes
receptors and coreceptors have been identified. target genes expression, such as those encoding
Many Wnt ligands act through the canonical Wnt Snail1, RAS components, MMP-7, TRPC6,
pathway in which β-catenin is a key mediator. FSP1, PAI-1, and fibronectin. These target genes
The Wnt–β-catenin cascade is silenced in healthy inhibit the expression of proteins associated with
adult kidneys and is reactivated in adult kidneys the podocyte slit diaphragm, facilitate cytoskele-
after injury. Aberrant activation of Wnt–β-catenin tal organization and contraction, or promote
signaling is associated with proteinuria, renal podocyte EMT or apoptosis, thereby leading to
function decline, and kidney fibrosis in many impairment of podocyte function and perturbing
forms of CKD, regardless of whether the injury slit-diaphragm integrity under pathological
initially occurs in the renal tubulointerstitium or conditions.
glomeruli [7, 43]. Wnt expression increases in The levels of many Wnt proteins and Fzd
the kidneys of animal models of receptors are evaluated in tubular epithelium in
CKD. Noncanonical Wnt pathways include the fibrotic kidneys. In CKD, Wnt and β-catenin not
planar cell polarity (Wnt–PCP) and Wnt–Ca2+ only show alterations of expression, but also par-
signals. Due to the importance of Wnt–β-catenin ticipate in initiation and progression of kidney
signaling, we will focus on the involvement of fibrosis. Overexpression active form of β-catenin
this signaling in kidney fibrosis. in tubular cells provokes dedifferentiation of tubu-
Increased Wnt activity has been observed in lar cells and EMT in mice. Consistent with this
glomeruli of mouse models of CKD. Wnt expres- result, reduced Wnt/β-catenin activation closely
sion increases in the podocytes of mice treated correlates with improvement of renal fibrosis.
with Adriamycin, a drug that induces podocyte Interventions into Wnt signaling at different levels
injury with features similar to those of FSGS [7]. have been studied. DKK1 is a Wnt antagonist that
Wnt expression increases in the podocytes of binds to receptor LRP5 or LRP6 and inhibits the
mice treated with adriamycin, a drug that induces canonical Wnt pathway. Injection of a vector
podocyte injury with features similar to those of encoding DKK1 into a mouse model of kidney
FSGS. Tail vein injection of exogenous Wnt1 fibrosis reduces β-catenin accumulation and fibro-
into BALB/c mice exacerbates podocyte dys- sis. Similarly, inhibition of Wnt–β-catenin signal-
function, as evidenced by decreased protein lev- ing by other antagonists including sFRP4, Klotho,
els of nephrin. Blocking Wnt signaling with and the small-molecule inhibitor ICG-001
DKK1 in adriamycin-injected mice ameliorates represses myofibroblast activation and reduces
albuminuria and counteracts the decrease in renal interstitial fibrosis. Emerging evidence indi-
nephrin levels [7]. Furthermore, a podocyte- cates that depending on the magnitude and dura-
specific knockout of β-catenin protects mice from tion of its activation, Wnt–β-catenin signaling
adriamycin-induced podocyte injury, including performs a dual function: promoting repair or
albuminuria and podocyte FPE [7]. ICG-001 also regeneration or facilitating progression to CKD
can effectively attenuate proteinuria in a model of after acute kidney injury (AKI). Transient activa-
adriamycin-induced nephropathy. Wnt signaling tion of the Wnt–β-catenin pathway is renoprotec-
elicits its biological effects by promoting the tive because it promotes adaptive repair and
expression of many different target genes. recovery, whereas sustained activation of the
Following Wnt’s binding to a cell membrane same signaling cascade is detrimental and triggers
receptor and induction of a series of downstream maladaptive responses, leading to the onset and
progression of CKD. Feng et al. have reported activity of the guanosine triphosphatase (GTPase)
that Wnt–β-catenin signaling in macrophages RAS homolog enriched in brain (Rheb) via its
stimulated by Wnt3a contributes to IL-4- or GTPase-activating protein activity. Rheb pro-
TGF-β- induced macrophage M2 polarization vokes mTORC1 activation when they are close to
and the phosphorylation and nuclear transloca- each other [45]. The mTORC2 kinase mainly
tion of STAT3 in vitro; by contrast, inhibition controls many cellular parameters and processes,
of Wnt–β- catenin signaling prevents these including protein synthesis, cell survival, rear-
IL-4- or TGF-β1-induced processes. Mice with rangement of cell cytoskeleton, and sodium
a macrophage-specific β-catenin knockout show homeostasis. Akt, serum, and glucocorticoid-
decreased macrophage accumulation, attenuated induced kinase 1 (SGK-1), and protein kinase Cα
M2 polarization, and alleviation of kidney fibrosis(PKCα) are all substrates of mTORC2 [46].
after UUO [44]. This evidence suggests that Wnt– Moreover, mTOCR2 can phosphorylate and
β-catenin signaling in macrophages as well as in sequester forkhead box proteins O1 (FOXO1)
tubular cells and fibroblasts is likely to play a key
and FOXO3 via Akt [47]. The function of
role in the pathogenesis of interstitial fibrosis. mTORC2 is not as clear as that of mTORC1 due
to lack of specific inhibitor of mTORC2 kinase.
Rapamycin as mTOR inhibitor induces sig-
2.4.4 mTOR Signaling nificant ultrastructural and molecular changes in
podocytes including increased foot process
mTOR, a highly conserved serine-threonine width, decreased Nephrin and Podocin mRNA
kinase, is recognized for a critical regulator of levels, which are associated with albuminuria in
cell proliferation, cell growth, and metabolism. BALB mice with normal renal conditions. These
Mounting evidence exhibits that mTOR performs manifestations are finally ameliorated at week 8
a pivotal function in the control of kidney cell after rapamycin-treated groups [48]. By contrast,
homeostasis and autophagy. mTOR kinase exists mice with adriamycin-induced nephropathy have
in two distinct protein complexes: mTOR com- significantly reduced proteinuria and preserve
plex 1 (mTORC1) and mTOR complex 2 renal function, with only mild histological abnor-
(mTORC2). mTORC1 as a “nutrient sensor” is malities [49]. Gene knockout approaches provide
activated by amino acids and suppressed by oxi- us to well understand the functions of mTORC1
dative stress and energy depletion. mTORC1 is and mTORC2 in podocyte. Genetic deletion of
also regulated by growth factors and cytokines mTOCRC1 in mouse podocytes induces protein-
via phosphoinositide 3-kinase (PI3K) signaling uria and progressive glomerulosclerosis, weight
pathway. Phosphatidylinositol (3, 4, 5) triphos- loss, and increased mortality [50]. Genetic dele-
phage (PIP3) generated by PI3K stimulates tion of mTORC2 in mouse podocytes does not
3-phosphoinositide-dependent protein kinase 1 manifest significant phenotypic differences from
(PDK1), which promotes Akt (protein kinase B) littermate controls. This result is suggestive of a
activity via phosphorylating of the activation less important role of mTORC2 in podocytes.
loop at threonine 308. Moreover, mTORC2- Nevertheless, abrogation of both mTORC1 and
mediated phosphorylation of both the turn motif mTORC2 in podocytes precipitates an early ful-
in AKT (Thr450) and hydrophobic motif in ATK minant proteinuric phenotype. This scenario may
(Ser473) stabilizes and activates Akt. The activa- suggest that interaction between mTORC1 and
tion of tuberous sclerosis complex 1 (TSC1)- mTORC2 may regulate podocyte development
TSC2 negatively regulates mTORC1 and is and homeostasis.
directly inhibited by Akt-dependent phosphory- Conversely, podocyte-specific deletion of
lation. TSC1-TSC2 complex therefore serve as Tsc1 results in excessive mTORC1 activity,
an intermediary between PI3K-Akt signaling and which can lead to severe pathological effects.
mTOR. TSC1 maintains but TSC2 suppresses the Increased activation of mTORC1 causes
increased pS6 expression, glomerular hypertro- 2.4.5 MicroRNAs (miRNAs)

phy, GBM thickening, podocyte foot process
broadening and effacement, and proteinuria, MiRNAs are endogenous single-stranded non-
which can be ameliorated by rapamycin [50]. coding RNA molecule (containing about 22
mTORC1 excessive activation in podocytes also nucleotides). MiRNAs have multiple key roles in
leads to the progression of glomerular crescents, regulating various biological functions such as
which is abrogated by rapamycin treatment. In cell differentiation, proliferation, development,
cellular crescents from patients with crescentic and immune responses. Thus, dysregulation of
glomerular diseases, mTORC1 signaling is miRNAs seems to result in disturbances of target
remarkably activated too [51]. A publication by gene networks and signal transduction culminat-
Canaud G et al. reveals that activation of Akt2 as ing in disease onset and/or development. The bio-
downstream of mTORC2 is essential to maintain genesis of miRNAs is detailed well in many
podocyte viability and function during chronic reviews [56]. RNA polymerases II and III are
kidney disease [52]. responsible for miRNA transcription to generate
In vitro, mTOR signaling pathway in fibro- precursors that is cleaved into mature
blasts is exclusively activated by TGF-β via the miRNA. The regulatory functions of miRNAs are
TSC2, and rapamycin abolishes TGF-β-induced executed by the RNA-induced silencing complex
upregulation of Rheb-mTORC1 signaling in (RISC). The latter is assembled from miRNA and
interstitial myofibroblasts. Genetically modified other components and is thus activated to target
mice with either ectopic expression of Rheb or messenger RNA (mRNA) specified by the
fibroblast-specific deletion of TSC1 exhibit acti- miRNA.
vated mTORC1 signaling in kidney interstitial MiRNAs are crucial modulators of nephron
fibroblasts and increased renal interstitial fibro- development. Dicer is an important RNase III
sis, which can be abrogated by rapamycin as well family enzyme cleaving precursor miRNAs into
[53]. Mounting evidence have revealed that treat- RNA duplexes during the biogenesis of miRNAs.
ment with rapamycin after renal damage, regard- Specific deletion of Dicer in podocytes leads to
less of etiology, slows the subsequent progression formation of FPE, proteinuria, interstitial fibrosis,
of interstitial fibrosis caused by ischemic- glomerulosclerosis, and eventually the animal
reperfusion injury (IRI), transplantation, UUO, dies several weeks later due to renal failure [57].
and/or glomerulopathy. Several miRNAs (miR-23b, miR-24, miR- 26a,
Li et al. have found that RICTOR–mTORC2 and the miR-30 family) are thought to be closely
signaling can be activated in normal rat kidney related with abnormalities of podocyte pheno-
cells (NRK-49F cell line) treated with TGF-β1 in type. The miR-30 family has been shown to target
a time-dependent manner, whereas a knockdown several mRNA that mediate podocyte apoptosis
of RICTOR with small interfering RNA inhibits and cytoskeletal arrangement. Drosha is another
the fibroblast activation characterized by the important enzyme accounting for miRNA synthe-
expression of fibronectin and smooth muscle sis, and specific deletion of Drosha in podocytes
actin. In vivo, mice with a fibroblast-specific present similar phenotypes as in mice with Dicer
knockout of RICTOR show lower collagen con- deficiency [58]. Dicer deficiency in renin-express-
tent and fibrosis, apoptosis, and inflammatory ing juxtaglomerular cells reduces cell number
cell infiltration in the UUO kidney as compared [59]. These results support the important roles of
with control littermates [54]. Our group has also miRNA in maintaining biological functions of
reported that RICTOR–mTORC2 signaling acti- nephron. In addition to podocytes, mesangial cells
vation in macrophages drives macrophage M2 are regulated by miRNAs too. MiR-34a and miR-
polarization, a release of multiple profibrotic fac- 335 potentially induce mesangial-cell senescence
tors and proliferation, which eventually induce by inhibiting mitochondrial antioxidative
kidney interstitial fibrosis [55]. enzymes superoxide dismutase 2 and thioredoxin
reductase 2. Akt activation through PTEN [66]. Based on this fact, clinically, miRNAs are
downregulation by miRNA-216a and miRNA- likely to be used as biomarkers for diagnosis and
217, which are regulated by upstream miR-192 prognostication of human diseases.
and TGF-β, leading to glomerular mesangial-cell
hypertrophy and survival, and playing important
roles in diabetic changes in kidneys. Moreover, 2.4.6 Hypoxia-Induced Factor (HIF)
miR-377 overexpression in mesangial cells can
trigger production of fibronectin and expansion of HIF, known as a basic heterodimeric transcrip-
the mesangial matrix by downregulating serine- tion factor, is composed of two protein subunits:
threonine protein kinase PAK1 and superoxide HIF-α and HIF-β. In normal oxygen condition,
dismutase. HIF-α subunit is sensitive to oxygen and regu-
The regulation of miRNAs is closely associ- lated by O2-dependent prolyl hydroxylation,
ated with profibrotic cytokine TGF-β in intersti- which targets the protein for ubiquitylation by
tial fibrosis. MiR-382 is induced in UUO-induced von Hippel-Lindau (VHL) tumor suppressor.
obstructed kidneys as well as in cultured proxi- Ubiquitylated HIF-α is rapidly targeted for deg-
mal tubular cells treated with TGF-β1. MiR-382 radation. Under hypoxic conditions or loss-of-
potentially suppresses Kallikrein 5, a crucial function VHL, HIF-α does not undergo
enzyme that mediates the degradation of ECM degradation and subsequently translocates into
components. Thus, blockade of miR-382 via a nucleus, where it binds to HIF-β to form constitu-
locked nucleic acid inhibitor apparently attenu- tively active HIF. After binding to the cis-acting
ates kidney tubulointerstitial fibrosis [60]. hypoxia-responsive element, HIF induces a vari-
Furthermore, TGF-β1 acts by causing SMAD3 ety of target gene expression, which are adaptive
to positively regulate miR-21 and miR-192 response to hypoxic conditions. More than that,
expression but negatively regulate the expression HIF-regulated target genes involved in angiogen-
of miR-29 or miR-200 families, thereby mediat- esis, erythropoiesis, and energy metabolism, also
ing renal fibrosis [61], whereas SMAD7 can favor adaptation to oxygen depletion and oxygen
antagonize the miR-21 induction [62]. MiR-21 delivery. As a transcription factor, HIF is involved
inhibition or deletion significantly reduces inter- in the regulation of many biological processes
stitial fibrosis after UUO possibly by targeting that facilitate both oxygen delivery and adapta-
the lipid metabolic pathway regulated by peroxi- tion to oxygen deprivation by regulating genes
some proliferator- activated receptor alpha that participate in glucose uptake, energy metab-
(PPAR-α) [63]. In addition, the TGF-β cascade is olism, angiogenesis, erythropoiesis, cell
responsible for the inhibition of miR-29 and proliferation, apoptosis, cell–cell and cell–matrix
miR-200 and for induction of miR-192 and miR- interactions, and barrier function.
491-5p in the UUO model; these effects in turn HIFs represent a critical initial signal for the
promote the development of renal injury [62]. inception of glomerular capillary morphogenesis
Besides, miR-192 is a major contributor to the [67]. In the settings of renal glomerular diseases,
phenotype switch of tubular cells during renal podocyte-specific activation of HIF induced by a
tubulointerstitial fibrosis. Additionally, it has VHL knockout induces activation and prolifera-
been suggested that renal miR-433 expression tion of podocytes and rapidly progressive glo-
induced by TGF-β promotes renal interstitial merulonephritis and renal failure [68]. Likewise,
fibrosis [64]. MiR-200 and miR-141 are neces- HIF-α hyperstabilization induces widespread
sary for the development and progression of podocyte foot process broadening, GBM thicken-
TGF-β1-dependent EMT and interstitial fibrosis ing, and ectopic deposition of collagen α1α2α1
in vitro and in vivo [65]. (IV) in GBM humps beneath podocytes [69].
Of note, miRNAs are detectable in various Endothelial cells are deeply involved in
body fluids such as saliva, tears, serum, and urine. CKD. Nonetheless, the functions of HIF-1 and
And they are much more stable than mRNAs HIF-2 in the glomerular endothelium may be dif-
ferent in the different contexts of kidney diseases. cesses. Disturbed production of ATP during
In a kidney chronically injured by Ang II-induced energy metabolism, e.g., mitochondrial dysfunc-
hypertension, elevated endothelial HIF-1α tion or dysregulation of key metabolic enzymes
amounts contribute to the initial glomerular by various insults, will cause a cellular structural
injury, leading to hypertension and progression abnormality, apoptosis, or differentiation.
of renal fibrosis. Endothelial HIF-2, but not HIF- Mitochondria supply most of ATP to the cell
1, regulates renal inflammation likely through via their oxidative phosphorylation (OXPHOS)
suppression of VCAM1 expression and protects system. Mitochondria are highly dynamic organ-
from hypoxia-induced renal damage [70]. Studies elles. One of the most unique features of mito-
by Kalucka et al. indicate that specific deletion of chondria is fusion and fission. Frequent cycles of
HIF-1α in endothelial cells of glomerular induces fusion and fission adapt the morphology of the
hypoxic cell death in vitro; however, a loss of mitochondrial compartment to metabolic needs
HIF-1α in endothelial cells does not significantly of the cell. Once the balance between fusion and
effect on the development profile of kidneys and fission is lost, the cellular functions change.
does not influence renal function or the expres- Meanwhile, mitochondrial biogenesis and the
sion of adhesion proteins in the pathogenesis of regulation of OXPHOS are important for satisfy-
fibrosis after UUO [71]. ing the specific energy demand of specialized
Accumulating evidence highlights chronic cells. PGC-1α itself is a master cotranscriptional
hypoxia in the tubulointerstitium as a final com- regulator that induces mitochondrial biogenesis
mon pathway to end-stage renal disease [72]. A by activating various transcription factors.
fibrotic kidney with advanced renal disease is Besides energy supply, mitochondria contribute
devoid of peritubular capillary blood supply to to calcium signaling, ROS production, and redox
(and oxygenation of) the corresponding region. homeostasis.
In this context, of note, hypoxia per se induces a On the other hand, β-oxidation of free fatty
fibrogenic response which would active renal acids is one of the major sources of ATP produc-
microvascular endothelial cells, tubular cells, and tion, particularly in the proximal tubule, which
interstitial fibroblasts. Hypoxia is also a profibro- has high energy demand and relatively low gly-
genic stimulation for changing the ECM homeo- colytic capacity. Several old studies indicate that
stasis of resident cells in kidney, and then leading ~60% of the energy in kidneys comes from burn-
to peritubular capillaries rarefaction. In the set- ing of fatty acids. The energy production of fatty
ting of hypoxia, tubular cells could transdifferen- acid β-oxidation is high: on average 106 ATP
tiate to myofibroblasts. In addition, severe and/or equivalents per fatty acid molecule, as opposed
prolonged hypoxia can cause kidney epithelia to 36 during oxidation of carbohydrates. The
dysfunction that accounts for energy metabolism high energy consumption of the proximal tubule
imbalance and subsequent cell apoptosis. The is due to the workings of fluid and electrolyte
reciprocal relation between hypoxia and develop- homeostasis, active solute secretion, and hor-
ment of renal failure may provide us new thera- mone production. Sometimes, glycolysis con-
peutic strategies for patients with chronic kidney tributes to energy production too, under certain
diseases. circumstances. Although this metabolic pathway
is a less efficient producer of ATP as compared
with mitochondria, glycolysis has several advan-
2.4.7 Defective Energy Metabolism tages. One is glycolysis that can generate addi-
tional energy when mitochondria show maximum
The kidney uses a large amount of energy, most performance. Another is generation of side prod-
of which is dedicated to cell structure mainte- ucts, including amino acids, nucleic acids, and
nance and solute reabsorption. ATP, which is lipids. Nonetheless, under stress, a switch to gly-
called the molecular unit of intracellular energy colysis may influence cellular biological
currency, is essential for normal cellular pro- functions.
The regulators of energy metabolism help to capacity is impaired. Research indicates that free-
balance the energy production and consumption fatty acid accumulation in podocytes is toxic and
for energy homeostasis. AMPK has been identi- induces endoplasmic-reticulum stress and podo-
fied as the critical molecule for the regulation of cyte death. Stimulation of fatty acid oxidation by
metabolism in various cells. AMPK can be acti- AMPK activators can abrogate the detrimental
vated during energy stress in response to a rise in effect of free-fatty acid accumulation. In contrast,
the AMP/ATP ratio. AMPK is known to be the inhibition of fatty acid oxidation by CPT-1 inhibi-
substrate of LKB1; the latter serves as a crucial tor etomoxir increases the toxic effect of palmitic
metabolic checkpoint factor and arrests cell cycle acid on podocytes [75]. Proteins involved in the
in response to low intracellular ATP concentra- transport and oxidation of fatty acids are affected
tion, e.g., during low nutrient availability. Thus, in podocytes of puromycine aminonucleoside
the LKB1–AMPK axis, as the key energy metab- (PAN) glomeruli [76]. It is also reported that gly-
olism regulator, plays a vital role in cellular colysis acts as a supplier of ATP in mouse podo-
energy homeostasis. mTOR is one of the main cytes although the main supplier is mitochondria
players that controls energy-consuming cellular and their OXPHOS system [77]. The podocyte’s
processes such as cell growth and proliferation. dependence on glycolysis for ATP production
mTOR as one of the main regulators controls might change in pathological conditions.
energy-consuming cellular processes including Mitochondrial abnormality facilitates the pro-
cell proliferation and growth. mTOR contributes gression of renal interstitial fibrosis, particularly
to the increase in oxygen consumption, mito- due to a reduction in mtDNA copy number, a loss
chondrial membrane potential, ATP-synthetic of mitochondrial membrane potential, and a drop
capacity, and mitochondrial content. Thus, of ATP production. Mitochondrial dysfunction is
mTOR and AMPK coordinately regulate cellular involved in the apoptosis and EMT of renal tubu-
energy homeostasis. mTOR increases mitochon- lar epithelial cells and in ROS production, thereby
drial membrane potential, oxygen consumption, contributing to the fibrogenic process. Stimulation
ATP-synthetic capacity, and mitochondrial con- of mitochondrial biogenesis by restoring cAMP
tent. Therefore, there is a complex relation levels by means of PDE4 inhibitor rolipram ame-
between AMPK and mTOR in terms of regulat- liorates UUO-induced renal fibrosis [78].
ing cellular energy homeostasis. Emerging evidence suggests that defective energy
Podocytes have many highly specialized foot metabolism—including fatty acid oxidation and
processes, which require high energy consump- glucose metabolism—is associated with CKD
tion to maintain their structure and functions. In [79]. Impaired energy metabolism in general, and
fact, a considerable number of mitochondrial sec- reduced fatty acid oxidation in particular, are
tions are observed in the narrow peripheral foot prominent and consistent features of CKD in both
processes. Morphological changes of mitochon- human biopsy samples and several animal mod-
dria are exclusively observed in podocytes among els. Additionally, the above study has revealed
glomerular cells in patients with mitochondrial that the increased tubule-specific triglyceride con-
cytopathy [73]. Mitochondrial activity loss mani- centration and higher long-chain fatty acid con-
festing itself as a smaller energy supply may be tent after overexpression of CD36 do not induce
accompanied by increased ROS production, thus significant renal fibrosis. These findings indicate
causing or accelerating podocyte injury. that a defect in β-oxidation of free fatty acids is
Furthermore, studies suggest that a reduction in crucial for CKD development [79]. Kang et al.
the amount of mitochondrial DNA (mtDNA, have reported that TGF-β1 can inhibit PPAR-α
which is involved in mitochondrial biogenesis and and PPARGC1A to induce EMT. In another study,
function in podocytes) is associated with the the AMPK activator 5-aminoimidazole-4-
pathogenesis of podocyte injury. CoQ-deficient carboxamide-1β riboside (AICAR) inhibited the
mice with Pdss2 conditionally knocked out only activation of myofibroblasts both in a UUO model
in podocytes have proteinuria and podocyte FPE and in response to stimulation of NRK-49F cells
[74]. In these mice, mitochondrial OXPHOS by TGF-β1 [80]. Recently, Ding et al. discovered
that a switch of metabolism from OXPHOS to 2.5 Conclusion

aerobic glycolysis (Warburg effect) in renal fibro-
blasts is the primary feature of fibroblast activa- The pathophysiology of CKD is largely dependent
tion during UUO-induced renal interstitial fibrosis on the primary insult, but common pathways exist
[81]. In addition, suppression of renal fibroblast across almost all subsets of kidney disorders. The
aerobic glycolysis significantly reduces UUO- pathophysiological mechanisms of CKD men-
induced interstitial fibrosis [81]. tioned above actively participate in the develop-
Meanwhile, an imbalance among regulators of ment and progression of CKD (Fig. 2.2); however,
energy metabolism may also contribute to other cytokines or mechanisms such as CTGF,
CKD. A loss of LKB1 in the distal tubular cells FGF, autophagy, oxidative stress, Notch signaling,
causes CKD characterized by increased matrix and VEGF signaling (which have not been men-
deposition [82]. That study has revealed that tioned) are equally important. Our goal in the
energy metabolism is diminished in LKB1 renal study on the pathophysiology of CKD is to find
tubular knockout mice with CKD, and this phe- approaches to effective therapy for CKD, but no
nomenon could be retarded by treatment with new medicines have been registered for the treat-
either the AMPK agonist A769662 or a PPAR-α ment of CKD since 2001. This situation also
agonist, fenofibrate. In agreement with this find- means (from another perspective) that the patho-
ing, the reduction in AMPK expression both in genesis of CKD is intricate. It is necessary to con-
kidney cell lines—and in AMPK-a2-null mice trol the prevalence of kidney disease in many ways
subjected to UUO—increases levels of markers worldwide, including prevention of CKD onset,
of EMT and fibrosis. Others have also found that earlier diagnosis of CKD, timely evaluation and
after various profibrotic stimuli, including TGF- management of patients with CKD, and preven-
β, Ang II, aldosterone, or high glucose and albu- tion and management of complications. Of course,
min levels, EMT is suppressed by the AMPK broad collaboration of academia and the industry
activators metformin and AICAR. may help to develop novel therapeutics for CKD.
Ang II TGF-β1 Wnt

Firzzied
AT1R TGFβRI TGFβRII Glucose

LRP5/6 LKB1
Glycolysis
Pyruvate
MAPK
Fission
FAO
Fatty acid TCA
NOX NF-κB MAPK Smads PI3K/AKT β-catenin
Hypoxia Fussion
ATP
mTOR HIFα
ROS
targeted mRNA
β-catenin p300 HIFβ
Inflammatory mRNA Fibrosis-related
TCF/ Fibrosis-related
NF-κB mRNA HIFα
LEF mRNA
DNA
Biological actions (dedifferentiation, transdifferentiation, hypertrophy, apoptosis, proliferation)
Fig. 2.2 Schematic presentation for molecular mediators or signaling pathways involved in the progression of chronic
kidney disease
8. Liu XL, et al. Characterization of the interac-

Key Messages tions of the nephrin intracellular domain. FEBS J.
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Diabetic Kidney Disease
3
Ting Cai and Junwei Yang
Abstract renin–angiotensin–aldosterone system block-

Diabetic kidney disease (DKD) is the leading ade. Patients who develop ESRD require renal
cause of end-stage renal disease (ESRD) and replacement therapy.
is strongly associated with mortality in
patients with diabetes. Persistent albuminuria
is the hallmark of DKD, and some patients
will finally develop ESRD with gradually 3.1 Introduction
decreased glomerular filtration rate (GFR) and
increased serum creatinine concentration. Diabetes mellitus, a disease no longer associated
Glomerular basement membrane thickening, with affluence, is on the rise across the world.
mesangial expansion, mesangial matrix accu- More than 425 million individuals currently have
mulation, Kimmelstiel–Wilson nodules, and diabetes, and this number may increase to
tubulointerstitial fibrosis are typical patholog- 693 million by 2045 if nothing is done [1]. The
ical changes in DKD. Screening for DKD incidence of diabetic kidney disease (DKD) has
should begin at 5 years after the diagnosis of more than doubled in the past decade, largely
type 1 diabetes and at the diagnosis of type 2 because of the increasing prevalence of type 2
diabetes, which should include measurement diabetes. As a potential devastating complication
of urinary albumin-to-creatinine ratio and of diabetes, DKD is currently the primary cause
serum creatinine concentration, estimation of of end-stage renal disease (ESRD) and is the sin-
GFR, and ophthalmologic examination. The gle strongest predictor of mortality in patients
progression of DKD may be slowed by opti- with diabetes that globally imposes an increased
mal therapeutic approaches, including life- social and economic burden [2].
style improvement, strict glycemic and blood
pressure control, control of dyslipidemia, and
3.2 Natural Course of DKD
T. Cai In the conventional course of DKD, pathological
changes develop progressively over a long clini-
J. Yang (*) cal silent period without evidence of proteinuria,
Centre for Kidney Disease, Second Affiliated
impaired glomerular filtration rate (GFR), or
Nanjing, Jiangsu, China hypertension. An increase in GFR, or hyperfiltra-
e-mail: jwyang@njmu.edu.cn tion, is one of the earliest changes which is

34 T. Cai and J. Yang
Table 3.1 Urinary ACR is a diagnostic test for microal- from diagnosis of diabetes to onset of proteinuria
buminuria and macroalbuminuria
is 19 years; in contrast, it is shorter and variable
Urinary ACR in patients with type 2 diabetes, as the disease
Condition (mg/g) Terms
may have already been present for several years
Normoalbuminuria <30 Normally to
mildly increased prior to the establishment of diagnosis. Renal
Microalbuminuria 30–300 Moderately function may loss progressively over several
increased years in patients with type 1 diabetes without
Macroalbuminuria/ >300 Severely intervention. Despite advances in interventions
overt proteinuria increased that slow down the progression of DKD, the
ACR albumin-to-creatinine ratio number of patients progressing to renal failure is
still increasing, making diabetes the major cause
observed in most patients with type 1 diabetes of ESRD [2].
and many with type 2 diabetes. Hyperfiltration is
accompanied by renal hypertrophy, an increase in
renal size. The next observable clinical manifes- 3.3 Renal Pathology in DKD
tation is the development of microalbuminuria. A
urinary albumin-to-creatinine ratio (ACR) After the onset of diabetes, kidney weight and
between 0 and 30 mg/g and between 30 and size keep increasing until the establishment of
300 mg/g is customarily referred to as normoal- overt nephropathy. Glomerular basement mem-
buminuria and microalbuminuria, respectively brane (GBM) thickening is the first change that
(Table 3.1). Microalbuminuria is currently can be measured. Mesangial expansion (Fig. 3.2)
accepted as a reliable marker to detect DKD at an develops later due to increased matrix accumula-
early stage. However, not all patients with micro- tion in the mesangial region [7]. When renal dys-
albuminuria will develop overt proteinuria and function occurs, increased mesangial expansion
reduced GFR. Caramori et al. reviewed a number and marked GBM thickening can be observed.
of clinical trials and revealed that only 30–40% Diffuse mesangial expansion can be linked with
of patients with microalbuminuria will develop nodular lesions containing areas of marked
macroalbuminuria (also called overt proteinuria, mesangial expansion forming large round fibril-
defined as urinary ACR >300 mg/g) (Table 3.1) lar mesangial zones with palisading of mesangial
[3]. Patients with established microalbuminuria nuclei around the nodules and compression of the
may have different outcomes: they may improve, associated glomerular capillaries (Kimmelstiel–
stay the same for a long period, or progress to Wilson nodules) (Fig. 3.3). The severity of glo-
macroalbuminuria and worse renal function. merular damage is associated with GFR and
Perkins et al. reported as high as 50% probability albuminuria.
for microalbuminuria to regress to normal levels Renal tubules and interstitium may also
in patients with type 1 diabetes [4]. undergo structural changes, particularly in the
Proteinuria, first characterized by Kimmelstiel later stages of DKD. The thickening of the tubu-
and Wilson in a pathological report, results from lar basement membrane (Fig. 3.2) closely cor-
complex damage in the glomerular filtration bar- relates with the thickening of the GBM.
rier, including the endothelial cells, basement Tubulointerstitial fibrosis and tubular atrophy
membrane, and podocytes [5]. Proteinuria not may be the best pathologic predictors of progres-
only is a marker of glomerular injury but also sive loss of GFR, which are more universal in
implicates tubular injury. The natural course of patients with type 2 diabetes. In fact, the renal
DKD, proposed by Mogensen, including changes pathologic change is heterogeneous in patients
in proteinuria and GFR, as well as stages of pre- with type 2 diabetes; only a subset of patients
ventive treatment, is shown in Fig. 3.1 [6]. In with type 2 diabetes has typical diabetic glomer-
patients with type 1 diabetes, the average time ulopathy, whereas a considerable proportion has
3 Diabetic Kidney Disease 35
Fig. 3.1 Nature course of diabetic kidney disease. GFR glomerular filtration rate; DKD diabetic kidney disease; GBM
glomerular basement membrane; BP blood pressure
Fig. 3.2 Histopathological manifestations in diabetic Fig. 3.3 Histopathological manifestations in diabetic

kidney disease. Mesangial expansion and mesangial kidney disease. Typical Kimmelstiel-Wilson nodule
matrix accumulation are presented. (periodic acid-Schiff (arrowhead), dissolve of mesangium (star) and thickening
staining, ×400) of TBM (arrow) are presented. (methenamine silver stain-
ing, ×400)
more advanced tubulointerstitial and vascular • Macroalbuminuria

damage [8]. Furthermore, the appearance of the • Diabetic retinopathy accompanied with
kidney in some patients with type 2 diabetes is microalbuminuria
more suggestive of glomerular ischemia or tubu- • Microalbuminuria in patients diagnosed with
lointerstitial disease. type 1 diabetes for more than 10 years
Screening for DKD should begin at 5 years

3.4 Diagnosis of DKD after the diagnosis of type 1 diabetes and at the
diagnosis of type 2 diabetes. Patients with diabe-
The main basis of the diagnosis of DKD is the test tes may annually undergo screening for DKD,
values of urinary protein excretion and estimated which should include measurement of urinary
GFR (eGFR). Renal injury may be considered to ACR and serum creatinine concentration, estima-
be caused by diabetes in most patients with diabe- tion of GFR, and ophthalmologic examination
tes who have any of the following features [9]: (Fig. 3.4).
Patients with
• Type 1 diabetes for more than 5 years
OR
• Type 2 diabetes
• Screen for ACR every 12 months

AND
• Estimate eGFR every 12 months
(ACR should be confirmed without urinary tract infection)
ACR ≥ 30 mg/g on two separate tests ACR < 30 mg/g
NO
30 mg/g < ACR < 300 mg/g ACR > 300 mg/g eGFR < 60mL/min/1.73m2
YES
• Presence of DR Typical clinical features of DKD Screen by
NO OR • Slow progression of ACR NO • Urine microscopy

• Slow decline of eGFR • Renal ultrasonography
• Duration of type 1 • Serology: ANCA, C3, C4
• No hematuria or GN
diabetes for more than
suspected
10 years
YES YES
DKD Renal biopsy if necessary
Fig. 3.4 Flowchart for the evaluation of DKD in patients thy; GN glomerulonephritis; DKD diabetic kidney dis-
with diabetes. ACR albumin-to-creatinine ratio; eGFR ease; ANCA anti-neutrophil cytoplasmic antibody; C3
estimated glomerular filtration rate; DR diabetic retinopa- complement 3; C4 complement 4
3.4.1 Measurement of Urinary ACR and macroalbuminuria also showed signs of dia-
betic retinopathy, whereas nearly half of the
Microalbuminuria is accepted as an independent patients with hypertension and type 2 diabetes
risk factor associated with the progression of who had macroalbuminuria did not have con-
chronic kidney disease (CKD) and GFR loss. comitant retinopathy [11]. Thus, the presence of
Measurement of microalbuminuria is currently retinopathy and macroalbuminuria in patients
widely available and easy to perform with rela- with type 1 diabetes strongly suggests DKD. In
tively low cost. As the interpretation of results contrast, as for patients with type 2 diabetes, the
for albumin concentration alone may be unreli- accompanied presence of retinopathy is only
able due to variations in urinary concentration partly useful in the discrimination of renal pathol-
and timed collections are inconvenient, the ACR ogy, and the absence of retinopathy does not rule
in a spot urine sample (preferably the first morn- out the presence of DKD.
ing specimen) is recommended. Metabolic per-
turbation, hemodynamic factors, and presence of
urinary tract infection may affect the appearance 3.4.4 Indications for Renal Biopsy
of albumin in the urine [10]. Hence, the Kidney
Disease Outcomes Quality Initiative (KDOQI) Due to the variability in clinical course and com-
guidelines recommend that elevated ACR be plexity of clinical manifestation, renal biopsy is
confirmed in the absence of marked hyperten- required for some patients with both diabetes and
sion, urinary tract infection, and cardiac failure CKD to discriminate the potential cause of the
with two additional tests during the next kidney disease. Renal biopsy should be consid-
3–6 months [9]. ered in the following patient situations:
1. eGFR rapidly declines, or renal dysfunction

3.4.2 Measurement of Serum without significant proteinuria is observed.
Creatinine Concentration 2. The onset of proteinuria is sudden and pro-
and eGFR gresses rapidly, particularly in patients with
duration of type 1 diabetes <5 years.
In clinical practice, the serum creatinine concen- Alternatively, the evolution of proteinuria is
tration is the most frequently used index to evalu- atypical (e.g., nephrotic syndrome develops in
ate renal function. However, it is not sensitive the absence of persistent microalbuminuria).
enough and may be highly misleading when 3. The presence of macroscopic hematuria or

patients have low muscle mass, especially in active nephritic urinary sediment containing
elderly patients with diabetes. Therefore, the acanthocytes and red blood cell casts, which
KDOQI guidelines recommend that the GFR be suggests glomerulonephritis, is detected.
estimated with the Modification of Diet in Renal
Disease Study equation; however, the evidence
shows that the usefulness of eGFR alone as a 3.5 Management of Patients
regular screening test for CKD in diabetes is less with Diabetes and CKD
secure [9].
For patients with diabetes, when GFR <60 mL/
min/1.73 m2, complications of CKD should be
3.4.3 Ophthalmologic Examination evaluated, which commonly include electrolyte
imbalance, metabolic acidosis, anemia, second-
A study including a cohort of patients with type 1 ary hyperparathyroidism, and CKD–mineral
diabetes and with type 2 diabetes revealed that a bone disorder. Adjustment of drugs’ dosage is
large proportion of patients with type 1 diabetes necessary (Table 3.2).
Table 3.2 Management of patients with diabetes and 3.5.1.2 Glycemic Control
CKD according to GFR Hyperglycemia is the primary cause of
GFR (mL/ DKD. Strict glycemic control through insulin or
min/1.73 m2) Recommendation
islet cell transplantation improves hyperfiltration,
All patients Screen for serum creatinine, ACR,
with diabetes eGFR, and serum potassium every
hyperperfusion, and glomerular capillary hyper-
12 months tension and decreases urinary albumin excretion
45–60 Consideration of dose adjustment of in experimental diabetic animals. Moreover,
drugs in use strict glycemic control slows the development
Screen for eGFR every 6 months and progression of DKD in patients with
Screen for serum electrolyte (Ca, P diabetes.
included), acid alkali balance,
hemoglobin, and parathyroid In the Diabetes Control and Complications
hormone Trial (DCCT), patients with type 1 diabetes who
Evaluation of vitamin D received intensive therapy (average hemoglobin
Consideration of test for bone mineral A1c [HbA1c] level of 7.2%) showed a 39% lower
density risk of developing microalbuminuria when com-
Nutritional consultation
pared to patients who received conventional ther-
Referral to nephrologist when
diabetes with non-DKD or the cause apy (average HbA1c level of 9.1%) at 6.5-year
of CKD is unknown follow-up. Furthermore, patients receiving inten-
30–44 Screen for eGFR every 3 months sive therapy showed a 54% reduction in progres-
Screen for serum electrolyte (Ca, P sion from microalbuminuria to macroalbuminuria
included), acid alkali balance, [12]. At the end of the DCCT, all patients in the
hemoglobin, parathyroid hormone,
albumin, and weight previous two groups received intensive therapy,
Consideration of dose adjustment of and nephropathy was evaluated based on urine
drugs in use specimens at 3 and 4 years after the original
<30 Referral to nephrologist DCCT. The average HbA1c level was 8.2% in the
GFR glomerular filtration rate; ACR urinary albumin-to- previous conventional therapy group, and 7.9%
creatinine ratio; eGFR estimated glomerular filtration in the previous intensive therapy arm. However,
rate; CKD chronic kidney disease; DKD diabetic kidney
the intensive therapy group still has advantage
disease
over the former conventional therapy group with
an 86% lower risk of new-onset albuminuria.
3.5.1 Treatment of DKD More recently, data from the DCCT and
Epidemiology of Diabetes Interventions and
Interventions deemed useful in preventing the Complications (EDIC) study suggested a 50%
progression of DKD include lifestyle improve- reduction of the long-term risk of impaired GFR
ment, strict glycemic and blood pressure (BP) in patients undergoing intensive therapy as com-
control, control of dyslipidemia, and renin– pared to their counterparts receiving conventional
angiotensin–aldosterone system (RAAS) block- therapy [13].
ade. Patients who develop ESRD may require A number of major studies have also reported
renal replacement therapy (Fig. 3.4). a lower risk of DKD in patients with type 2 dia-
betes undergoing stricter glycemic control. As
3.5.1.1 Lifestyle Improvement shown in the United Kingdom Prospective
The KDOQI guidelines recommend a dietary Diabetes Study (UKPDS), newly diagnosed
protein intake of 0.8 g/kg body weight per day for patients with type 2 diabetes were randomly
individuals with diabetes and stage 1–4 CKD [9]. divided into intensive therapy (HbA1c level of
For patients with diabetes on hemodialysis (HD), 7.0%) treated with sulfonylurea or insulin and
1.3 g/kg weight per day is suggested. Smoking conventional therapy (HbA1c level of 7.9%) with
should immediately be stopped upon the diagno- diet alone [14]. The reduction in the risk of devel-
sis of diabetes. oping microalbuminuria over 9 years and of
p rogression from microalbuminuria to protein- Table 3.3 Dose adjustment of oral hypoglycemic drugs
uria was 24% and 42%, respectively, in the inten- in patients with diabetes and CKD
sive therapy group. After study termination, Medication class
patients were observed for another 10 years. and agents CKD stages 3, 4, and 5
First-generation sulfonylureas
Although the HbA1c level between the two
• Acetohexamide • Avoid using
groups was comparable within 1 year, lower risk • Tolazamide • Avoid using
of microvascular disease and myocardial infarc- • Tolbutamide • Avoid using
tion persisted. This phenomenon of prolonged Second-generation sulfonylureas
beneficial effects on complications of diabetes • Glipizide • No dose adjustment
achieved through strict glycemic control even • Gliclazide • No dose adjustment
• Glyburide • Avoid using
being followed by less intensive glycemic control • Glimepiride • Start carefully with a dose of
has been described as “metabolic memory” or 1 mg daily
“legacy effect.” Meglitinides
Considering the impressive results from sev- • Repaglinide • Start carefully at 0.5 mg with
eral major clinical trials, the American Diabetes • Nateglinide meals when GFR <30 mL/
min/1.73 m2
Association (ADA) suggests an HbA1c level of • Start carefully at 0.5 mg with
<7% for all patients with diabetes in order to meals when GFR <30 mL/
reduce their risk of developing DKD [15]. The min/1.73 m2.
target blood glucose level can be achieved Biguanides
through treatment with insulin, oral hypoglyce- • Metformin • Avoid using if serum
creatinine >1.5 mg/dL in men,
mic drugs, or a combination of both. Insulin can or >1.4 mg/dL in women,
be used at any stage of DKD. However, oral suggested by the US FDA
hypoglycemic drugs should be carefully used • Avoid using when GFR
according to one’s renal function (Table 3.3) <30 mL/min/1.73 m2,
recommended by British
[16]. The use of most first- and second-genera- National Formulary and the
tion sulfonylureas should be avoided when the Japanese Society of
eGFR is ˂60 mL/min/1.73 m2. Biguanides (met- Nephrology
formin) should not be used if GFR is <30 mL/ Alpha-glucosidase inhibitors
min/1.73 m2 or the serum creatinine concentra- • Acarbose • Avoid using when GFR
<30 mL/min/1.73 m2.
tion is >1.5 mg/dL in men and >1.4 mg/dL in
DPP-4 inhibitor
women. Thiazolidinediones can be safely used in
• Sitagliptin • GFR >50 mL/min/1.73 m2:
patients with DKD. 100 mg daily
• GFR 30–50 mL/min/1.73 m2:
50 mg daily (1/2 of regular
3.5.1.3 BP Control dose)
In patients with type 1 diabetes, microalbumin- • GFR <30 mL/min/1.73 m2:
uria is typically prior to hypertension. Conversely, 25 mg daily (1/4 of regular
hypertension may have already been present in dose)
some patients with type 2 diabetes when microal- • Saxagliptin • GFR >50 mL/min/1.73 m2:
5 mg daily
buminuria is detected [17]. The appropriate BP at
• GFR ≤50 mL/min/1.73 m2:
which therapy should be started, and the target of 2.5 mg daily
BP are topics that are still under debate. Higher • Linagliptin • No dose adjustment
BP is associated with increasing albuminuria and • Vildagliptin • GFR ≥50 mL/min/1.73 m2:
higher risk of renal failure in diabetes. In the 50 mg twice daily
Action to Control Cardiovascular Risk in • GFR <50 mL/min/1.73 m2:
50 mg daily (1/2 of regular
Diabetes (ACCORD) Blood Pressure trial,
dose)
patients with type 2 diabetes were assigned to
CKD chronic kidney disease; FDA Food and Drug
receive either intensive treatment with a systolic Administration; GFR glomerular filtration rate; DPP-4
BP goal of <120 mmHg or standard therapy aim- dipeptidyl peptidase 4
ing for <140 mmHg [18]. However, no difference shown the value of ACEIs in slowing disease pro-
in the risk of major cardiovascular events was gression. In the Collaborative Study Group trial,
observed between the two groups. In a secondary which evaluated the renoprotective properties of
analysis of the Irbesartan Diabetic Nephropathy captopril among patients with type 1 diabetes,
Trial (IDNT), progressive systolic BP decline up captopril decreased urinary albumin excretion
to 120 mmHg was associated with increased and delayed the progression of kidney disease
renal survival, but with higher mortality [19]. compared with the placebo, although no differ-
Thus considering the detrimental effect of high ence of the median BP was observed between the
BP on renal function and from a safety concern, two groups [20]. Other randomized controlled
the National Kidney Foundation (NKF) and ADA trials have reported that reduction in proteinuria
have recommended an optimal BP target of appears to delay the progression of kidney dis-
<130/80 mmHg for renal and cardiovascular ben- ease among patients with overt nephropathy.
efit in patients with diabetes who have nephropa- For patients with type 2 diabetes, results from
thy. As for patients with diabetes and ACR different clinical studies are less consistent and
<30 mg/g, a BP target of 140/90 mmHg or less is flawed, possibly due to smaller sample sizes and
recommended by the Kidney Disease: Improving the use of surrogate outcomes. Furthermore, the
Global Outcomes (KDIGO) and Eighth Joint protective property of decreasing urinary albu-
National Committee guidelines. min excretion seems to be less significant in
Patients with BP >120/80 mmHg should be patients with type 2 diabetes and DKD. Long-
suggested on BP reduction through lifestyle term benefit achieved from ACEIs was best
changes, which consist of weight loss, decreased shown in a 7-year study which compared the
sodium intake, and increased physical excise, effects of enalapril and placebo in normotensive
among others. Patients with confirmed BP patients with type 2 diabetes who had microalbu-
>140/80 mmHg should initiate pharmacological minuria. The study period covered 5 years for the
therapy promptly to reach the optimal comparison between ACEI and placebo, followed
BP. Treatment of hypertension may require selec- by another 2 years, at which period patients could
tion from several different classes of antihyper- choose either enalapril or placebo. Initial therapy
tensive drugs, and combination therapy is with enalapril stabilized renal function and uri-
recommended with special considerations for nary albumin excretion and reduced the risk of
hypertensive patients with diabetes. nephropathy by 42%. Urinary albumin excretion
Pharmacological therapy should include a RAAS increased among patients initially treated with
blocker (either an angiotensin-converting enzyme enalapril after stopping ACEI therapy but
inhibitor [ACEI] or an angiotensin receptor decreased among those treated with placebo who
blocker [ARB]); in addition, it is recommended chose enalapril therapy [21].
to titrate up to the maximum approved dose if tol- ARBs share many effects with ACEIs and
erated. Diuretics, calcium channel blockers, and have a superior safety property, which includes
β-blockers can be used as additional therapy to lower risk of cough, angioedema, and hyperkale-
achieve the BP target goal in patients already mia. The Reduction of Endpoints in NIDDM
treated with a RAAS blocker or as alternative with the Angiotensin II Antagonist Losartan trial
therapy in individuals with poor tolerance of (RENAAL) compared losartan with conven-
these drugs. tional antihypertensive therapy in patients with
type 2 diabetes and DKD. Fewer patients treated
3.5.1.4 RAAS Blockade with losartan attained the primary composite
In patients with diabetes who have established endpoint of doubling of serum creatinine con-
DKD, RAAS blockade using ACEIs or ARBs centration, ESRD, or death; moreover, protein-
confers preferential renoprotection independent uria level was reduced with losartan [22]. In the
of BP reduction. Several clinical trials investigat- IDNT, irbesartan also showed renoprotective
ing a series of progressive kidney diseases have properties as compared to the calcium channel
blocker or placebo [23]. Concerning the shared inhibitors reduce glucose reabsorption, thereby
RAAS-inhibiting effects of ACEIs and ARBs, decreasing blood glucose levels, and are the
both are believed to be effective in the treatment only insulin-independent glucose- lowering
of DKD. drugs. Currently, empagliflozin, dapagliflozin,
canagliflozin, and ertugliflozin are approved
3.5.1.5 Lipid-Lowering Therapy by the FDA. In experimental diabetic mice,
Dyslipidemia is prevalent in patients with SGLT2 inhibitor was shown to decrease hyper-
DKD. It can promote the development of filtration independent of reduction in blood
DKD. In non-dialysis patients with type 2 diabe- glucose level. In addition, SGLT2 inhibitor
tes and DKD, treatment with statins provides may reduce early kidney growth and inflam-
marked cardiovascular benefit. A recent meta- mation by lowering the blood glucose level. In
analysis suggested a slight positive effect of the Empagliflozin Cardiovascular Outcome
statins on albuminuria and renal function. The Event Trial in Type 2 Diabetes Mellitus
KDIGO Clinical Practice Guideline for Lipid Patients—Removing Excess Glucose (EMPA-
Management in CKD recommends treatment REG OUTCOME) study, patients with type 2
with statins for adult patients with diabetes and diabetes at high cardiovascular risk were
CKD who are not treated using chronic dialysis. assigned to receive placebo or empagliflozin at
a target dose of 10 mg or 25 mg [26]. Compared
3.5.1.6 Renal Replacement Therapy with placebo, empagliflozin decreased the risk
Available renal replacement modalities for of new-onset of or worsening nephropathy by
patients with diabetes who have GFR ˂15 mL/ 39%. Also, patients who received empa-
min/1.73 m2, uncontrolled heart failure, or hyper- gliflozin had a lower rate of doubling of serum
kalemia include peritoneal dialysis (PD), HD, creatinine concentration, initiation of renal
and renal transplantation. Patients with diabetes replacement therapy, and death due to kidney
on HD have lower rate of hospitalization and disease. In addition to the EMPA-REG
infection but higher rate of intradialytic hypoten- OUTCOME study, several studies investigat-
sion and cardiac death than those on PD. PD is a ing the effects of SGLT2 inhibition on cardio-
better option for those with sclerosed forearm vascular and kidney outcomes are underway,
vessels, which seems to have a higher survival which will be issued in the next few years. The
rate than HD in patients with diabetes who have findings of these studies will complement
residual renal function, except for the very those of the EMPA-REG OUTCOME study
elderly, and facilitates BP control and prevention and help in further understanding the therapeu-
of heart failure owing to slow and sustained ultra- tic potential and safety of SGLT2 inhibition.
filtration [24, 25]. However, PD is less effective • Bardoxolone Methyl
than HD, and patients on PD are prone to protein Bardoxolone methyl is a synthetic com-
loss and obesity. pound derived from oleanolic acid, which
activates the Keap1–Nrf2 pathway and regu-
3.5.1.7 Emerging Therapies lates inflammation in the kidney. In the
Considering the complex pathophysiology of Bardoxolone Methyl Treatment: Renal
diabetes and DKD, a number of new therapeutic Function in CKD/Type 2 Diabetes (BEAM)
agents to prevent or treat DKD have been study, patients with CKD and diabetes were
attempted. randomly assigned to receive either bardoxo-
lone methyl or placebo for 52 weeks [27].
• Sodium–Glucose Cotransporter (SGLT) 2 Bardoxolone methyl significantly increased
Inhibitor the mean eGFR compared with placebo at
The kidney reabsorbs all filtered glucose 24 weeks. The improvement lasted for another
through SGLT1 and SGLT2, with SGLT2 28 weeks. Adverse events, particularly muscle
being responsible for most of this task. SGLT2 spasms, were more frequent in the bardoxo-
lone methyl group. The Bardoxolone Methyl References

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IH, Goldstein-Fuchs J, et al. Diabetic kidney dis-
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8. Musso C, Javor E, Cochran E, Balow JE, Gorden
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• GBM thickening, mesangial expansion, 11.
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14. UK Prospective Diabetes Study (UKPDS) Group.
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1998;352(9131):837–53.
by optimal therapeutic approaches, such
15.
American Diabetes Association. Clinical
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Hypertensive Kidney Disease
4
Xiaobing Ji
Abstract 4.1 Introduction

Hypertensive kidney disease is defined as the
damage to the kidney resulted from chronic Hypertension is currently the second leading
high blood pressure (BP), which is pathologi- cause of kidney failure after diabetes mellitus [1,
cally classified as benign and malignant arte- 2]. Most hypertensive patients develop only mild
riolar nephrosclerosis. Given the increasing to moderate hypertensive nephrosclerosis.
morbidity and mortality in patients with However, the rate of renal failure due to high
hypertensive kidney disease, therapeutic strat- blood pressure (BP) is increasing because of the
egies for controlling BP and maximal reduc- high prevalence of hypertension in the general
ing albuminuria are needed for delaying the population. Traditionally, hypertensive kidney
progression of hypertensive nephropathy to disease entails nephroangiosclerosis and hyalino-
end-stage renal disease. Most individuals with sis with glomerular damage. However, recent
hypertensive kidney disease require combined evidence suggests that high BP also results in
use of three or more antihypertensive medica- injury to the tubular cells, inducing epithelial–
tions. Weight loss, exercise, and restriction on mesenchymal transition and tubulointerstitial
salt and alcohol intake may aid in BP control. fibrosis. The consensus is that both accelerated
The early recognition and adoption of potent and malignant hypertension can rapidly lead to
approach to evaluate and manage patients with renal failure and end-stage renal disease (ESRD);
resistant hypertension may be effective strate- furthermore, cardiovascular outcomes of patients
gies to achieve the BP targets. The malignant with chronic kidney disease (CKD) are often
hypertension is life-threatening and requires related to hypertension. The identification of
immediate BP reduction for preventing irre- principal determinants of hypertension is impera-
versible target organ damage. tive to break this vicious circle. Despite improve-
ments in hypertension awareness and treatment,
30–60% of hypertensive patients, particularly
those with CKD, do not achieve the BP targets
regardless of the use of three or more antihyper-
tensive agents. The early recognition and adop-
tion of potential approach to the evaluation and
X. Ji (*)
Division of Nephrology, Nanjing First Hospital, management of resistant hypertensive patients
Nanjing Medical University, Nanjing, Jiangsu, China may be an effective strategy to achieve the BP
e-mail: xbji@njmu.edu.cn targets.

46 X. Ji
Table 4.1 BP classification in adults (age ≥18 years) Table 4.2 Risk factors for the development of
hypertension
Systolic BP Diastolic BP
Classification (mmHg) (mmHg) Unmodifiable risk
Normal <120 AND <80 Modifiable risk factors factors
Prehypertension 120–139 OR 80–89 • Being overweight or obese • Age
Stage I HTN 140–159 OR 90–99 • Sedentary lifestyle (lack of • Race
physical activity) • Family
Stage II HTN ≥160 OR ≥100
• Tobacco use history
BP classification was based on the eighth report of the • Unhealthy diet (high in sodium)
Joint National Committee on Prevention, Detection, • Excessive alcohol consumption
Evaluation, and Treatment of High Blood Pressure • Stress
(Reproduced with permission from James PA, et al. [3]) • Sleep apnea
BP blood pressure; HTN hypertension • Diabetes
Essential hypertension, otherwise called pri- resistance vessels due to long-standing poorly
mary hypertension or idiopathic hypertension, is controlled hypertension.
a form of hypertension with—by definition—no
identifiable cause. BP classification in adults is
shown in Table 4.1. 4.2.2 Causes and Risk Factors
No acceptable unified definition of hyperten-
sive kidney disease exists to date. Studies from The exact causes of high BP remain unclear,
the past decade showed that apolipoprotein L1 although some specific genetic variants have
gene (APOL1)-associated glomerulosclerosis can been identified to be associated with hyperten-
occur with arteriolar nephrosclerosis, which can sion. Several risk factors are linked to hyperten-
develop into mild to moderate systemic hypertension, some of which are modifiable (e.g., being
sion [4, 5], suggesting that genetic variants in overweight or obese, low physical activity,
glomerulosclerosis can lead to syndromes clini- tobacco use, unhealthy diet, and excessive alco-
cally indistinguishable from systemic hol consumption), whereas others are unmodifi-
hypertension- related renal arteriolar disease. able (e.g., age, race, and family history). Risk
Because genetic testing for APOL1 variants and factors for the development of hypertension are
other glomerulosclerosis-associated genetic vari- listed in Table 4.2.
ants is available and can precisely define disease Older age, long-standing poorly controlled
pathogenesis, some experts suggest the abandon- hypertension, and intrinsic kidney diseases are the
ment of the term “hypertensive nephrosclerosis.” main risk factors for hypertensive kidney disease.
However, studies on the subject have only been Some degree of benign nephrosclerosis is very
restricted to African Americans. Furthermore, common among individuals aged >60 years, and
most experts agree that hypertensive kidney dis- African Americans have been observed to be more
ease should be defined as damage to the kidney prone to develop hypertensive nephrosclerosis and
due to high BP. Hypertensive kidney disease can ESRD. The Multiple Risk Factor Intervention Trial
be classified as either benign or malignant showed that hypertensive nephrosclerosis occurs
according to the severity and rapidity of hyper- earlier and is more severe in African Americans.
tension and arteriolar changes. Additionally, men are more prone to develop
hypertensive nephrosclerosis than women [6].
4.2 Benign Nephrosclerosis

4.2.3 Prevalence
4.2.1 Definition
Although benign nephrosclerosis slowly pro-
Benign nephrosclerosis, also called hypertensive gresses to ESRD in only a small percentage of
nephrosclerosis, is characterized by a very slowly individuals, it remains one of the most common
progressive thickening and sclerosis of the renal causes of ESRD owing to the high prevalence of
4 Hypertensive Kidney Disease 47
hypertension. In the United States, hypertensive Therapy in Patients Living with Systolic
nephropathy accounts for approximately 27.5% Hypertension trial reported that the histological
of incident dialysis patients according to the dataprogression of diabetic nephropathy persisted
from the 2016 US Renal Data System [7]. despite the maintenance of normal BP and micro-
Moreover, new patients starting dialysis contrib- albuminuria [9]. This trial illustrates the limita-
uted to the continuously increasing prevalence of tions of using microalbuminuria as a surrogate
hypertension. The reported prevalence rate of marker for CKD and a prognostic tool for the
hypertensive nephropathy greatly varies world- progression of CKD. In fact, microalbuminuria
wide, accounting for 27% of new patients with might represent vascular dysfunction and serve
ESRD in France, 21% in Italy, 7% in China, 6% as a marker of cardiovascular risk instead of the
in Japan, and approximately 12% in the European progression of CKD. Conversely, macroalbumin-
Dialysis and Transplant Association registry [8]. uria may accurately represent renal parenchymal
This variation may reflect differences in criteria damage and should serve as a prognostic marker
for and accuracy of diagnosis of hypertensive for the progression of CKD and a therapeutic tar-
nephropathy among various countries. get in the treatment of CKD.
Persistent increases in serum creatinine con-
centration reflect substantial renal parenchymal
4.2.4 Clinical Manifestations damage and some degree of irreversible kidney
dysfunction. However, the serum creatinine con-
Most patients are observed to be hypertensive centration does not provide an accurate measure
with nonspecific symptomatology on routine of the rate of progression of renal dysfunction. It
physical examination. Hypertension is usually is essential to utilize more accurate and sensitive
present for many years, with persistent BP eleva- measures for the estimation of glomerular filtra-
tion and evidence of the following hypertension- tion rate (GFR), which may guide targeted thera-
related target organ damage: pies to more effectively prevent disease
progression and associated complications. The
• Proteinuria less than 0.5 g/day identification of an appropriate marker of early
• Hypertensive retinal changes renal dysfunction remains challenging and
• Left ventricular hypertrophy depends on the underlying etiology of kidney dis-
• Heart attack or heart failure ease. Hypertension-induced kidney injury can be
• Stroke associated with obvious markers of renal paren-
• Atherosclerosis chymal disease, such as proteinuria. However, in
• Aneurysm the absence of overt glomerular disease such as
in hypertensive nephrosclerosis or early diabetic
Physical examination may reveal changes in nephropathy, evidence of early kidney injury
the retinal vessels, and <5% of patients with remains elusive.
poorly controlled BP will develop renal failure In the past decade, numerous researchers
during the subsequent 10–15 years. showed that serum cystatin C level could serve as
Proteinuria develops in up to 40% of patients. an early marker of hypertension-induced kidney
Microalbuminuria has long been recognized as a dysfunction and may accurately reflect the esti-
major biomarker of hypertensive nephrosclero- mated GFR (eGFR) in various populations [10].
sis, and measurement of microalbuminuria level Investigators of the Heart and Soul Study evalu-
at screening and during treatment is widely rec- ated the effect of baseline systolic BP by measur-
ommended. However, research has consistently ing the serum cystatin C level and estimating the
shown that it is clinically relevant only when GFR based on the serum creatinine concentration
increases in the macroalbuminuric range and reported that serum cystatin C level was bet-
(>300 mg/day) occur in the presence of appropri- ter correlated with systolic BP than serum creati-
ate BP control. Investigators of the Avoiding nine concentration in individuals with an eGFR
Cardiovascular Events through Combination >60 mL/min/1.73 m2 [11].
48 X. Ji
4.2.5 Pathological Manifestations epithelial–mesenchymal transition and tubuloint-

erstitial fibrosis. Recent investigations have
Benign nephrosclerosis is histologically charac- reported the association of podocyte effacement
terized by a series of vascular injuries, including and loss with benign nephrosclerosis [12].
afferent arteriolar hyalinization and interlobular Benign nephrosclerosis-induced changes are
thickening of the artery and arcuate artery endo- summarized in Table 4.3.
mysium. Renal pathology in benign nephroscler-
osis is shown in Fig. 4.1. Cumulative evidence
over the past years has suggested that high BP 4.2.6 Diagnosis
results in injury to the tubular cells, inducing
The diagnosis of hypertensive kidney disease
is dependent on clinical manifestations and
exclusion of other primary kidney diseases. A
confirmed history of hypertension and signs
of target organ damage, such as left ventricu-
lar hypertrophy, hypertensive retinal changes,
and proteinuria, should establish the diagno-
sis. However, clarifying the diagnosis is occa-
sionally very difficult in clinical practice when
hypertension and CKD coexist. A flowchart
for the diagnosis of benign nephrosclerosis is
shown in Fig. 4.2.
Home and ambulatory BP monitoring
(ABPM) is becoming increasingly recommended
for the clinical evaluation of hypertension
Fig. 4.1 Histopathological manifestations in benign
because of its ability to identify white-coat hyper-
nephrosclerosis. Hyaline degeneration (arrowhead) and
intimal thickening (arrow) of renal arterioles are present tension and masked hypertension [13]. Reference
(periodic acid-Schiff staining, ×400) values for normal ambulatory BP in nonpregnant
Table 4.3 Benign nephrosclerosis-induced changes in the vascular, glomerular, and tubulointerstitial compartments
Compartment Changes Effects
Vessels • Transition from smooth muscle cells to • Wall stiffness, with little or no effect on the
myofibroblasts, intimal thickening of the small lumen caliber
arterioles
• Thinning of the media, hyalinosis of the • Reduced filtration
afferent arteriole
• Occlusion of the intraglomerular capillaries by • Hypoxia
hyaline material
• Breakdown of elastic fibers in the large arteries • Laminar-to-pulsatile flow shift in the
arcuate, interlobular, and afferent arterioles
Glomeruli Not applicable • Increased intraglomerular pressure and
microalbuminuria
• ECM accumulation • FSGS
• Glomerular tuft entirely replaced by collagen • Global glomerulosclerosis
• Capsular adhesion and segmental scars • Reduced filtration
Tubules • Cell dilation and flattening, cell atrophy and • Proteinuria
loss
• EMT • Tubulointerstitial fibrosis and CKD
ECM extracellular matrix; FSGS focal segmental glomerulosclerosis; EMT epithelial–mesenchymal transition; CKD
chronic kidney disease
Table 4.5 Diagnostic threshold values for ABPM (in

A history of hypertention
mmHg) based on cardiovascular outcome [13]
ABPM High-risk
characteristic Men Women patients
Proteinuria
Nocturia Awake (mean)
Elevated level of serum creatinine/cystatin C SBP 135 125 120
DBP 85 80 75
Asleep (mean)
Changes in retinal vessels SBP 120 110 105
And/or other signs of target organ damage DBP 70 65 60
ABPM ambulatory blood pressure monitoring; SBP sys-
tolic blood pressure; DBP diastolic blood pressure
Exclude other kidney
diseases Undiagnosed
tial time-aware and sensitive information for
state-of-the-art individualized diagnostic cat-
Renal biopsy egorization, treatment efficacy evaluation, and
cardiovascular outcome prediction.
High-risk patients include those who are diag-
Benign nephrosclerosis nosed with diabetes or CKD and have experi-
enced a previous cardiovascular event.
Fig. 4.2 Flowchart for diagnosis of benign The differential diagnosis of hypertensive
nephrosclerosis
nephrosclerosis should include the following:
Table 4.4 Reference values for normal ambulatory • Renal atherosclerotic disease

blood pressure in nonpregnant adults
• Renal vascular hypertension
Hypertension
• Malignant hypertension
Time Normal threshold
24-h average <115/75 mmHg 130/80 mmHg
• Mildly active primary kidney disease
Daytime <120/80 mmHg 135/85 mmHg • Lead nephropathy
(awake)
Nighttime <105/65 mmHg 120/75 mmHg Hypertension is strongly associated with ath-
(asleep) eromatous renal disease (ARS), especially in the
elderly. The diagnosis of ARS can be established
adults are summarized in Table 4.4, whereas using Doppler ultrasonography, computed
diagnostic threshold values for ABPM (in mmHg) tomography (CT) angiography, magnetic reso-
based on cardiovascular outcome are shown in nance (MR) angiography, or intra-arterial renal
Table 4.5. angiography. Comparative studies on patients
White-coat hypertension (elevated clini- indicate that both Doppler studies and CT angi-
cal BP but normal ambulatory BP) is defined ography may fail to detect significant lesions.
as persistently elevated BP (>140/90 mmHg) However, MR angiography can provide valuable
in the clinical setting but normal 24-h average information about the location and severity of
BP levels (<130/80 mmHg). White-coat hyper- atherosclerotic vascular lesions. Intra-arterial
tension was previously believed to be a benign renal angiography should be considered when
finding but is currently thought to increase the persistent and accelerated hypertension, unknown
risk of cardiovascular complications similar to renal insufficiency, or circulatory congestion
essential hypertension. Masked hypertension develops.
(normal clinical BP but elevated ambulatory Renal biopsy findings in patients with lead
BP), the opposite of white-coat hypertension, nephropathy can resemble those in patients
carries a similarly increased risk of cardiovas- with hypertensive nephrosclerosis. Lead
cular complications. ABPM provides the essen- nephropathy should be considered as part of
50 X. Ji
differential diagnosis in patients who present Table 4.6 Nonpharmacologic approaches to hyperten-
sion management and their effects
with renal failure and new-onset hypertension
and have past history of potential exposure, and Systolic BP
Modification Description reduction
blood lead levels should be measured. The eth-
Weight Attaining normal 5–20 mmHg/10-kg
ylenediaminetetraacetic acid (EDTA) lead- reduction weight weight loss
mobilization test is used to evaluate the body’s DASH diet Rich in fruits, 8–14 mmHg
lead burden. Radiographic fluoroscopy is vegetables, and
another test that could be used to determine low-fat dairy with
reduced saturated
skeletal lead stores.
fat, total fat, and
sodium
Reduced Decreasing 2–8 mmHg
4.2.7 Management Principles dietary sodium intake to
sodium 65–100 mmol/day
intake
The optimal strategy to prevent hypertensive kid-
Increased Regular aerobic 4–9 mmHg
ney disease is the identification of patients who physical exercise for
are predetermined to develop ESRD or are in the activity 30 min/day
course of progressing to ESRD from a large num- during most
working days
ber of patients with essential hypertension. A pre-
Moderate Limiting alcohol 2–4 mmHg
vious history of AKI, a family history of ESRD, alcohol consumption to
black race, and microalbuminuria are all poten- intake two drinks/day
tial risk factors. for men and one
As noted in the National Kidney Foundation’s drink/day for
women and those
Kidney Disease Outcomes Quality Initiative with lower weight
guidelines, the success of strategies for BP man- Increased Increasing Variable
agement will ultimately depend on patients’ self- potassium potassium intake
management, their ability and willingness to intake to 120 mmol/L
adopt and maintain healthy behaviors, and their Alternative Medication, yoga, Variable up to
approaches biofeedback, 2–10 mmHg
adherence to medication regimens [14]. device-guided
breathing,
4.2.7.1 Nonpharmacologic Approaches acupuncture,
Several nonpharmacologic approaches with well- other relaxation
therapies
established efficacy in reducing BP include life-
BP blood pressure; DASH dietary approaches to stop
style modification, weight reduction, Dietary
hypertension
Approaches to Stop Hypertension (DASH) diet,
restriction on salt and alcohol intake, increased
physical activity, increased potassium intake, and 4.2.7.2 Pharmacologic Treatment
alternative approaches (Table 4.6). The DASH If nonpharmacologic approaches are ineffective
trial provides strong evidence on the BP-lowering in managing high BP, pharmacologic therapy
effectiveness of dietary sodium restriction and should be initiated. First-line antihypertensive
weight loss in prehypertensive and hypertensive medications include thiazide diuretics, long-acting
patients [15]. These approaches may control BP calcium channel blockers (CCBs), angiotensin-
without the concomitant use of antihypertensive converting enzyme inhibitors (ACEIs), and angio-
agents or with the reduction in the frequency or tensin II receptor blockers (ARBs). The updated
dosage of antihypertensive medications. Eighth Joint National Committee (JNC-8) guide-
Nonpharmacologic approaches to hypertension lines do not include beta-blockers as part of initial
management and their effects are summarized in treatment. Combination therapy can be used as
Table 4.6. initial therapy if systolic BP is >160 mmHg and/
or diastolic BP is >100 mmHg or if systolic BP is creatinine and potassium concentration. However,

>20 mmHg above the target and/or diastolic BP is combining an ACEI with an ARB is not
>10 mmHg above the target. If two medications recommended.
are insufficient to achieve the BP target, a third
medication can be added. Alternative agents for 4.2.7.3 Target Goals
hypertension can be administered if the BP target There has been continuing debate about the tar-
has not been achieved using first-line agents. get goals. The 2012 Kidney Disease: Improving
Thiazide and thiazide-like diuretics have been Global Outcomes (KDIGO) guidelines recom-
the mainstay of primary hypertension manage- mend that BP be lowered to <130/80 mmHg in
ment for a longer period than any other antihy- patients with nephropathy (stage 3 or higher)
pertensive agents. Their widespread and who have proteinuric kidney disease (>300 mg/
continued use is based on consistent evidence on day) [14]. The BP target goals recommended in
their ability to reduce the risk of heart disease, the KDIGO guidelines are shown in Table 4.7.
stroke, heart attack, and death. Thiazide diuretics Renin–angiotensin–aldosterone system block-
used for hypertension include indapamide, meto- ers exert beneficial effects on the progression
lazone, chlorthalidone, and hydrochlorothiazide, of nephropathy, especially in the subgroup
with the latter two being the most commonly of hypertensive patients with nephropathy,
used. However, metolazone may be effective in late-stage CKD (stage 3), and proteinuria
patients with poor renal function when other thia- (>300 mg/day).
zide diuretics prove to be ineffective. Compared with previous guidelines on hyper-
CCBs used for hypertension include amlodip- tension treatment, the JNC-8 guidelines advise
ine, felodipine, isradipine, sustained-release higher BP goals <140/90 mmHg [3]. The BP tar-
nicardipine, long-acting nifedipine, and nisoldip- get goals stipulated in the JNC-8 guidelines are
ine. CCBs bind to calcium channels in the blood listed in Table 4.8. Achieving target levels of
vessels, resulting in reduced BP. Vasodilatory <140/90 mmHg for BP control clearly slows the
side effects include flushing and peripheral
edema. CCB-related peripheral edema is attenu-
ated by coadministration of an ACEI. Chest pain Table 4.7 Blood pressure target goals recommended in
the 2012 KDIGO guidelines
is one of the serious adverse events upon initia-
tion of CCB therapy. CCBs are a useful compo- Patient
characteristics Goal Evidence grade
nent of multidrug regimens for patients with
Diabetic and ≤140/90 mmHg 1B
resistant hypertension, such as those with diabe- nondiabetic
tes or CKD. adults with
ACEIs and ARBs have been shown to prevent CKD and
death in patients with congestive heart failure and albumin
excretion
in all patients at high risk of cardiac complica- <30 mg/24 h
tions and to reduce the rate of progression of kid- Diabetic and ≤130/80 mmHg 2D
ney disease in patients with diabetes. Because of nondiabetic
their benefits, several international guidelines adults with
CKD and
recommend them as first-line antihypertensive albumin
agents for patients diagnosed with diabetes. An excretion
acute increase in serum creatinine concentration ≥30 mg/24 h
and hyperkalemia are a concern in patients with KDIGO kidney disease: improving global outcomes;
CKD. One approach to initiation of ACEI/ARB CKD chronic kidney disease
The strength of recommendation is indicated as levels 1
therapy for hypertensive kidney disease is to start
(“We recommend”) and 2 (“We suggest”), whereas the
it at a low dose and then to gradually titrate the quality of supporting evidence is designated as A (high),
dose upward every few weeks with monitoring of B (moderate), C (low), or D (very low)
52 X. Ji
Table 4.8 Blood pressure target goals recommended in 4.3.2 Causes and Risk Factors
the JNC-8 guidelines
Patient Evidence Malignant hypertension is a multifactorial disease
characteristics Goal grade
that may develop in patients with long-standing or
• <60 years <140/90 mmHg E
• Diabetes secondary hypertension. Common causes of
• CKD malignant hypertension are listed in Table 4.9.
• ≥60 years <150/90 mmHg A This section focuses on essential hypertension as
JNC-8 Eighth Joint National Committee; CKD chronic cause of malignant hypertension.
kidney disease
The quality of supporting evidence is indicated as A
(strong recommendation), B (moderate recommendation),
C (weak recommendation), D (recommendation against), 4.3.3 Prevalence
or E (expert opinion)
Malignant hypertension is not common, occurring
progression of nephropathy due to hypertension in approximately 1–2% of hypertensive patients,
regardless of the presence of albuminuria. and may lead to acute impairment in one or more
Although the proportion of patients achieving organ systems, including the renal system, with
the recommended BP targets has improved over varying degree of severity. Malignant hyperten-
the past several decades, many patients do not sion most likely develops in previously hyperten-
reach these targets and are considered to have sive patients with inadequate BP control and
resistant hypertension (rHTN), which is particu- affects more men than women, with a higher inci-
larly common among patients with CKD. Notably, dence in black men and Asian patients. The age of
patients with uncontrolled hypertension are more onset ranges from 30 to 50 years, with the disease
likely to develop target organ damage, including being also present in children and the elderly. The
progressive CKD and ESRD. incidence of malignant hypertension has been
In 2008, the American Heart Association decreasing with improvement in BP control, use of
issued a scientific statement that defined rHTN as antihypertensive medications, and better under-
BP persistently greater than >140/90 mmHg standing of the need for treatment. In Australia and
despite the concurrent use of three or more anti- New Zealand, there is a dramatic decrease in the
hypertensive agents of different classes [16], one annual incidence of malignant hypertension as a
of which should be a diuretic. Patients with rHTN cause of ESRD over the last 25 years [18].
are more likely to develop target organ damage,
including progressive CKD and ESRD. Achieving
the recommended BP goals for these patients is 4.3.4 Clinical Manifestations
challenging. Early recognition of rHTN using a
standardized definition and adoption of a consis- Patients with malignant nephrosclerosis often
tent approach to evaluation and management may have a history of malignant hypertension and
increase the probability of success in implement- have experienced withdrawal from beta-blockers,
ing therapeutic approaches. Figure 4.3 shows a alpha-blockers, or some other antihypertensive
systematic approach to the evaluation of patients agents. Alcohol and cocaine may also lead to a
with suspected rHTN [17]. hypertensive emergency.
A thorough physical examination should be
performed, with BP measured in both arms. A
4.3 Malignant Nephrosclerosis significant difference (>20 mmHg) may suggest
aortic dissection, with BP increasing in few min-
4.3.1 Definition utes and hours (usually systolic BP >180 mmHg,
diastolic BP >130 mmHg). Head and neck exam-
Malignant nephrosclerosis, also called acceler- ination must include a complete funduscopic
ated nephrosclerosis, refers to acute kidney examination. Keith–Wagener grade III (hemor-
impairment due to severe hypertension (diastolic rhages and exudates) and grade IV (papilledema)
BP often ≥130 mmHg). retinal changes are the hallmarks of malignant
BP exceeds individualized target

while on >3 medications
Yes
No Assess BP using home and
Accute BP measurement
confirmed? ambulatory BP measurements
Yes
No
Health lifestyle practices and Assess sodium intake/excretion
sodium restriction reviewed? reinforce lifestyle modifications.
Yes
No
Adherence to antihypertensives/ Review side effects, adequate
appropriate dosing confirmed? dosing, consider alternatives
Yes
No
Recreational drugs and other Discontinure medications that raise
medications that raise BP absent? BP and address substance abuse
Yes
No
Diuretic included in Add diuretic medications and titrate
antihypertensive regimen to proper dose
Yes
No
Secondary causes of hypertension Perform workup for secondary
excluded if BP still not at target cause of hypertension
Yes
Resistant hypertension
Fig. 4.3 Systematic approach to evaluate the patient with suspected resistant hypertension. (Reproduced with permis-
sion from Braam et al. [17])
hypertension. New diastolic murmurs could be • Cerebrovascular event

detected on cardiovascular examination, support- • Hypertensive encephalopathy
ing the diagnosis of aortic dissection. • Dissecting aortic aneurysm
Clinical presentation reflects the deleterious • Eclampsia
effects of high BP on target organs. Renal abnor-
malities include a rapid increase in serum creatinine
concentration, hematuria (with 50–60% and 20% 4.3.5 Pathological Manifestations
of patients having microscopic and gross hematu-
ria, respectively), red blood cell casts, and protein- The classic gross pathological manifestation is a
uria. Nephrotic syndrome is not often observed. “flea-bitten” appearance of the kidney due to pin-
point petechiae on the cortical surface, whereas
Presenting symptoms can also include the micropathological manifestations include fibri-
following: noid necrosis of the arterioles and hyperplastic
• Acute heart failure arteriolitis (onion skinning) due to concentric
• Pulmonary edema layering of collagen (Fig. 4.4). The presence of
54 X. Ji
Table 4.9 Common causes of malignant hypertension malignant hypertension with kidney injury and
Essential hypertension progressive CKD.
Renal parenchymal diseases
Glomerulonephritis
Tubulointerstitial diseases
Systemic sclerosis 4.3.6 Diagnosis
Diabetes
Systemic lupus erythematosus A sudden BP elevation (often diastolic
Renal vascular diseases BP ≥130 mmHg) with acute progressive deterio-
Atherosclerotic renal artery stenosis
Aortitis
ration in renal function could establish the
Fibromuscular dysplasia diagnosis.
Acute renal artery occlusion It is crucial to distinguish hypertensive emer-
Endocrine diseases gency from hypertensive urgency, with the latter
Pheochromocytoma involving no target organ damage. History taking
Primary aldosteronism
Cushing syndrome and physical examination could provide clues,
Drugs and some diagnostic tests such as electrocardiog-
Cocaine raphy and chest radiography can provide impor-
Amphetamine tant information on end-organ damage.
Monoamine oxidase inhibitor
Erythropoietin
Ciclosporin
Tumors 4.3.7 Management Principles
Renal carcinoma
Lymphoma Precise and rapid BP control is the principal ther-
Coarctation of the aorta
apeutic goal. Patients should be immediately
Obstetrics-related diseases
Preeclampsia admitted to an intensive care unit with continu-
Eclampsia ous BP monitoring. BP should be reduced within
minutes to an hour using a parenteral and titrat-
able antihypertensive agent. The ideal target goal
remains unknown, but reducing the mean arterial
pressure by 10% during the first hour and an
additional 15% during the subsequent second to
third hours is recommended. Aggressive BP
reduction may notably result in hypotension and
worsen end-organ damage. Patients should be
restricted to bed rest until severe hypertension is
under control.
A number of short-acting agents of various
drug classes are available for hypertension treat-
ment. The optimal strategy is to tailor drug selec-
tion according to patients’ characteristics. Both
Fig. 4.4 Histopathological manifestations in malignant patient-specific and drug-specific factors should
nephrosclerosis. Scarring concentric thickening of vessel be carefully considered to ensure the selection of
wall by myointimal cells and deposition of basement
an appropriate drug. The use of ACEIs and ARBs
membrane type material (onion skinning, arrow), tubular
atrophy, and glomerular shrinkage are shown (periodic is not recommended for malignant nephrosclero-
acid-Schiff staining, ×200) sis because of the potential risk of worsening
renal function and hyperkalemia. Fenoldopam is
red blood cells and red blood cell casts in the a selective D1 receptor partial agonist that acts
urine is sometimes a clinical manifestation. There as a peripheral vasodilator and a diuretic.
is convincing evidence on the association of Approved by the Food and Drug Administration
Table 4.10 Parenteral agents used in the management of hypertension in patients with malignant nephrosclerosis
Drug Mechanism of action Onset of action Duration of action
Nitroglycerin Nitrate receptors 2–5 min 5–10 min
Fenoldopam Dopamine D1 receptor agonist >5 min 30 min
Nicardipine Calcium channel blocker 5–10 min 15–30 min
Labetalol α1- and β-blocker 30–120 min 6–8 h
in September 1997, fenoldopam has been shown

to be a rapid-acting, well-tolerated, and renopro- nosis of hypertensive kidney disease is
tective intravenous agent. Other options for this dependent on clinical manifestations
patient population include nitroglycerin, nicar- and exclusion of other primary kidney
dipine, and labetalol. Previous studies have diseases.
reported that all these drugs lower BP when intra- • Most individuals with benign nephro-
venously administered, with no evidence that one sclerosis require the use of multiple anti-
is better than the other. Parenteral agents used in hypertensive medications. Weight loss,
the management of hypertension in patients with exercise, and restriction on salt and alco-
malignant nephrosclerosis are listed in Table 4.10. hol intake can also aid in BP control.
• Malignant nephrosclerosis is one of the
end-organ damages of malignant hyper-
tension. Malignant hypertension most
Key Messages
likely develops in previously hyperten-
• Hypertensive kidney disease should be
sive patients with inadequate BP control
defined as damage to the kidney due to
and affects more men than women, with
high BP, which can be classified as
a higher incidence in black men and
either benign or malignant depending
Asian patients. The age of onset ranges
on the severity and rapidity of hyperten-
from 30 to 50 years.
sion and arteriolar changes.
• Patients with malignant nephrosclerosis
• Older age, long-standing poorly con-
often have a history of malignant hyper-
trolled hypertension, and intrinsic kid-
tension and have experienced withdrawal
ney diseases are the main risk factors for
from beta-blockers, alpha-blockers, or
hypertensive kidney disease. African
some other antihypertensive agents.
Americans have been observed to be
Alcohol and cocaine may also lead to a
more prone to develop hypertensive
hypertensive emergency.
nephrosclerosis and ESRD.
• Clinical presentation reflects the delete-
• Although benign nephrosclerosis slowly
rious effects of high BP on target organs,
progresses to ESRD in only a small per-
with systolic and diastolic BP often
centage of individuals, it remains one of
being >180 mmHg and >130 mmHg,
the most common causes of ESRD
respectively. Keith–Wagener grade III
owing to the high prevalence of hyper-
and grade IV retinal changes are the
tension. The reported prevalence rate of
hallmarks of malignant hypertension.
hypertensive nephropathy greatly varies
• Patients with malignant nephrosclerosis
worldwide.
should be immediately admitted to an
• Most patients with benign nephrosclero-
intensive care unit with continuous BP
sis usually have a history of hyperten-
monitoring. BP should be reduced within
sion and present with persistent BP
minutes to an hour using a parenteral and
elevation, with evidence of hypertension-
titratable antihypertensive agent.
related target organ damage. The diag-
56 X. Ji
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versus creatinine in determining risk based on kidney
function. N Engl J Med. 2013;369(10):932–43.
1. Botdorf J, Chaudhary K, Whaley-Connell
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A. Hypertension in cardiovascular and kidney dis-
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Pregnancy in Chronic Kidney
Disease 5
Weichun He

Although the pregnancy rate of women with
chronic kidney disease (CKD) and the overall With advances in medicine, the pregnancy rate of
survival rate of their fetuses have improved, female patients with chronic kidney disease
pregnancy in women with CKD still have a (CKD) has improved, along with an apparent
high risk of adverse maternal and fetal out- increase in the overall survival rate of fetuses.
comes. To achieve better outcomes for this However, women with CKD remain a major part
particular population, managing pregnancy in of the patient population that carries the highest
women with CKD has become a considerable risk of adverse maternal and fetal outcomes.
challenge shared by both nephrologists and Adverse maternal outcomes include aggravated
obstetricians. Strengthened management, renal damage, acute kidney injury, pregnancy-
including prepregnancy preparation, preg- associated kidney disease, increased proteinuria,
nancy management, peripartum management, hypertension, and preeclampsia (PE).
and postpartum care, could prevent or mitigate Furthermore, adverse fetal outcomes include
maternal renal damage and adverse maternal stillbirth, fetal growth restriction (FGR), and pre-
and fetal outcomes. Women with CKD require term delivery. Therefore, managing pregnancy in
risk assessment of pregnancy before conceiv- patients with CKD has become a considerable
ing, close follow-up by both nephrologists and challenge shared by both nephrologists and
obstetricians to monitor disease activity and obstetricians. To mitigate maternal renal damage
detect obstetric complications during preg- and adverse maternal and fetal outcomes, both
nancy, evaluation of indications for termina- nephrologists and obstetricians need to assess the
tion of pregnancy and selection of delivery risk of pregnancy in patients with CKD in a stan-
mode, and assessment of disease activity and dardized manner, determine the optimal timing
emotional support to prevent depression after of pregnancy, stabilize the condition of patients,
delivery. and closely monitor any changes during preg-
nancy for the early detection of maternal and
fetal complications.
W. He (*)
Centre for Kidney Disease, Second Affiliated
Nanjing, Jiangsu, China
e-mail: heweichun@njmu.edu.cn

58 W. He
5.2 Risk Assessment stage 3a, GFR 45–59 mL/min/1.73 m2; stage 3b,
of Pregnancy in Patients GFR 30–44 mL/min/1.73 m2; stage 4, GFR
with CKD 15–29 mL/min/1.73m2; and stage 5, GFR ˂15 mL/
min/1.73 m2 or maintenance dialysis [4].
5.2.1 Renal Physiological In pregnancy studies, early stage CKD was
Alterations During Pregnancy defined as SCr ˂1.4 mg/dL (125 μmol/L) or creati-
nine clearance ≥70 mL/min. In contrast, advanced
A series of physiological adaptations occur in the CKD was defined as SCr ˃1.4 mg/dL (125 μmol/L)
maternal kidney during pregnancy to meet the and was often further subclassified into moderate
needs for fetal development and maintain mater- (1.4–2.4 mg/dL or 125–220 μmol/L) or severe
nal health. The size of the kidney increases, and (˃2.4 mg/dL or 220 μmol/L) CKD in earlier litera-
the function of glomeruli and tubules changes. ture. In recent years, the definition and staging of
Renal plasma flow and glomerular filtration rate GFR have been gradually introduced to obstetric
(GFR) markedly increase, reaching their peak (an nephrology [7]. In view of renal physiological
increase of more than 50%) in the second trimes- adaptations during pregnancy, CKD staging crite-
ter of pregnancy. The concentration of serum cre- ria can only be theoretically used to assess renal
atinine (SCr), urea nitrogen, and uric acid is function prior to pregnancy. More recent studies
slightly lower in pregnant women than in non- have used eGFR cutoff levels endorsed by the
pregnant women because of the increased excre- KDIGO and KDOQI, which define moderate
tion of metabolites from the body during CKD as an eGFR between 30 and 60 mL/
pregnancy. Although the SCr in gravid women is min/1.73 m2 (stage 3 CKD) and severe CKD as an
within the normal range, their kidney may have eGFR between 15 and 30 mL/min/1.73 m2 (stage
been damaged [1]. One study reported a U-shaped 4 CKD), despite the lack of validation of these
relationship between estimated GFR (eGFR) formulas in pregnancy [7].
level and adverse events in the second trimester
of pregnancy, suggesting that gravid women with
eGFR 120–150 mL/min/1.73 m2 had the best 5.2.2 Assessment of Kidney
pregnancy outcome, whereas those with too high Disease Conditions
or too low eGFR had the worse outcome in the
renal function assessment [2]. It is well known that pregnancy may pose hazards
CKD is defined by the Kidney Disease to both the gravida and fetus as women progress
Outcomes Quality Initiative (KDOQI) and Kidney through each stage of CKD, especially in the
Disease: Improving Global Outcomes (KDIGO) as presence of significant proteinuria and/or hyper-
renal damage or GFR <60 mL/min/1.73 m2 present tension as well as comorbidities such as diabetes
for more than 3 months, with implications for and lupus. The more difficult blood pressure con-
health. Renal damage refers to structural or func- trol becomes and the more advanced CKD is, the
tional abnormalities in the kidney, including abnor- higher the risk of poor pregnancy outcome.
mal blood and urine composition, abnormal
imaging findings, and pathomorphological changes 5.2.2.1 Stages of CKD
in the renal tissues [3, 4]. As GFR is the best index The degree of CKD is recognized to be an impor-
for the evaluation of renal function, CKD staging is tant determinant of pregnancy outcome. Women
consequently based on the GFR level, which is with normal kidney function or only mild CKD
typically measured using creatinine-based estima- do not typically exhibit worsening kidney func-
tion formulas, such the Modification of Diet in tion in the absence of significant hypertension
Renal Disease Study equation and Chronic Kidney and/or proteinuria. However, women with more
Disease Epidemiology Collaboration equation [5, advanced CKD are at risk of kidney function loss
6]. CKD is categorized into five stages according during pregnancy. Pregnancy complications,
to the GFR level: stage 1, GFR ≥90 mL/min including preterm delivery (˂37 weeks of gesta-
/1.73 m2; stage 2, GFR 60–89 mL/min/1.73 m2; tion), small for gestational age (SGA) births, and
5 Pregnancy in Chronic Kidney Disease 59
need for neonatal intensive care unit (NICU) Therefore, pregnant women with early stage
admission and cesarean section, may be more CKD, mild renal damage, normal prepregnancy
common in patients with CKD than in the general renal function, normal blood pressure, and nor-
population, with rates increasing with each CKD mal albuminuria or microalbuminuria have lower
stage. Even stage 1 CKD is an independent risk risk of progression of renal damage, and their
factor for poor pregnancy outcomes such as prepregnancy outcomes are better. However, preg-
term delivery, SGA births, and need for NICU nancy complications remain more common in
admission [8]. these women than in the general population. In
pregnant women with advanced CKD, the risk of
5.2.2.2 Hypertension declining renal function and undesirable preg-
The incidence of hypertension is higher in nancy outcomes is significantly increased.
patients with CKD than in ordinary individuals,
which further increases after pregnancy. The rate
of new hypertension in pregnant women with 5.2.3 Timing of Conception
stage 1 CKD and stage 4–5 CKD is 7.9% and
50%, respectively [9]. Poorly controlled hyper- In view of the above risk assessment of preg-
tension significantly adds to the risk of pregnancy in patients with CKD, patients with early
nancy, including the risk of early pregnancy loss, stage CKD who have well-controlled blood pres-
superimposed placental ischemia and PE, and sure and proteinuria <1 g/24 h may consider
premature delivery and FGR [10]. The recently pregnancy; however, it is recommended that the
published Control of Hypertension in Pregnancy risks of pregnancy be suitably recognized.
Study confirmed that treating hypertension in Pregnancy is not recommended for the follow-
pregnancy to a lower diastolic blood pressure tar- ing patients with CKD [1, 12–14]:
get is not associated with adverse neonatal events
or pregnancy outcomes. A blood pressure target • Patients with stage 3–5 CKD.
<140/90 mmHg has been recommended for • Patients with uncontrollable hypertension are
women with CKD during pregnancy [7]. advised to postpone pregnancy until their
blood pressure becomes normal.
5.2.2.3 Proteinuria • Patients with proteinuria are counseled to post-
Proteinuria is an independent risk factor for the pone pregnancy until proteinuria is managed
progression of CKD but exerts the smallest effect and reduced to <1 g/24 h for at least 6 months.
on pregnancy outcome compared with CKD stag- • Pregnancy in women with active lupus nephri-
ing and hypertension. Gestation can aggravate tis (LN) is not recommended owing to the
proteinuria in patients with CKD. Doubling of increased risk of flare, preterm delivery, and
proteinuria occurs in approximately 20% of PE. Pregnancy should be postponed until LN
patients with stage 1 CKD and approximately has been treated with achievement of com-
70–80% of patients with stage 3 or higher plete remission or the condition has become
CKD. Severe proteinuria leads to maternal hypo- stable with near complete remission for at
albuminemia, which can result in FGR. Moreover, least 6 months.
the decrease in plasma albumin level results in • Pregnancy is not recommended for patients
reduced uteroplacental blood flow, poor placental with diabetic nephropathy who have moderate
perfusion, insufficient supply of fetal oxygen and or severe renal impairment because of higher
nutrients, and chronic fetal anoxia, which leads risks of irreversible renal function decline and
to FGR, neonatal asphyxia, and even intrauterine progression to severe proteinuria after
fetal death [8]. In addition, pregnancy itself is a pregnancy.
prothrombotic state, and nephrotic syndrome • For systemic diseases such as LN and diabetic
with severe hypoalbuminemia (albumin level nephropathy, refer to relevant guidelines for
˂25 g/L) is associated with an increased risk of the assessment of extrarenal lesions not suit-
venous thromboembolic disease [11]. able for pregnancy.
60 W. He
If a patient with CKD mentioned above 5.3 Pregnancy Management

strongly desires to be pregnant, a close follow-up in Patients with CKD
for high-risk pregnancy by nephrologists and
obstetricians and NICU support treatment are To achieve better outcomes for pregnant women
indispensable [12, 13]. with CKD, multidisciplinary support is required
Fertility in patients on dialysis declines, and to strengthen management, including prepreg-
increasing the dialysis duration to >36 h/week is nancy preparation, pregnancy management, peri-
necessary to increase the fetal survival rate. The partum management, and postpartum care. In
risk of poor pregnancy outcome remains very particular, treatment of primary kidney diseases,
high despite treatment with intensive dialysis. hypertension, and related complications should
When a dialysis patient has a pathological preg- be emphasized [1, 13].
nancy, the risk of massive hemorrhage and other
risks due to termination of pregnancy by medica-
tions or surgical interventions are significantly 5.3.1 Prepregnancy Preparation
increased [15]. Therefore, pregnancy is not usu-
ally recommended for patients on hemodialysis The use of an immunosuppressant considered safe
or peritoneal dialysis. in pregnancy for 3–6 months before conception is
Under the guidance of medical professionals, recommended for women with CKD to achieve
renal transplant recipients should select the proper disease remission. Strict contraception is required
time for pregnancy in accordance with their condi- prior to disease remission, and progesterone-only
tion and treatment. In most cases, there is no sig- preparations are recommended. For women of
nificant difference in long-term graft function childbearing age, try to avoid the use of drugs with
between pregnant and nonpregnant women; never- effects on their fertility.
theless, the risk of poor pregnancy outcome is
higher in recipients than in the healthy population. 5.3.1.1 Contraception
The incidence of fetal loss, PE, and infection is also Strict contraception should be implemented prior
higher in recipients, especially in patients with SCr to disease remission, with progesterone-only
>150 μmol/L before pregnancy who have concom- contraceptive methods, including tablets, intra-
itant hypertension and diabetes [16]. The overall muscular injections, and intrauterine birth con-
incidence rate of transplant rejection during preg- trol devices, being recommended. As estrogen
nancy is 4.2% [17]. If renal transplant recipients may increase the risk of thrombosis and worsen
desire to be pregnant, it is recommended that they hypertension, women with hypertension, vascu-
wait for at least 1 year before conceiving to ensure lar disease, or heavy proteinuria or those who
stable graft function and enable switching of smoke should avoid being prescribed with prepa-
immunosuppressive drugs to nonteratogenic medi- rations containing estrogen. The use of an estro-
cations (e.g., mycophenolate mofetil replaced with genic drug is particularly prohibited in patients
azathioprine) [17]. The European Renal Best with vascular disease [20]. Contraception using
Practice guidelines recommend that women should birth control devices is not reliable and is not rec-
not conceive until at least 24 months after trans- ommended as the only contraceptive method.
plantation [18]. More recent recommendations
from the American Society of Transplantation 5.3.1.2 Fertility
advise that conception may be considered after Both primary diseases and therapeutic drugs may
12 months, provided that all of the following crite- affect patients’ fertility. Aggravation of renal dys-
ria are met: no rejection in the previous year, ade- function and abnormal hormone levels can increase
quate and stable renal function (i.e., SCr the rate of infertility. Adverse drug reactions,
˂133 μmol/L) with no or minimal proteinuria, no fatigue, depression, and use of immunosuppressive
acute fetotoxic infections (e.g., cytomegalovirus agents can all lead to sexual dysfunction and fertil-
infection), and stable kidney function with nontera- ity decline [21]. Cyclophosphamide can directly
togenic maintenance immunosuppression [19]. cause ovarian damage, with its oral administration
having more lasting effect on amenorrhea than nosuppressant considered safe in pregnancy
intravenous administration. Intravenous adminis- for at least 3–6 months before attempting to
tration with careful selection of treatment dosage conceive. Renin–angiotensin system (RAS)
and course is recommended. Try to avoid prescrib- inhibitors are the main drugs used to reduce
ing cyclophosphamide to women of childbearing proteinuria in patients without administer-
age [22]. Other immunosuppressants such as ing an immunosuppressant. The use of RAS
mycophenolate mofetil, calcineurin inhibitor, aza- inhibitors could be continued until conception
thioprine, and rituximab are appropriate for the is attempted [23].
treatment of immune glomerular diseases such as
LN, nephrotic syndrome, and vasculitis. Assisted
reproductive technology can possibly facilitate 5.3.2 Pregnancy Management
conception in women with CKD, but there is no
study to guide clinical practice. Gestational management in patients with CKD
includes medication adjustment, blood pressure
5.3.1.3 Optimized Management of CKD control, laboratory examination, fetal monitor-
Any active kidney disease may lead to adverse ing, and matters requiring attention during deliv-
pregnancy outcome. It is recommended that ery (Table 5.1). Nephrologists should focus on
disease remission be achieved using an immu- drug management during pregnancy (Table 5.2),
Table 5.1 Aspects of pregnancy management in patients with CKD

Classification
of aspects Aspects of management
Medications • Selection and adjustment of immunosuppressant and other medications for CKD (Table 5.2)
• Low-molecular-weight heparin, which is recommended to prevent thrombosis in patients with nephrotic
syndrome and high risk of thrombus formation
• Low-dose aspirin (50–100 mg/day) until 28 weeks of gestation
• Calcium monitoring and supplementation
• Folic acid (5 mg/day)
Blood • Use of antihypertensive drugs considered safe in pregnancy to enhance blood pressure control
pressure (Table 5.2)
• Blood pressure target of 130–140/80–90 mmHg
• Use of family self-test sphygmomanometer and recording of daily blood pressure at home
• Recording of blood pressure at each follow-up
Laboratory • Renal function (including SCr and serum urea levels, CCr rate, and proteinuria) should be examined at
examination least once a month, depending on the severity and progression of kidney disease
• Recording of baseline serum uric acid and liver enzyme levels, platelet count, and proteinuria, which is
useful for the differential diagnosis of suspected PE after pregnancy
• Glucose tolerance test, especially for pregnant women treated with glucocorticoid or calcineurin
inhibitors
Fetal • Biophysical profile
monitoring • Assessment of fetal growth and development
• Evaluation of placental function once a month in the first trimester of pregnancy, once every 2 weeks in
the second trimester of pregnancy, and once a week in the third trimester of pregnancy
Delivery • If the condition is stable and no obstetric-related indication for cesarean section exists, vaginal delivery
is performed as much as possible
• Termination of pregnancy if the condition is aggravated, endangering the lives of both the fetus and
pregnant woman
• If delivery is expected to be less than 34 weeks, glucocorticoid is administered prior to delivery to
promote fetal lung maturation
• Intermittent oxygen therapy, if necessary
• Stress dose of hydrocortisone may be administered, if necessary
CKD chronic kidney disease; SCr serum creatinine; CCr creatinine clearance; PE preeclampsia
(Adapted from Guidelines for pregnancy management in patients with chronic kidney disease. Natl J Med China.
2017;97(12):3604–11 [40])
62 W. He
Table 5.2 Drug management during pregnancy in patients with CKD [40]
Permeability
of the Effects on the fetus Safety in
Drugs placenta Teratogenic effects and newborn pregnancy Safety in lactation
Immunosuppressant
Prednisone Limited The incidence of Infrequent; large Maternal side Yes;
cleft palate may dosage can lead effects include breastfeeding is
be increased to cataract, bone loss and not
infection, and osteonecrosis, recommended at
adrenal gestational doses greater
insufficiency diabetes, than 60 mg/day
hypertension,
cataract, and
adrenal
insufficiency
Azathioprine Yes No Transient Yes Yes
immune changes
in newborns
Tacrolimus/ Yes No Hypokalemia and Yes; increasing Yes; 0.23–0.50%
Cyclosporine A renal the dose is often of dose adjusted
insufficiency required for maternal
body weight is
secreted into
breast milk
Mycophenolate Yes The incidence No No; should be No
mofetil rate of congenital stopped before
malformations is conception
22.9%, which
include cleft lip
and palate;
absence of the ear
canal;
considerable
distance between
organs; small ear,
fifth finger, and
limb deformities;
and toe
hypoplasia
Cyclophosphamide Yes Yes Chromosomal No; should be No
abnormalities and stopped before
leukopenia conception
Antihypertensive agents
Methyldopa Yes No No Top choice; Yes
restrict use
when adverse
events such as
lethargy occur
Beta blocker Yes No Some studies Labetalol is It can be
indicate limited preferred secreted to
fetal growth; the breast milk, but
use of atenolol in no adverse
the first trimester reactions have
of pregnancy been reported
leads to
bradycardia
Table 5.2 (continued)
Permeability
Calcium channel Yes No No Second-line It can be
blocker (nifedipine, drugs commonly secreted to
amlodipine) used in breast milk
combination (<5%
with methyldopa therapeutic
and labetalol dose), but no
adverse
reactions have
been reported
Diuretic Yes No Can cause fetal In theory, it can Mother will
(furosemide, diuresis reduce exhibit
hydrochlorothiazide) intravascular polydipsia, and
volume and large doses can
placental inhibit lactation
perfusion. It can
be carefully
used in patients
with excess fluid
or refractory
hypertension
Hydralazine Yes No No Often combined It can be
hydrochloride with secreted to
sympathetic breast milk, but
nerve blockers no adverse
to prevent reflex reactions have
tachycardia been reported
ACEI/ARB Yes Teratogenic Owing to renal No; should be A small amount
effects include papillary atrophy stopped before of enalapril,
neonatal anuria and disorders that conception captopril, and
and renal prevent the quinapril is
insufficiency, establishment of secreted to
limb contracture, renal medullary breast milk, and
craniofacial concentration no adverse
deformity, gradients, reactions have
pulmonary long-term been reported
dysplasia, and application can
patent ductus lead to renal
arteriosus insufficiency and
impaired kidney
function with
regard to the
concentration of
urine
Other drugs
Recombinant EPO No No reports No reports Yes; increase May be safe;
the dose protein may be
according to the damaged in the
need, which gastrointestinal
may cause tract of the
hypertension infant
Intravenous iron Yes No reports No reports Yes May be safe
Calcium-containing Yes No reports No reports Yes May be safe
phosphate binder
(calcium carbonate)
(continued)
64 W. He
Table 5.2 (continued)
Permeability
Calcium-free NA Animal studies NA No; should be No
phosphate binder show reduction in stopped before
(sevelamer, osteogenesis or conception
lanthanum osteogenic
carbonate) irregularity
Calcimimetics NA Animal studies NA Its use in No
(cinacalcet) show low risk patients with
hypercalcemia
can be
continued
Sodium hydrogen Yes No reports No reports Yes May be safe
carbonate
CKD chronic kidney disease; ACEI/ARB angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; EPO
erythropoietin; NA not applicable
(Adapted from Guidelines for pregnancy management in patients with chronic kidney disease. Natl J Med China.
2017;97(12):3604–11 [40])
especially the use of immunosuppressive and into the fetus through the placenta. Hence,
antihypertensive agents. prednisone is generally safe for the fetus, but
its high dosage may be associated with prema-
5.3.2.1 Immunosuppressants ture rupture of membranes [24]. Other side
Immunosuppressive agents deemed safe in preg- effects of corticosteroids are similar to those
nancy include corticosteroids, hydroxychloro- in nonpregnant patients, including increased
quine, azathioprine, and calcineurin inhibitors. risk of diabetes, hypertension, osteoporosis,
The use of rituximab is the last treatment option weight gain, infection, cataract, and mood
in the first trimester of pregnancy and should be changes during pregnancy.
considered only if its potential benefit outweighs • Hydroxychloroquine
the potential fetal risk. Cyclophosphamide, Hydroxychloroquine has no teratogenic effect.
mycophenolate mofetil, leflunomide, and metho- During pregnancy, hydroxychloroquine
trexate should be contraindicated in pregnant should be continued or started to maintain kid-
women because of their teratogenic effect, and ney disease remission or control lupus activity
their use should be discontinued at least outside the kidney. Stopping hydroxychloro-
3–6 months prior to conception (Table 5.2). quine will increase the risk of relapse during
pregnancy [25].
• Corticosteroids • Azathioprine
Corticosteroid dosage should be minimized Azathioprine is usually used during pregnancy
during pregnancy based on the status of kid- to maintain disease remission. Animal studies
ney disease. Methylprednisolone at high dos- have reported the teratogenicity of azathio-
age may be used when disease activity prine. However, azathioprine exerts no terato-
becomes severe. Prednisone or prednisolone genic effect on the human fetus because the
is appropriate, but it is not recommended to liver of the human fetus lacks hypoxanthine
use fluorinated glucocorticoids, such as dexa- nucleotide pyrophosphorylase, which can
methasone and betamethasone, which are only metabolize azathioprine into 6-mercaptopurine.
used in the third trimester of pregnancy to pro- After administration of azathioprine in renal
mote fetal lung maturation. Approximately transplant recipients during pregnancy, the
10% of maternal prednisone dosage can enter incidence of congenital malformation in
newborns was not different from that in the the effect of intrauterine exposure to ritux-
general population, indicating that azathio- imab on fetal immune system development
prine had no teratogenic effect [26]. remains uncertain. B cells in newborns whose
• Calcineurin inhibitors mothers were treated with rituximab should
Studies on renal transplant recipients have be monitored before routine vaccination; if
shown that calcineurin inhibitors such as necessary, vaccination should be delayed.
cyclosporine A and tacrolimus do not increase
the risk of teratogenicity and, thus, can be 5.3.2.2 Hypertension Management
safely used during pregnancy. Considering the The blood pressure target during pregnancy is
change in the distribution volume of cyclospo- 130–140/80–90 mmHg. Avoid excessive hypo-
rine A and tacrolimus and the increase in liver tension, which could result in insufficient placen-
metabolism during pregnancy, the dosage tal perfusion that affects fetal growth and
should be gradually increased by 20–25% of development. Antihypertensive agents consid-
the dosage before gestation starting from the ered safe in pregnancy include methyldopa,
second trimester of pregnancy [27]. labetalol, and long-acting nifedipine (Table 5.2).
Furthermore, individual differences should be
considered to reduce the side effects of drugs, • Blood pressure target
and the effective minimum dosage should be The blood pressure during pregnancy has been
selected to reduce potential drug toxicity. The suggested to be maintained at 130–140/80–
drug concentration needs to be carefully 90 mmHg. It should be noted that the blood
titrated, maintaining the effective concentra- pressure should be steadily decreased. The
tion within the lower treatment window. amplitude of blood pressure reduction should
Postpartum dosage should be quickly reduced not be too large. The appropriate amplitude is
to the prepregnancy level [28]. 10–25% of the mean arterial pressure and
• Mycophenolate mofetil and should be achieved within 24–28 h, avoiding
cyclophosphamide excessive hypotension that may lead to insuf-
The use of mycophenolate mofetil and cyclo- ficient placental perfusion, which affects fetal
phosphamide is avoided during pregnancy growth and development. The Control of
owing to their teratogenicity. The use of Hypertension in Pregnancy Study confirmed
mycophenolate mofetil in the first trimester of that treating hypertension in pregnancy to a
pregnancy may result in a high abortion rate lower diastolic blood pressure target is not
and severe congenital defects in the fetus, associated with adverse neonatal events or
including cleft lip and palate, microtia, and pregnancy outcomes. Furthermore, women
external auditory canal atresia. A prescription with less tight control more frequently devel-
of cyclophosphamide in the first trimester of oped a blood pressure ≥160/110 mmHg,
pregnancy may lead to abnormal fetal skull, which may aggravate potential kidney dis-
ear, and head, as well as abnormal and delayed eases; hence, a blood pressure target
development of the limbs and internal organs. <140/90 mmHg has been recommended for
In addition, its prescription in the third trimes- women with CKD during pregnancy [31].
ter of pregnancy can lead to FGR, hematopoi- • Antihypertensive drugs
etic suppression, and nerve injury [29]. Antihypertensive drugs considered safe in
• Rituximab pregnancy include methyldopa, labetalol, and
Rituximab can pass through the placenta and long-acting nifedipine. Studies have reported
cause neonatal B-cell depletion, the incidence that adverse outcomes in perinatal and preg-
and severity of which increase from midterm nant women, including SGA births, preterm
to full-term pregnancy. Therefore, rituximab delivery, severe hypertension and PE, infant
is recommended as the last treatment option in respiratory distress syndrome, sepsis, and epi-
the first trimester of pregnancy [30]. However, lepsy, were fewer in the methyldopa group
66 W. He
than in the labetalol group, suggesting that dosis occurs. Studies on the safety of drugs
methyldopa is more beneficial in hypertensive commonly used as treatment for calcium and
pregnant women than labetalol [32, 33]. Long- phosphorus metabolic disorders and secondary
acting nifedipine and amlodipine are second- hyperparathyroidism during pregnancy are lim-
line drugs, often with methyldopa and ited. Calcium carbonate can be used during preg-
labetalol. Other beta blockers (such as meto- nancy, although there exists no study reporting
prolol) and calcium channel blockers (such as the safety of calcium carbonate, lanthanum car-
nimodipine and nicardipine) are substituted bonate, and calcimimetics during pregnancy.
only when pregnant women cannot tolerate Thrombosis in patients with severe proteinuria
these recommended safer antihypertensive and serum albumin <20 g/L should be prevented
drugs. As diuretic can lead to increased plasma throughout the entire pregnancy period, whereas
concentration, effective reduction in the circu- anticoagulation therapy for patients without
lating blood volume, and hypercoagulability, severe nephrotic syndrome but with other high-
loop diuretics such as furosemide can only be risk factors, such as obesity, lack of ambulatory
used when pregnant women have systemic, capacity, membranous nephropathy, or vasculitis,
pulmonary, or cerebral edema, renal insuffi- should also be considered. Low-molecular-
ciency, and acute cardiac failure. Antisterone weight heparin for anticoagulation can be subcu-
can pass through the placenta to produce an taneously injected. Thrombosis prevention is
antiandrogenic effect on the fetus and, thus, usually stopped during delivery. However, the
should be avoided during pregnancy. The use risk of postpartum thrombosis is particularly
of RAS inhibitors can lead to fetal heart and high, and anticoagulation therapy should con-
kidney defects, including atrial septal defect, tinue as long as possible until at least 6 weeks
ventricular septal defect, pulmonary stenosis, postpartum. See the American College of Chest
patent ductus arteriosus, renal hypoplasia, oli- Physicians guidelines [35] and the American
gohydramnios, and complications such as Diabetes Association guidelines on the use of
limb contracture, pulmonary hypoplasia, and glucose-lowering agents during pregnancy [36].
craniofacial malformation, and is therefore
absolutely prohibited during pregnancy [34]. 5.3.2.4 Diet Management
For pregnant women with CKD at any stage or
5.3.2.3 Other Drugs Commonly renal transplant recipients, the energy intake is
Used in Patients with CKD 35 kcal/kg/day in the first trimester of pregnancy;
Pregnant women with advanced CKD may have however, this energy intake should be increased
several complications, including anemia, acido- by an additional 300 kcal/day from the baseline
sis, hyperphosphatemia, and bone disease. during the second and third trimesters of preg-
Owing to the relative lack of erythropoietin nancy. For pregnant women with stage 1–3 CKD,
(EPO) in pregnancy and EPO resistance due to with stage 4–5 CKD, and on dialysis, the protein
pregnancy-related inflammatory factors, severe intake is 0.8, 0.6, and 1.2–1.3 g/kg/day, respec-
anemia, which affects placental and fetal growth, tively, and a daily increase of 10 g protein should
may occur in pregnant women with CKD. It is be added on this basis [37]. Daily supplementa-
recommended that the hemoglobin level be main- tion with 0.63 g/8–10 kg keto acid based on the
tained at 100 g/L in pregnant women with CKD ideal body weight may reduce SGA births [38].
[9]. The use of EPO and oral iron to correct ane-
mia is safe, and the dosage usually needs to be
increased; nevertheless, there are no adequate 5.3.3 Follow-Up During Pregnancy
and well-controlled studies for intravenous iron
in pregnant women. The blood pH in pregnant During pregnancy, women with CKD require
women is alkalescent, and no bicarbonate supple- close follow-up by both nephrologists and obste-
mentation is required for them unless severe aci- tricians to monitor disease activity and detect
obstetric complications (Table 5.1) and follow-up the third trimester of pregnancy during the period
at least once per 4–6 weeks in the nephrology of >2 weeks. In case of the above situation, a full
department. The monitoring frequency can be course of dexamethasone to promote lung matu-
increased according to the severity and progres- ration should be routinely administered. Cesarean
sion of kidney disease. Patients are followed up section should be performed to end the labor if
to monitor blood pressure (measurement and the fetus is abnormal before parturition or dur-
recording at home are recommended), renal func- ing labor, adverse conditions occur during
tion (including SCr and serum urea levels and induced labor, or induced labor fails. All new-
creatinine clearance rate), serum uric acid level, borns with birth weight <1500 g, gestational
24-h urinary protein quantitative analysis, urine age <34 weeks, and Apgar score <7 at 5 min and
red blood cell count, midstream urine culture those in need of intubation should be transferred
(especially in patients with pyelonephritis), and to the NICU [39].
blood glucose level (glucose tolerance tests, if
necessary, especially for pregnant women taking 5.3.4.2 Delivery Mode
hormone or calcineurin inhibitors). Recording If the condition is stable and no obstetric-related
the platelet count and levels of basal uric acid, indication for cesarean section exists, an
liver enzymes, and urinary proteins is helpful for attempted vaginal delivery may be considered.
the differential diagnosis of suspected PE after Otherwise, if the condition is aggravated and it is
pregnancy. For systemic diseases such as LN and estimated that vaginal delivery within a short
vasculitis, related immunological parameters period of time is impossible, cesarean section
need to be monitored at each follow-up visit. At should be performed.
baseline and every 10–12 weeks, nutritional
parameters should be monitored, including iron,
folic acid, vitamin D, vitamin B12, albumin, and 5.3.5 Postpartum Management
total protein. While following the instructions
from nephrologists, pregnant women with CKD Postpartum management of patients with CKD
should simultaneously follow the instructions of includes monitoring kidney disease activity,
obstetricians during regular follow-up. blood pressure, and GFR; performing urine anal-
ysis; paying attention to plasma concentration
assessment in patients treated with calcineurin
5.3.4 Peripartum Management inhibitors; continuously preventing thrombosis
until 6 weeks after delivery in patients at high
5.3.4.1 Indication for Termination risk of thrombosis, if necessary; encouraging
of Pregnancy patients to breastfeed their infants; and providing
The pregnancy should be terminated if the condi- emotional support to prevent postpartum
tion of the gravida or fetus severely deteriorates depression.
before 32 weeks of gestation or does not deterio- Patients with CKD are encouraged to use the
rate too seriously after 32 weeks of gestation. In minimum dose of drugs safely used during preg-
addition, when typical PE or HELLP syndrome nancy and breastfeeding. Only a small amount of
occurs, the condition of pregnant women gradu- prednisone, azathioprine, and tacrolimus can be
ally deteriorates, showing severe and uncontrol- secreted into breast milk, with cyclosporine A
lable hypertension and nephrotic syndrome being almost undetectable in breast milk; there-
accompanied by a rapid increase in proteinuria fore, the use of these drugs can be continued dur-
and/or SCr. The condition of the fetus also gradu- ing lactation. Because of the change in postpartum
ally deteriorates, presenting abnormal fetal heart maternal physiology, the plasma concentration of
rate at any gestational week, umbilical artery dia- calcineurin inhibitors will increase. It is neces-
stolic blood flow deficiency at ≥32 weeks on sary to reassess and adjust the dose as soon as
Doppler ultrasonography, and no fetal growth in possible to avoid nephrotoxicity to the mother
68 W. He
and possibly to the infant. Do not breastfeed

when patients require treatment with mycophe- • Gestational management in patients
nolate mofetil or cyclophosphamide for obvious with CKD includes blood pressure con-
disease activity. As macromolecules, particularly trol, medication adjustment, laboratory
monoclonal antibodies, are not secreted into examination, fetal monitoring, and mat-
breast milk, active postpartum nephritis can be ters requiring attention during delivery.
treated using rituximab. With respect to antihy- Nephrologists should focus on drug
pertensive therapy, methyldopa, labetalol, and management, especially the use of
long-acting nifedipine are the most commonly immunosuppressive and antihyperten-
used drugs. Diuretic-induced dehydration may sive agents.
impede milk secretion; thus, the use of diuretics • During pregnancy, women with CKD
is usually avoided. Several RAS inhibitors, require close follow-up to monitor blood
including enalapril, captopril, and quinapril, are pressure, renal function, serum uric acid
not detected in breast milk and should be used as level, 24-h urinary protein quantitative
early as possible to reduce proteinuria. analysis, urine red blood cell count,
Considering patients’ experience of a very risky midstream urine culture, and blood glu-
pregnancy, attention should be paid to their mood cose level.
changes to prevent postpartum depression. • If the condition of the patient is stable
and no obstetric-related indication for
cesarean section exists, vaginal delivery
Key Messages is performed as much as possible; other-
• Women with CKD remain a part of the wise, if the condition is aggravated,
patient population that carries the high- endangering the lives of both the fetus
est risk of adverse maternal and fetal and pregnant woman, the pregnancy
outcomes; therefore, managing preg- needs to be immediately terminated.
nancy in patients with CKD has become • Postpartum management of patients
a considerable challenge shared by both with CKD includes monitoring kidney
nephrologists and obstetricians. disease activity, blood pressure, and
• To achieve better outcomes for pregnant GFR, performing urine analysis, encour-
women with CKD, strengthened managing patients to breastfeed their infants,
agement is required, including pre- and providing emotional support to pre-
pregnancy preparation, pregnancy vent postpartum depression.
management, peripartum management,
and postpartum care.
• The more difficult blood pressure con- References
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Aging and Chronic Kidney Disease
6
Tao Zhang
Abstract of ESRD and of the REIN score to predict

With renal aging, a complex interplay of the risk of mortality in older patients with
genetics, environmental changes, and cellu- stage 5 CKD. Further studies are required
lar dysfunction leads to the histological and for solving the controversy concerning CKD
functional changes. The faster expanding in the elderly.
population of elderly is more likely to expe-
rience chronic kidney disease (CKD) and
progress to end-stage kidney disease
(ESRD). Glomerular filtration rate (GFR) is 6.1 Introduction
the most important indicator commonly used
for the diagnosis and grading of CKD. The Aging is a natural process in all species that
MDRD and CG formulas are the most widely results in degenerative changes in many organs
applied, and the CKD-EPISCr–cys formula is and is determined by genetic, environmental, and
an acceptable choice for the elderly. The stochastic factors [1]. Age-related changes in the
treatment of CKD in older patients requires structure of the kidney usually begin at the age of
overall consideration because the risk of car- 40 years and accelerate at approximately
diovascular disease mortality is greater than 50 years. These changes include gradual nephron
the risk of developing ESRD at the same loss, glomerulosclerosis, tubular atrophy, and
GFR level. An individualized patient-cen- interstitial fibrosis, resulting in renal function
tered approach may offer more benefits than decline and hemodynamic and water electrolyte
a traditional disease-oriented approach in disturbance [2]. Kidney aging poses a serious
old patients. There are few clinical practice health risk in the elderly.
guidelines on the management of the elderly The proportion of the elderly population is
with CKD. The European guideline recom- steadily increasing worldwide, especially in
mends the use of four variables (age, sex, lower- and middle-income countries [3]. This
eGFR, and albuminuria) to predict the risk demographic change is related to social and
economic development and prolongation of
life [4]. As chronic kidney disease (CKD) can
impose serious disease burden and consume
T. Zhang (*) huge amounts of health resources and the prev-
Division of Nephrology, Department of Geriatrics,
alence rate of CKD is higher in the elderly
First Affiliated Hospital, Nanjing Medical University,
Nanjing, Jiangsu, China population than in the general population,
e-mail: zht779100@njmu.edu.cn more attention should be paid to research on

72 T. Zhang
CKD and aging. CKD is one of the multiple associated with diagnosed diabetes (odds ratio
risk factors for death in elderly patients. Other [OR], 3.58; 95% confidence interval [CI], 3.12–
risk factors include diabetes, hypertension, 4.12) and hypertension (OR, 1.70; 95% CI,
heart disease, and stroke [5–7]. Therefore, in 1.10–1.92), as well as older age and all race
2014, the International Society of Nephrology groups (P < 0.001), but not with higher BMI
and the International Federation of Kidney (P = 0.12). Of individuals aged >65 years with
Foundations established “chronic kidney dis- CKD (higher than stage 3), 11% developed ure-
ease in the elderly” as the theme of the World mia (Fig. 6.1) [9]. Murphy et al. examined the
Kidney Day to raise awareness about and 1988–1994 and 1999–2012 NHANES data and
enhance the recognition of CKD in the elderly reported that the prevalence of stage 3–4 CKD
[8]. This chapter mainly describes the diagno- adjusted for sex, race/ethnicity, and diabetes sta-
sis, management, and treatment of CKD in tus was higher in older individuals (estimated
elderly patients and also discusses some related glomerular filtration rate [eGFR] calculated
controversial issues pertaining to CKD in the using the Chronic Kidney Disease Epidemiology
elderly. Collaboration [CKD-EPI] formula: 15–59 mL/
min/1.73 m2). However, in all age groups, the
prevalence of stage 3–4 CKD had largely stabi-
6.2 Epidemiology of CKD lized since 2003–2004 (Fig. 6.2) [10, 11]. A
in the Elderly 2015 study reported that the prevalence rate of
CKD was 11.5%, 16.3%, and 64.1% in Chinese
Few studies have investigated the prevalence of people aged >45 years, 60–79 years, and
CKD in the elderly population aged >65 years >80 years, respectively [12]. The prevalence of
to date. Although the prevalence of CKD CKD increases with aging but has been differ-
increases with age, data on this quite vary. The ently reported in various studies owing to the
National Health and Nutrition Examination lack of adjustment for age, sex, race/ethnicity,
Survey (NHANES) is the most consummate and diabetes status.
epidemiologic study on US civilian residents
with CKD in the United States. Serial analyses
of the NHANES data indicate that the preva-
lence of CKD significantly increased in the
Prevalence of CKD (%)
aging US population. Coresh et al. compared 60

the prevalence of CKD in the 1988–1994 50
NHANES with that in the 1999–2004 NHANES 40
and determined that the prevalence rate of stage 30
1–4 CKD in the adult population increased from 20
10 to 13.1%, whereas the prevalence rate of 10
CKD in the elderly (aged >70 years) increased 0
20-39 40-59 60-69 >70
from 36.8 to 47.8%. Further adjustment for the Age Group (Years)
higher prevalence of diagnosed diabetes and 1988-1994 1999-2004
hypertension and higher body mass index (BMI)
Fig. 6.1 Prevalence of chronic kidney disease by age
practically explained all of the difference in group in the National Health and Nutrition Examination
addition to older age. In fully adjusted models, Survey (NHANES) for 1988–1994 and 1999–2004.
the prevalence of albuminuria was strongly (Reproduced with permission from Coresh et al. [9])
6 Aging and Chronic Kidney Disease 73
70.0
60.0
Prevalence of CKD (%)
50.0
40.0
30.0
20.0
10.0
0.0
1988-1994 1999-2000 2001-2002 2003-2004 2005-2006 2007-2008 2009-2010 2011-2012
Study Year
20-39 40-64 65-79 80
Fig. 6.2 Prevalence of chronic kidney disease by age group in the National Health and Nutrition Examination Survey
(NHANES) for 1988–1994 and every 2 years from 1999 to 2012 [10])
6.3 Diagnosis elderly, which leads to unnecessary medical

of and Controversy expenses due to the inappropriate use of CKD
Concerning CKD definition based on measured GFR or eGFR [17,
in the Elderly 18]. It is debatable whether the diagnosis of stage
1–2 CKD in the elderly should be cut off.
Beginning at the age of 40 years, the glomerular Although the 2012 KDIGO clinical practice
filtration rate (GFR) declines by approximately guideline proposed a “special concern” for the
8 mL/min/1.73 m2 per decade in a healthy indi- diagnosis of CKD in the elderly, no special rec-
vidual although the rate of decline is highly vari- ommendation concerning the diagnostic criteria
able. After approximately 75 years of age, the for CKD in the elderly has been put forward. In a
rate of GFR decline may accelerate; however, meta-analysis that included 46 cohort studies and
such progressive GFR decline is not fast enough approximately two million patients, Hallan et al.
to cause kidney failure throughout the human life discussed in 2012 the correlation between pro-
span [13, 14]. According to contemporary diag- gression to end-stage renal disease (ESRD), mor-
nostic criteria for CKD, any subject, regardless of tality, age, proteinuria, and GFR level.
age, with a measured or estimated GFR <60 mL/ Furthermore, their analysis showed that eGFR
min/1.73 m2 present for at least 3 months is con- decline and urinary protein level were indepen-
sidered to have CKD (stages 3–5) irrespective of dent risk factors and were associated with the
the presence or absence of other signs of kidney relative risk of all-cause mortality and ESRD in
injury, as recommended in the 2012 Kidney the general population, supporting the current
Disease: Improving Global Outcomes (KDIGO) KDIGO guideline on the analysis of GFR and
clinical practice guideline [15, 16]. Consequently, proteinuria level [19, 20]. It is also based on these
a great majority of the elderly can be “diagnosed” findings that the 2012 KDIGO clinical practice
with CKD although this can and does occur in guideline does not have specific diagnostic crite-
healthy aging [9]. Therefore, considerable con- ria for CKD in the elderly. Findings from the
troversy exists as to whether the GFR decline in study of Dousdampanis et al. also supported the
the elderly indicates disease status or occurs with diagnostic criteria for CKD without the boundary
natural aging. This has been suggested as an value for age [18, 21, 22]. However, the lack of
example of “overdiagnosis” of CKD in the evidence from studies on CKD in the elderly
74 T. Zhang
underlines the need for a large number of pro- EPIcys formula, which is based on cystatin C, and
spective studies on the diagnostic criteria for CKD-EPISCr–cys formula, which is based on the
CKD in elderly patients. combination of SCr and cystatin C. However,
there were considerable controversies as to which
GFR estimation formula might be more suitable
6.4 Renal Function Evaluation for the elderly. Studies using GFR estimation for-
Formula for the Elderly mulas were not specifically designed for the
elderly, and there was no medical evidence sup-
GFR is the most important indicator for the diag- porting the evaluation of these formulas in older
nosis and staging of CKD. Inulin clearance is the patient populations.
gold standard for GFR determination, but its high Drenth-van Maanen et al., Péquignot et al.,
price and complex operation limit its clinical use. and Helou considered the CG formula to be the
Thus far, a total of more than 25 GFR estimation most accurate in older patients, especially those
formulas based on serum creatinine (SCr) exist, with malnutrition and chronic inflammatory dis-
with the simplified version of the Modification of ease, because values corrected by the ideal body
Diet in Renal Disease (MDRD) Study formula mass are used in the CG formula [32–34].
and Cockcroft–Gault (CG) formula being the However, Flamant et al. recommended the use
most widely applied [23, 24]. of MDRD and CKD-EPI formulas for the
The MDRD formula was designed based on elderly, as the CG formula underestimated the
patients with CKD, and its applicability has been renal function in older individuals [35]. In the
widely validated in patients with CKD. With study of Nyman et al., which had a small
respect to its application in healthy individuals European elderly sample, the deviation and
with normal renal function and patients with accuracy of the CKD-EPI formula were better
CKD who have mild renal insufficiency (GFR than those of the improved simplified version of
>60 mL/min/1.73 m2), the equation appears to the MDRD formula [36]. Dowling et al. believed
provide a low estimate of the true value, resulting that the CG formula should be used when the
in error in estimating the clinical renal function. drug dosage is adjusted according to the renal
Owing to the limitation of the MDRD formula, function of older patients [37]. Many studies
the CKD-EPI research group in 2009 proposed examined the bias in different GFR estimation
the CKD-EPI formula and performed a larger formulas in relation to measured GFR [37–39].
investigation [25]. This study included healthy SCr-based renal function evaluation often
individuals and patients with CKD as subjects, showed deviation due to reduced physical func-
and the MDRD formula was subsequently further tion and chronic diseases in older patients [40].
modified. The CKD-EPI formula is better than Owing to the overestimation of the prevalence
the MDRD formula with respect to accuracy and rate of stage 3a CKD (GFR, 45–59 mL/
relevance, especially in population with high min/1.73 m2) by the SCr-based GFR equation,
GFR [26–28]. Recent studies have shown that the 2012 KDIGO clinical practice guideline fur-
cystatin C is an ideal endogenous marker of glo- ther recommended the use of GFR estimation
merular function that cannot be affected by formulas based on cystatin C to validate whether
inflammation, tumor, age, sex, muscle mass, patients were diagnosed with stage 3a CKD in
stress, immunity, and endocrine diseases. the absence of evidence of renal injury in order
Cystatin C can be used for the early detection of to reduce excessive diagnosis of stage 3a
CKD, as its concentration sensitively reflects CKD. According to the guideline, GFR estima-
impaired renal function [29]. With the wide- tion formulas based on cystatin C had less bias
spread use of cystatin C, some GFR estimation than other formulas used to calculate GFR in the
formulas have been based on cystatin C measure- elderly [16, 41]. In 2016, the European clinical
ment [30, 31]. In 2012, the CKD-EPI research practice guideline on the management of older
group also advanced two improvements: CKD- patients with stage 3b or higher CKD (GFR
<45 mL/min/1.73 m2) advised the use of estima- angiotensin-converting enzyme inhibitors

tion formulas instead of SCr measurements to (ACEIs)/angiotensin II receptor blockers (ARBs)
assess renal function in older patients. No equa- to delay the progression of CKD in most older
tion was preferred, and the CKD-EPISCr–cys for- patients with CKD remains lacking. There is an
mula was considered an acceptable choice [42, increasing risk of renal injury under the circum-
43]. In view of current controversies, epidemio- stances of hypovolemia, excessive diuresis, renal
logic studies on the elderly are required to artery stenosis, severe left heart failure, and the
develop a more suitable GFR estimation for- use of nonsteroidal anti-inflammatory drugs
mula for this particular group. (NSAIDs).
No randomized controlled trials have com-
pared dialysis and nondialysis treatment in older
6.5 Treatment and Intervention patients diagnosed with ESRD [53]. In a retro-
for Older Patients with CKD spective analysis of patient survival among those
older than 75 years with CKD stage 5, the first-
The elderly, particularly those with comorbidi- and second-year survival rates of the dialysis
ties, are not enrolled in most reported studies, andgroup were superior to those of the conservative
clinical guidelines for them are lacking [44–46]. group. However, this survival advantage was lost
Some treatments proposed by clinical guidelines in patients with multiple comorbidities [54].
for older patients with CKD, including the use of Decisions about whether to receive dialysis or
renin–angiotensin system blockers, are contro- not are difficult before dialysis, and the choice
versial [47]. Treatment for adults with CKD is between hemodialysis and peritoneal dialysis
different from that of older patients with CKD, as should remain individualized in the elderly [55–
the clinical manifestations of the latter mainly 57]. Age alone does not necessarily preclude can-
include eGFR reduction and unapparent protein- didacy for renal transplantation. In 2011, 60% of
uria or albuminuria. For the elderly without albu- renal transplant recipients were older than
minuria, the benefit of renoprotection therapy is 50 years, of whom 18% were older than 65 years
very limited [48]. Clinicians could not mechani- [58]. Improvement in the quality of life is the
cally apply CKD guidelines in the elderly and most important goal and should be evaluated
should pay attention to delaying the progression from various aspects such as organ function,
of CKD. It is more important to reduce renal prognosis, cognitive status, social support, treat-
damage under stress and preserve renal function ment burden, and nutritional status. Renal
because older individuals could have more seri- replacement therapy (RRT) is an appropriate
ous injury and more difficult recovery than option for older individuals with good baseline
younger individuals under the same stress [49]. quality of life.
Many risk factors could be avoided, including the
use of nephrotoxic drugs, cardiac surgery, inter-
ventional therapy, ischemia, and inflammation 6.5.1 Changes in the Management
[50]. At the same GFR level, the risk of death, of the Elderly with CKD
myocardial infarction, and stroke in older patients
with CKD is greater than the risk of developing Well-defined disease-oriented models
ESRD [51]. A high risk of all-cause and cardio- (Table 6.1) for different conditions exist. These
vascular disease mortality in community- models show the relationship between signs
dwelling elderly individuals with CKD has been and symptoms and the pathophysiology of
reported [52]. These patients could benefit from underlying diseases. Treatment plans target
slowing down renal impairment and improving pathophysiological mechanisms, with improve-
metabolic acidosis, anemia, and hyperphosphate- ment in disease-related outcomes as their goal
mia, and the risk of cardiovascular events could [59]. Furthermore, these models have the
be reduced. Sufficient evidence on the use of advantage of providing a systematic framework
76 T. Zhang
for guidance, diagnosis, evaluation, and mea- 6.5.2 C

linical Practice Guideline
surement in patients. This disease-oriented on the Management of Older
method provides a simple and clear framework Patients with CKD
that is easy to be applied to a defined popula-
tion [60]. Considering that the proportion of older patients
Because GFR can be affected by the aging with severe CKD increased at the end of 2016
process, the prevalence of CKD increases with based on the increasing number of older patients
advancing age [61, 62]. However, several fea- with infirmity although evidence from existing
tures of aging may limit the utility of disease- studies remains limited, the European Renal Best
oriented models of care. In older individuals, Practice released the clinical practice guideline
complex comorbidities and geriatric syndromes on the management of older patients with CKD
are common, and signs and symptoms often do stage 3b–5 [43]. The new guideline is based on
not reflect a single underlying pathophysiologi- the old CKD-related research data, and its main
cal process. Information on the safety and effi- contents include renal function evaluation in
cacy of recommended interventions is often elderly patients with CKD and assessment of the
lacking [63, 64]. For all these reasons, an indi- benefits of diagnosing CKD during follow-up.
vidualized patient-centered model of care tends Renal function evaluation is recommended in
to be applied to the elderly over more tradi- the selection section of the renal function for-
tional disease-oriented approaches (Table 6.1). mula. The guideline recommends the four-
An individualized patient-centered approach variable Kidney Failure Risk Equation (KFRE),
prioritizes patient preferences and embraces the as it performs sufficiently well for use in older
notion that observed signs and symptoms often patients with advanced CKD and eGFR <45 mL/
do not reflect a single unifying disease process min/1.73 m2 [67, 68]. The four-variable KFRE
but instead reveal the complex interplay among (age, sex, eGFR, and albuminuria) predicted the
several different factors, including aging, risk of ESRD at 2 and 5 years and achieved
social, pathological, and psychological factors excellent discrimination (pooled c-statistic 0.91
[65]. This model focuses on alterable outcomes and 0.88 at 2 and 5 years, respectively) in further
that matter to the patient. Prognostic informa- validation cohorts that included 721,357 indi-
tion related to these and other outcomes is gen- viduals with CKD stage 3–5 in North America,
erally used to shape rather than dictate treatment Asia, Europe, and Australasia [19, 69]. This
decisions. For older populations with CKD, an guideline suggests the use of the Bansal score to
individualized patient- centered approach to predict the individual 5-year risk of mortality
care may offer more than a traditional disease- before ESRD in non-frail older patients with
oriented approach [64, 66]. CKD stage 3–5 and recommends that an assess-
Table 6.1 Changes in the decision-making model for the treatment of chronic kidney disease in the elderly
Model Disease-oriented model Patient-centered model
Primary • Diagnosis, prevention, and treatment of the • Particularity and priority of patients
concern disease
Treatment • Pathophysiology of the disease • Variable factors affecting the health of
target patients
Clinical • Determined by the disease • Determined by the specific priority of
outcome patients
Survival • The first goal of treatment and prevention • One of the goals
Pathogeny • Pathological causes of the disease (mental, • The state of health is due to the interaction
environmental, social, and other secondary of complex factors, such as hereditary,
factors) are not the main determinants of the religious, environmental, and social
disease factors
ment of frailty be performed for patients at low older patients with CKD stage 3b or higher and
risk based on the Bansal score [70, 71]. The final suggests that a score including serum albumin
risk prediction model includes nine readily avail- concentration, BMI, SCr normalized to body
able demographic, clinical, and biochemical pre- surface area, and normalized protein nitrogen
dictors: age, sex, ethnicity, eGFR, urinary appearance may be used to assess the nutri-
albumin-to- creatinine ratio, diabetes, smoking tional status of older patients on hemodialysis
status, history of heart failure, and stroke. It is [90, 91]. The elderly are mostly in a high-
recommended that patients at low risk based on energy consumption risk state, and nutritional
the Bansal score be evaluated for physical weak- assessment can predict the survival rate of
ness [72–74]. High-risk management should be patients on dialysis, which has important clini-
implemented for patients with physical weak- cal implication [92, 93].
ness who require dialysis. The guideline also
recommends that the Renal Epidemiology and
Information Network (REIN) score be used to 6.5.3 R
RT vs. Conservative
predict the risk of mortality in older patients Treatment
with CKD stage 5 [75]. The risk prediction
model developed from 12,500 French incident Some scholars believe that the survival benefit
dialysis patients and validated in 11,848 dif- from RRT is not obvious in elderly patients with
ferent dialysis patients, includes nine predic- CKD [94, 95]. Taking into account the reduced
tors: age, sex, history of congestive heart organ functional status and poor quality of life in
failure, peripheral vascular disease, dysrhyth- patients with CKD, complicated treatment pro-
mia, cancer, severe behavioral disorder, mobil- cesses, and increased medical expenses, conser-
ity, and baseline serum albumin concentration vative treatment is considered appropriate [96,
[69, 76, 77]. 97]. The European guideline recommends a com-
The guideline recommends that a simple score prehensive assessment of renal function and sur-
be regularly used to assess functional status in vival risk and selection of appropriate RRT
older patients with CKD stage 3b–5d in order to method. With respect to the choice of manage-
identify those who would benefit from a more in- ment methods for ESRD, conservative treatment
depth geriatric assessment and rehabilitation is recommended in the shared decision-making
[78–80]. Furthermore, according to this guide- [98, 99]. The REIN score is recommended to pre-
line, most simple scores, including self-report dict short-term (6-month) prognosis in RRT
scales and field tests (sit-to-stand, gait speed, and patients [100]. At the same GFR level, the risk of
6-min walk tests), have comparable and suffi- death, myocardial infarction, and stroke in older
cient discriminating power to identify patients patients with CKD is greater than the risk of
with decreased functional status [81–83]. As developing ESRD. Slowing down renal damage
exercise has a positive effect on the functional and improving metabolic acidosis, anemia, and
status of older patients with CKD stage 3b or hyperphosphatemia can reduce the risk of cardio-
higher, the guideline recommends that exercise vascular events and benefit elderly patients with
training be offered in a structured and individual- CKD [95, 99].
ized manner to avoid adverse events. The formu- For most elderly patients with CKD, evidence
lation of sports training programs should be on the use of ACEIs/ARBs to delay the progres-
systematized and individualized to avoid the sion of the disease, especially in combination
occurrence of adverse events [84–86]. Exercise with insufficient blood volume or excessive
training under supervision at 2 hours before dial- diuretic use, remains lacking [101]. Renal artery
ysis and regular follow-up are very important for stenosis, obvious left-sided heart failure, and
patients on dialysis [87–89]. The guideline pro- NSAID use also increase the risk of kidney
poses subjective global assessment as the gold injury. There is no unified answer as to whether
standard for assessing the nutritional status of elderly patients with end-stage CKD require dial-
78 T. Zhang
ysis or conservative treatment [102, 103]. In

developed countries, older patients with end- widely applied, and the CKD-EPISCr–cys
stage CKD have gradually switched from conser- formula is an acceptable choice in the
vative treatment to dialysis. Under suitable elderly.
conditions, age is not a contraindication for renal • For the management of CKD in older
transplantation [104, 105]. Improvement in the populations, an individualized patient-
quality of life is the most important goal and centered approach may offer more ben-
should be evaluated from various aspects such as efits than a traditional disease-oriented
organ function, prognosis, cognitive status, social approach.
support, treatment burden, vision or hearing, and • The treatment of CKD in older patients
nutritional status [106, 107]. RRT is a suitable requires overall consideration because
option for the elderly with good baseline quality the risk of cardiovascular disease mor-
of life. tality is greater than the risk of develop-
ing ESRD at the same GFR level.
• In 2016, the European Renal Best
6.6 Conclusions Practice released the clinical practice
guideline on the management of the
Many problems concerning the diagnosis and elderly with CKD stage 3b–5. This
treatment of CKD in the elderly still exist, such guideline recommends the use of four-
as the suitable diagnostic criteria, causes of CKD, variable KFRE (age, sex, eGFR, and
therapeutic targets, and related complications. albuminuria) to predict the risk of ESRD
The treatment for these patients requires a com- and of the REIN score to predict the risk
prehensive balance, and management using a of mortality in older patients with CKD
patient-centered approach rather than a disease- stage 5.
oriented approach should be established.
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Acute Kidney Injury and Chronic
Kidney Disease 7
Yu Chen and Weichun He
Abstract eral management include specific treatment

Chronic kidney disease (CKD) is a potent risk of the underlying cause, fluid management,
factor for acute kidney injury (AKI) and a electrolyte management, adjustment of drug
modifier for the relationship between AKI dosing, nutritional support, renal replacement
and adverse outcome, while AKI increases therapy, and specific pharmacologic
the risk of de novo CKD and is an accelerator therapies.
for the progression of underlying CKD. When
patients with CKD develop dialysis-requiring
AKI, available data suggest that the recovery
of kidney function is less likely than in 7.1 Introduction
patients without CKD. Patients with AKI
were more likely to develop CKD compared Recent epidemiological studies have shown
with matched control patients without complex interactions between acute renal injury
AKI. For CKD patients at high risk for devel- (AKI) and chronic renal disease (CKD). An
oping AKI, preventive measures for AKI increasing body of evidence supports bidirec-
include adequate fluid repletion in those with tional relationships between these two clinical
hypovolemia, avoidance of hypotension by events, that is, the existence of CKD increases
providing inotropic support as needed, and the risk of AKI, while AKI causes CKD or wors-
readjustment of nephrotoxic medications ens prior CKD. Given that the presence of
based on close monitoring of renal function potential CKD may change the correlation of
and drug levels, if available. For CKD patients AKI with adverse outcomes, CKD not only
developing AKI, the basic principles of gen- remains one of the most powerful predictors of
AKI, but also acts as an effective modifier for
AKI and its associated outcomes [1]. In this
chapter, we will review the evidence that CKD
predisposes to AKI, which in turn contribute to
Y. Chen aggravate the preexisting CKD and the evidence
Division of Nephrology, Shanghai Fifth People’s that recovery after AKI to baseline renal func-
Hospital, Fudan University, Shanghai, China tion relates to an increase in the risk of de novo
W. He (*) CKD. In addition, we will focus on the diagnos-
Centre for Kidney Disease, Second Affiliated tic criteria for AKI in patients with CKD, and
Hospital, Nanjing Medical University, the strategy for preventing and managing AKI
e-mail: heweichun@njmu.edu.cn on CKD.

84 Y. Chen and W. He
7.2 Acute Kidney Injury to 7 days originally included in the Acute Dialysis
Quality Initiative’s RIFLE criteria.
7.2.1 Definition and Criteria
7.2.1.2 KDIGO’s Staging Criteria for AKI
AKI, formerly known as acute renal failure, is Using the KDIGO’s criteria, AKI is staged as fol-
characterized by abrupt deterioration of renal lows [2]:
function [2]. A sudden decline in renal function
causes the accumulation of nitrogen-containing • Stage 1—A 1.5–1.9-fold increase in SCr con-
wastes such as urea in the body as well as the centration from baseline, an increase in SCr
disturbance in extracellular fluid volume, electro- concentration by ≥0.3 mg/dL (≥26.5 μmol/L),
lyte, and acid-base. The replacement of the term or a reduction in urine output to <0.5 mL/kg/h
AKI for acute renal failure to a large extent for 6–12 h.
reflects the realization that even a smaller decline • Stage 2—A 2.0–2.9-fold increase in SCr con-
in renal function that does not result in obvious centration from baseline or a reduction in
organ failure has important clinical significance urine output to <0.5 mL/kg/h for ≥12 h.
and is related to an increase in morbidity and • Stage 3—A 3.0-fold increase in SCr concen-
mortality. The definition of AKI used in clinical tration from baseline, an increase in SCr con-
and epidemiologic studies is based on specific centration to ≥4.0 mg/dL (≥353.6 μmol/L), a
criteria that have been sequentially developed, reduction in urine output to <0.3 mL/kg/h for
with the Kidney Disease: Improving Global ≥24 h or anuria for ≥12 h, the initiation of
Outcomes (KDIGO) definition being the most renal replacement therapy (RRT), or in
recent and preferred [3]. Other criteria include patients aged <18 years, a decrease in esti-
the Risk, Injury, Failure, Loss of kidney function, mated glomerular filtration rate (eGFR) to
and End-stage kidney disease (RIFLE) criteria <35 mL/min/1.73 m2.
[4] and its subsequent modification proposed by
the Acute Kidney Injury Network (AKIN) [5] The KDIGO criteria differ from the RIFLE
and others. criteria in that, instead of changes in glomerular
filtration rate (GFR), the KDIGO criteria only
7.2.1.1 KDIGO’s Definition for AKI utilize changes in SCr concentration and urine
The KDIGO guidelines define AKI as follows [3]: output for staging, except for children aged
<18 years for whom an acute decrease in eGFR
1. An increase in serum creatinine (SCr) concen- to <35 mL/min/1.73 m2 is included in the criteria
tration by ≥0.3 mg/dL (≥26.5 μmol/L) within for stage 3 AKI. As with the RIFLE and AKIN
48 h or staging systems, the KDIGO suggested that
2. A ≥1.5-fold increase in SCr concentration patients be classified according to criteria that
from baseline, which is known or presumed to result in the highest (i.e., most severe) stage of
have occurred within the prior 7 days or injury.
3. Urine output <0.5 mL/kg/h for 6 h
The KDIGO criteria allow for correction of 7.2.2 Epidemiology

volume status and obstructive causes of AKI
prior to classification. Before diagnosing and AKI is an important complication of inpatients,
classifying AKI, one should assess and optimize accounting for 15% of all hospitalized patients
volume status and exclude obstruction. The time- according to previous studies. Among more than
frame for the absolute increase in SCr concentra- 3.5 million hospitalized patients in a meta-
tion ≥0.3 mg/dL is retained from the AKIN analysis that included 143 studies, the global inci-
definition (i.e., 48 h), whereas the timeframe for dence rate of AKI, as defined in accordance with
a ≥50% increase in SCr concentration is reverted KDIGO guidelines, was estimated to be 22%, the
7 Acute Kidney Injury and Chronic Kidney Disease 85
equivalent of one in five hospitalized patients [6]. • Selective renal ischemia—Bilateral or unilateral
However, a more recent cross-sectional study per- renal artery stenosis in a solitary functioning kid-
formed in 97 intensive care units (ICUs) from 33 ney is frequently worsened by treatment with
countries and based on data from 1802 patients angiotensin-converting enzyme inhibitor (ACEI)
during their first week of ICU admission reported or angiotensin II receptor blocker (ARB).
a much higher AKI burden. Of enrolled patients, • Drugs affecting glomerular hemodynamics—
57% fulfilled the KDIGO criteria for AKI [7]. Drugs that affect glomerular hemodynamics
AKI is responsible for approximately two mil- can reduce GFR by lowering the intraglomer-
lion deaths worldwide every year [8–10], and it is ular pressure that drives this process. This can
becoming more and more common in critically occur by decreasing either afferent arteriolar
ill patients. The mortality rate of the most severe dilatation (e.g., with nonsteroidal anti-
AKI patients in need of RRT is 50–80% [10]. inflammatory drug [NSAID] or calcineurin
inhibitor) or efferent arteriolar constriction
(e.g., with ACEI or ARB).
7.2.3 Etiology • Nephrotic syndrome—Mostly in adults with
minimal change disease, nephrotic syndrome
The etiology of AKI is not involved in its defini- can lead to AKI. Decreased renal perfusion,
tion, so the diagnosis of AKI is based on its clini- reduced glomerular permeability, and exces-
cal syndrome without considering its sive diuresis are among the mechanisms that
pathogenesis. Nevertheless, determining the may contribute to AKI.
cause of AKI is important for identifying appro-
priate treatment strategies to improve the progno- Hypovolemia is the commonest cause of prer-
sis of patients. In general, the causes of AKI can enal AKI, followed by impairment of intrarenal
be classified into three categories, i.e., prerenal autoregulation which is usually due to NSAIDs
AKI, renal AKI, and postrenal AKI [11–13]. or reduction of cardiac output. When kidney fil-
tration capacity cannot be maintained owing to
7.2.3.1 Causes of Prerenal AKI reduced renal plasma flow and concomitant
Prerenal AKI may result from the following decrease in intraglomerular pressure, the occur-
causes: rence of prerenal AKI is inevitable. Although
prerenal AKI often appears to be recoverable
• True volume depletion—Volume depletion with returning of SCr to baseline level, it may
may be due to gastrointestinal disease (vomit- cause a permanent renal tissue damage.
ing, diarrhea, bleeding); renal losses (diuret-
ics, glucose-induced osmotic diuresis); 7.2.3.2 Causes of Postrenal AKI
cutaneous or respiratory losses (insensible Postrenal AKI is caused by obstruction of the uri-
losses, sweat, burns); and third space seques- nary tract, and the obstruction may occur anywhere
tration (crush injury or skeletal fracture). in the urinary tract. Causes include abdominal or
• Hypotension—Severely reduced blood pres- pelvic cancer, ureteral obstruction owing to kidney
sure may result from shock (hypovolemic, stones, or surgical or post-traumatic ureteral injury,
myocardial, or septic) and posttreatment of neurogenic bladder owing to diabetes, spinal cord
severe hypertension. injury or multiple sclerosis, benign prostatic hyper-
• Edematous states—Heart failure and cirrhosis plasia, and urethral stricture.
may result in marked reductions in kidney One of the initial actions for patients with AKI
perfusion that parallel the severity of the is to exclude urinary outflow obstruction which
underlying disease. The respective mecha- may possibly be relieved by appropriate mea-
nisms are decreased cardiac output in heart sures. If left untreated, obstructive nephropathy
failure and splanchnic venous pooling and may lead to irreversible tubulointerstitial
systemic vasodilation in cirrhosis. fibrosis.
7.2.3.3 Causes of Renal AKI cidofovir, tenofovir, intravenous immunoglobu-

Renal AKI may be associated with nephrotoxic lin, mannitol, hydroxyethyl starch, and synthetic
drugs (e.g., aminoglycoside antibiotic), other cannabinoids. All causes of severe prerenal AKI,
nephrotoxins (e.g., contrast, myoglobin, hemo- particularly if accompanied by hypotension, sur-
globin, light chain), sepsis, local infections, renal gery, and/or sepsis, can lead to ischemic
ischemia, inflammation (e.g., glomerulonephri- ATN. Sepsis-induced ATN is often associated
tis, vasculitis, allergic reactions), or malignant with prerenal factors such as reduced renal perfu-
hypertension. The causes leading to renal AKI sion and systemic hypotension, and other factors,
can usually be classified into three categories including cytokine release and neutrophil activa-
according to the anatomical site involved tion by cytokines, can also contribute.
(Table 7.1) [13]. Among all causes of renal AKI, drugs, con-
Acute tubular necrosis (ATN) is the most com- trast, cardiac surgery, and sepsis are relatively
mon histopathological change among various common. AKI-related drugs include NSAIDs,
pathogenesis of renal AKI. Nephrotoxins, renal several antimicrobial agents, and several chemo-
ischemia, and sepsis are three major causes of therapeutic drugs [17]. The incidence of contrast-
ATN [14–16]. A number of drugs and exogenous induced AKI following coronary angiography is
and endogenous toxins can cause ATN. These about 2.6–13% [18]. Although noncardiac sur-
include aminoglycosides, heme pigments, cispla- gery is deemed to be related to AKI at a lower
tin, radiocontrast media, pentamidine, foscarnet, risk than cardiac surgery [19], one study showed
that 7% developed AKI which was defined as a
>50% increase in SCr levels after noncardiac sur-
Table 7.1 Causes of renal AKI
gery [20]. The incidence of AKI in patients
Tubuli and Nephrotoxins undergoing cardiac surgery ranged from 1 to
interstitium • Contrast
• Medications 50%, relying on the classification of AKI and the
• Hemolysis type of surgery [21]. AKI is common in patients
• Rhabdomyolysis with sepsis, while hospital mortality in septic
• Myeloma shock patients with AKI has almost doubled [22].
Allergic reaction
• NSAID
• Antibiotics
• Proton pump inhibitors 7.2.4 Risk Factors for AKI
• 5-ASA
Ischemia
Sepsis Some patient-specific factors, including old age,
Local infection diabetes, left ventricular systolic dysfunction,
Tumor lysis syndrome dehydration, and CKD, may predispose the
Glomerulus Inflammatory systemic disease patient to develop AKI when exposed to the etiol-
involving kidney
ogy of AKI [2, 23]. Besides these high risk fac-
• Systemic lupus erythematosis
• Systemic vasculitis tors, several conditions that may occur during
Primary glomerulonephritis some particular operations are related to the
Infections with secondary development of AKI. For patients who need
glomerulonephritis
intra-aortic balloon counterpulsation, who need
• Hepatitis B
• Hepatitis C to use cardiopulmonary machines for too long, or
• HIV who need blood transfusion to supplement blood
Vessel Atheroembolic renal disease volume, the risk of developing AKI is signifi-
Renal vein thrombosis cantly increased [24]. When patients with CKD
Thrombotic microangiopathy
Antiphospholipid syndrome encounter with any cause of AKI, they are prone
NSAID nonsteroidal anti-inflammatory drug; 5-ASA
to progress to a more serious AKI requiring RRT,
5-aminosalicylic acid; HIV human immunodeficiency and they are also more likely to deteriorate to
virus end-stage renal disease (ESRD) [25].
For preventing the development of AKI, espe- [30]. The relationship between baseline renal
cially in patients with CKD, estimating and identi- function and the occurrence of AKI was
fying patients who may be at high risk before assessed in one study and the findings dis-
exposure to potential nephrotoxic drugs or other played that patients with eGFR <30 mL/
nephrotoxins or before surgery is of great min/1.73m2 were 18 times more likely to
importance. develop AKI than those with eGFR >60 mL/
min/1.73 m2, which suggested that the inci-
dence of AKI evidently increased following
7.3 Bidirectional Relationship the decline of baseline eGFR [31].
Between AKI and CKD
7.3.1.2 CKD Worsens Renal Outcome
7.3.1 E
ffect of CKD on Development After AKI
or Outcome of AKI Some studies have shown that AKI-related attri-
butional mortality is higher in patients with CKD
7.3.1.1 CKD Is a Potent Risk Factor than in those with normal renal function.
for AKI Actually, not only does the risk of AKI increase
It can be predicted that the decrease of renal significantly in patients with CKD, but the exis-
mass and nephron number, vascular insuffi- tence of CKD does alter or, rather, increase the
ciency, and reduced tissue repair ability in correlation between AKI and its adverse out-
patients with CKD may decrease the renal comes. Observational studies have also found
homeostasis under the action of acute stressor, that renal function in patients with CKD after an
thus making this population more vulnerable to episode of dialysis-requiring AKI is less likely to
the influence of AKI. Almost all AKI risk pre- return to baseline levels than that in those with-
diction scores have confirmed that CKD is one out CKD [1].
of the strongest risk factors for AKI, which has A study enrolled 48 patients initiating dialysis
been proved in many large retrospective cohort for AKI showed that the survivors with preexist-
studies. ing CKD were more likely to be dialysis-
The proportion of preexisting CKD has dependent at 90 days (50% vs. 11% of those
been 30–35% in most studies on AKI in hospi- without preexisting CKD) [16]. Similar findings
talized patients [10, 26–29] but as high as 75% were noted in a review of 299 critically ill patients
in one large series [15]. An analysis showed with dialysis-requiring AKI, 102 of whom had
that the risk of developing dialysis-requiring underlying CKD. Among survivors, the rate of
AKI increased from twofold in patients with dialysis dependence at hospital discharge was
CKD whose baseline estimated GFR (eGFR) higher in those with underlying CKD (34%) than
was in stage 3a to 40-fold in those with CKD in those without CKD (5%) [29]. A stratified
whose baseline eGFR was in stage 5 when analysis of postdischarge outcomes of inpatients
compared with the risk in control patients with with medical insurance showed that AKI patients
baseline eGFR ≥60 mL/min/1.73 m2, which with prior CKD had a 41-fold increased risk of
suggested that CKD is a potent predictor of developing ESRD, while patients with AKI alone
dialysis-requiring AKI in hospitalized patients had a 13-fold increased risk of progression to
[15]. This study was also the first to report that ESRD [32]. Another analysis displayed that indi-
proteinuria is a strong risk factor for AKI [15]. viduals with a baseline eGFR <30 mL/
Another analysis of data from a CKD cohort min/1.73 m2 and severe AKI had a 4.71-fold
with an eGFR <30 mL/min/1.73m2 showed increase in the risk of long-term outcome of
that, within a median 19-month follow- up, ESRD or death, which suggested that there is a
44.9% of patients had, at least once, an epi- consistent and graded relationship between both
sode of AKI which is defined as a 25% baseline eGFR and severity of AKI and long-
decrease in eGFR over a period of 25 days term adverse outcomes [31].
7.3.2 E
ffect of AKI on Onset or Several reports suggest that an episode of AKI
Progression of CKD is related to an elevated hazard for CKD even
among patients without any detectable kidney
Numerous studies have linked AKI to occurrence disease. For example, 1610 patients enrolled in a
and progression of CKD. Indeed, in AKI survi- cohort study developed AKI during hospitaliza-
vors, the duration, severity, and recovery of AKI tion and their kidney functions were normal
are related to the subsequent development of de before AKI. Their kidney functions recovered to
novo CKD or deterioration of underlying CKD, at least 90% of the baseline levels within 3 months
and a growing body of evidence have confirmed after the onset of AKI, and in 81% of these
the influence of AKI on CKD. Furthermore, patients, the kidney function recovered to pre-
patients with CKD who develop AKI are more AKI levels within 4 days. However, compared
likely to progress to ESRD than those who never with matched control patients who didn’t develop
have an AKI episode. The KDIGO clinical prac- AKI, patients were more prone to develop CKD
tice guideline on AKI recommended the evalua- at 3.3 years after the episode of AKI [36]. In
tion of patients by clinicians at 3 months after another cohort study, 3809 patients with AKI and
AKI for resolution, new onset, or worsening of normal pre-AKI kidney function were observed,
preexisting CKD [3]. and it was found that AKI had a correlation with
a high risk of CKD at 2.5 years in these patients
7.3.2.1 AKI Increases the Risk of Both [37].
De Novo CKD and Deterioration
of Underlying CKD 7.3.2.2 Factors Affecting Effect of AKI
A population-based matched cohort study that on Onset or Progression of CKD
included 3769 patients with dialysis-requiring • Effect of AKI severity on onset or progres-
AKI who survived free of dialysis for at least sion of CKD
30 days after discharge reported a 3.2-fold • In a population-based cohort study, patients
increase in the risk of incidence of chronic dialy- who developed reversible AKI, i.e., whose
sis [33]. An analysis of matched data obtained renal function recovered to more than 75% of
from US Medicare beneficiary claims and the US baseline, had better clinical outcomes than
Renal Data System showed that patients aged those with irreversible AKI. Compared to
67 years or older who developed AKI were 6.7 patients with reversible AKI, the irreversible
times more likely to develop ESRD at 2 years group had a 1.26-fold increase in the risk of
after discharge than those without AKI. Patients death and a 4.13-fold increase in the risk of
with a history of CKD who developed AKI had a composite renal outcomes which included
41-fold increase in the risk of ESRD [32]. In an doubling of SCr level and ESRD [38].
analysis that compared 36,980 patients admitted • Several studies linked dialysis-requiring AKI
to a US Department of Veterans Affairs facility to progression of CKD. Dialysis-requiring
between 1999 and 2005 with patients admitted AKI means that AKI is so severe that RRT is
with myocardial infarction (MI) alone, those indispensable, and the “dialysis” in this phrase
admitted with AKI or AKI plus MI had a 2.07- refers to various acute RRT modalities, e.g.,
fold or 2.30-fold increase in the risk of having an continuous RRT, peritoneal dialysis, or inter-
adverse kidney outcome (defined as a >25% mittent hemodialysis. In an analysis of
decline in eGFR, need for long-term dialysis, or information from a large integrated healthcare
death) at a maximum of 6 years of follow-up, delivery system concerning patients with
respectively [34]. A meta-analysis that included baseline eGFR ≥45 mL/min/1.73 m2 who
13 cohort studies showed an 8.8-fold and 3.1-fold underwent an episode of dialysis-requiring
increase in the risk of developing CKD and AKI and recovered to be released from RRT at
ESRD in patients who developed AKI than in one month after hospital discharge, an associ-
those who did not, respectively [35]. ation between a 28-fold higher risk of deterio-
rating stage 4 or 5 CKD and the previous Affairs healthcare system. The findings showed
dialysis-requiring AKI was observed [14]. a 3.6-fold increase in the risk of stage 4 CKD in
Another analysis of data from the same sys- patients with one episode of AKI, compared to
tem showed a 47% higher risk of ESRD in the patients without AKI. In addition, for every
following 30 days after discharge in patients additional episode of AKI, this risk increased
with underlying CKD (baseline eGFR by an extra double [43]. These observations
<45 mL/min/1.73 m2) who went through further increase the likelihood of the phenom-
dialysis-requiring AKI, comparing to CKD enon observed in other studies, that is,
patients with same level of baseline eGFR repeated episodes of AKI promote the pro-
who did not have AKI [41]. gression of CKD, which is characterized by a
• In one study enrolled in children with AKI in no-linear decline in kidney function [45–48].
ICU who developed subsequent CKD that was Nowadays, it has been generally accepted that
defined as albuminuria or eGFR <60 mL/ the progression of CKD isn’t at a constant rate
min/1.73 m2, incidence of CKD elevated from with a nonlinear trajectory of decline in eGFR.
5% in patients with AKIN stage 1 AKI (defined • Reversible AKI is associated with a risk of
as an increase in SCr concentration by ≥50% developing CKD
or by ≥0.3 mg/dL from baseline) to 17% in • An analysis of data from a large integrated
patients with stage 3 AKI (defined as a ≥3-fold healthcare delivery system in Central
increase in SCr concentration from baseline, Pennsylvania suggested that an increase in the
an increase in SCr concentration to ≥4 mg/dL risk of subsequent CKD development was
with an absolute increase by 0.5 mg/dL, or even correlation with reversible AKI, which
requirement for RRT) in the following was defined as that the increase in SCr levels
1–3 years after AKI. It suggested that an fall back to within no more than 10% of base-
increase of CKD incidence was closely related line values in the following 3 months after AKI
to the grading of previous AKI [49]. in patients without CKD at baseline. The inci-
• An analysis of data from the Department of dence of CKD in the patients who suffered
Veterans Affairs healthcare system presented from reversible AKI was 1.9-fold higher than
that the increase in the severity of AKI at each that in matched controls who did not experi-
stage (based on the RIFLE criteria) was asso- ence AKI [51]. In another study, data from a
ciated with a 4.4-fold increase in odds ratio of large integrated healthcare delivery system in
progressing stage 4 or 5 CKD. In addition, Utah was analyzed and it was found that AKI
dialysis-requiring AKI alone was related to a with almost complete renal function recovery
53-fold increase in odds ratio of progressing which was defined as that the return of SCr
stage 4 or 5 CKD. These results demonstrated values is less than 1.1 times of the baseline val-
that the severity of AKI could be used as a risk ues was significantly related to the incident of
stratification factor for CKD progression [50]. stage 3 CKD. At a median follow-up of
• Cumulative effect of repeated AKI episodes 30 months, the incidence of CKD was 15% in
on progression of CKD individuals with recovery AKI, showing a 3.8-
• According to a study focusing on recurrent AKI fold increase in the risk of CKD development
which was defined as one episode of AKI hap- compared to the risk in individuals who did not
pened again in the following 12 months after a experience AKI [37]. The analysis of Veterans
previous AKI, the prevalence rate of recurrent Health Administration data revealed that even
AKI was 25% [44]. Although most studies paid the individual experienced stage 1 AKI accord-
more attention to the consequence of one epi- ing to KDIGO criteria with quick recovery
sode of AKI for the risk of CKD, the effects of which was defined as the return of SCr levels
multiple episodes of AKI on the progression of from peak to no more than 0.3 mg/dL above
CKD were analyzed in patients with diabetes baseline values within 48 h had a 1.4-fold
mellitus from the US Department of Veterans increase in the risk of CKD development [52].
• CKD is one of possible factors leading to 7.4 KI on CKD (Also Applicable

A
irreversible AKI to AKI Alone)
• Several studies suggested that the decline of
renal function owing to AKI was more pos- 7.4.1 Diagnosis
sible to be irreversible in patients with lower
baseline GFR, old age, heart failure, hyper- As mentioned above, AKI is a powerful accelera-
tension, or hypoalbuminemia [36, 39]. An tor to push forward the progression of CKD. For
analysis of data from 281 patients who patients with CKD, it is important to make a diag-
developed in-hospital dialysis-requiring nosis in time when AKI occurs. When AKI occurs,
AKI and continued outpatient dialysis after however, patients rarely develop symptoms and
discharge showed that renal function signs owing to AKI, and symptoms and signs are
returned at a median of 8 months in 52 more likely to be related to underlying causes
(19%) patients, in which most (94%) exhib- than AKI itself. Therefore, examination and treat-
ited recovery within 6 months. The findings ment should depend on the clinical background
suggested that ATN secondary to surgery or and underlying causes (see “common causes of
sepsis and higher level of baseline eGFR AKI” in this chapter). In addition to the condition
were two independent factors for predicting of CKD, other medical histories, including expo-
recovery of renal function while heart fail- sure to nephrotoxic drugs and other nephrotoxins,
ure independently predicted no recovery should be reviewed in detail. Obstruction of any
within 6 months after AKI. The first RRT in part of the urinary tract should be excluded ini-
ICU and catheter access for dialysis were tially. Ultrasound should be performed to exam-
not independent predictors. Even with a ine the size of bilateral kidneys, and the length of
higher level of baseline eGFR, the decline kidneys <8 cm may indicate CKD rather than
of renal function in patients with heart fail- AKI, but does not rule out AKI-on-CKD [11].
ure who developed AKI was more prone to Blood samples should be collected for analyz-
be irreversible [40]. ing SCr, electrolytes, standard bicarbonate, blood
• Proteinuria aggravates the effect of AKI on cell count, and serum albumin. Dipstick urine
the progression of CKD analysis and analysis of urine sediment should be
• In addition to eGFR, proteinuria is also an used routinely to investigate the AKI causes.
important parameter reflecting the severity of Urine volume should be regularly measured as
CKD. The relationship between baseline oliguria and anuria is common in patients with
eGFR, proteinuria, and AKI was studied in a AKI, and urine volume is an earlier marker of the
large database of nearly one million adults in progression in AKI than level of SCr [2]. For
Alberta, Canada. The results of observation patients with CKD, the diagnosis of AKI com-
showed that a higher risk of AKI was corre- plies with the KDIGO criteria. Meanwhile, deter-
lated with the lower levels of baseline eGFR mination of the cause of AKI is essential. The
and the higher levels of urinary protein excre- activity or rapid progression of the primary cause
tion, and the further analysis revealed that of CKD should also be taken into account.
massive proteinuria could serve as a predic-
tor for long-term prognosis of kidney, e.g., 7.4.1.1 Differential Diagnosis Between
doubling of SCr levels or ESRD, after an Prerenal and Renal AKI
AKI episode. These studies confirmed that In some patients, prerenal and renal AKI need be
the effects of an AKI episode on the long- distinguished. There are three major diagnostic
term decline in kidney function at all levels approaches that, in the appropriate clinical set-
of baseline eGFR can be aggravated by pro- ting, are used to distinguish prerenal disease from
teinuria [42]. ATN and other causes of renal AKI:
1. Urinalysis. 7.4.2 Biomarkers of Kidney Injury

2. Fractional excretion of sodium and, to a lesser
degree, urinary sodium concentration. The It is assumed that delayed detection of AKI is one
fractional excretion of urea may be helpful in of the reasons for the failure of intervention trials
patients being treated with diuretics. designed to treat AKI. Hence, kidney injury bio-
3. Response to fluid repletion in patients with markers for early detection of the clinical process
evidence of volume depletion, which is the of AKI and for predicting the need of dialysis or
gold standard for the diagnosis of prerenal other complications before the changes of the
disease. This does not apply to prerenal dis- functional biomarkers (i.e., SCr) have been
ease due to heart failure (cardiorenal syn- searching by a lot of efforts. These biomarkers
drome) or cirrhosis (hepatorenal syndrome). including kidney injury molecule 1 (KIM-1),
neutrophil gelatinase associated lipocalin
Other parameters that may be helpful in (NGAL), liver-type fatty acid-binding protein
selected patients include the following: blood urea (l-FABP), interleukin 18 (IL-18), insulin-like
nitrogen/SCr ratio, rate of increase in SCr concen- growth factor binding protein 7 (IGFBP-7), and
tration, urine osmolality, and urine volume. tissue inhibitor of metalloproteinase-2 (TIMP-2)
In patients with prerenal AKI due to cardiore- can provide information about tubular damage,
nal syndrome or abdominal compartment syn- usually before renal function declines.
drome, definitive diagnosis should be established The well-studied biomarkers are listed as
through cardiac functional evaluation (e.g., echo- below:
cardiography, invasive hemodynamic monitoring)
or bladder pressure transduction, respectively. • l-FABP—After ischemic injury, the expres-
sion of l-FABP was induced in renal proximal
7.4.1.2 Concurrent of Prerenal tubules. One hour after injury, the amount of
and Renal AKI this protein in urine increases to detectable
Prerenal and renal AKI often overlap in many levels, reaching a peak 6 h after AKI [55].
patients. Concomitant prerenal and renal AKI • NGAL—An enzyme that can activate protec-
may occur in patients with rhabdomyolysis, tive enzymes and prevent production of
hypercalcemia, or sepsis, and may also be oxygen-free radicals is released from dam-
observed in patients after cardiac surgery. aged proximal and distal tubular cells after
Rhabdomyolysis is usually related to hypovole- kidney injury. The neutrophils and liver cells
mia which may result in prerenal AKI, mean- in septic patients also release this enzyme. It
while, myoglobin and heme proteins may induce can be detected in urine and serum 3 h after
intraluminal cast formation and tubular obstruc- AKI, reaching a peak 6 h after AKI [56].
tion, which is the direct toxic effects on the kid- • IL-18—A pro-inflammatory cytokine that is
ney. Hypercalcemia is also a disorder which may upregulated in proximal tubule after ischemic
cause both prerenal and renal AKI owing to the AKI. It is detectable in urine and serum 6 h
severe hypovolemia and the simultaneously after AKI and peaks 12–18 h after AKI [57].
nephrotoxicity of calcium [53]. The causes of • IGFBP-7 and TIMP-2—Both proteins can
AKI in sepsis are multifactorial, which include induce G1 cell cycle arrest in G1 phase,
hypotension, activation of sympathetic nerves thus preventing endothelial cells prolifera-
system, and mediating effects of hormones and tion. They are detectable in urine 12 h after
inflammatory factors [54]. The causes of AKI AKI [58].
after cardiac surgery are usually ischemia, hypo- • KIM-1—A protein produced by proximal
tension, embolism, inflammation, and free hemo- tubular cells after injury can activate immune
globin in blood transfusions. cells resulting in elimination and reconstruct-
ing of damaged tubule. It is detectable in urine Because nephrotoxic drugs is an important

12–24 h after AKI and peaks 48–72 h after risk factor for AKI, monitoring the SCr concen-
AKI [59]. tration (i.e., renal function evaluation) and drug
level (if possible) is important, as it enables
appropriate adjustment of drug dosing based on
7.4.3 Prevention the knowledge of altered pharmacokinetics in
early AKI. In addition, clinicians should monitor
For patients with CKD, measures for the preven- drug efficacy and toxicity.
tion of AKI are similar to that for general popula-
tion or patients with non-CKD. Nonetheless,
patients with CKD are susceptible to the damage 7.4.4 Treatment and Management
which may lead to AKI, preventive measures
should be particularly emphasized. General pre- 7.4.4.1 General Principles
ventive measures are as follows: The main purpose of treatment for AKI is to limit
the continuous damage and block the further
1. Fluid administration in some situations, such decline in renal function. For patients who
as hypovolemia, tumor lysis syndrome, or develop AKI on the basis of CKD, the strategy of
hemoglobinuria. treatment complies with the general principles
2. Prevention of hypotension by providing ino- for patients with AKI and includes the
tropic support following adequate volume following:
repletion.
3. Readjustment of nephrotoxic medications
• Specific treatment of the underlying cause.
based on close monitoring of renal function • Fluid management.
and drug levels. • Electrolyte management.
• Acid-base balance adjustment.
Fluid administration in the following situa- • Drug dosing adjustment.
tions may effectively prevent renal AKI: • RRT.
• Nutritional support.
• Prerenal AKI due to hypovolemia—For patients • Specific pharmacologic therapies.
with a history and physical findings consistent
with hypovolemia, administration of an intrave- These are several key principles that should be
nous (IV) fluid bolus with normal saline (10– followed, the most important of which is etio-
20 mL/kg over 30 min) may prevent more logical treatment and maintenance of normal
severe renal AKI and can be repeated twice, if blood volume and stability of hemodynamics.
necessary, until urine output is re-established. Furthermore, it is necessary to correct the elec-
Fluid challenge is contraindicated for patients trolyte disorders, to stop the use of nephrotoxic
with obvious volume overload or heart failure. drugs or to adjust the dosage, and to adjust the
• Patients at risk of AKI—Volume expansion dosage of the drugs excreted through the kidney
with IV normal saline is effective in prevent- accordingly. In order to prevent the deterioration
ing AKI in patients at risk of AKI with the fol- of AKI and the occurrence of hyperkalemia, the
lowing conditions: hemoglobinuria and use of potassium-sparing diuretics and ACEIs or
myoglobinuria; administration of potential ARBs need to be stopped. In addition, acid-base
nephrotoxins including aminoglycosides, imbalances need to be corrected. The main type
amphotericin B, radiocontrast media, cispla- of acid-base imbalances is metabolic acidosis,
tin, and IV acyclovir; tumor lysis syndrome; which is more common in patients with stage 2
surgical procedures in which the intravascular and stage 3 AKI. For all patients with AKI, moni-
volume is reduced during either the intraop- toring urine volume and SCr several times per
erative or postoperative period. day is the essential measure of management [11].
7.4.4.2 Hemodynamic Optimization • Optimization—When the patient’s hemo-

1. Fluid management dynamics is stable, the fluid is carefully
For all patients who suspect that hypovole- given to maintain hemodynamic
mia is the main etiology of AKI, the most stability.
urgent task is to regain fluid balance for • Stabilization—When the patient is in a sta-
increasing cardiac output, stabilizing hemo- ble state, the goal is zero or negative fluid
dynamics, and maintaining adequate renal balance.
blood flow without causing fluid overload. In • De-escalation—In the de-escalation phase,
clinical practice, the evaluation of patients’ the excess fluid should be removed.
hydration status is difficult. Recently, several 4 . Vasoactive drugs
methods such as measuring bioimpedance Vasoactive drugs can cause systemic vaso-
and assessing the size of vena cava and left constriction and elevated blood pressure,
ventricle by ultrasound have been utilized. which may lead to increased renal perfusion.
Rehydration rate should be evaluated indi- Proper dose of norepinephrine can reduce the
vidually [60, 61]. risk of AKI in patients with vasodilation
2. Types of rehydration liquid shock. In patients with vasogenic shock after
It is considered that high concentration of cardiac surgery, increased mean arterial pres-
chloride at macula densa increases the tubulo- sure (MAP) by norepinephrine led to eleva-
glomerular feedback, resulting in the constriction of GFR and increased renal oxygen
tion of afferent glomerular anteriole and the delivery [66]. A higher MAP with norepi-
decrease of renal perfusion. One study found nephrine has also been shown to reduce the
that high chloride crystal solutions may dam- requirement for dialysis in septic patients
age the kidneys and worsen renal function [67]. As a drug that can also increase blood
[62]. A meta-analysis displayed a link between pressure, vasopressin is usually used as a
resuscitation and liquids containing high chlo- second-line drug in combination with nor-
ride, with an increase in the risk of AKI, meta- adrenaline for stabilizing hemodynamics
bolic acidosis, and time on mechanical [68]. As a calcium sensitizer, levosimendan
ventilation [63]. Conversely, a randomized can improve right ventricular function, reduce
trial in an intensive care environment showed central venous pressure, and decrease renal
that there was no difference in the risk of AKI venous congestion. In addition, levosimendan
or dialysis in patients between treated with can dilate afferent glomerular arterioles and
balanced crystal solutions and saline [64]. In improve renal circulation [69]. The current
spite of this controversy, the use of balanced recommendation is not to use dopamine in
crystal solutions as a rehydration liquid for patients with AKI.
patients with AKI is still recommended.
3. Prevent fluid overload 7.4.4.3 Drug Treatment for AKI
Fluid overload may cause increased intra- Several drugs such as acetylcysteine, diuretics,
abdominal pressure and kidney edema, while sodium bicarbonate, and statins have been tested
the kidney is surrounded by a nonexpansive for treatment of AKI; however, none of them has
fibrous capsule, which may reduce renal per- been determined as standard treatment in clinical
fusion pressure. For preventing fluid overload, practice because the results from different studies
the Acute Dialysis Quality Initiative proposed have been inconsistent. Among these drugs,
a new fluid resuscitation strategy, which con- although it is difficult to reach a clear consensus
sists of four phases: rescue, optimization, sta- due to the heterogeneity of study results, the
bilization, and de-escalation phases [65]. KDIGO group has recommended that oral acetyl-
• Rescue—A large amount of fluid is given cysteine combining with intravenous isotonic
under life-threatening hemodynamic crystalloid solutions should be used in patients at
instability. high risk of contrast-induced AKI [70].
7.4.4.4 Indications for RRT events have explored that AKI and CKD contrib-
With regard to the timing of the start of RRT, cur- utes to each other. For improving the outcomes of
rent recommendations include life-threatening patients, identification of potential best opportuni-
fluid imbalances, electrolyte and acid-base disor- ties for intervention is essential, which requires
ders, or uremic complications [2]. Generally, rigorous epidemiological studies to discern the
RRT is required when patients with AKI develop weights of these interrelated components.
the following indications:
• Fluid overload refractory to diuretics.

• Hyperkalemia (serum potassium
level >6.5 mEq/L) or rapid increase in potas- Key Messages
sium levels refractory to medical therapy. • The proposed criteria for AKI include an
• Metabolic acidosis (pH <7.1) in patients with increase in SCr level by ≥0.3 mg/dL
contraindications for bicarbonate administra- (26.5 μmol/L) within 48 h; a ≥1.5-fold
tion, such as those with volume overload (who increase in SCr level from baseline, which
would not tolerate the required sodium load) is known or presumed to have occurred
or those with lactic acidosis or ketoacidosis, in within the prior 7 days; or a decrease in
whom bicarbonate administration has not urine volume to <0.5 mL/kg/h over 6 h.
been shown to be effective. • Many observations have indicated that
• Signs of uremia, including pericarditis, neu- CKD is a potent risk factor for AKI and
ropathy, or an otherwise unexplained decline a modifier for outcome of AKI, whereas
in mental status. AKI is a trigger of development and
progression of CKD. Patients should be
It should be pointed out that the benefits of evaluated at 3 months after AKI for res-
early compared with late initiation of RRT have olution, new onset, or worsening of pre-
still been controversial, in which early initiation existing CKD.
of RRT means that treatment of RRT is started • For CKD patients at high risk for devel-
before life-threatening complications occur. oping AKI, preventive measures for
Although the best initiation time for RRT has AKI include adequate fluid repletion in
not been obtained from the data accumulated those with hypovolemia, avoidance of
from different observational studies and clinical hypotension by providing inotropic sup-
trials, the results from several recent random- port as needed, and readjustment of
ized clinical trials have displayed that the mor- nephrotoxic medications based on close
tality, length of hospitalization and duration of monitoring of renal function and drug
RRT were reduced in critically ill patients with levels, if available.
AKI performed early starting continuous RRT • For patients with CKD, it is important to
compared to those in patients with late initiation make a diagnosis in time when AKI occurs.
of RRT [11]. In addition to the condition of CKD, other
medical histories, including exposure to
nephrotoxic drugs and other nephrotoxins,
7.5 Summary should be reviewed in detail.
• For CKD patients developing AKI, the
Over the past decade, we have made great progress basic principles of general management
in comprehending the relationship between AKI include specific treatment of the underly-
and CKD, but there is still a lot of work to be done. ing cause, fluid management, electrolyte
It has been believed that AKI is a trigger of devel- management, adjustment of drug dosing,
opment and progression of CKD, while CKD is a nutritional support, renal replacement ther-
potent risk factor for AKI. Observations focusing apy, and specific pharmacologic therapies.
on the correlation between these two clinical
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Int. 2016;90:100–8.
Advanced Image Techniques
in Chronic Kidney Disease 8
Zhuo Xu

Chronic kidney disease (CKD) is increasingly
recognized as a global public health problem. Chronic kidney disease (CKD) is increasingly
How to accurate assessment this irreversible recognized as a global public health problem, and
disease process is a key point for the second- affects more than 10% of the population world-
ary treatment. Over the past decade, applica- wide [1]. CKD progression to end-stage renal
tions of novel image methods provide disease (ESRD), which requires dialysis, is still
noninvasive, reliable, quantitative data of considered irreversible, although many anti-
renal perfusion, glomerular filtration, intersti- fibrotic agents are in various stages of clinical tri-
tial diffusion, and the degree of renal fibrosis. als [2]. Thus, detection, monitoring, and
Moreover, these techniques also offer patho- prediction of the disease process are key points
physiologic data such as energy dys- for early intervention and prevention of subse-
metabolism in the initial disease stage. This quent development of renal dysfunction.
chapter reviews advanced applications of the In progressive CKD, common pathological
image techniques including ultrasound-based changes include parenchyma capillary rarefac-
techniques, multi-detector computed tomog- tion, reduction of microvascular blood flow,
raphy, magnetic resonance imaging, and reduction of glomerular filtration rate (GFR), and
nuclear-based techniques in CKD. The knowl- tubulointerstitial injury. Renal fibrosis is the
edge of the applications, advantages, and dis- common pathway for progression of CKD, which
advantages of these techniques could open a leads to increased tissue stiffness and eventually
framework for nephrologists to make informed reduction in size. Tissue hypoxia is an additional
decisions in clinical practice. However, there characteristic of CKD, which can initiate and
remains a gap between theoretical studies and promote kidney injury.
clinical applications. Standard protocol and Percutaneous renal biopsy and radionuclide
generic analysis model are needed for large- imaging are the gold standards for assessment of
scale clinical application in the future. renal morphology and function. However, the
biopsy is an invasive examination with signifi-
cant clinical risks, such as bleeding [3]; thus, it
cannot be used repeatedly. Additionally, kidney
lesions are often heterogeneously distributed,
Z. Xu (*) whereas tissues for renal biopsy analysis are
Centre for Kidney Disease, Second Affiliated approximately 2 mm in diameter (<1% of one
Nanjing, Jiangsu, China kidney); this approach is inherently subject to

100 Z. Xu
sampling bias. Nuclear medicine-based tech- 8.2.2 Color-Doppler Ultrasound

niques are further limited by the radioisotope
exposure of the contrast agents injected, and time Renal resistive index (RRI) is measured by the
is required for the excretion of radioisotopes Doppler spectrum of intrarenal vessels (typically
from the body. segmental or interlobar arteries), defined as the
Recently, new imaging technologies that can peak systolic (PS) and end-diastolic (ED) blood
provide noninvasive, reliable, quantitative data velocities divided by the peak systolic velocity
regarding morphologic structural information (PSV). In adults, RRI typically ranges from 0.47
and signal-kidney function to quantify the pro- to 0.70.
gression of CKD are expanding in terms of appli- Initially, RRI was used to assess intrarenal
cations, both in research and in clinical contexts; vascular resistance; accumulating evidence has
thus far, most approaches remain experimental. shown that RRI >0.75 is an indicator for both the
onset and progress of renal damage. Notably, a
value >0.8 indicates irreversible damage in
8.2 Ultrasound (US)-Based CKD. The causative mechanism for increased
Techniques RRI remains unknown; however, it is generally
accepted that the interaction of interstitial fibrosis
US-based techniques play a key role in the diag- with post-glomerular vessels could increase
nosis of CKD. A complete ultrasonic examina- resistance to renal cortical blood flow and reduce
tion involves assessing structure, vascularization glomerular perfusion [6, 7].
(both extrarenal and intrarenal), and functional Recently, it has been suggested that systemic
changes in kidneys. These techniques are conve- (e.g., pulse pressure) influences the predictive
nient, uniquely real-time in nature, and exhibit role of RRI. In younger hypertensive people with
good repeatability; thus, they remain first-line normal renal function and no sign of albumin-
techniques to assess and monitor progressive kid- uria, RRI is an early marker of renal damage.
ney injuries. Conversely, in older subjects, the predictive abil-
ity of RRI is weak, as it is influenced by systemic
vascular stiffness [8]. However, the importance
8.2.1 B-Mode Ultrasound of RRI requires a long-term clinical follow-up
study [9].
Until recently, B-mode US has been the most
widely used approach to clinically evaluate the
morphological changes of CKD. In this tech- 8.2.3 Contrast-Enhanced
nique, maximum renal diameter and cortical Ultrasound (CEUS)
thickness are the most valuable parameters. Many
studies have shown relationships between these In CEUS, by using contrast agents as red blood
parameters and deterioration of renal function cell tracers, continuous imaging of the vascula-
(reduction of GFR) [4]. Recently, renal volume ture and blood flow can be achieved; a time-
was measured in vivo by three-dimensional dependent intensity curve is generated with
(3D)-ultrasound, and direct correlations were respect to selected regions of interest (ROI) in the
found between this volume and both functional renal cortex and medulla, in order to calculate
nephrons and GFR [5]. Moreover, the volume several perfusion parameters, including peak
measured by US is similar to the actual size mea- intensity (PI), rise time (RT), time to peak (TTP),
sured intraoperatively. However, ultrasound- mean transit time (MTT), and area under the
detected morphological changes are often visible curve (AUC).
in late stages of disease, so this approach is lim- Conventional applications of CEUS for diag-
ited in its ability to monitor and predict CKD in nosis are limited to parenchymal masses, espe-
early stages. cially to differential diagnosis of benign and
8 Advanced Image Techniques in Chronic Kidney Disease 101
malignant diseases [10]. Due to the excellent spa- qualitative tissue stiffness might be obtained by
tial resolution that enables it to detect slower flow comparing two US acquisitions before and after
in smaller blood vessels, CUES recently began to compression. It is broadly accepted that cortical
be used in studies of renal microvascular perfu- elasticity values are higher than medullary values
sion and renal blood flow (RBF) in healthy indi- in healthy kidney, and that these values vary with
viduals, as well as in patients with various kidney age. However, no reference values for normal
diseases, including CKD (especially in patients renal elasticity have been reported thus far [16].
with diabetes) [11]. US elastography has been demonstrated in liver
In normal kidneys, CEUS-derived RBF fibrosis; in kidney diseases, this approach has
parameters have been reported to exhibit a good found value primarily in differential diagnosis of
correlation with those obtained by para- renal masses. In transplanted kidneys, several
aminohippurate, which is a gold standard for limited studies have shown a moderate correla-
RBF [12]. Notably, CEUS can correctly validate tion between renal stiffness, quantified by US,
renal perfusion following pharmacologic inter- and the degree of interstitial fibrosis [17, 18].
vention, such as with angiotensin II, captopril, However, data regarding this novel US tech-
noradrenaline, and dopamine [13, 14]. nique in CKD are rare and preclinical. Kidney
In CKD, perfusion parameters obtained by stiffness is not solely related to fibrosis. The fill-
CEUS (e.g., PI, RT, and AUC) have shown differ- ing pressure of the renal collecting system, the
ences with respect to measurements in healthy ratio of arterial to venous blood flow, and other
controls; of note, this change exists in early dis- mechanical and functional parameters can also
ease stages (CKD stages 1–2). Another exciting influence the degree of stiffness, making data
finding involves DKD cases without reductions analysis quite complex. In addition, a variety of
in GFR (CKD stage 1): CEUS-derived parame- technical factors (e.g., operator experience;
ters change with respect to urinary microalbu- patient state, such as obesity; direction of the
min/creatinine, which is an early biomarker for sound wave with respect to the kidney; and depth
DKD, indicating that CEUS offers great potential that the US wave can reach, typically <5 cm)
for both monitoring and prediction of disease affect the elasticity values and increase the diffi-
processes [15]. culty in obtaining stable and reproducible data.
Compared with other imaging techniques for
hemodynamic abnormalities, the greatest advan-
tages of CEUS are its high degree of safety, renal 8.3 Multi-Detector Computed
tolerance, and lack of radiation. The fundamental Tomography (MDCT)
compositions of contrast agents used in this
approach are microbubbles comprising gases The utility of CT in CKD is limited and contro-
embedded within a shell; because these exhibit versial. Recently, some small, single-center stud-
no known nephrotoxicity, CEUS is safe for regu- ies showed that unenhanced MDCT could
lar use in patients with CKD at any stages. estimate renal volume (both cortical and medul-
Although it lacks systematic evaluation and mul- lary) in CKD cases, and found a moderately posi-
ticenter, large-scale clinical trials involving dif- tive correlation between renal volume and GFR
fuse renal lesions, CEUS has a great advantage in as measured by the serum creatinine level; this
its ability to assess renal perfusion, as well as to suggests that MDCT can serve as a surrogate
monitor and assess the progression of CKD. marker for the assessment and monitoring of
renal function.
Contrast-enhanced MDCT can provide nonin-
8.2.4 Ultrasound Elastography vasive, standardized, quantitative measurements
of single-kidney or global hemodynamics data
The intrarenal shear-wave velocity varies with (e.g., regional renal perfusion, RBF, and GFR).
external mechanical wave pressure. In theory, In this technique, by administering exogenous
102 Z. Xu
Fig. 8.1 Clinical usage

of magnetic resonance Magnetic Resonance Imaging
imaging. DCE dynamic
contrast-enhanced; ASL
arterial spin labeling;
DWI diffusion-weighted
imaging; DTI diffusion
tensor imaging; BOLD 31P
DCE ASL DWI DTI BOLD MRE MR
blood oxygen level-
dependent; MRE
magnetic resonance
elastography; P MR P
magnetic resonance Perfusion Microstructure and Fibrotic Energy
spectroscopy; GBCA and GFR Perfusion Hypoxia and
spatial organization metabolism
gadolinium-based with stiffness
contrast agents GBCA
iodine contrast agents, the density kinetics (which applications), MRI with or without exogenous
are linear with the concentration of contrast contact agents has begun to assess the pathologi-
agents) passing though vascular space and tissues cal processes of CKD [22]; however, this research
are measured sequentially, and a time-density has solely been performed as a signal-center,
curve is obtained to calculate renal hemodynam- experimental study, without a standard protocol,
ics parameters by mathematical modeling. Today, and remains controversial. This is considered a
two primary types of analysis modeling are used: novel approach to assess renal function and struc-
the gamma variate and Patlak methods. Contrast- ture noninvasively (Fig. 8.1).
enhanced MDCT plays a role in noninvasive, lon-
gitudinal monitoring of the reduction of blood
perfusion related to renal injury, in both animal 8.4.1 Dynamic Contrast-Enhanced
models and clinical cases [19–21]. (DCE)
However, the clinical application of this tech-
nique remains limited. This technique is based on Gadolinium-based contrast agents (GBCA) are
a bolus injection of iodine contrast agents used worldwide for DCE-MRI examinations.
(2 × 0.5 mL/kg for gamma variate modeling; The tissue containing GBCA exhibits shortened
100–150 mL for the Patlak method), and nephro- tissue T1 and T2∗ values, through the so-called
toxicity must be considered for patients with relaxation effect. By acquiring a series of
impaired renal function. Moreover, bolus injec- dynamic tissue T2∗ data, an MR signal-time
tion increases preloading of the heart, so greater curve is depicted, which is typically used to
attentions should be given to patients with seri- describe the exchange rates between compart-
ous cardiac problems and pulmonary disease. ments (e.g., GFR) and hemodynamic parameters
Finally, the risk of exposure to X-rays should be such as RBF, renal blood volume, MTT, and
considered, especially in patients who undergo regional filtration fraction, within more sophisti-
repeated tests. cated models that involve two or more compart-
ments. Therefore, DCE-MRI could be useful for
the assessment of parenchymal perfusion, includ-
8.4 Magnetic Resonance ing dysregulation, atherosclerosis, and microvas-
Imaging (MRI) cular rarefaction. Another application of
DCE-MRI images is noninvasive estimation of
With the development of higher magnetic field GFR. Contrast media in the blood rapidly circu-
strengths, sophisticated pulse sequences, and lates through the parenchymal vasculature, but
mathematics modeling (particularly in research slowly accumulates in the tubule, which is s imilar
to the behavior of other body fluids; thus, it can Brownian motion of water molecules in the kid-
be used to calculate the single-kidney GFR by neys. In DWI-MRI, water molecules accumulate
mathematical modeling. A correlation has been in a strong magnetic gradient field (positive diffu-
reported between standard radioisotope measures sion gradient), and un-accumulate in a second gra-
and the DCE-MRI approach [23]. dient field (negative diffusion gradient). When
However, the limitations of this technique are moving between these two fields, water molecules
obvious. (1) Nephrotoxicity of the contrast agent: in motion exhibit an MR signal loss; when water
GBCAs have been reported to cause nephrogenic molecules exhibit greater freedom of movement, a
systemic fibrosis and gadolinium body storage greater signal loss occurs. By adjusting the applied
[24, 25], and they are primarily excreted from the gradient pulse with respect to different diffusion
body by the kidneys; thus, safety should be thor- sensitivities (b-values, where a higher b-value
oughly considered in cases with severe renal dys- requires stronger diffusion weighting), the signal
function. (2) DCE-MRI requires an extensive intensity-time curve is fitted to calculate the appar-
duration (3–10 min), such that it is clearly ent diffusion constant (ADC), a quantitative mea-
impacted by respiratory motion [26]. (3) Lacking sure of MR signal loss. Lower ADC values indicate
standard mathematics models and internal con- slower free water movement, which is more com-
trols, the sensitivity and specificity of this tech- mon in pathological conditions.
nique must be considered. It has been reported DWI-MRI has shown high potential for use in a
that DCE-MRI is reliable in cases with severe variety of acute and chronic kidney diseases. In
renal injury (e.g., artery stenosis >80%) [27]. CKD, the ADC value is reduced in both cortex and
There remains a gap between DCE-MRI results medulla, compared with healthy kidneys; it corre-
and “real” renal perfusion and function. lates with kidney injury in histological analysis of
core biopsy specimens [29–31]. There is a statisti-
cally significant association between reduced ADC
8.4.2 Arterial Spin Labeling (ASL) values and deterioration of renal function [32].
Paired comparisons show that ADC values exhibit
ASL-MRI is an imaging technique to obtain a statistically significant differences among CKD
series of perfusion-weighted images by using stages; the sensitivity and specificity were 75.44%
inflowing blood as an endogenous contrast agent, and 69.81% to detect CKD stages 3–5 [33]. Several
which temporarily alters blood flow magnetiza- factors might lead to alterations of ADC value,
tion. ASL is primarily used for measurement of such as the reduction of glomerular filtration and
cortex perfusion, but rarely for such measure- tubular reabsorption functions, and the accumula-
ment of the medulla. Recently, ASL was applied tion of cellularity and extracellular matrixes.
to assess renal perfusion in patients with meta- The advantages of this technique are obvious:
bolic syndrome, and to detect hemodynamic it does not require exogenous contrast agents and
responses to pharmacologic interventions [28]. it acquires images in a short time (<1 min), within
However, because of its low signal-to-noise ratio a few breath-hold intervals, such that it is mini-
(SNR), and because it requires complex imaging mally affected by breath movement. However,
sequences and mathematical modeling to analyze DWI-MRI remains limited in research use, and
the resulting data, ASL-MRI remains largely the “true” meaning of ADC values is controver-
used for research. sial. Thus far, research involving DWI-MRI com-
prises small, single-center studies; larger,
multicenter studies must be performed to ascer-
8.4.3 Diffusion-Weighted Imaging tain the power of ADC to diagnose
(DWI) CKD. Moreover, ADC values vary along with b
values, such that a standard protocol and generic
DWI-MRI is a powerful imaging technique to pro- analysis model are needed for large-scale clinical
vide diffusivity information by detecting random application.
104 Z. Xu
8.4.4 Diffusion Tensor Imaging (DTI) consumption. Thus, the renal medulla is more
sensitive to hypoxia. In healthy tissue, the demar-
Compared with DWI-MRI, the DTI technique cation of cortex and medulla is sharp in MR R2∗
provides more information regarding the diffu- images, and R2∗ gradually increases from the
sion direction of free water in tissues. This infor- cortex to the medulla near the renal hilus. This
mation can be provided by markers such as effect is validated by administering furosemide,
fractional anisotropy (FA), a measure of direc- an inhibitor of the Na/K/Cl cotransporter. There
tional diffusivity within a range of 0–1. When is no difference in R2∗ value between the left and
FA = 0, water molecule diffusion occurs in all right kidney; this value is positively related to
directions, whereas FA = 1 reflects restricted dif- age, but not to gender. The acquisition time of
fusion along a single orientation. In healthy kid- BOLD-MRI is relatively short (1–5 min) and is
ney, both cortex and medulla are highly organized collected over several breath-hold intervals,
and exhibit high integrity, so water may theoreti- which is also an advantage in clinical
cally diffuse preferentially along a fixed orienta- applications.
tion (e.g., the direction of the tubules). Recently, It has been reported that renal R2∗ (especially
several small clinical studies have shown that FA in the medulla) is suitable for the assessment of
is more reflective of microstructure and spatial different pathologic conditions in kidney, includ-
organization related to CKD, compared with ing CKD [37, 38]. Recent studies in an animal
ADC [34–36]. However, like other novel func- model of diabetic nephropathy have shown that
tional MRI techniques, DTI-MRI is limited in R2∗ values increase in the outer medulla, sug-
clinical application by the required sophisticated gesting lower tissue oxygenation [31, 39].
analysis model and time-intensive data acquisi- However, this change only occurs in advanced
tion processing. stages of disease. Some studies have also shown
differences in baseline T2∗ in diabetic kidneys in
humans. However, other research showed that
8.4.5 Blood Oxygen Level- medullary BOLD signals were nonspecific and
Dependent (BOLD) did not reflect renal function in diverse chronic
renal diseases [40]. Thus, the correlation between
Tissue hypoxia is a distinctive characteristic of measured T2∗ and disease stage remains
CKD; in some degree, hypoxia is consistent with controversial.
the morphometric and functional changes that However, the sensitivity and specificity of this
contribute to the progression to ESRD. BOLD- technique must be considered. Firstly, CKD is a
MRI was initially developed for neuroimaging; sophisticated pathologic condition. Its hemody-
in the kidney, it has attracted much attention namics, such as microvascular density and
because it can provide information regarding regional renal blood flow, can influence the MRI
blood oxygenation and tissue hypoxia in vivo. signal, as indicated by the R2∗. Secondly, with
Deoxyhemoglobin is a paramagnetic molecule the assumption that the blood and tissue are in
that can act as an endogenous T2∗ contrast agent. strict accordance with tissue oxygenation, some
With increasing concentration of deoxyhemoglo- pathological conditions, such as fibrosis, may
bin, the MR signal decay becomes more rapid restrict oxygen diffusion across the microvascular
(shorter T2∗). Tissue parameter R2∗ (1/T2∗) has lumen, and may cause heterogeneity between the
been considered to be associated with renal oxy- vascular and renal parenchyma. Finally, kidneys
gen levels. are retroperitoneum organs, so intestine gas might
In healthy kidney, PO2 in the medulla is increase R∗ values of a specific area of kidney
approximately 10–20 mmHg, which is much leading to misdiagnosis as a region of hypoxia or
lower than that in cortex (50 mmHg). Active kidney scars. Nevertheless, BOLD-MRI remains
reabsorption by the Na/K/Cl cotransporter in the the most popular and effective technique to inva-
thick ascending limb is a process of high energy sively measure tissue oxygenation in vivo.
8.4.6 Magnetic Resonance ous, such as relatively high radiation exposure,

Elastography (MRE) as well as low quantitation and spatial resolu-
tion with respect to morphological
Based on the assumption that excessive extra- abnormities.
cellular matrix deposition in fibrotic tissues The development of scintigraphic methods,
increases the stiffness of the kidneys, MRE- such as positron emission tomography (PET)
MRI is used to estimate tissue stiffness, as an and combined PET/CT imaging, enhanced the
index of fibrosis, by using translocation of value in acquisition of reliable renal blood flow
mechanical shear waves. Some studies have (using 82Rb or 64Cu-PTSM as a tracer) and GFR
shown the utility of this technique in patients (using 68Ga-EDTA or 55Co-EDTA as a tracer)
with transplant and renal artery stenosis [41– information because of good correlation with
43]. However, similar to US elastography, the gold standard determination by radioactive
results are influenced by anisotropy, vascular- microspheres [47]; moreover, this information
ization, hydronephrosis, and external pressure. is more valuable when fused with anatomic
Therefore, advanced development of appropri- information. However, the clinical usage
ate models is likely to increase the use of this remains limited because of its high cost and
novel technique. complicated process.
Another attractive but limited aspect, pre-
dominately used in experimental studies, is that
8.4.7 Molecular Imaging nuclear-based technique can directly assess
molecular targets, such as membrane trans-
Energy dys-metabolism with a loss of ATP is an porters, receptors, signal transduction, and
important early functional change in renal fail- gene expression; this makes it quantitative
ure. 31P MR spectroscopy, which can detect the and suitable for in vivo assessment of tissue
ratio of phosphomonoesters to inorganic phos- hypoxia, apoptosis, and endothelial dysfunc-
phorus, is able to evaluate renal metabolism tion in pathological conditions. It has been
in vivo. This technique was initially used to reported in studies of other organs that hypoxia
evaluate posttransplant graft function, and is could by visualized by PET with
now used to assess CKD progression [44]. 18
F-fluoroazoycinarabinofuranoside or
However, this technique remains limited by low 18
F-fluoromisonidazole [48]; the expression of
SNR and the advanced data acquisition some molecules, such as integrin, could be
approach. monitored in vivo by 18F-labeled integrin antag-
onists [49]. However, the usage of this approach
in CKD is likely in the distant future.
8.5 Nuclear-Based Technique
Radionuclide imaging, which is a functional 8.6 Conclusion

imaging technique that uses different types of
radioisotopes bound to non-metabolized mole- Image techniques in the kidney have become
cules with known pharmacokinetics (tracers), an indispensable research tool (Fig. 8.2).
is considered to show glomerular filtration Some tools, such as DCE-MRI and Doppler
(99mTc-DTPA and 99mTc-MDP), tubular func- US, have been extensively investigated in the
tion (99mTc-DMSA), and effective renal plasma clinic. However, there remains a gap between
flow (99mTc-MAG3M and 131I-OIH) [45, 46]. theoretical studies and clinical applications.
Both noninvasive and non-nephrotoxic, it is More sophisticated analysis models and the
widely used in the clinic to evaluate total and combined utilization of these novel tools are
partial divide kidney functions in CKD needed to maximize clinical values in the
patients. Importantly, its disadvantage is obvi- future.
106 Z. Xu
How to exam a kidney?
Structure Function
Parenchyma Vessel GFR Blood flow and perfusion Energy and metabolism
B-Mode US Color-Doppler US Nuclear-based Enhanced CT MRI-BOLD

US Elastography Enhanced CT technique CEUS 31P MR
MDCT DSA Enhanced CT MRI-DCE PET or
MRI-DWI MRI-DCE MRI-ASL PET/CT
MRI-DTI
MRE
Fig. 8.2 Clinical application of image techniques in kid- subtraction angiography; DCE dynamic contrast-
ney disease. GFR glomerular filtration rate; US ultrasonic; enhanced; CEUS contrast-enhanced ultrasound; ASL arte-
MDCT multi-detector computed tomography; MRI mag- rial spin labeling; BOLD blood oxygen level-dependent; P
netic resonance imaging; MRE magnetic resonance elas- MR P magnetic resonance spectroscopy; PET positron
tography; CT computed tomography; DSA digital emission tomography
Key Messages • Recent developments in imaging pro-

• US remain a first-line and indispensable vide unique insights into metabolism
tool for acquiring qualitative and quantita- and fibrosis that surpass simple anat-
tive information regarding morphology omy. However, most techniques require
and vasculature in CKD patients. This sophisticated analysis models and time-
technique provides a large advantage for sensitive data acquisition processing,
real-time imaging analysis, high safety and which limit their use in research. A stan-
renal tolerance, and radiationless; how- dard protocol and generic analysis
ever, it is limited by operator experience, model is needed for large-scale clinical
patient state, and poor space resolution. applications.
• Nuclear-based technique remains the
gold standard for evaluating GFR, while
MDCT and MRI are becoming widely
applied in the clinic.
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Part II
Complications of Chronic Kidney Disease
Cardiovascular Disease in Chronic
Kidney Disease 9
Jining Wu, Wenjin Liu, and Hongdi Cao
Abstract and mortality in patients with chronic kidney dis-

Cardiovascular disease (CVD) is a leading ease (CKD). Arteriosclerosis and disorders of left
cause of death among patients with chronic ventricular (LV) structure and function are com-
kidney disease (CKD). In addition to the tradi- mon in patients with CKD. In addition to the tra-
tional risk factors associated with the condi- ditional risk factors observed in the general
tion, uremic toxins may contribute directly to population, numerous CVD-related risk factors
the pathogenesis of CVD in patients with are specifically relevant in patients with CKD
CKD. Because of the multifactorial pathogen- and are related to the development of
esis, treating patients with CKD and concomi- CVD. Patients with CKD demonstrate a very
tant CVD is challenging. Treatable factors high prevalence of traditional risk factors for
such as anemia, hyperphosphatemia, hyper- CVD such as diabetes and hypertension.
calcemia, and hyperparathyroidism cannot However, they are also exposed to other nontradi-
completely explain the broad spectrum of tional uremia-related cardiovascular risk factors
CVD observed in this patient population. To including abnormal calcium-phosphorus metabo-
date, no study has identified effective drug lism and inflammation. In this chapter, we will
therapy to control cardiovascular outcomes in discuss the epidemiology and pathophysiology of
patients with CKD. CVD in patients with CKD. We shall also discuss
the primary diagnostic and therapeutic principles
and pathophysiology of different types of CVD
in patients with CKD.
9.1 Introduction
Cardiovascular diseases (CVD) including coro- 9.2 Epidemiology

nary artery disease (CAD), congestive heart fail-
ure (CHF), arrhythmias, and sudden cardiac CVD is the leading cause of death in patients
death are the primary contributors to morbidity with CKD and end-stage renal disease (ESRD),
accounting for approximately 50% of all CKD-
related mortality [1]. The latest data obtained
J. Wu · W. Liu · H. Cao (*) from the 2015 United States Renal Data System
Centre for Kidney Disease, Second Affiliated Annual Data Report show that to date, CVD
Hospital, Nanjing Medical University, remains the primary cause of death in patients
Nanjing, Jiangsu, China with ESRD. CVD in patients with CKD primar-
e-mail: wujining@njmu.edu.cn;
liuwenjin@njmu.edu.cn; caohongdi@njmu.edu.cn ily manifests as myocardial and arterial vascular

112 J. Wu et al.
diseases [2]. Left ventricular hypertrophy (LVH) Table 9.1 Traditional and nontraditional cardiovascular
risk factors
and myocardial fibrosis constitute the common
myocardial pathologies in patients with CKD, Nontraditional risk factors
whereas arteriosclerosis and atherosclerosis con- Traditional risk Hemodynamic
factors factors Metabolic factors
stitute the primary arterial vascular diseases in
Old age Volume Proteinuria
this patient population. These etiological contrib- overload
utors to CVD can lead to clinical manifestations Male sex Anemia Chronic
of ischemic heart disease (IHD), CHF, cerebro- inflammatory
vascular, and peripheral vascular disease. The state
Menopause Arteriovenous Malnutrition
prevalence of CVD even in patients with CKD
fistula
stage 1 and 2 (indicating milder disease) is sig- Smoking habit Arteriosclerosis Disorders of lipid
nificantly higher than that in the general popula- metabolism
tion. Proteinuria, which manifests as either Diabetes Oxidative stress
micro- or macroalbuminuria, is an independent Hypertension CKD–MBD
risk factor for a higher prevalence of CVD and Dyslipidemia Thrombogenic
factors
CVD outcomes.
Physical
The incidence and mortality rates associated inactivity
with CVD tend to increase following a decline in Family history
renal function. This high burden of CVD mortal- of CVD
ity is well illustrated by comparing between the CKD–MBD chronic kidney disease-mineral bone disor-
CVD-related mortality in patients with ESRD ders; CVD cardiovascular disease
and that in the general population. It has been
shown that approximately 75% of patients with teinuria, oxidative stress, and disorders of cal-
ESRD present with LVH. Moreover, the preva- cium and phosphorus metabolism. Traditional
lence of hypertension increases progressively and nontraditional risk factors for CVD are sum-
with the decline in renal function in patients with marized in Table 9.1.
CKD, and 75–85% of patients undergoing dialy- Progressive kidney damage leads to cardiac
sis demonstrate hypertension. In addition to damage through a variety of mechanisms and
hypertension, anemia, vascular noncompliance, factors, culminating in the unique risks that
and volume overload are all known contributors ESRD patients experience secondary to the dial-
to LVH. Based on echocardiographic studies, ysis procedure itself. Volume overload occurring
85–90% of patients with ESRD show LV ejection in patients with ESRD may be attributable to dia-
fraction (LVEF) ≥50%; however, CHF is com- stolic dysfunction or circulatory congestion. As
mon in these patients. mentioned earlier, in terms of IHD and CAD, the
relationship between CKD and CVD may involve
shared risk factors, a reflection of widespread
9.3 isk Factors for CVD
R vascular disease and endothelial dysfunction,
in Patients with CKD and/or the toxicity caused by the uremic milieu.
Furthermore, IHD itself can contribute to CAD
The risk factors associated with CVD in patients and predispose to arrhythmia. LVH and cardiac
with CKD can be categorized as traditional and failure are the most common complications
nontraditional risk factors. Traditional risk fac- observed in patients with CKD, which are pri-
tors refer to the usual/universal risk factors for marily attributable to fluid overload and, usually,
CVD that are observed in the general population hypertension. Myocardial fibrosis occurs sec-
including smoking habits, and history of hyper- ondary to impaired angio-adaptation, reduced
tension and diabetes, among others. capillary angiogenesis, myocyte-capillary mis-
Nontraditional risk factors primarily refer to the match, and micro-arteriopathy. The vascular tree
risk factors for CVD related to CKD, such as pro- is affected by both arteriosclerosis and
9 Cardiovascular Disease in Chronic Kidney Disease 113
atherosclerosis with widespread arterial media mately 20% of these cases are secondary to car-
calcification and the deposition of lipid-rich diac arrest. Cardiac arrhythmia is usually
plaques [3]. associated with hyperkalemia in patients with
CKD.
9.4 Clinical Manifestations

of CVD in Patients with CKD 9.4.5 Pericarditis
9.4.1 Cardiomyopathy Untreated uremic pericarditis is rare, although

dialysis-related pericarditis is common in patients
LVH is the most important cardiovascular struc- with ESRD and usually occurs in those with
tural change in patients with CKD, particularly in insufficient dialysis. Echocardiography should be
those with ESRD. LVH in patients with CKD is performed in patients presenting with pericardial
not only related to hypertension and volume load, pain and fever or when auscultation reveals peri-
but is also associated with activation of the local cardial friction sounds.
renin-angiotensin-aldosterone system and
increased aortic wall stiffness. LVH is associated
with diastolic dysfunction, which suggests an 9.4.6 Heart Valve Disease
unfavorable prognosis in patients with CKD.
Disorders of calcium and phosphorus metabo-
lism, long dialysis vintage, hypoalbuminemia,
9.4.2 Coronary Atherosclerotic and old age are significant risk factors in patients
Heart Disease with CKD complicated with valvular disease and
calcification. Valvular calcification with regurgi-
Secondary to the occurrence of autonomic neu- tation can cause stenosis and hemodynamic
ropathy in patients with CKD and the volume instability, as well as conduction disorders in
overload, myocardial ischemia may atypically patients with CKD.
present as asymptomatic acute myocardial infarc-
tion (AMI), which may be misdiagnosed, and
thus patients may not receive prompt treatment. 9.4.7 Peripheral Vascular Diseases
Diabetic patients and those with atherosclerosis

9.4.3 Congestive Heart Failure undergoing dialysis are at a high risk of periph-
eral vascular disease. The occurrence of periph-
Patients with CKD, particularly those with ESRD eral vascular diseases in patients undergoing HD
undergoing dialysis, demonstrate the hypervol- is related to dialysis vintage and hypoalbumin-
emia that can lead to LVH, LV enlargement, emia. Peripheral arterial calcification does not
edema, and acute pulmonary edema. always lead to occlusive disease; however, occlu-
sive small vessel disease causes gangrene.
9.4.4 Arrhythmia and Sudden

Cardiac Death 9.5 iagnosis of CVD in Patients
D
with CKD
Arrhythmia is a common clinical complication in
patients with ESRD, particularly during the Although CVD is highly prevalent in patients
course of hemodialysis (HD). Sudden death is with CKD, its clinical diagnosis remains chal-
known to occur in patients with ESRD, primarily lenging because of atypical signs and symptoms
related to ventricular fibrillation, and approxi- observed in patients. The diagnostic criteria used
114 J. Wu et al.
in the general population are not always prognosis; therefore, a higher cutoff value is rec-
applicable to patients with CKD owing to the ommended for cTnT for prompt diagnosis and
decline in renal function in this patient popula- treatment in patients with ACS undergoing dialy-
tion. For example, symptoms of heart failure sis. Regular and close monitoring of hs-cTn is
(e.g., dyspnea, fatigue) and physical signs of vol- important in patients with CKD for clinical man-
ume overload are highly prevalent in patients agement rather than using a single value that is
with CKD even in the absence of cardiac dys- higher than the upper limit of normal [4].
function. It has also been reported that patients
with ESRD with AMI may not always present 9.5.1.2 Estimation of Brain Natriuretic
with chest pain. Peptide and
N-Terminal-pro-BNP
Brain natriuretic peptide (BNP) and N-terminal-
9.5.1 Serological Tests pro-BNP (NT-pro-BNP) levels are commonly
tested in symptomatic patients with suspected
9.5.1.1 Cardiac Troponins acute CHF exacerbation. Previous reports have
Although the estimation of single myocardial shown elevated levels in 56% of asymptomatic
enzymes does not show high diagnostic specific- patients with CKD. LV myocytes release BNP
ity, the dynamic changes in levels of enzymes and NT-pro-BNP from precursors in response to
such as creatine kinase-MB and lactate dehydro- increased stretch or tension. BNP is an active
genase can effectively diagnose AMI. Positive molecule with a short plasma half-life and is
serum cardiac troponin T (cTnT) and troponin I metabolized in the circulation by enzymatic
(cTnI) indicate acute ischemia, and the sensitiv- action. NT-pro-BNP is the inactive form of BNP,
ity of these tests in assessing the extent of myo- with a longer half-life and primarily undergoes
cardial infarction is greater than that of renal clearance. A reduced estimated glomerular
myocardial enzymes. High-sensitivity-cardiac filtration rate (eGFR) correlates with elevated
troponin (hs-cTn) is the preferred cardiac marker plasma NT-pro-BNP levels to a greater extent
to diagnose acute coronary syndrome (ACS). than with elevated BNP levels. An increased
However, the upper reference limits for cTnT and NT-pro-BNP/BNP ratio shows a significant cor-
cTnI were originally established in patients with- relation with progression of CKD, particularly
out CKD, and these biomarkers are elevated in with eGFR <30 mL/min/1.73 m2. However, both
approximately 80% of patients with asymptom- BNP and NT-pro-BNP are associated with sur-
atic CKD and ESRD. Notably, cTn elevation rogate markers and serious clinical outcomes in
does not necessarily indicate acute ischemia sec- asymptomatic patients with CKD [4]. A previous
ondary to coronary atherosclerosis. Elevated cTn study involving 150 asymptomatic patients
levels may be secondary to decreased renal clear- undergoing HD with a mean follow-up of
ance or chronic myocardial injury. Multifactorial 24 months showed that the correlation between
pathomechanisms are involved including myo- NT-pro-BNP and all-cause and cardiovascular
cardial strain from hemodynamic alterations, mortality was significantly stronger than that
inflammation, endothelial dysfunction, and sub- with cTnT. A recent cross-sectional study has
endocardial ischemia. In contrast to cTnI, cTnT shown that NT-pro-BNP levels of 6000 and
assays are standardized. In asymptomatic patients 10,000 pg/mL are the optimal cutoff values to
with CKD, cTn levels are associated with various diagnose CAD and LV systolic dysfunction,
surrogate markers such as LVH, doubling of respectively. Therefore, estimation of the NT-pro-
serum creatinine levels, and CKD progression, as BNP level prior to the initiation of dialysis is an
well as serious clinical outcomes such as death important screening tool for cardiac abnormali-
and cardiovascular events. Patients with ESRD ties. A recent prospective cohort study involving
presenting with an initial cTnT concentra- 3483 patients with CKD without heart failure
tion >0.35 ng/mL demonstrate an unfavorable showed that the potential rate of heart failure was
higher in patients with the highest levels of cardiovascular morbidity associated with CKD
NT-pro-BNP (>433 pg/mL) with a risk ratio of may be attributed to significantly increased levels
9.57. Therefore, NT-pro-BNP and BNP are use- of systemic ADMA and l-NMMA [6].
ful biomarkers for LV dilatation, and systolic and
diastolic dysfunction in patients undergoing dial-
ysis. Notably, they serve as biomarkers for the 9.5.2 Instrumental Examinations
prediction of cardiovascular mortality in patients
with CKD not undergoing dialysis [5]. 9.5.2.1 Electrocardiography and 24-H
Dynamic Electrocardiography
9.5.1.3 Serum Mineral and Bone Static electrocardiography (ECG) performed in
Biomarkers patients undergoing HD show prolonged PR and
Patients with CKD-MBD demonstrate increased QRS intervals and nonspecific ST-T segment
serum intact parathyroid hormone (iPTH) levels, changes. These changes are more pronounced
vitamin D deficiency, and hyperphosphatemia, during intra- and extracellular fluid shifts during
which serve as independent risk factors of dialysis. Typical ECG changes can be observed
CVD. The fibroblast growth factor 23 (FGF23) in patients with acute coronary ischemia.
regulates phosphorus and vitamin D metabolism Monitoring with 24-h dynamic ECG is helpful to
and its levels increase progressively in early diagnose premature beats and other arrhythmias
CKD, partially as an adaptation to the uremic in patients with CKD.
environment and also as a primary pathophysio-
logical event that may account for several clinical 9.5.2.2 Echocardiography and Doppler
manifestations including bone and cardiovascu- Ultrasonography
lar complications. Increased plasma FGF23 lev- Echocardiography is the primary tool used to
els are associated with LVH, vascular evaluate ventricular and valvular structures and
calcification, cardiovascular dysfunction, and cardiac function. This noninvasive diagnostic
increased mortality in patients with CKD. modality used in clinical practice performs real-
time qualitative and quantitative evaluation.
9.5.1.4 Other Serum Biomarkers Echocardiography demonstrates signs of volume
In addition to cTnT and BNP, C-reactive protein, overload, particularly left and right ventricular
asymmetric dimethylarginine (ADMA), dysfunction in patients with ESRD and those
N-monomethyl-l-arginine (l-NMMA), undergoing HD. Volume overload is indicated by
plasminogen-activator inhibitor type I, homocys- increased atrial volumes or areas, pleural or peri-
teine, serum amyloid A protein, ischemia modi- cardial effusion, and lung comets. Valvular calci-
fied albumin, and several others serve as fication (related to secondary
biomarkers that progressively increase with a hyperparathyroidism) and features of right-sided
decline in the eGFR. Many of these are indepen- cardiac dysfunction such as high pulmonary
dently associated with CVD in patients with artery pressures or right chamber dilatation are
CKD. C-reactive protein is a well-known inflam- commonly observed. Echocardiography and
matory biomarker that is strongly associated with Doppler ultrasonography can also diagnose com-
vascular disease. In addition to being a biomarker, plications of uremic cardiomyopathy such as
it is considered potentially causally related to coronary and peripheral artery disease, LVH,
vascular disease. ADMA and l-NMMA are vascular and valvular calcifications, and myocar-
endogenous inhibitors of nitric oxide synthases dial fibrosis. LVH is usually assessed by perform-
that attenuate nitricoxide production and enhance ing standard two-dimensional (2-D)
the generation of reactive oxidative species. echocardiography, which though not very accu-
Increased plasma levels of ADMA and/or rate, is cost-effective. The accuracy of echocar-
l-NMMA are strong and independent risk factors diography depends upon the technique used, the
for CKD and various types of CVD. The increased timing of the test relative to the dialysis session,
116 J. Wu et al.
and the index used for “normalization” of the nephropathy and deterioration of renal function
data generated. Estimation of the LV mass in following the administration of contrast agents. All
patients with CKD and ESRD can be performed patients with CKD are also at risk for cholesterol
using 2-D and 3-D echocardiography techniques. embolism. Therefore, coronary angiography
Assessment of LV mass, volume, and EF using should be cautiously performed in patients with
real-time 3-D echocardiography shows higher CKD. Coronary angiography is warranted in
accuracy than that with 2-D echocardiography. patients with unstable angina or myocardial infarc-
The accuracy of this modality is close to that of tion prior to undergoing coronary angioplasty.
cardiac magnetic resonance imaging (CMRI).
Tissue Doppler imaging scores over conventional 9.5.2.5 Doppler Angiography
Doppler echocardiography in evaluating CKD- and Intravascular Ultrasound
related cardiac complications and early diastolic Imaging
dysfunction based on its ability to accurately The development of ultrasound imaging technol-
record local and global myocardial velocity ogy has enabled the real-time analysis of blood
changes. With the development of advances in vessels and vascular blood flow. Waveforms typi-
ultrasonographic technology might provide bet- cally vary across vascular beds, and abnormal
ter and a greater number of radiological tech- waveforms indicate arteriopathy. The lesions and
niques to evaluate cardiac abnormalities in plaques in surrounding vessels and the coronary
patients with CKD. arteries, as well as changes in the endovascular
cavity, can be identified using high-frequency
9.5.2.3 Cardiac Computed Tomography probes and intravascular imaging.
and Cardiac Magnetic
Resonance Imaging 9.5.2.6 Ambulatory Blood Pressure
Cardiac computed tomography (CT) and cardiac Monitoring
magnetic resonance imaging (CMRI) are useful to Ambulatory blood pressure monitoring (ABPM)
evaluate complications of uremic cardiomyopathy. is essential for the accurate determination of BP
Cardiac CT detects coronary artery calcifications levels, particularly in patients with CKD [7].
and can diagnose coronary atherosclerosis in ABPM scores over traditional office BP measure-
patients with CKD. CMRI is considered the gold ments in that it can avoid the white coat effect and
standard for the accurate evaluation of the LV mass, provide additional information regarding a
to define the volume and pattern of LVH (eccentric, patient’s BP including short-term BP variability
concentric or asymmetric), and to assess the mag- and circadian rhythm (i.e., “dipping” or “non-
nitude of fibrosis. Compared with CMRI, classical dipping” status). It is also essential to diagnose
echocardiography often overestimates the LV mass “white coat hypertension” and “masked hyperten-
in patients undergoing dialysis; however, CMRI is sion.” In our previous study, we observed that
not a practical option for widespread use owing to approximately 50% of the patients undergoing
the higher costs. Therefore, echocardiography dialysis who were considered to show controlled
remains the primary tool to evaluate LV mass in BP actually demonstrated “masked uncontrolled
clinical practice. CMRI allows complete assess- hypertension” and that this condition is associated
ment of arterial function through measurement of with hypertensive end-organ damage [7].
aortic distensibility (AD); a reduction in the AD is Therefore, physicians should routinely use ABPM
observed in the early stages of the evolution of in these patients.
CKD-related cardiomyopathy.
9.5.2.7 Measures of Arterial Elasticity,
9.5.2.4 Coronary Angiography Endothelial Function, and Pulse
Coronary angiography is the gold standard to diag- Wave Velocity
nose CAD. Patients with CKD in the pre-dialysis Previous studies have shown that a few noninva-
stage are at a high risk of developing contrast sive modalities that are not widely adopted in
clinical practice are useful to assess cardiovascu- (ACEIs)/angiotensin receptor blockers

lar health and for risk prediction in patients with (ARBs) and calcium channel blockers
CKD. Assessment of vascular function including (CCBs) or diuretics in patients with
the estimation of arterial elasticity and endothe- CKD. ACEIs/ARBs are more effective than
lial function serves as a potentially valuable indi- other antihypertensive drugs in reducing pro-
cator of cardiovascular health and should be teinuria in patients with CKD. Serum potas-
considered in the care of patients with CKD [8, sium and creatinine levels should be closely
9]. Measurement of pulse wave velocity is a stan- monitored in patients with CKD who receive
dard measure of arterial stiffness and can be per- ACEIs or ARBs. Thiazide diuretics are con-
formed with several commercially available traindicated and loop diuretics can be used in
devices [10]. The “flow-mediated dilation” test is patients with CKD demonstrating eGFR
the traditional method to assess endothelial func- <30 mL/min/1.73m2. Probing dry weight can
tion; however, it requires a highly experienced improve BP among hypertensive patients
operator, and its reproducibility is usually unsat- undergoing HD. Intra- and interdialytic phar-
isfactory. A device based on peripheral arterial macokinetics, effect on cardiovascular
tonometry has recently been developed for auto- reflexes, treatment of comorbidities, and the
matic measurement of peripheral endothelial adverse effect profile are important factors
function. We adopted this measurement method that determine individualization of therapy.
in a dialysis cohort to test if it could overcome the Beta-blockers and dihydropyridine CCBs
challenge of the fistula and predict cardiovascular constitute the first- and second-line antihy-
outcomes in patients undergoing maintenance pertensives, respectively, that are commonly
HD [11]. prescribed. ACEIs and ARBs are third-line
choices because there is limited evidence
supporting their use in patients undergoing
9.6 reatment of CVD in Patients
T dialysis. Diuretics have little to no role in
with CKD patients with ESRD [12].
• Correction of abnormal lipid metabolism
9.6.1 Risk Factor Intervention • The short-term efficacy and safety of statins
have been confirmed in patients with CKD,
9.6.1.1 Intervention and statins are the most effective drugs to
for the Management reduce low-density lipoprotein (LDL)-
of Traditional Risk Factors cholesterol in these patients. The long-term
• Antihypertensive treatment effects of statins on cardiovascular outcomes
• Hypertension is highly prevalent among in patients with CKD have also been well doc-
patients with CKD and contributes to the umented, and they are known to reduce pro-
high burden of CVD-related morbidity and teinuria. Statins are recommended in patients
mortality. Strict volume control via sodium presenting in the early stages of CKD because
restriction constitutes the first-line approach their use during this period significantly
for the treatment of hypertension in this reduces the relative risk of CVD. The contin-
patient population; however, antihyperten- ued role of statins in patients who require
sive drug therapy is often needed to control dialysis is controversial because previous tri-
BP. Selection of an optimal antihypertensive als that investigated statin use in patients
regimen should be individualized. The latest undergoing dialysis have shown negative
2018 European Society of Cardiology/ results. All patients with CKD are considered
European Society of Hypertension guide- to be at a high risk, and lipid-lowering therapy
lines for the management of hypertension is indicated in patients with LDL-cholesterol
recommend initial combination therapy with >100 mg/dL except in patients undergoing
angiotensin-converting enzyme inhibitors dialysis.
118 J. Wu et al.
9.6.1.2 Intervention for PTH levels is 150–300 pg/mL. Severe

for the Management vascular calcification is closely associated
of Nontraditional Risk Factors with mortality in patients with CKD. In
• Correction of anemia patients with severe secondary hyperparathy-
• Anemia is an important risk factor associated roidism undergoing dialysis, parathyroidec-
with the prognosis of CVD in patients with tomy should be performed to correct the
CKD. However, in patients with CVD under- deranged calcium and phosphorus
going HD, normalizing the hemoglobin may metabolism.
not reduce mortality. In contrast, higher tar- • Correction of coagulation disorders
get hemoglobin values are associated with • Aspirin is widely accepted as an effective
higher mortality in patients with agent for the primary prevention of CAD in
CKD. Therefore, patients with CKD require patients without CKD. However, aspirin may
close and regular monitoring of hemoglobin aggravate platelet dysfunction in patients
levels and indicators of iron metabolism. The with CKD, particularly those undergoing HD
target hemoglobin value should be set at and may increase the risk of bleeding.
110–120 g/L. Routine use of aspirin is not recommended in
• Control of inflammation patients with CKD without clinically proven
• CKD is characterized by a state of chronic CVD. However, low-dose aspirin therapy
inflammation, which serves as a strong pre- may reduce cardiovascular events in patients
dictor of morbidity and mortality in this pop- with CKD concomitant with significant
ulation. Chronic inflammation plays an CVD.
important role in the pathogenesis of CVD in
patients with CKD. Increased levels of spe- Intervention measures for reducing the risk of
cific cytokines (interleukin 6 and tumor cardiovascular disease in patients with CKD are
necrosis factor α) or acute phase proteins summarized in Table 9.2.
(C-reactive protein) are associated with CVD
in patients undergoing HD. To date, no spe-
cific intervention strategy is known to treat Table 9.2 Intervention measures to reduce the risk of
chronic inflammation in patients with cardiovascular disease in patients with chronic kidney
disease
CKD. Aspirin and statins can be used in the
general population as well as in patients with Intervention for traditional risk factors
• Smoking cessation
CKD to control inflammation. Advanced
• An appropriate increase in exercise
blood purification technology such as • Controlling blood glucose levels
improvements in the biocompatibility of dial- • Controlling BP
ysis membranes and the popularization of a • Dietary restrictions/modifications
high-throughput dialyzer could control Intervention for nontraditional risk factors
• Reduction in the volume overload and
chronic inflammation in patients undergoing determining an appropriate dry weight
dialysis. • Correction of anemia
• Management of disorders of calcium and • Prevention of inflammation and correction of
phosphorus metabolism hypoalbuminemia
• Statin therapy for correction of deranged lipid
• Judicious use of active vitamin D and phos- metabolism
phorus binders is recommended to correct • Administration of active vitamin D and
disorders of calcium and phosphorus metabo- phosphorus binders to correct CKD-MBD
lism and to maintain optimal blood levels of • Judicious administration of ACEIs/ARBs to
reduce proteinuria
calcium, phosphorus, and PTH within the rec- • Judicious administration of aspirin
ommended range. The target range for serum
ACEIs/ARBs angiotensin-converting enzyme inhibitors/
calcium levels is 2.2–2.4mmoL/L, for serum angiotensin receptor blockers; BP blood pressure; CKD–
phosphorus levels is 0.81–1.78mmoL/L, and MBD chronic kidney disease–mineral bone disorders
9.6.2 Treatment of CKD 1. Predialysis BP goal of >140/90 mmHg while

Concomitant with Various avoiding intradialytic hypotension.
Types of CVDs 2. Serum LDL-cholesterol level <100 mg/dL in
patients with known atherogenic disease.
9.6.2.1 Left Ventricular Hypertrophy 3. Strict control of diabetes guided by frequent
LVH represents a challenging therapeutic target. blood glucose assessments.
Modifying the risk factors for LVH (and subse-
quent heart failure) such as anemia, hyperten- Optimal control of BP may be accomplished
sion, extracellular volume overload, by maintaining an appropriate dry weight and the
abnormalities of mineral metabolism, and arte- administration of antihypertensive drugs.
riovenous fistulae may reduce the incidence of Coronary angiography should be performed fol-
LVH. However, few clinical trials performed in lowed by immediate revascularization if the pro-
this context have included patients with cedure reveals significant CAD. However,
CKD. Data from several small observational patients with CKD demonstrate a higher risk of
studies and non-randomized trials have sug- complications after myocardial vascularization
gested that LVH can be treated by modifying and an unfavorable long-term prognosis. Data
risk factors including anemia and hypertension from a Danish nationwide cohort study have
and performing daily dialysis for strict manage- shown that the administration of clopidogrel was
ment of fluid volume. However, multiple ran- associated with improved outcomes in patients
domized trials, including studies involving both with non-end-stage CKD during a 1-year follow-
patients undergoing dialysis and those with up after MI. Moreover, ticagrelor significantly
CKD stages 3 and 4, have not demonstrated a reduced ischemic endpoint events and mortality,
significant relationship between regression of with no significant increase in major bleeding in
LVH or a decrease in LV mass and near-normal- patients with CKD and concomitant ACS [13].
ized hemoglobin levels. Current treatment for
LVH focuses on afterload reduction and the 9.6.2.3 Congestive Heart Failure
management of fluid volume through the admin- Treatment of acute heart failure differs between
istration of ACEIs or ARBs, often in combina- patients based on the stages of CKD. Diuretics
tion with diuretics. are commonly used in patients during the predi-
alysis stage, whereas ultrafiltration effectively
9.6.2.2 Ischemic Heart Disease reduces acute fluid overload in patients undergo-
An elevation in cardiac biomarkers may indi- ing dialysis. Several patients undergoing dialysis
cate IHD and chronic injury even in the benefit from the use of longer treatments or more
absence of ECG-documented changes. frequent short treatments. Two randomized
Diagnosis of AMI is primarily based on the placebo-controlled trials have established the
dynamic changes in levels of troponins and efficacy of ARBs in reducing the risk of heart
other cardiac injury biomarkers. A sequential failure. Theoretically, further benefits may be
rise and fall in blood levels of these markers is achieved by aldosterone blockade. However,
consistent with acute cardiac damage. The combination therapy using ACEIs and ARBs pre-
principles of treatment for both acute and non- cipitates hyperkalemia, which therefore limits its
acute CAD in patients with CKD are similar to use in clinical settings. Beta-blockers, another
those applicable to the general population. mainstay of heart failure therapy in the general
However, the incidence of asymptomatic isch- population, are beneficial in patients with
emia is relatively higher in patients with CKD CKD. Cardiac glycosides (e.g., digoxin) decrease
secondary to the autonomic neuropathy caused morbidity but not mortality in the general popula-
by uremia and diabetes. tion with heart failure. However, no specific
The recommended targets for optimal man- study has investigated their efficacy in patients
agement of risk factors are as follows: with CKD. It is recommended that they should be
120 J. Wu et al.
used cautiously, with particular attention to 9.6.2.7 Atrial Fibrillation

appropriate dosages and monitoring of serum Optimal management of atrial fibrillation
potassium levels. Reportedly, angiotensin recep- involves control of the heart rate with or without
tor neprilysin inhibitors (ARNIs) are superior to restoration of sinus rhythm. Beta-blockers and
enalapril in reducing the mortality risk and rate of CCBs are useful for rate control, and amiodarone
hospitalization for heart failure [14]. In July is effective for chemical cardioversion. The risk-
2015, the United States approved ARNIs for the benefit ratio of anticoagulation in patients under-
treatment of CHF, which is expected to serve as going dialysis should be judiciously assessed and
the basis of future treatment in patients with heart individualized.
failure. However, further data are needed to sup-
port the use of ARNIs in patients with CKD. 9.6.2.8 Ventricular Arrhythmias
and Sudden Death
9.6.2.4 Pericardial Disease Potential strategies to reduce the risk of fatal
Treatment of pericardial diseases is dependent upon cardiac arrhythmias include close surveillance
symptoms and effusion size. Small, asymptomatic of the dynamic changes in fluid volume and
pericardial effusions are relatively common in serum electrolyte levels. HD units equipped
patients undergoing dialysis and require no acute with automated external defibrillators and well-
intervention. Heparin is avoided during dialysis to trained staff may effectively prevent arrhyth-
avoid hemorrhagic tamponade. Adjuvant medical mia-induced deaths. Potential medical
therapies including the oral and intravenous admin- interventions include the routine administration
istration of glucocorticoids and nonsteroidal anti- of beta-blockers.
inflammatory medications are ineffective. Patients
with hemodynamic instability require emergency
drainage of the pericardial effusion.
9.6.2.5 Endocarditis
Endocarditis should be treated with appropriate Key Messages
antibiotics; however, the survival rate is often • CVD is the leading cause of death in
poor. Surgical intervention may be an alternative, patients with CKD and ESRD, account-
and indications for surgery are similar to those ing for approximately 50% of all CKD-
applicable to the general population including related mortality.
progressive valvular destruction and heart failure, • Progressive kidney damage leads to car-
recurrent systemic emboli, and failure to respond diac damage through a variety of
to antibiotic treatment. pathomechanisms and factors, both tra-
ditional and nontraditional.
9.6.2.6 Aortic Calcification • The diagnostic criteria used in the gen-
and Stenosis eral population are not always applica-
Treatment of aortic stenosis requires a multi- ble to patients with CKD owing to the
pronged approach including the prevention of decline in renal function in this patient
progression and the development of endocarditis population.
and eventually valve repair. Management of min- • Despite the known and currently used
eral metabolism disorders theoretically inhibits strategy of managing traditional and
the progression of aortic stenosis. Valve replace- nontraditional risk factors, treating
ment can be considered in patients with critical patients with CKD and concomitant
aortic stenosis. The timing of surgery is depen- CVD is challenging.
dent on the patient’s condition.
References 8. Hirata Y, Sugiyama S, Yamamoto E, et al. Endothelial

function and cardiovascular events in chronic kidney
disease. Int J Cardiol. 2014;173(3):481–6.
1. House AA. Cardio-renal syndrome type 4: epidemiol- 9. Flammer AJ, Anderson T, Celermajer DS, et al. The
ogy, pathophysiology and treatment. Semin Nephrol. assessment of endothelial function: from research into
2012;32(1):40–8. clinical practice. Circulation. 2012;126(6):753–67.
2. Tonelli M, Karumanchi SA, Thadhani R. Epidemiology 10. Townsend RR, Anderson AH, Chirinos JA, et al.

and mechanisms of uremia-related cardiovascular dis- Association of Pulse Wave Velocity with Chronic
ease. Circulation. 2016;133(5):518–36. Kidney Disease Progression and Mortality: findings
3. Wanner C, Amann K, Shoji T. The heart and vascular from the CRIC study (chronic renal insufficiency
system in dialysis. Lancet. 2016;388(10041):276–84. cohort). Hypertension. 2018;71(6):1101–7.
4. Colbert G, Jain N. de Lemos JA etc. utility of tradi- 11. Liu W, Meng M, Chen J, et al. Reactive hyperemia
tional circulating and imaging-based cardiac bio- index in patients on maintenance hemodialysis:
markers in patients with predialysis CKD. Clin J Am cross-sectional data from a cohort study. Sci Rep.
Soc Nephrol. 2015;10(3):515–29. 2017;7:45757.
5. Wang AY, Wai-Kei Lam C. The diagnostic utility of 12. Georgianos PI, Agarwal R. Pharmacotherapy of

cardiac biomarkers in dialysis patients. Semin Dial. hypertension in chronic Dialysis patients. Clin J Am
2012;25(4):388–96. Soc Nephrol. 2016;11(11):2062–75.
6. Liu X, Xu X. Shang R etc. asymmetric dimethy- 13. James S, Budaj A, Aylward P, et al. Ticagrelor versus
larginine (ADMA) as an important risk factor for clopidogrel in acute coronary syndromes in relation
the increased cardiovascular diseases and heart to renal function: results from the platelet inhibition
failure in chronic kidney disease. Nitric Oxide. and patient outcomes (PLATO) trial. Circulation.
2018;78:113–20. 2010;122(11):1056–67.
7. Liu W, Wang L, Sun Z, et al. Masked uncontrolled 14. McMurray JJ, Packer M, Desai AS. Etc. angiotensin-
hypertension in patients on maintenance hemodialy- neprilysin inhibition versus enalapril in heart failure.
sis. Hypertens Res. 2017;40(9):819–24. N Engl J Med. 2014;371(11):993–1004.
Anemia in Chronic Kidney Disease
10
Yi Fang and Weichun He

Anemia is an important and frequent complication
in patients with chronic kidney disease (CKD), Anemia, an important clinical manifestation of
and its prevalence increases as renal function the complications of chronic kidney disease
declines. The etiology of anemia in CKD is multi- (CKD), may occur in patients with stage 1 CKD
factorial, including absolute or relative lack of and becomes more prevalent with progression of
erythropoietin, iron deficiency, blood loss, short- the disease [1]. The anemia induced by CKD is
ened red blood cell survival, and other factors. primarily due to reduced production of erythro-
Anemia in CKD is associated with impaired qual- poietin (EPO) by the kidneys, as well as iron defi-
ity of life and elevated morbidity and mortality of ciency, which results in a hypoproliferative state
cardiovascular diseases. Patients with CKD should of erythropoiesis. Anemia leads to higher rates of
monitor hemoglobin levels regularly. If the degree morbidity and mortality [2], thus diminishing
of anemia is not consistent with that of renal dys- quality of life in patients with CKD. Since the
function in patients with CKD, it is necessary to late 1980s, the use of exogenous erythropoiesis-
rule out the existence of other diseases that can stimulating agent (ESA) has greatly advanced the
cause anemia. Erythropoiesis-stimulating agent management of renal anemia, significantly reduc-
(ESA) and iron supplementation are the primary ing the need for blood transfusion and improving
treatment for anemia in CKD. Hemoglobin levels quality of life for many patients with CKD. The
and iron status should be monitored regularly dur- most common therapeutic options for correction
ing treatment. It is generally recommended that of anemia include ESA administration, iron sup-
hemoglobin concentration not exceed 115 g/L in plementation, and transfusion of red blood cells.
patients undergoing ESA maintenance; the However, the optimum target hemoglobin con-
monthly hemoglobin growth rate should be lim- centration and anemia management practices in
ited in ≥10 g/L, but <20 g/L. Transfusions should patients with CKD remain controversial.
be avoided as much as possible. Inhibitors of
hypoxia-inducible factor prolyl hydroxylase is a
kind of new promising therapeutic drugs. 10.2 Definition
Y. Fang (*) · W. He (*) Anemia is a state of reduction in blood hemoglo-

Centre for Kidney Disease, Second Affiliated bin concentration or hematocrit, which can lead
Hospital, Nanjing Medical University, to insufficient oxygen delivery to tissues and
Nanjing, Jiangsu, China organs. The normal ranges for hemoglobin and
e-mail: fangyi@njmu.edu.cn;
heweichun@njmu.edu.cn hematocrit depend on gender, race, age, and other

124 Y. Fang and W. He
factors. According to the 2012 Kidney Disease more severe among patients with DKD, relative
Improving Global Outcome (KDIGO) guide- to patients with non-DKD [6–8]. Elderly patients
lines, the definition of anemia in adults and chil- with CKD exhibit a high incidence of anemia.
dren >15 years of age with CKD is hemoglobin Particularly, the incidence of anemia gradually
concentration <130 g/L in males and <120 g/L in increases with increasing age among male
females; the definition of anemia in children patients with CKD. However, the incidence of
under 15 years of age with CKD is hemoglobin anemia among young women is higher than
concentration <110 g/L in children 0.5–5 years, among elderly women [9], which may be related
<115 g/L in children 5–12 years, and <120 g/L in to the loss of iron due to menses. In comparison,
children 12–15 years [3]. the incidence of anemia also shows a gradually
increasing trend with age in elderly female
patients [10]. Calcium-phosphorus metabolic
10.3 Prevalence disorder is also correlated with the high incidence
of anemia. In particular, CKD patients with hypo-
The prevalence of anemia in patients with CKD calcemia or hyperphosphatemia, with or without
has been widely studied. Notably, the reported elevated serum parathyroid hormone (PTH) level,
prevalence depends upon how GFR is estimated, also exhibit a high incidence of anemia [11, 12].
how anemia is defined, and the characteristics of Additionally, the incidence of anemia in patients
the study population. Community-based analyses who are current smokers is lower than that in
are most useful for avoiding the inherent biases in never smoking patients, which may be related to
studies of clinic-based populations. In general, smoking-induced hypoxia [11]. Because of the
the prevalence of anemia in patients with CKD high prevalence of anemia in CKD patients with
increases with deteriorating renal function. It GFR <60 mL/min/1.73 m2, it is recommended
begins to increase significantly when GFR is that these populations should be screened for
<60 mL/min/1.73 m2, and becomes more fre- anemia, especially among individuals with diabe-
quent or severe when GFR is <30 mL/ tes or in elderly adults.
min/1.73 m2. Stauffer and co-workers reported
their studies of 12,077 adults from the National
Health and Nutrition Examination Survey in 10.4 Pathogenesis
2007–2010. They found that the prevalence of
anemia in people with CKD (15.4%) was twofold Although its etiology is multifactorial, abundant
greater than that in the general population (7.6%); evidence indicates that the anemia associated
moreover, the prevalence of anemia increased with CKD arises primarily from inadequate EPO
with stage of CKD: 8.4% at stage 1, 12.2% at produced by the kidneys [13]; thus, anemia in
stage 2, 17.4% at stage 3, 50.3% at stage 4, and CKD is often characterized by a normochromic
53.4% at stage 5 [1]. This trend has been reported and normocytic appearance of peripheral circu-
by several other authors [4, 5]. In China, recent lating erythrocytes. Other contributors include
studies found that the prevalence of anemia in impairment of the erythropoietic response to
patients with CKD not undergoing dialysis was endogenous or exogenous EPO, iron deficiency,
51.5%, and that it increased with advancing CKD blood loss, hemolysis, and other factors [14].
stage; stage 1: 22.4%, stage 2: 30.0%, stage 3:
51.1%, stage 4: 79.2%, and stage 5: 90.2% [6].
These data suggest that the reduced production of 10.4.1 Absolute or Relative Lack
endogenous EPO may be attributed to reductions of EPO
in estimated GFR.
Patients with diabetic kidney disease (DKD) Absolute or relative EPO deficiency is the pri-
tend to have a higher incidence of anemia, which mary factor that leads to anemia among patients
typically occurs at earlier stages of CKD and is with CKD. Endogenous EPO is a circulating
10 Anemia in Chronic Kidney Disease 125
glycoprotein of 165 amino acids with one decline in renal excretory and endocrine func-
O-linked and three N-linked carbohydrate chains. tions [19, 20]. A prior study showed that the
Its molecular weight is 30,400 Da, and its half- serum EPO level can partially increase or
life is 5 h. EPO is synthesized primarily by peri- decrease in the presence of aggravated anemia, or
tubular type I interstitial cells located in the because of an increase in hemoglobin due to
cortex or outer layer of the renal medulla between blood transfusion [20].
the basolateral membrane of the proximal tubules
and peritubular capillaries [15]. The gene that
encodes EPO is located on chromosome 7 (q11- 10.4.2 Iron Deficiency
q22) [16], and its gene transcription is activated
by hypoxia-inducible factor (HIF) [17], which is Iron deficiency is an important factor that leads to
a transcription factor that responds to hypoxia anemia development and progression in patients
and activates the transcription of all hypoxia- with CKD. The total iron amount in healthy
induced genes, including EPO, vascular endothe- adults is approximately 4000 mg. Iron is actively
lial growth factor, platelet-derived growth factor, recycled in the body, and the daily circulating
and glycolytic enzymes. In response to hypoxia level of iron can approach approximately 20 mg
and anemia, the concentration of EPO in the cir- during the destruction and production of erythro-
culation can vary up to 1000-fold, compared with cytes. However, the iron absorption and secretion
its concentration under basal conditions [18]. pathways are extremely limited and comprise
Indeed, compared with normal persons who approximately 1–2 mg daily. The small intestine
do not exhibit anemia, CKD patients with mild or is the sole site of iron absorption, and Fe3+ in food
moderate renal hypofunction have normal or can be reduced to Fe2+, then transported through
higher serum EPO levels, and their hemoglobin intestinal epithelial cells. Additionally, heme can
levels negatively correlate with EPO levels. Thus, be absorbed and degraded by intestinal epithelial
lower hemoglobin levels may result in higher cells to release Fe2+. Importantly, Fe2+ absorbed
EPO levels in these patients [19]. However, the through the above pathways can be stored in the
EPO levels in CKD patients with anemia are liver, small intestine, and macrophages in the
lower than those in non-kidney disease patients form of ferritin for the use by body when neces-
with different degrees of anemia; this is also sary. Further, Fe2+ can penetrate the intestinal epi-
referred to as relative EPO deficiency. thelial basilar membrane under the joint action of
When renal tissue is increasingly destroyed ferroportin 1 (FPN1) and hephaestin (Hp) and be
with the progression of kidney disease, the dis- released into the blood, where it is oxidized to
eased kidney cells reduce their response to ane- Fe3+ and can bind with transferrin. Hepatocytes
mia and hypoxia, causing reduced EPO synthesis can internalize the bound iron by using transfer-
and secretion. Under inflammatory conditions, rin receptor (TfR) 2. A proportion of the absorbed
excessive PTH level and elevated levels of iron reaches the bone marrow through blood and
inflammatory factors, such as interleukin (IL)-1α, is then used in hemoglobin synthesis and erythro-
IL-1β, and tumor necrosis factor (TNF)-α, also cyte production. Alternatively, it may bind with
inhibit EPO synthesis. In patients with severe TfR1 on normoblasts and enter reticulocytes for
renal insufficiency, when the creatinine clearance hemoglobin synthesis during the erythrocyte dif-
rate (CCR) declines to <40 mL/min/1.73 m2, the ferentiation process.
serum EPO level begins to decrease greatly, in a Patients with stage 3–5 CKD may exhibit
manner that is not regulated by the current sever- reduced appetite or food restriction, which
ity of anemia; this is known as absolute EPO defi- causes reduced iron uptake from the digested
ciency [19, 20]. The clinical manifestations of food. Additionally, antacid/acid-inhibitory
anemia become more obvious at this time. The drugs and calcium carbonate, as well as phos-
serum EPO concentration in these patients is pos- phate and carbonate in food, may suppress iron
itively correlated with CCR, indicating parallel absorption. Long-term blood loss in small vol-
umes, such as residual blood in the dialyzer 10.4.3 Inhibitors of Erythropoiesis

and pipeline after each episode of hemodialy-
sis (iron loss of approximately 1–2 g/year), Certain substances in plasma inhibit erythrocyte
regular blood extraction examination, blood production in patients with CKD, which play a
loss during vascular access surgery, and intes- crucial role in the pathogenesis of renal anemia.
tinal blood loss in some patients, may ulti- However, the precise mechanism of their action
mately result in body iron consumption. The remains unclear at present. Currently, inhibitors
application of ESAs can stimulate erythrocyte of erythropoiesis have been suggested to mainly
synthesis, which also leads to increased iron include polyamines, PTH, and cytokines.
depletion. Insufficient iron uptake and Polyamines are the metabolites of amino acids,
increased iron depletion may lead to insuffi- which include spermine, spermidine, putrescine,
cient iron reserve (absolute deficiency). The and cadaverine. Due to the reduced scavenging
micro-inflammatory status in patients with capacity of polyamines by the kidney, poly-
CKD can lead to impaired iron utilization amines accumulate in the plasma of patients with
(functional deficiency) [21, 22]. renal insufficiency, which can inhibit the produc-
Hepcidin is a cysteine-enriching antibacterial tion of colony-forming unit-erythrocytes (CFU-
polypeptide that is synthesized and secreted by E) [25]. In CKD patients with secondary
the liver. It plays a crucial role in regulating iron hyperparathyroidism, the high PTH level can
metabolism by binding with FPN1 to promote its downregulate the erythrogenin receptor located
degradation. In patients with iron overload or at the CFU-E membrane, thus reducing its sensi-
inflammatory status, hepcidin gene expression tivity to EPO [26]. In addition, PTH can also
can be upregulated, and its synthesis and secre- inhibit the calcitriol receptor on the CFU-E mem-
tion by the liver can be increased, thus accelerat- brane surface, inhibit CFU-E proliferation and
ing FPN1 degradation and reducing iron differentiation, directly suppress bone marrow
transportation from intestinal epithelial cells and hematopoiesis, and cause reduced erythropoiesis
macrophages to blood. However, hepcidin gene [27]. Furthermore, PTH can also induce renal
expression and its synthesis can be downregu- osteopathia and myelofibrosis, which results in
lated by iron deficiency, increased erythrocyte reduced CFU-E numbers, thereby leading to ane-
production, or hypoxia. In addition, micro- mia [27]. In patients with CKD, multiple cyto-
inflammatory status in patients with CKD can kines produced under micro-inflammatory
induce elevations in circulatory cytokines and conditions, such as TNF-α, IFN-1, and IL-1, can
pro-inflammatory factors, particularly IL-6, directly suppress or indirectly inhibit CFU-E for-
which may lead to elevated synthesis of hepcidin mation through IFN-β. In addition, IL-1β and
[23, 24]. Concurrently, in patients with CKD, the TNF-α can also reduce the responsiveness of
excretion of hepcidin from kidney is reduced, bone marrow to EPO, resulting in anemia [28].
which causes elevations in circulatory hepcidin Other factors can also inhibit erythropoiesis in
levels, thus resulting in reduced intestinal iron patients with CKD. For example, ribonuclease
absorption and iron retention in macrophages. activity in the plasma of uremia patients is
Ultimately, the available iron cannot satisfy the remarkably enhanced, which can inhibit the for-
requirement of erythrocyte production. Iron defi- mation of CFU-E in a dose-dependent manner
ciency gives rise to slow synthesis of hemoglo- [29]. N-acetyl-seryl-aspartyl-lysyl-proline
bin, which affects erythrocyte production, leading (AcSDKP) can inhibit erythropoiesis by suppress-
to anemia and ESA resistance in patients with ing hematopoietic stem cells. Notably, the plasma
CKD. In addition, iron deficiency also results in AcSDKP level in uremia patients is higher than in
neurotransmitter dys-synthesis and affects myeli- normal persons; this is more obvious in patients
nogenesis, which can lead to central nervous sys- using ACEI [30]. Quinolinic acid [31], an oxida-
tem disorder, maldevelopment, and restless leg tion product of tryptophan, as well as uremia tox-
syndrome. ins, such as 3-carboxyl-4-methyl-5-propyl furan
levulinic acid, can also induce renal anemia by due to inflammation and oxidative stress, which
inhibiting the production of CFU-E [32]. cause erythrocyte damage. Hemodialysis can
also induce hemolysis through a variety of fac-
tors. The average life span of erythrocytes in nor-
10.4.4 Malnutrition mal persons is approximately 120 days, while it
is approximately 40–60 days in patients with
Some patients with CKD suffer from malnutrition. CRF.
Low serum albumin can result in hemoglobin syn- Multiple uremia toxins in the plasma of CRF
thetic disorder and malnutrition-inflammation patients under uremic conditions can lead to
complex syndrome (MICS), thus inducing ane- chronic hemolysis. For instance, an elevated PTH
mia. CKD patients with renal insufficiency, also level may activate the erythrocyte membrane cal-
known as chronic renal failure (CRF), especially cium pump activity and induce influx of calcium
patients undergoing hemodialysis, frequently ions into erythrocytes, thus increasing the
experience nutrient deficiencies, such as folic acid osmotic fragility of the erythrocytes, such that
and L-carnitine, due to insufficient intake and dial- they are easily destroyed [37]. Additionally, PTH
ysis removal. Folic acid is an essential material for may suppress Na-K-ATPase activity in erythro-
hematopoiesis and its deficiency can deteriorate cytes, blocking energy metabolism and shorten-
renal anemia. In addition, L-carnitine deficiency ing their lifespans.
may accelerate erythrocyte osmotic fragility [33]; A large quantity of free radicals is produced
it may also reduce the deformability [34] and under an oxidative stress state in CRF patients.
membrane stability of RBCs [35] and is associated High concentrations of free radicals may induce
with renal anemia. lipid peroxidation of erythrocyte membranes,
reduce the deformability of erythrocytes, and
increase their fragility. Therefore, they may be
10.4.5 Aluminum Poisoning eliminated by the reticuloendothelial system
before the end of their lifespans, which consti-
Aluminum poisoning may occur in the presence tutes hemolysis.
of excessive aluminum content in water for Generally, macrophages can remove aging
hemodialysis or the application of aluminum- erythrocytes in blood circulation. However, in an
containing drugs [36], although this is currently inflammatory status in patients with CKD,
rare. Aluminum can bind with transferrin and because erythrocytes are enveloped by immuno-
block the binding of iron with hemoglobin, thus globulin or immune complexes, macrophages
affecting the synthesis of erythrocytes. In addi- may accelerate the removal of erythrocytes after
tion, aluminum can suppress the activities of activation by inflammatory signals, thus shorten-
some enzymes for synthesizing hemoglobin ing the erythrocyte lifespan [38].
(such as ferrochelatase, uroporphyrinogen decar- Hemodialysis may be related to hemolysis. If
boxylase, and delta-aminolevulinic acid dehydra- impure water for dialysis contains oxidizing
tase), thus resulting in anemia. Moreover, agents, such as chloramines, copper, and nitrate,
aluminum poisoning can cause reduced EPO erythrocyte fragility may be increased, leading to
responsiveness, further aggravating anemia. hemolysis. In addition, disinfecting formalin res-
idue in the dialyzer or dialysis channel may sup-
press glycolysis and ATP formation in
10.4.6 Shortened Life Span erythrocytes, which may cause acute hemolysis.
of Erythrocytes Moreover, extreme dialysate temperature
and Hemodialysis (>45 °C) or the application of hypotonic dialy-
sate may induce acute hemolysis. Blood pump
The erythrocyte membrane function in patients rotation may induce hemolysis through mechani-
with CKD may change under uremic conditions, cal injury.
Hypophosphatemia, which may be induced 10.5 Clinical Symptoms

by large doses of phosphate binder or malnutri- of Anemia
tion, is a factor for hemolysis in patients with
CKD. When the serum phosphorus concentra- Anemia can result in reduced tissue oxygen sup-
tion is lower than 0.32 mmol/L, erythrocyte fra- ply and oxygen consumption in patients with
gility may increase due to reduced ATP CKD, thus resulting in a series of clinical
production, thus causing hemolysis [34]. In symptoms.
addition, other factors that complicate CKD,
such as hypersplenism, incompatible transfu-
sion, microvascular lesion, or excessive zinc 10.5.1 Reduction in Quality of Life
concentration in the blood, may result in
hemolysis. In patients with CKD, some non-specific symp-
toms induced by anemia may reduce their quality
of life, including fatigue, weakness, fear of cold,
10.4.7 Certain Drugs Affecting anorexia, tachypnea, dyspnea, impaired exercise
Erythrocyte Production tolerance, difficulty in focusing attention, head-
ache, dizziness, insomnia, depression, and sexual
ACEI could block the generation of angiotensin dysfunction.
II (Ang II), which acts as a growth factor for ery-
throid progenitors and an erythropoietin secre-
tion agonist; notably, Ang II is an important 10.5.2 Cognitive Impairment
physiological regulator of erythropoiesis, which
can increase red blood cell numbers. Some clini- Reduced oxygen supply in the central nervous
cal studies have reported that the administration system may reduce the intelligence quotient,
of ACEI or ARB may reduce serum EPO levels attention, memory, and speed of information pro-
[39], which may subsequently reduce hematocrit cessing in patients with CKD.
or cause anemia in patients with renal insuffi-
ciency or renal transplantation who use these
medicines. The reduction of EPO by ACEI or 10.5.3 Increased Morbidity
ARB is dose-dependent. and Mortality
In patients with CKD with diabetes, the use of in Cardiovascular Diseases
thiazolidinediones may reduce hemoglobin lev-
els by downregulating the erythroid lineage tran- The blood oxygen-carrying capacity is reduced
scription factor GATA-1 [40], inducing reductions accordingly in anemic conditions; as a result,
in testosterone levels [41] and increasing fluid cardiac output increases through enhanced
retention [42]. heart rate and stroke volume, in order to main-
Diuretic drugs reduce tubular oxygen contain tissue oxygen supply. Moreover, the left
sumption by inhibiting active sodium reabsorp- ventricular end-diastolic volume and left ven-
tion. Acetazolamide, acting at proximal tubular tricular wall thickness may be increased in a
sites, can significantly reduce EPO formation in compensatory manner. In patients with CKD,
response to normobaric hypoxia, in a dose- the severity of anemia is closely related to the
dependent manner [43]. morbidity of left ventricle hypertrophy [2, 45],
Theophylline is a nonselective antagonist of which is also associated with increased risks of
adenosine that has been shown to increase the myocardial infarction, stroke, and death.
secretion of EPO. The administration of theoph- Additionally, anemia may lead to increased
ylline has been reported to attenuate the produc- susceptibility to infection and may accelerate
tion of EPO through modulation of adenosine the progression of kidney lesions in patients
[44]. with CKD.
10.6 Diagnosis of Renal Anemia • At least once per month in CKD stage 5
patients undergoing hemodialysis.
The diagnosis of anemia primarily depends on 3. For CKD patients with anemia receiving ESA
hemoglobin detection. To avoid the impact of therapy, the frequency of hemoglobin moni-
long dialysis interval on blood volume and the toring is as follows:
effect of blood concentration after dialysis, the • At least once per month at the initiation of
blood sample for hemoglobin in hemodialysis ESA therapy.
patients should be collected in the middle of the • At least every 3 months in non-dialysis
week (Wednesday or Thursday, in accordance patients and at least once per month in dial-
with the hemodialysis schedule), before or at the ysis patients during the maintenance of
beginning of a hemodialysis session. The timing ESA therapy.
of blood testing for hemoglobin is not important
in patients with non-dialysis CKD.
In the 2012 KDIGO guidelines, the diagnosis of 10.6.2 Differential Diagnosis
CKD-induced anemia is defined in adults and chil- of Anemia
dren >15 years of age with CKD as hemoglobin
concentration of <130 g/L in males and <120 g/L CKD patients that meet the above criteria can be
in females; in children with CKD, the diagnosis of diagnosed with renal anemia if there are no
CKD-induced anemia is defined as hemoglobin other causes of anemia. If the degree of anemia
concentration of <110 g/L in children 0.5–5 years, is not consistent with that of renal dysfunction
<11.5 g/dL in children 5–12 years, and <12.0 g/dL in patients with CKD (i.e., early renal dysfunc-
in children 12–15 years [3]. tion is accompanied by moderate to severe ane-
mia), it is necessary to rule out the existence of
other diseases that can cause anemia. The fol-
10.6.1 Assessment Frequency lowing examination should be performed for
of Anemia differential diagnosis with anemia caused by
other diseases.
Hemoglobin levels should be monitored regu-
larly in patients with CKD [3]. 1. Complete Blood Cell Count
Complete blood cell count includes hemato-
1. For patients without anemia, the frequency of crit/hemoglobin; red blood cell-related indica-
hemoglobin monitoring is as follows: tors, such as mean corpuscular volume
• Upon occurrence of clinical symptoms in (MCV), mean corpuscular hemoglobin
patients with CKD stage 1–2. (MCH), and mean corpuscular hemoglobin
• At least once per year in patients with CKD concentration; white blood cell count and
stage 3. classification; and platelet count.
• At least twice per year in non-dialysis • Microcytic anemia is associated with iron
patients with CKD stage 4–5. deficiency, aluminum toxicity, or
• At least every 3 months in patients under- hemoglobinopathy.
going hemodialysis and peritoneal • Macrocytic anemia is associated with defi-
dialysis. ciency of vitamin B12 or folic acid, and may
2. For CKD patients with anemia that is not
also be due to the entry of immature reticu-
treated with ESA, the frequency of hemoglo- locytes into the circulation, promoted by
bin monitoring is as follows [3]: iron overload and/or EPO treatment.
• At least every 3 months in non-dialysis • In cases of abnormal counts of white blood
patients with CKD stage 3–5 and in CKD cells and platelets, aplastic anemia, leuke-
stage 5 patients undergoing peritoneal mia, tumors, hypersplenism, and vasculitis
dialysis. should be excluded.
2. Reticulocyte Count Even if anemia caused by other diseases is

• Increased reticulocyte counts indicate the excluded, hyperparathyroidism, inflamma-
possibility of hemolytic anemia; sickle cell tion, malnutrition, and insufficient dialysis, all
anemia, sepsis, and thrombotic thrombocy- of which might aggravate anemia, should be
topenic purpura should be considered. Iron considered in patients with CKD. It is clini-
deficiency anemia and megaloblastic ane- cally and economically significant to correct
mia may also be accompanied by slightly reversible causes of anemia.
increased reticulocyte counts.
• Reduced reticulocyte counts suggest
reduced hematopoietic function of bone 10.7 T
herapy of Renal Anemia
marrow, such as aplastic anemia. in CKD
3. Iron Store and Iron Utilization Indicators
Iron is necessary for hemoglobin synthesis. 10.7.1 The Therapeutic Target Value
Detection of serum iron and total iron-binding of Renal Anemia
capacity can determine iron availability in
patients. Serum iron and transferrin saturation Studies have demonstrated that the incidences of
(TSAT) reflects the iron that can be readily all-cause mortality, fistula thrombosis, refractory
used for hemoglobin synthesis, while ferritin hypertension, and myocardial infarction in
represents the total iron store in the body. A patients with a high-level target of hemoglobin
reduction in any of the above indicators indi- (135 g/L) are significantly higher than those in
cates a lack of iron in the body, and its cause patients with a low-level target of hemoglobin
must be clarified. (115 g/L), whereas a lower target of hemoglobin
• Acute or chronic blood loss (90 g/L) also negatively affects the end point.
Chronic blood loss is the most common Therefore, the 2012 KDIGO guidelines for clini-
cause, commonly observed in gastrointes- cal practice suggest that the hemoglobin concen-
tinal bleeding, including peptic ulcers and tration generally should not exceed 115 g/L in
polyps, which can be assessed by fecal patients undergoing ESA maintenance; for all
occult blood examination. Patients under- patients, it is not recommended to increase the
going ESRD may also lose blood during hemoglobin concentration by more than 130 g/L
the vascular access procedure; blood loss by ESA [3].
can occur after hemodialysis, where blood
is left in the dialyzer and tubing; coagula-
tion might exacerbate blood loss during 10.7.2 Treatment with ESAs
dialysis. In addition, hemoptysis and
female menorrhagia can lead to blood loss. ESAs are a group of drugs that mimic the effects
• Iron absorption disorders of EPO; they promote erythropoiesis, cell prolif-
Iron absorption disorders are observed eration, and differentiation, and can also inhibit
after subtotal gastrectomy, in gastric can- cell apoptosis, primarily by binding to receptors
cer, and in malabsorption syndrome. on CFU-E. Prescription of ESAs is the primary
• Reduced iron intake therapeutic approach for renal anemia. Presently,
Iron intake is reduced in certain CKD ESAs can be classified into the following groups:
patients because of limited protein intake
or loss of appetite. 1
.
Recombinant human erythropoietin
4. Serum Folate and Vitamin B12 Levels (rHuEPO), the ESA most commonly applied
Deficiency of vitamin B12 or folic acid is found in clinic, is a sialic acid protein hormone with
in cases of malnutrition or upon administra- immunological and biological properties that
tion of antiretroviral drugs. closely resemble human EPO, primarily com-
5. Other Indicators Related to CKD Status prising rHuEPO-α and rHuEPO-β. The half-
life of rHuEPO is short, such that it should be dialysis, ESA therapy is recommended when
administered one to three times per week to hemoglobin level is within the range of
ensure sustained stimulation of RBC 90–100 g/L. Because quality of life is improved
production. in some patients at higher hemoglobin concentra-
2. Long-acting ESA preparations, including dar- tions, individualized ESA may be given at hemo-
bepoetin alfa and continuous erythropoietin globin >100 g/L. ESA treatment should be
receptor activator (CERA). Darbepoetin alfa cautiously managed for patients with a history of
is an improved version of rHuEPO, whose stroke or malignancy, and those who harbor
half-life is twofold longer than that of tumors that are expected to be curable.
rHuEPO-α, either by intravenous or subcuta-
neous injection; it can be administered every 10.7.2.2 ESA Access
2–3 weeks. CERA is the only agent capable of Intravenous and subcutaneous routes of ESA
maintaining ESA by monthly administration, administration are both effective to treat renal ane-
with a half-life of 134–139 h. CERA can be mia. Subcutaneous injection exhibits better phar-
administered once every 2 weeks or once macodynamics than intravenous injection and can
every 4 weeks to effectively correct renal ane- extend the maintenance time of effective drug con-
mia and maintain hemoglobin levels [46, 47]. centration in the body; however, it is accompanied
3. Novel ESA agents, including HIF stabilizers, by increased pain compared with intravenous
activin traps, EPO mimetic peptides, EPO injection. For CKD hemodialysis patients,
fusion proteins, antibody agonists to EPO although intravenous administration can reduce
receptors, and EPO gene therapy, are all in pain, either intravenous or subcutaneous adminis-
clinical research stages and are not available tration of ESA is recommended. For patients with
for treatment. non-dialysis or peritoneal dialysis CKD, subcuta-
neous injection of ESA is recommended.
10.7.2.1 Initiation and Timing
of the Use of ESAs 10.7.2.3 ESA Dose
Before the initiation of ESA therapy, all other • Initial dose
potential causes of anemia should be addressed, The initial dose of ESA is determined on the
including iron deficiency inflammatory condi- basis of the level of hemoglobin, body weight,
tions, and so on. The pros and cons of ESA treat- clinical status, and type of ESA used for the
ment should be weighed at the time of initiation, patient, as well as the access of administration.
and maintenance therapy with ESA should be The initial dose of rHuEPO is recommended as
assessed. The benefits of ESA treatment include 80–120 U/(kg·w), 2–3 times per week by sub-
reduction of blood transfusions and alleviation of cutaneous injection, or 120–150 U/(kg·w),
anemia-related symptoms; however, the potential three times per week by intravenous injection.
therapeutic risks, such as stroke, loss of vascular The initial dose of darbepoetin is recom-
access, and hypertension, should be carefully mended as 0.45 μg/kg once per week, or
evaluated. 0.75 μg/kg every 2 weeks. The degree of ane-
In patients with non-dialysis CKD, ESA ther- mia should be considered when selecting the
apy is unnecessary in patients with hemoglobin initial dose. For patients with hemoglobin
>100 g/L. In patients with hemoglobin <100 g/L, <70 g/L, the initial dose should be appropri-
personalized decisions regarding ESA therapy ately increased. For non-dialysis patients or
should be made by considering the rate of hemodialysis patients with better residual renal
globin decline, previous responses to iron ther- function, the initial dose may be appropriately
apy, the risk of transfusion, the risks associated reduced. For patients with a history of hyper-
with ESA treatment, and the presence or absence tension, diabetes, cardiovascular disease, vas-
of symptoms due to anemia. For patients with cular embolism, or epilepsy, ESA should
CKD stage 5 who are undergoing maintenance initially be administered at a low dose.
• Adjustment of dose tored and doses of antihypertensive drugs

Hemoglobin levels should be regularly moni- should be adjusted accordingly.
tored during ESA treatment. If the monthly • Thrombosis of dialysis access
growth rate of hemoglobin is under 10 g/L, Studies have shown that the risk of thrombosis
after ruling out other causes of anemia, the in hemodialysis access increases in response
dose of ESA should be increased by 25%. In to increased levels of hemoglobin, which may
contrast, a sharp increase in hemoglobin levels be related to improved platelet function and
may cause an increased incidence of cardio- stimulation of proliferation of vascular endo-
vascular adverse events. In patients whose thelial cells and vascular smooth muscle cells
hemoglobin growth rate within 2 weeks is by EPO treatment; this may lead to stenosis of
>10 g/L, the dose of ESA should be reduced vascular access [53]. Vascular access of hemo-
by 25%, but not immediately discontinued. dialysis patients should be assessed during
Cessation of ESA, especially prolonged with- EPO treatment. However, there is insufficient
drawal, may lead to sustained reduction in evidence that the current target of hemoglobin
hemoglobin, such that it declines below the will increase the incidence of thrombosis of
target range. hemodialysis access.
• Tumor progression
10.7.2.4 Frequency of ESA ESA treatment may promote tumor progres-
Administration sion and increase mortality among tumor
The administration frequency should be based on patients [54]. Some scholars have shown that
the CKD stage, degree of anemia, therapeutic the activation of EPO receptors (EPORs) on
strategy, efficacy, patient tolerance and prefer- the surface of tumor cells can promote tumor
ence, and type of ESA. It is not recommended to cell proliferation and inhibit apoptosis, subse-
administer high-dose ESA therapy once per quently reducing the sensitivity of anti-tumor
week, either via subcutaneous or intravenous therapy [54]. However, recent studies have
administration of rHuEPO. Instead, multiple found that many tumor cell lines express very
injections at lower doses are recommended to low levels of EPORs, and that many of these
minimize fluctuations in the serum concentration EPORs are nonfunctional [55]. Despite the
of rHuEPO, in order to optimize the effect of unclear mechanism, based on previous results
rHuEPO. of clinical studies, ESA therapy should be
cautiously administered in CKD patients with
10.7.2.5 Side Effects of ESA Therapy tumors [3]. Closer monitoring is necessary
• Hypertension after treatment with ESA.
• Hypertension is the most common side effect • EPO antibody-mediated pure red cell apla-
of ESA. ESA causes a direct increase in the sia (PRCA)
level of endothelin-1 [48, 49], which con- The appearance of EPO antibodies after EPO
stricts blood vessels and subsequently leads to treatment is rare, but is often very serious. If,
hypertension. In addition, ESA increases cal- after EPO treatment for >4 weeks, the hemo-
cium influx in vascular smooth muscle cells in globin level declines rapidly at a rate of
a dose-dependent manner, thereby reducing 5–10 g/(L·w) and the number of reticulocytes
the response of vascular smooth muscle cells is <1% or <10 × 109/L, while the numbers of
to NO and increasing vascular resistance, ulti- white blood cells and platelets are normal,
mately increasing blood pressure [50, 51]. PRCA should be suspected. The diagnosis of
ESA also upregulates the expression levels of PRCA should be based on the presence of
renin, angiotensinogen, and angiotensin EPO antibodies and support from bone mar-
receptor in vascular smooth muscle cells [52], row findings. The occurrence of PRCA may
thereby inducing hypertension. Thus, during be associated with increased antigenicity with
ESA therapy, blood pressure should be moni- subcutaneous injection of EPO, as well as
adjuvant components in some products. status should be assessed more frequently when
Confirmed patients should discontinue EPO ESA treatment is initiated or the dose is increased,
treatment, and blood transfusion and immuno- if blood loss occurs, or in other conditions associ-
suppressive therapy may be effective [56]. ated with depletion of iron stores. Furthermore,
• ESA hyporesponsiveness the efficacy after one intravenous iron therapy
ESA hyporesponsiveness occurs in 5–10% of cycle should be monitored [3]. The indicators of
ESRD patients who are prescribed ESA. The assessment of iron deficiency include:
definition of ESA hyporesponsiveness is an
ESA requirement of >300 IU/kg per week of • Bone marrow iron staining
subcutaneous epoetin, 400–450 IU/kg per Bone marrow iron staining is the gold stan-
week of intravenous epoetin, or 1.5 μg/kg per dard for diagnosis of iron deficiency, but its
week of darbepoetin [57, 58]. ESA hypore- application is limited due to the inherent
sponsiveness may be associated with increased trauma required to obtain usable specimen.
morbidity and mortality in chronic hemodial- • Serum ferritin (SF) and TSAT
ysis patients [59]. Pre-transplantation ESA A combination of SF and TSAT is currently
hyporesponsiveness in renal transplantation used to diagnose iron deficiency. If the TSAT
recipients may be related to increased kidney is <20% and SF is <100 μg/L in non-dialysis
allograft failure [60]. Iron deficiency, infec- and peritoneal dialysis patients, or if TSAT is
tion, and other pro-inflammatory conditions <20% and SF is <200 μg/L in hemodialysis
are important causes of ESA hyporesponsive- patients, the body iron store is judged to be
ness. Other causes of ESA hyporesponsive- deficient, a state known as absolute iron defi-
ness include secondary hyperparathyroidism, ciency. If TSAT is <20% and SF is >100 μg/L
inadequate dialytic clearance, active blood in non-dialysis and peritoneal dialysis patients,
loss, deficiency in vitamin B12 and folic acid, or if TSAT is <20% and SF is >200 μg/L in
malnutrition, aluminum overload, multiple hemodialysis patients, deficiency of available
myeloma, hemolysis, hemoglobinopathy, iron is suggested, a state known as relative
administration of ACE inhibitors and ARBs, iron deficiency. However, patients with CKD
and erythropoietin-associated PRCA. For often exhibit a co-existing inflammatory state,
patients with ESA hyporesponsiveness, the and acute phase reactions can lead to increased
dose of ESA should not be increased indefi- SF [61].
nitely; instead, appropriate treatment should • Reticulocyte hemoglobin content (CHr)
be performed by identifying relevant causes. CHr represents early changes in iron defi-
ciency, which are not affected by the acute
phase response; these can more accurately
10.7.3 Iron Therapy reflect the status of body iron deficiency [62].
In patients receiving ESA therapy, the diag-
Iron deficiency is an important cause of renal nostic threshold for functional iron deficiency
anemia and poor response to ESA therapy. Iron is 29 pg [63].
supplementation can significantly improve the • Red blood cell distribution width (RDW),
efficacy of ESA and can reduce the amount of MCH, MCV
ESA required for a desired outcome. An increase in RDW, accompanied by reduc-
tions in MCH and MCV, indicates iron
10.7.3.1 Assessment of Iron Status deficiency.
The body’s iron status should be monitored in • Liver iron content (LIC)
CKD patients with anemia. During ESA treat- LIC is a primary indicator of iron overload in
ment, iron status should be assessed at least once the body. Liver biopsy is the “gold standard”
every 3 months, including at the time of the deci- for measuring liver iron content, but has been
sion to initiate or continue iron treatment. Iron gradually replaced by noninvasive technology
due to its invasiveness. Noninvasive methods liposomal iron exhibit a high absorption rate
for measuring LIC include magnetic reso- in the gastrointestinal tract with high bioactiv-
nance imaging and super-conducting quantum ity, but the gastrointestinal side effects remain
interference device biomagnetic liver [65].
susceptometry. • Intravenous iron
• Other new parameters Intravenous iron includes iron sucrose, feru-
Soluble TfR is not affected by inflammation, moxytol, ferric carboxymaltose, ferric gluco-
and can be used to distinguish absolute iron nate, and iron dextran. Intravenous iron has
deficiency from functional iron deficiency the advantages of high bioavailability, low
[24]. However, its clinical diagnostic efficacy incidence of gastrointestinal reactions, and
requires further investigation. Other parame- lack of susceptibility to effects from other
ters include hepcidin, non-transferrin-bound drugs; moreover, it can improve the efficacy
iron, and labile plasma iron. of ESA, thus reducing the ESA dose required
to achieve and maintain the target value of
10.7.3.2 The Timing of Iron Therapy hemoglobin [66, 67]. However, intravenous
The benefits and risks should be weighed before iron is associated with hypersensitivity [68];
initiating iron therapy by assessing potential ben- in this regard, iron sucrose, ferumoxytol, and
efits and therapeutic risks to reduce blood trans- ferric carboxymaltose are safer, whereas iron
fusions and alleviate anemia-related symptoms dextran may cause serious allergic reactions
(e.g., allergic reactions and other acute reactions, and is generally not recommended. I ntravenous
or unknown long-term risks). Patients with active iron may increase the risk of infection [69,
infection should avoid the administration of iron. 70]; furthermore, free iron from circulation or
In adult CKD patients with SF ≤500 μg/L and iron overload can lead to oxidative damage of
TSAT ≤30%, iron therapy should be adminis- blood vessels and other tissues [71, 72].
tered on the basis of criteria for anemia in CKD,
not on the basis of criteria for iron or ESA ther- 10.7.3.4 Medication with Iron
apy, in order to increase hemoglobin levels. In Non-dialysis patients and peritoneal dialysis
patients who have received ESA therapy but not patients may initially attempt oral iron therapy or
iron therapy, iron therapy should be administered intravenous iron therapy, on the basis of the sta-
if increased hemoglobin levels or reduced ESA tus of iron deficiency. Intravenous iron therapy is
doses are desired [3]. Iron therapy is not routinely given priority in hemodialysis patients. Iron sta-
administered in patients with SF >500 μg/L; tus should be assessed after 1–3 months of oral
however, iron therapy can be attempted if high- iron therapy; modification of intravenous iron
dose ESA fails to alleviate anemia; in these therapy is recommended in cases where the target
patients, acute inflammation, iron overload, and values of iron status and hemoglobin could not be
other conditions should be ruled out [64]. reached, or in cases of intolerance of oral iron
Pediatric CKD patients with anemia should be therapy [3].
administered iron therapy when SF is ≤100 μg/L Dose of oral iron: Daily supplementation of
and TSAT is ≤20% [3]. elemental iron is recommended at 200 mg and
2–3 mg/kg (body weight) in adult and children,
10.7.3.3 Categories of Iron Therapy respectively; this should be orally administered
• Oral iron 2–3 times per day.
Oral iron formulations include ferrous sulfate,
ferrous succinate, ferrous gluconate, and fer- Dose of intravenous iron:
rous fumarate. Oral iron is less expensive, but • Loading dose: In non-dialysis and peritoneal
is poorly absorbed. A subset of patients dialysis patients, 750–1000 mg of elemental
(approximately 30%) may experience gastro- iron should be supplemented within 1–2 weeks
intestinal side effects. New formulations of by 2–3 intravenous injections each week. In
maintenance hemodialysis patients, 100– tion of anemia to stabilize the patient (for exam-
125 mg iron should be injected intravenously ple, in cases of acute bleeding or unstable
each week; the cumulative dose of one course coronary heart disease).
of iron is 1000 mg. If iron status fails to reach
standard levels, injection can be repeated as
necessary. 10.7.5 Other Adjuvant Therapy
• Maintenance dose: A low dose of iron (for
example, 50–60 mg per week in adult hemo- Consideration should be given to the existence of
dialysis patients and 1 mg/kg/week in pedi- folic acid and vitamin B12 deficiency in patients
atric patients) is provided to maintain iron with renal anemia. Hemodialysis can remove
stores after the iron status has been met [73]. folic acid and vitamin B12; thus, patients under-
• The dose and time interval of intravenous iron going maintenance hemodialysis should be sup-
therapy should be adjusted based on the plemented with appropriate doses of folic acid
response to iron, iron status, hemoglobin lev- and vitamin B12. In addition, for hemodialysis
els, ESA dose, ESA response, and recent com- patients, the application of l-carnitine may be
plications of patients. beneficial, but is not recommended as a routine
treatment; it should be handled accordingly in
10.7.3.5 Precautions of Iron Therapy clinical practice.
• Avoid intravenous iron in patients with active
systemic infections.
• For first-time intravenous administration 10.7.6 Emerging Therapy
of iron dextran, or for first-time intrave-
nous non-dextran administration, patients It has been demonstrated that HIF prolyl hydroxy-
should be monitored for 1 h after infusion; lase inhibitors, a kind of new promising therapeu-
resuscitation equipment (including medi- tic drugs for treatment anemia in patients with
cation) and training should be provided to CKD, can take effects through multiple pathways.
react to possible serious adverse reactions. In addition to increasing EPO levels, they also
• During the application of intravenous iron, play a role in iron handling and inflammation.
iron indicators should be regularly monitored Recent reports from two phase 3 clinical trials
to prevent iron overload. performed in China have showed that HIF prolyl
hydroxylase inhibitor was superior to placebo in
increasing hemoglobin levels in anemia patients
10.7.4 Transfusion Therapy with non-dialyzed CKD and was noninferior to
EPO in increasing hemoglobin levels in anemia
Transfusions should be avoided as much as pos- patients with maintenance hemodialysis [74, 75].
sible to reduce the risks associated with transfu-
sions and with allogeneic sensitization in patients
eligible for organ transplantation. In patients 10.8 Summary
with chronic anemia, simple hemoglobin levels
should not be used as a threshold for transfu- High prevalence of anemia is seen in patients
sions. Red blood cell transfusion can be per- with CKD, and the shortage of EPO and iron is
formed in case where the benefits outweigh the the main cause of anemia in this population.
risks from ESA in patients with cardiovascular Since anemia contributes to increased morbidity
and neurological symptoms, patients for whom and mortality of cardiovascular diseases, it is
ESA therapy has been ineffective, or patients important to evaluate the state of anemia regu-
with a history of malignancy and stroke. In acute larly in patients with each stage of CKD. A sche-
clinical conditions, red blood cell transfusion matic presentation of evaluation for anemia in
can be conducted as necessary for rapid correc- CKD adults is shown in Fig. 10.1.
Fig. 10.1 Flowchart for

Patients with CKD stages 1–5
the evaluation of anemia
in patients with chronic
kidney disease. TIBC
total iron-binding Hemoglobin detection
capacity; TSAT Periodic follow-up
transferrin saturation; SF
serum ferritin; ESA No <130 g/L in males?
erythropoiesis- <120 g/L in females?
stimulating agent
YES
Complete blood cell, Blood loss, Serum folate
Reticulocyte; and vitamin B12,
TIBC, Fe, TSAT, SF Hemoglobinopathy
YES No No
Normal? Fe deficiency?
YES
Treat with ESA
if indicated Treat with iron
No
Anemia corrected?
YES
Periodic follow-up
Key Messages should be monitored regularly during

• KDIGO defines anemia in patients with treatment. It is generally recommended
CKD as hemoglobin <130 g/L in adult that hemoglobin concentration not
males and <120 g/L in adult females, exceed 115 g/L in patients undergoing
<110 g/L in children 0.5–5 years, ESA maintenance; the monthly hemo-
<115 g/L in children 5–12 years, globin growth rate should be ≥10 g/L,
and <120 g/L in children 12–15 years. but <20 g/L. Transfusions should be
• Anemia is a frequent complication in avoided as much as possible. HIF prolyl
patients with CKD, and its prevalence hydroxylase inhibitors is a kind of new
increases as renal function declines. promising therapeutic drugs.
Hemoglobin levels should be regularly
monitored in patients with CKD.
• The etiology of anemia in CKD is mul-
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Chronic Kidney Disease-Mineral
and Bone Disorder, Vitamin D 11
Deficiency, and Secondary
Hyperparathyroidism
Mingxia Xiong
Abstract Improving Global Outcomes (KDIGO) published

Chronic kidney disease-mineral and bone dis- a position statement proposing a new approach to
order (CKD-MBD) encompasses laboratory classification of bone and mineral disorders,
and bone abnormalities and vascular or other termed as “chronic kidney disease-mineral and
soft tissue calcification and has adverse effects bone disorder” (CKD-MBD) [1]. KDIGO views
on clinical prognosis. The 2017 KDIGO clini- CKD-MBD as a systemic disorder manifested by
cal practice guideline recommends monitor- one or more of the following: (1) abnormalities
ing serum levels of calcium, phosphate, PTH, of calcium, phosphorous, parathyroid hormone
and alkaline phosphatase activity beginning in (PTH), or vitamin D metabolism, (2) abnormali-
CKD G3a. Treatments of CKD-MBD should ties in bone pathology and histomorphometry
be based on serial assessments of phosphate, marked by changes in bone turnover, mineraliza-
calcium, and PTH levels, considered together. tion, volume, linear growth, or strength (TMV
In patients with CKD G3a–G5D with severe system), and (3) the presence of vascular or other
hyperparathyroidism who fail to respond to soft tissue calcification [1].
pharmacological therapy, we suggest parathy-
roidectomy. The ambiguity and lack of
unequivocally actionable recommendations 11.2 Pathophysiology
highlight potential challenges for implementa-
tion and underscore the need for future There exists evidence on bone remodeling that
research in this important area. progresses with advanced kidney disease to stage
3 CKD, which is referred to as renal osteodystro-
phy. Interestingly, these changes may occur ear-
lier [2, 3]. In a large cross-sectional study on
11.1 Introduction MBD biochemical markers, serum PTH elevated
in 12% of patients with an estimated glomerular
Disorders in calcium, phosphorus, and parathy- filtration rate (eGFR) >80 mL/min/1.73 m2,
roid hormone (PTH) are common in chronic kid- whereas other biochemical parameters, serum
ney disease (CKD). In 2006, Kidney Disease: phosphorous (Pi) and calcium (Ca) levels,
remained within the normal range until eGFR
M. Xiong (*) <40 mL/min/1.73 m2 [3]. These bone changes are
Centre for Kidney Disease, Second Affiliated responsible for fractures, bone pain, immobility,
Hospital, Nanjing Medical University, and weakness [2, 4, 5], and the associated MBD
e-mail: xiongmingxia@njmu.edu.cn biochemical disorders were associated with an

142 M. Xiong
increase in cardiovascular events and all-cause treatment. The dual-energy X-ray absorptiometry
mortality [6–11]. Observational studies that (DEXA), a two-dimensional bone density scan
included hemodialysis patients have reported the used to diagnose osteoporosis, may not be useful
correlation of cardiovascular events with serum in differentiating these two disorders and, in fact,
Pi, serum Ca and Pi product, and PTH levels, may sometimes overestimate bone mineral den-
whereas a few observational studies that included sity (BMD) in moderate CKD [16]. Quantitative
predialysis patients showed that cardiovascular computerized tomography (qCT) and micro-
events have a similar correlation with elevated magnetic resonance imaging (mMRI) better dis-
serum Pi and PTH levels [11, 12]. Elevation in criminate changes in the cortical and trabecular
PTH level in CKD patients is an adaptive bone and changes in bone volume [16] and might
response to an increase in serum Pi level from aid in the differential diagnosis. However, the
reduction of eGFR, a low serum Ca2+ level from a gold standard for differentiating these two disor-
decrease in 1,25-dihydroxy vitamin D3 ders is the two-phase tetracycline labeling bone
(1,25[OH]2D3, calcitriol) level, an increase in biopsy [16, 17].
fibroblast growth factor (FGF)-23 level, and a
decrease in calcitriol level from a reduction in
1-α-hydroxylase production, which is correlated 11.3 Biochemistry in CKD-MBD
with both renal osteodystrophy and the adverse
clinical outcomes. Hyperphosphatemia, hypocalcemia, low cal-
The term “renal osteodystrophy” was previ- citriol level, elevated FGF-23 level, and elevated
ously used to describe both bone histology and serum PTH level, all play important roles in the
biochemistry findings and is currently defined development and progression of CKD-MBD at
based on only by histology and histomorphomet- different periods. As renal function declines,
ric findings obtained by bone biopsy at an ideal serum Pi level increases, which can stimulate the
site such as the iliac crest [2, 4]. Bone biopsy secretion of FGF-23 from osteocytes. There is a
should be considered in advanced CKD patients decline in the production of the 1-α-hydroxylase
with unexplained fractures, persistent bone pain, in the proximal convoluting tubule (PCT). The
unexplained hypercalcemia, unexplained hypo- inactivity of the Na-Pi transporter can result in
phosphatemia, possible aluminum toxicity, and phosphaturia. Low calcitriol levels commonly
prior to therapy with bisphosphonates [4]. There seen in renal failure may be secondary to inhibi-
are four types of renal osteodystrophy: (1) osteitis tion by FGF-23 rather than by a decrease of
fibrosis (high turnover) related to an elevated 1-α-hydroxylase in renal parenchymal [18–20].
serum PTH level, (2) adynamic bone disease (low More recently, FGF-23 and klotho also have been
turnover), (3) osteomalacia (low turnover), and (4) identified as important regulators of mineral
mixed uremic osteodystrophy [2, 4, 12–14]. The metabolism. Klotho deficiency and high circulat-
2017 KDIGO guideline states: “in patients with ing FGF-23 levels precede secondary hyperpara-
CKD G3a–G5D, it is reasonable to perform a bone thyroidism in CKD patients. Levels of FGF-23
biopsy if knowledge of the type of renal osteodys- and PTH increase with the progression of CKD
trophy will impact treatment decisions” [15]. to overcome end-organ resistance and to main-
The prevalence of CKD and osteoporosis is tain mineral homeostasis [21–23]. It is difficult to
particularly increased in the elderly population in define when the increase of both hormones
whom they commonly coexist, which may further becomes maladaptive. The components of the
complicate MBD [16, 17]. Osteoporosis is an mineral bone abnormalities and their contribu-
absorptive process, whereas CKD-MBD is an tion to MBD will be discussed individually. The
imbalance of bone formation, mineralization, and 2017 KDIGO clinical practice guideline recom-
volume, and both can result in fractures. Therapy mends monitoring the serum levels of calcium,
differs for these two disorders; hence, differential phosphate, PTH levels, and alkaline phosphatase
diagnosis is very important to avoid inappropriate activity beginning in stage G3a CKD [15].
11 Chronic Kidney Disease-Mineral and Bone Disorder, Vitamin D Deficiency, and Secondary… 143
11.3.1 Calcium unbound Pi is filtrated by the glomerulus freely,

of which 80–90% is reabsorbed in the PCTs (60–
Calcium is one of the main cations in the human 70%) and distal nephron (20–30%) [24]. In early
body, which can maintain the structure of bone CKD, the serum Pi level is maintained by reduced
and regulate cell function. Furthermore, 99% of absorption in the GI tract due to decreased cal-
the body’s calcium is contained in skeletal and citriol level [24] and increased Pi excretion
the intracellular compartment, and only 1% is through decreased expression of the Na-Pi 2a co-
available for calcium homeostasis [24, 25]. The transporter in the PCTs via the action of PTH [24,
normal serum calcium range in adults is 8.4– 26] and FGF-23 [22, 27].
10.4 mg/dL, and 50% of serum calcium circu- Hyperphosphatemia is associated with a
lates freely, whereas the remainder is bound to higher prevalence of soft tissue calcification,
albumin or anions. Serum calcium is maintained such as coronary arteries, descending aorta, aor-
by various hormones such as PTH, calcitonin, tic valve, and mitral valve [7]. Besides extra-
and calcitriol, which in turn regulate the intes- skeletal calcification, hyperphosphatemia is also
tine, kidney, and bone to maintain serum calcium responsible for other adverse outcomes in CKD
level [24]. patients. A study reported that rats with CKD fed
In advanced CKD, calcium absorption in the with high phosphate diet had higher heart weights
small intestine is reduced secondary to a decrease than corresponding control rats [28].
of calcitriol and dietary intake. Elevation in Pi
and a low serum Ca2+ level result in an increase of
PTH secretion via the Ca2+ sensing receptor 11.3.3 Parathyroid Hormone
(CaSR) [24, 25]. This increase in serum PTH
level can stimulate renal distal tubules to reab- PTH is the major modulator of bone and mineral
sorb more Ca2+ and an increase of bone resorp- metabolism through its regulation of calcium and
tion for attempting to maintain normal serum Pi homeostasis. Synthesis and cleavage of PTH
Ca2+ level. occur within the parathyroid gland. PTH is a
polypeptide synthesized in the endoplasmic retic-
ulum following two successive cleavages: 115
11.3.2 Phosphate amino acid pre-pro-PTH cleaved to 90 amino
acid pro-PTH. Pro-PTH is then cleaved again to
Phosphorus (Pi) is an abundant element in the form an active mature full-length 84 amino acid
body and is essential for a wide variety of key PTH, with the first 6 amino acids accounting for
biological processes. It plays an important role its activity, while the 7–84 amino acids fragment
in cellular energy metabolism and cell signaling, protein is inactive [4]. The whole process of PTH
e.g., adenosine and guanosine triphosphates synthesis, its cleavage and storage, is fast and has
(ATP, GTP), and in the composition of phospho- been estimated to take less than an hour. After
lipid membranes and bone, and is an integral release, PTH is rapidly removed from the serum
part of DNA and RNA [24, 26]. In the body, by the kidney and the liver.
80–85% of Pi is in the skeleton [24], 1% is in the PTH has a major biological function in main-
serum in an inorganic form [26], whereas the taining ionized calcium and phosphate within the
remainder is in other intracellular and extracel- reference range by stimulating specific receptor-
lular compartments. mediated responses in cells throughout the body.
Pi homoeostasis is maintained by a balance If a decrease in circulating ionized calcium
between dietary Pi absorption by the gut, mobili- occurs, PTH increases and has three major
zation from bone, and renal excretion. The serum functions that help to restore a normal circulating
Pi is largely unbound [24], ranging from 2.5 to concentration: receptor-mediated tubular reab-
4.5 mg/dL. Pi is absorbed in the small bowel sorption of calcium (kidney); stimulation of
under the influence of calcitriol. In the kidney, osteoclast resorption to release skeletal calcium
144 M. Xiong
(bone); and increasing activity of renal The FGF-23 receptor complex, Klotho–
1-α-hydroxylase, resulting in production of FGFR1, is expressed in the parathyroid cells, and
1,25[OH]2D3 and increasing calcium absorption a challenge with recombinant FGF-23 activates
(bowel). The increase in calcium in response to the mitogen-activated protein kinase (MAPK) 1
these effects mediated by PTH acts via a classic pathway to decrease PTH mRNA levels and PTH
endocrine feedback loop on the CaSR, decreas- secretion both in vivo and in vitro [35, 36]. In
ing secretion of PTH [29–33]. PTH is a major both experimental CKD and in parathyroid tissue
regulator of bone turnover and acts directly on from patients with CKD, serum PTH and FGF-23
osteoblasts and indirectly on osteoclasts [24]. levels are markedly increased, suggesting a resis-
Increased serum PTH levels are prone in African tance of the parathyroid gland to FGF-23. This
Americans, the obese, and nondiabetic patients resistance is caused by a decreased expression of
with CKD [11]. Although initial evaluation of the Klotho–FGFR1 complex in the parathyroid
MBD is recommended for patients with stage 3 gland in stage 5 CKD and prolonged experimen-
CKD, some observational studies suggest that tal renal failure but not in short-term experimen-
SHPT might occur earlier [3, 11]. In one study, tal renal failure [37, 38].
elevated PTH levels were detected in 50.1% of par-
ticipants with stage 3 CKD, which appeared to
increase the risk for cardiovascular disease. Li et al. 11.3.5 Vitamin D
evaluated the association of iPTH with all-cause
mortality in a cohort, comprising 8530 maintain Vitamin D3 (cholecalciferol), the natural form of
hemodialysis patients who underwent 6–70 months vitamin D, is a steroid hormone that can be syn-
follow-up (with a median of 40 months). thesized endogenously or taken in from the diet.
Multivariate Cox regression analysis showed that In the skin, irradiation of 7-dehydrocholesterol
patients with a low iPTH level (<75 pg/mL) at produces pre-vitamin D3 that is immediately
baseline had greater risk of mortality (HR = 1.36, converted to cholecalciferol. The production of
95% CI 1.16–1.60) than those with an iPTH level vitamin D in the skin is the most important source
within 150–300 pg/mL at baseline [34]. Therefore, of vitamin D and depends on the intensity of UV
close surveillance for hyperparathyroidism should exposure. Vitamin D can also be provided to a
be recommended in patients with CKD. small extent in the diet, being mainly present in
fish oils and fortified dairy products [39]. Vitamin
D3 is transported to the liver by vitamin D-binding
11.3.4 Fibroblast Growth Factor 23 protein (VDBP), which is subsequently con-
verted to calcidiol by 25-hydroxylase (CYP2R1).
FGF23 is mainly produced in the bone and, upon Serum calcidiol reflects total body vitamin D
secretion, forms a complex with a FGF receptor from dietary intake, skin, and liver stores [39].
and coreceptor αKlotho [19, 33], induces renal Circulating calcidiol bound to VDBP is taken up
phosphaturia by decrease 1,25[OH]2D3 synthesis, by megalin-mediated endocytosis in the PCTs
through enhanced expression of 24-hydroxylase, and converted to calcitriol, the active form, by
whereas 1,25[OH]2D3 itself increases FGF-23 1-α-hydroxylase (CYP2B1) [40]. Serum cal-
transcription. An increase in PTH follows [18, citriol level is under the control of phosphorous,
19, 34]. Healthy medical students on a high Pi FGF-23, PTH, and calcitriol (negative feedback)
diet showed an increase in serum FGF-23 levels [18, 19, 39, 40].
at 16 h [33]. Their serum 1,25[OH]2D3 levels Vitamin D deficiency (<20 ng/mL) and insuf-
declined, and urinary Pi excretion increased. ficiency (20–29 ng/mL) are common among
These parameters remained unchanged in the patients with CKD, particularly the elderly and
group on a normal Pi diet [33]. An elevated level advanced CKD [39, 40]. In addition to nutritional
of FGF-23 may be a mechanism to maintain Pi and sunlight exposure deficits, factors that affect
homeostasis in early CKD [32, 33]. vitamin D deficiency include race, gender, age,
obesity, dietary intake and impaired vitamin D The term renal osteodystrophy (ROD) is
synthesis and metabolism [39]. With the deterio- defined as alterations in bone physiology that can
ration of renal function, serum 1,25[OH]2D3 lev- be detected histologically and includes CKD-
els also decrease progressively because of mediated changes in bone turnover, mineraliza-
vitamin D3 deficiency, together with impaired tion, and volume (TMV). Double tetracycline
availability of CYP2B1 by renal PCTs, high labeled bone biopsy is thus far the gold standard
FGF-23. for the diagnosis and classification of ROD. Over
Vitamin D is involved in the regulation of the past few years, bone biopsy studies have
bone metabolism, skeletal muscle strength and yielded several clinically important insights into
mobility, and in the maintenance of calcium and CKD-related bone dysfunction and have defined
phosphate homeostasis [39, 40]. Observational a critical role for bone as an endocrine organ,
studies showed that vitamin D has some benefi- responsible for many of the complications that
cial extraosseous functions involving cardiac and accompany CKD-MBD. The 2009 guideline rec-
immune system. Insufficient vitamin D is related ommended a bone biopsy prior to anti-resorptive
to high-renin hypertension and diabetes [39, 40], therapy in patients with stage G4–G5D CKD and
whereas sufficient vitamin D is associated with evidence of biochemical abnormalities in CKD-
improved outcomes in these diseases [41]. MBD, low BMD, and/or fragility fractures [4].
Together with the progressive decline of serum However, the KDIGO work group understands
calcitriol, vitamin D deficiency leads to SHPT clinical experience concerning the performance
and its complications, tertiary hyperparathyroid- and evaluation of bone biopsies may be limited.
ism and hypercalcemia, which require surgical There is growing evidence that anti-resorptive
parathyroidectomy or calcimimetics. As in the therapies are effective in patients with stage G3a–
general population, this condition is associated G4 CKD; however, no robust evidence suggests
with increased morbidity and poor outcomes. that anti-resorptive medications induce adynamic
bone disease. Therefore, the 2017 guideline
update no longer suggests performing bone
11.3.6 Bone biopsy be performed prior to initiation of these
medications [15].
Owing to the lack of evidence showing that BMD
measured by DEXA predicts fractures in patients
with CKD as it does in the general population, and 11.3.7 Vascular Calcification
to the inability of DEXA to indicate the histologi-
cal type of bone disease, the 2009 guideline rec- Cardiovascular complications are the main clini-
ommended that BMD measurement be not cal problems in patients with CKD, and the main
routinely performed in patients with stage CKD cause of death in patients with end-stage renal
G3a–G5D and CKD-MBD [4]. An evidence- disease [46, 47]. The combination of vascular
based review of the 2017 KDIGO CKD-MBD calcification and disturbed bone metabolism in
guideline update identified four prospective cohort CKD has been termed as CKD-MBD by the
studies on adults [15], showing that BMD mea- KDIGO in 2009 [4]. Increased vascular calcifi-
sured by DEXA predicted fractures in the entire cation in CKD patients is an important risk fac-
spectrum from stage CKD G3a–G5D [42–45]. tor for poor prognosis in overall survival,
These studies represent a significant progress cardiovascular morbidity and mortality [47–49].
since the publication of the original 2009 guide- Vascular calcification, previously considered as
line. Based on these insights, the KDIGO work a passive deposition of calcium and phosphate
group concluded that BMD assessment by DEXA hydroxyapatite, is now considered as a cellular
is recommended if low or declining BMD will regulatory process in which vascular smooth
lead to additional interventions for the reduction muscle cells (VSMCs) undergo molecular and
in falls or the use of medications for osteoporosis. phenotypic changes similar to bone formation
146 M. Xiong
during embryogenesis. Paradoxically, in both 11.4.1 Treatment Targeted at

patients with CKD and animal models of CKD, Lowering High Serum
bone loss occurs simultaneously with increased Phosphate Level
vascular calcification [50], suggesting that dif- and Maintaining Serum
ferent intrinsic signals in tissue-specific micro- Calcium Level
environments may dominate bone and vascular
mineralization. The exact mechanism of vascu- With the deterioration of renal function, the iPTH
lar calcification in CKD and the contribution of level increases earlier than Pi as a response to
impaired bone metabolism to vascular calcifica- maintain serum Pi, the later does not increase until
tion have not been fully elucidated. Systemic the eGFR falls below 40 mL/min/1.73 m2 [3], and
uremic factors and bone metabolic disorders FGF-23 acts similarly to iPTH. In an animal study
play an important role in the pathogenesis of performed in dogs, when the dietary Pi intake was
vascular calcification in CKD. The regulation of titrated to renal function decline, serum iPTH and
Runt-related transcription factor 2 (Runx2), a Pi levels, and excretion of Pi remained unchanged
key transcription factor for bone formation, and [51]. This study highlights the importance of
the emerging role of Runx2-dependent receptor dietary Pi restriction in patients with CKD. When
activator of nuclear factor kappa-B ligand kidney disease progresses, for PTH and FGF-23, it
(RANKL) in vascular calcification of CKD were is harder to maintain serum Pi in normal range
emphasized. without damaging other organs. The serum Pi
For patients with CKD G3a–G5D, we recom- level target for the patient with stage G3a–G5D
mend that abdominal lateral radiographs be used CKD is toward the normal range, and phosphate
to detect the presence or absence of vascular cal- binders will be prescribed if this target is not
cification, and echocardiography be used to achieved by diet Pi restriction alone. The available
detect the presence or absence of valvular calcifi- Pi binders are classified as either calcium based or
cation, as a reasonable alternative to CT-based non-calcium based [52–54]. The former includes
imaging. We recommend that patients with CKD calcium carbonate and calcium acetate, whereas
G3a–G5D with known vascular or valvular calci- the latter includes sevelamer carbonate or hydro-
fication be considered to have highest cardiovas- chloride (an anion exchange resin), lanthanum car-
cular risk. It is reasonable to use this information bonate, and aluminum hydroxide. Aluminum
to guide the management of CKD-MBD. hydroxide is now restricted in patients with
advanced CKD [55, 56] because of the extrarenal
side effects which include low turnover bone
11.4 Treatment of CKD-MBD decrease, skeleton fractures, encephalopathy, skel-
etal muscle weakness, and microcytic anemia
Management of CKD-MBD requires under- without iron shortage [19, 57, 58]. Chertow GM
standing of the complex interactions between et al. compared calcium acetate with sevelamer
ions, hormones and their target organs. Since with respect to the development and progression
the release of KDIGO CKD-MBD guidelines in of calcification in coronary artery and aorta using
2009, our understanding of the pathophysiology electron beam technique (EBT) in dialysis patients
has improved. However, there is still a lack of [60]. At baseline, both groups had severe extensive
high-quality clinical evidence to support spe- vascular calcifications. At the end of the 2-year
cific interventions. Using available data, follow-up, there was no further progression of cal-
KDIGO has now updated diagnosis and treat- cification in the sevelamer group, but a significant
ment recommendations for patients with CKD- increase in calcification in the coronary artery and
MBD. In patients with CKD G3a–G5D, the aorta was observed in the calcium acetate group
therapy of CKD-MBD should be based on a [60]. A systematic review [63] of 60 trials found
series of measurements of phosphate, calcium, that although sevelamer hydrochloride signifi-
and PTH levels. cantly reduced serum Pi and PTH levels compared
with calcium-based binders, the use of sevelamer does not predict high turnover osteopathy, so it is
was associated with a higher risk of gastrointesti- not necessary to correct the slightly elevated PTH
nal side-effects but lower risk of hypercalcaemia. levels to normal levels in CKD. The KDOQI
There was no significant reduction in all-cause work group agreed with the update and its rea-
mortality with sevelamer hydrochloride compared sons, particularly in view of the high variability
with calcium-based phosphate binders. of PTH levels within and between individuals
In adult patients with stage G3a–G5D CKD, [64–67].
we suggest that hypercalcemia be avoided. In We recommend unconventional prescriptions
children with stage G3a–G5D CKD, we suggest of calcitriol and vitamin D analogues in adult
that the serum calcium level be maintained in the patients with stage G3a–G5 CKD not on dialysis.
age-appropriate normal range. In patients on It is reasonable to retain the use of calcitriol and
maintain hemodialysis, we suggest the use of a vitamin D analogues for patients with stage G4–
dialysate calcium concentration between 1.25 G5 CKD with severe or progressive hyperpara-
and 1.50 mmol/L (2.5 and 3.0 mEq/L). The asso- thyroidism. In children, calcitriol and vitamin D
ciation between calcium-based Pi binders and analogues can be used to maintain serum calcium
extraskeletal calcifications has led to the pre- levels within normal age-appropriate ranges. The
scription of non-calcium-based Pi binders. If PRIMO and OPERA studies demonstrated that in
calcium-based Pi binders are prescribed, the dose patients with non-dialysis-dependent CKD, the
should be limited to 1.5 g of elemental calcium use of vitamin D analogues may be associated
per day [14, 59–62]. In adult patients with stage with significant reductions in PTH levels, no
G3a–G5D CKD receiving phosphate-lowering change in cardiovascular end points, and signifi-
treatment, we suggest that the dose of calcium- cant increases in risk for hypercalcemia [68, 69].
based phosphate binders should be restricted. In For patients with stage G5D CKD, we recom-
children with CKD G3a–G5D, it is reasonable to mend that iPTH levels be maintained within
base the choice of phosphate-lowering treatment about 2–9 times the normal upper limit of the
on serum calcium levels. test. We suggest that significant changes in iPTH
levels beyond this range should be avoided, either
in therapy or not. For patients with stage G5D
11.4.2 Treatment of Abnormal PTH CKD requiring PTH reduction therapy, we rec-
Levels in CKD-MBD ommend the use of calcimimetics, calcitriol, vita-
min D analogues, or a combination of
In patients with stage G3a–G5 CKD not on dialy- calcimimetics with calcitriol or vitamin D ana-
sis, the appropriate PTH level is yet not known logues. Calcimimetics, calcitriol, and vitamin D
until now. Even so, we recommend that patients analogues have shown efficacy in lowering the
with iPTH levels gradually increasing or continu- PTH level in the patients with stage G5D CKD in
ally exceeding the upper normal limit should be the United States [70–72]. Although pre-specified
assessed for modifiable factors, such as hyper- secondary analysis and post hoc analysis of the
phosphatemia, hypocalcemia, hyperphosphate EVOLVE data noted improvement in some out-
diet, and vitamin D deficiency. comes in a subgroup of patients (e.g., a reduction
The updating of the KDIGO guidelines in in fracture incidence when treated with cinacal-
2017 gives the following reasons for its emphasis cet vs placebo in patients aged >65 years) [73],
on not starting treatment for a single elevated the results of preliminary analysis were not posi-
PTH value: (1) the optimal PTH level is still tive. Since the advantage of cinacalcet over other
unclear; (2) a moderate increase in PTH level is drugs has not been established, the selection of
an appropriate adaptive response that contributes PTH reduction treatment in patients with stage
to phosphaturia in CKD and may therefore be G5D CKD may be based on cost, adverse events,
conducive to maintain normal serum phosphate and presence of other mineral metabolism
levels as GFR decreases; and (3) high PTH level abnormalities.
148 M. Xiong
11.4.3 Parathyroidectomy in conjunction with clinical judgments, and

emphasize the need for future research in this
For patients with stage G3a–G5D CKD with vital area.
severe hyperparathyroidism who fail to respond
to medical or pharmacological treatment, we rec-
ommend parathyroidectomy. In tertiary hyper- Key Messages
parathyroidism, the parathyroid gland becomes • CKD-MBD is a systemic disorder mani-
autonomous, nodular in composition, and unre- fested by one or more of the following:
sponsive to feedback inhibition by vitamin D (1) abnormalities of calcium, phospho-
analogues or cinacalcet owing to a reduction in rous, PTH, or vitamin D metabolism,
VRD and CaSR. For more than six decades, (2) abnormalities in bone pathology and
many patients with advanced CKD have under- histomorphometry marked by changes
gone surgical parathyroidectomy (PTX) for in bone turnover, mineralization, vol-
severe SHPT mainly according to historical clini- ume, linear growth, or strength (TMV
cal practice patterns. Mugurel Apetrii et al. con- system), and (3) the presence of vascu-
ducted a meta-analysis to evaluate the benefits lar or other soft tissue calcification.
and hazards of PTX in patients with SHPT [74]. • The 2017 KDIGO clinical practice
The final analysis included 15 cohort studies, guideline recommends monitoring the
comprising 24,048 participants. Compared with serum calcium, phosphate, and PTH
standard therapy, PTX significantly reduced all- levels and alkaline phosphatase activity
cause mortality (RR 0.74 [95% CI, 0.66 to 0.83]) beginning in stage G3a CKD.
in patients with end-stage renal disease who had • Treatments of CKD-MBD should be
biochemical and/or clinical evidence of SHPT. In based on serial assessments of phos-
six observational studies involving nearly 10,000 phate, calcium, and PTH levels, consid-
patients, PTX was also associated with reduced ered altogether.
cardiovascular mortality (RR 0.59 [95% CI, 0.46 • In patients with stage G3a–G5D CKD
to 0.76]). In conclusion, the results of this meta- with severe hyperparathyroidism who
analysis suggest that PTX has a significant clini- fail to respond to medical or pharmaco-
cal benefit in all-cause and cardiovascular logical therapy, we suggest parathyroid-
mortality in CKD patients with SHPT. Our study ectomy.
showed that total parathyroidectomy without
autotransplantation could improve BMD at the
L1–L4 level and the hip in SHPT patients [75].
However, in view of the observational nature of References
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Immune Deficiency and Infection
in Chronic Kidney Disease 12
Lei Jiang and Ping Wen
Abstract adaptive immune system. The deficiency of the

Chronic kidney disease (CKD) has long been immune system may induce an increased inci-
recognized to be associated with immune defi- dence of infections among patients with CKD,
ciency. CKD-associated immune deficiency is which could increase the morbidity and mortality
orchestrated by the innate immune system and in this population [1].
adaptive immune system. Immune deficiency
could lead to graft dysfunction and impaired
response to vaccination. Owing to the immune 12.2 CKD-Associated Immune
deficiency of CKD patients, opportunistic Deficiency
infections such as fungal, Pneumocystis jir-
oveci, and virus are more common in patients The development of CKD is associated with a
with CKD than in the general population. The significant increase in the risk of morbidity and
high mortality risk of patients with CKD has mortality, which is linked to aberrant immune
been partly attributed to the infected diseases. responses. Recent research has revealed that ure-
Interventions targeting the immune dysfunc- mic toxins (Table 12.1), malnutrition, immuno-
tion and infection can improve the outcomes suppressive and cytotoxic drugs, increased
of CKD. oxidative stress, priming of immune cells, aber-
rant apoptosis, and metabolic kidney activities
[such as hormone erythropoietin (EPO), vitamin
D, parathyroid hormone, and renin] lead to the
12.1 Introduction immune dysfunction in CKD [2–4].
Chronic kidney disease (CKD) has long been rec-

ognized to be associated with immune deficiency, 12.2.1 Immune Deficiency Caused by
and the CKD-associated immune dysfunction is Immunosuppressive Agents
orchestrated by the innate immune system and
Immunosuppressive drugs have become some of
the most successful treatments for some
L. Jiang (*) · P. Wen glomerular-nephritis patients and transplant
Centre for Kidney Disease, Second Affiliated patients, but these patients also appear to show
Nanjing, Jiangsu, China increased susceptibility to infections because of
e-mail: jianglei@njmu.edu.cn; wenping@njmu.edu.cn immune deficiency (Table 12.2) [5–9].

154 L. Jiang and P. Wen
Table 12.1 Functional disturbances of immune cells 12.2.2 CKD-Associated Innate

caused by uremic toxins
Immune Deficiency
Uremic toxins Effects on immune cells
Low molecular weight (LMW) toxins The innate immune system consists of monocytes,
Phenylacetic acid Macrophages: inducible nitric
(PAA) oxide synthase
macrophages, polymorphonuclear leukocytes
PMNLs: oxidative burst, (PMNLs), neutrophils, eosinophils, basophils,
phagocytosis, increased dendritic cells, and natural killer cells. The effects
integrin expression, and of CKD on the innate immune system may be due
decreased apoptosis
to the accumulation of uremic toxins, increased
Dinucleoside Leukocytes: oxidative burst
polyphosphates levels of proinflammatory molecules, alterations
Guanidino Monocytes/macrophages: of TLRs, increased oxidative stress, decreased
compounds pro- and anti-inflammatory erythropoietin production, and increased parathy-
Indoxyl sulfate Endothelial cells: upregulation roid hormone concentration. The disturbances of
of E-selectin innate immune cells associated with CKD are
P-cresyl sulfate Leukocytes: oxidative burst
summarized in Table 12.3 [10].
Homocysteine (Hcy) Increased ICAM-1 expression,
damage of DNA and proteins
Methylglyoxal PMNLs: increased apoptosis Table 12.3 The dysfunction of innate immune cells
(MGO) and oxidative burst associated with CKD
Monocytes: increased Innate-
apoptosis immune-cell CKD-associated
Middle molecular weight (MMW) proteins type changes Altered functions
Immunoglobulin PMNLs: chemotaxis and Monocytes CD14+CD16+ Production of
light chains (IgLCs) decreased apoptosis and subset expansion cytokines
Retinol-binding PMNLs: chemotaxis, oxidative macrophages Decreased
protein (RBP) burst, and decreased apoptosis phagocytic
Leptin PMNLs: chemotaxis and capacity
decreased apoptosis ROS
Resistin PMNLs: chemotaxis and Production of
decreased apoptosis osteoactivin
Tamm–Horsfall PMNLs: decreased chemotaxis PMNLs Increased Decreased
protein (THP) and apoptosis, increased apoptosis of phagocytic
phagocytosis PMNLs capacity
High-density Loss of anti-inflammatory Dendritic Reduction in Impaired defense
lipoprotein (HDL) properties cells numbers of DCs against microbial
Functional infection and a
PMNLs polymorphonuclear leukocytes (Adapted from anomalies of DCs poor response to
Cohen G, Horl WH. Toxins. 2012;4:926–90 [3]) vaccination
Neutrophils Reduction in the Reduced ability
killing capability to kill
Table 12.2 The mechanism of action of immunosup- of neutrophils microorganisms
pressive agents Unchanged and increased
number of susceptibility to
Drug Mechanism neutrophils infection
Steroids Reductions in leukocyte capable of
migration, in neutrophilic and phagocytosis and
monocytic phagocytosis, and in producing ROS
T-cell function Eosinophils Increased number Associated with
Azathioprine Proapoptotic effects on T vascular disease
6-Mercaptopurine lymphocytes in CKD patients
methotrexate Natural killer Decreased Associated with
Cyclosporine Induction of antibody, cells number of high levels of the
Tacrolimus leukocyte, and lymphocyte NKG2D-positive circulating
(FK506) formation and of differentiation NK cells HLA-related
into proinflammatory Th17 cells molecule MICA
Mycophenolate Inhibition of both T-lymphocyte PMNLs polymorphonuclear leukocytes; DCs dendritic
mofetil (MMF) and B-lymphocyte activities cells; ROS reactive oxygen species
12 Immune Deficiency and Infection in Chronic Kidney Disease 155
12.2.3 CKD-Associated Adaptive adaptive immune system. The deficiency of the

Immunity Deficiency immune system may induce an increased inci-
dence of infections among patients with CKD.
Patients with CKD exhibit T-cell lymphopenia,
which is primary due to loss of naïve CD4+ and
CD8+ T cells and central memory CD4+ T cells; 12.3 Immune Deficiency-
aberrant activation of terminally differentiated Associated Infection in CKD
memory cells; and an imbalance between sup-
pressive regulatory T cells (Treg cells) and T Owing to the immune deficiency in patients with
helper 17 cells (TH17 cells). The aberrations of T CKD, the incidence of infection is higher than in
cells are related to uremic toxins, oxidative stress, the general population, and the high mortality
secondary hyperparathyroidism, an iron over- risk among patients with CKD has been partly
load, and inflammation. attributed to infectious diseases. The spectrum
Significant B-cell deficiency and dysfunction of infections among immunocompromised
have been demonstrated in CKD, which are patients is quite broad. Among such patients,
mediated by increased apoptosis and impairment opportunistic pathogens should not be ignored.
of maturation. Uremia toxin-induced B-cell lym- Given the toxicity of antimicrobial agents and
phopenia may increase the frequency of infec- the need for rapid remission of infection, early
tions and cause a defective response to vaccination specific diagnosis is essential in this population.
in patients with CKD. The T-cell and B-cell
anomalies associated with CKD are summarized
in Table 12.4 [11–13]. 12.3.1 Etiology
Immune deficiency in patients with CKD patients

12.2.4 Conclusions due to the immune dysfunction is induced by ure-
mic toxins, nutrient deficiencies, kidney trans-
The CKD-associated immune dysfunction is plant, use of drugs, obesity, and so on (see upper
orchestrated by the innate immune system and section).
Table 12.4 The T-cell and B-cell anomalies associated with CKD
Type of adaptive
immune cells CKD-associated changes Mechanism and altered function
Naïve T cells Loss of circulating naïve CD4+ and CD8+ Increased apoptosis
T cells, central memory CD4+ T cells Reduced IL-17 homeostatic signals
Remaining naïve T cells show aberrant Impaired thymic output
activation and higher expression of CD24,
CD69, CXCR3, and CXCR5
Effector memory T Increased number of CD8+ TEMRA cells Transplant rejection
cells
Treg and Th17 cells Decreased number of Treg cells Increased apoptosis
Increased number of Th17 cells Increased angiogenin
Increased production of 2,3-dioxygenase and
arginase
Decreased production of interleukin 2
B cells Decreased numbers of CD5+ innate B Increased apoptosis
cells and CD27+ memory B cells BAFF downregulation
Reduced antibody production
Increased production of proinflammatory
cytokines
12.3.2 Immunosuppressive Agents- • Detection of galactomannan (GM) in bron-

Induced Infection choalveolar lavage (BAL) or cerebrospinal
fluid (CSF) (specific for IA).
12.3.2.1 Fungal Infection • Quantification of the 1,3-β-D glucan
1. Pathogens (BDG) (panfungal diagnostic method)
The incidence of infection increases signifi- (cutoff value: 80 pg/mL; sensitivity: >65%,
cantly among patients using immunosuppressive specificity rates: >80%).
drugs. CKD patients with immunodeficiency • Detection of cryptococcal antigen in serum
are at a risk of opportunistic infection with a or CSF.
variety of fungal pathogens, the most impor- • Polymerase chain reaction (PCR)-based
tant of which are Candida species (53%), methods (sensitivity: 80%, specificity
Aspergillus spp. (19%), C. neoformans (8%), rates: 70%).
non-Aspergillus spp. (8%), endemic fungi • Other molecular based diagnostic methods
(5%), and zygomycete (2%) [14]. such as sequence, hybridization and mass
• Candida spectroscopy.
–– Candida spp. is the most frequent agent • High-resolution chest CT is recommended
of fungal pathogen. Candia infections for detecting pulmonary aspergillosis, cra-
manifest as mucocutaneous candidal nial fungal infection, sinonasal fungal
infection, pneumonia, peritonitis, uri- infection, liver microabscess, or fungal
nary tract infection, empyema, candi- abscesses in kidney, liver or spleen.
demia, surgical anastomosis infection, or • Magnetic resonance imaging (MRI) is rec-
oesophagitis. The mortality of invasive ommended for detecting cranial fungal
candidiasis is 34% at 12 months [15]. infection, cryptococcosis, sinonasal fungal
• Aspergillus Species infection, skin and soft tissue fungal infec-
–– Invasive aspergillosis (IA) is the most tion, or fungal abscesses in kidney, liver or
deadly infection in solid organ trans- spleen.
plantation [16]. Aspergillosis mainly • Ultrasound is the recommended method
causes tracheobronchitis or invasive for detecting fungal abscesses in kidney,
pulmonary disease (the most common liver, or spleen [17, 18].
clinical form with about 67–82% of
high mortality). Corticosteroid usage, 3. Treatment
long time renal replacement therapy, • Fluconazole (400–800 mg/day, adjustment
and leukopenia are the major risk fac- for renal dysfunction) is usually used as ini-
tors for IA. tial therapy, unless the patient is critically
• C. neoformans ill or with fluconazole-resistant species
–– The incidence of cryptococcosis is infection (e.g., Candida glabrata or C. kru-
higher in patients with kidney transplan- sei). In fluconazole-resistant species infec-
tation, high doses usage of corticoste- tion, echinocandin or amphotericin B in
roids, alemtuzumab or infliximab. lipid preparation is recommended to use.
Flucytosine is an adjunctive therapy in
2 . Diagnosis resistant infections, which must be guided
The methods utilized to detect fungal infec- by drug levels with attention to hematopoi-
tion are as follows: etic toxicity.
• Positive blood culture, sputum culture, skin • Voriconazole is recommended for IA
culture, or urine culture. (4 mg/kg twice daily for 2 weeks). Plasma
• Combined detection of mannan and anti- levels is recommended to maintain the
mannan antibodies (specific for Candida range between 2 and 4 mg/L. Liposomal
spp.). amphotericin B is recommended in
patients who are resistant, hepatotoxic, 2. Therapy

intolerant, or allergic to voriconazole. • Antipneumocystis treatment: TMP (15–
Nephrotoxicity must be considered. In 20 mg/kg/day)-SMX (75–100 mg/kg/day)
severe disease, a combination of antifun- is the first-line therapy for PCP.
gals treatment with voriconazole plus • Glucocorticoids: glucocorticoids are rec-
caspofungin or anidulafungin is ommended to administer in patients with
recommended. hypoxia (PaO2 <70 mmHg); adjunctive
• For cryptococcosis, combination of liposo- glucocorticoids are recommended in HIV
mal amphotericin B (3–4 mg/kg/day) plus patients with PJP [19, 20].
flucytosine (25 mg/kg/6 h) is recommended
as induction therapy. Next, fluconazole is 12.3.2.3 CMV-Induced Pneumonia
used at 400–800 mg/day for 8 weeks and at (CMP)
200 mg/day for 6–12 mouth as mainte- Diagnosis involves detection of a CMV pathogen
nance [17, 18]. and of a specific antibody to a CMV antigen in
respiratory secretions, saliva, or lung biopsy sam-
12.3.2.2 Pneumocystis jirovecii ples. CMV PCR detection or anti-CMV-IgM
Pneumonia (PCP) positivity or an increase in the anti-CMV IgG
P.jirovecii is a common cause of community- level more than fourfold is helpful for the diagno-
derived opportunistic fungal infections, and PCP sis of CMP. In the treatment of CMP, nucleoside
is commonly associated with the use of immuno- drugs such as ganciclovir and phosphonic acid
suppressive drugs such as corticosteroids or are commonly used.
cyclosporine, or is a coinfection with CMV.
12.3.2.4 Legionella Pneumonia
1. Diagnosis Detection of a Legionella antigen in urine is useful
The diagnostic basis for PCP infection for early diagnosis. Macrolides are the first choice,
includes clinical manifestations, laboratory whereas quinolones, tetracycline, and rifampicin
tests, and auxiliary examinations as follows: are effective too. Erythromycin is the most effec-
• Typical clinical symptoms are typically tive treatment. New macrolide antibiotics, such as
pneumonia, fever, non-productive cough, clarithromycin, azithromycin, and roxithromycin,
worsening chest pain, shortness of breath, are expected to replace erythromycin. In severe
and low arterial-oxygen tension. cases, rifampicin or fluoroquinolones can be added.
• Elevated serum lactic dehydrogenase
(LDH) (>300 international units per milli-
liter) while the C-reactive protein (CRP) is 12.3.3 Vascular-Access-Associated
not elevated. Infections
• Elevated levels of 1,3-β-d-glucan in serum.
• Chest CT: bilateral peripheral interstitial These diseases are the most common infections
infiltrates, ground glass opacities in early among hemodialysis patients and account for
PCP; predominant consolidation in the lat- 28–60% of septicemia cases among these patients.
ter stages of PCP. The most common risk factors for infection in
• Microbiological diagnosis includes posi- hemodialysis patients include the type, site, and
tive pathogen staining from sputum, BALF, duration of access; the puncture technique of
oral wash, or lung tissue. nurses; and the immune state of the patients.
• Genetic testing includes PCR or loop- Epidemiological studies have revealed that the
mediated isothermal amplification (LAMP) infection prevalence rate for an arterial venous
from sputum, BALF, or oral wash. graft is higher than that for arterial venous fistula
and lower than the infection prevalence rate for a ∗According to evidence-based levels (A, B, C,
central venous catheter. The spectrum of patho- and D), the guidelines can be divided into two
gens is presented in Chap. 17 “Hemodialysis.” categories: recommendations and suggestions.
Recommendations can be applied to the majority
12.3.3.1 Treatment of Infection- of patients, and the evidence-based level is higher
Associated HD Access than A and B. Suggestions can be applied to some
(KDOQI Guideline) patients, and a physician needs to consider the
1. An infected HD catheter or port patients’ individual differences, and the evidence-
Treatment of an infected HD catheter or port based level is mostly C and D [21–23].
should be based on the type and extent of
infection.
• The catheter exit site or port cannulation 12.3.4 Peritoneal-Dialysis-Associated
site should be examined for roper position Infections
of the catheter or port catheter system and
the absence of infection by experienced For details, see Chap. 18 “Peritoneal dialysis.”
personnel during each HD session before
opening and accessing the catheter/port
catheter system. (B) Key Messages
• The dressing of a catheter exit site should • Chronic kidney disease (CKD) has long
be changed during each HD treatment, to been recognized to be associated with
either a transparent dressing or gauze and immune deficiency and infectious
tape. (A) diseases.
• The aseptic technique should be used to • Recent research indicates that uremic
prevent contamination of the catheter or toxins, immunosuppressive and cyto-
port catheter system, including the use of a toxic drugs, increased oxidative stress,
surgical mask for the staff and patient and priming of immune cells, aberrant apop-
clean gloves for all catheter or port catheter tosis, and metabolic kidney activities
system connection, disconnection, and [such as hormone erythropoietin (EPO),
dressing procedures. (A) vitamin D, PTH, and renin] lead to the
2. Fistula infection immune dysfunction in CKD.
Infections of primary arteriovenous fistulas • Due to immunodeficiency of patients
are rare and should be treated (as subacute with CKD, opportunistic infections with
bacterial endocarditis) with 6 weeks of anti- such pathogens as fungi, Pneumocystis
biotic therapy. Surgical excision of the fistula jiroveci, and/or viruses are more com-
should be performed in cases of septic mon among patients with CKD than in
emboli. (B) the general population.
3. AVG infection
• Initial antibiotic treatment should cover
both gram-negative and gram-positive
microorganisms. (B)
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2015;7(6):371–8.
Nervous System Disorders
in Chronic Kidney Disease: 13
Neurocognitive Dysfunction,
Depression, and Sleep Disorder
Wenjin Liu
Abstract human body. Brain injury is a remarkable exam-

Nervous system disorders, including cogni- ple of the systemic nature of CKD. Various ner-
tive impairment, depression, and sleep disor- vous system disorders, including cerebrovascular
der, are highly prevalent in patients with diseases, cognitive impairment, depression, and
chronic kidney disease (CKD). The mecha- sleep disorder, are found at a higher prevalence
nisms leading to the increased prevalence are in individuals with renal dysfunction than in the
usually multifaceted. These complications general population. The reasons for CKD-
can pose great threat to patients’ health and related nervous system disorders are multifac-
quality of life, but sometimes could be eted and include the direct neurotoxic effects of
neglected or unrealized in clinical practice. accumulated uremic toxins as well as contribu-
Therefore, physicians should be aware of the tions from other risk factors secondary to CKD
features of these conditions in CKD patients (e.g., hypertension, fluid overload, and inflam-
and need to consider performing routine mation). Although such complications can pose
screening tests, especially in those with a significant threat to patients’ health and qual-
advanced renal dysfunction. Management of ity of life, they are sometimes neglected or unre-
these complications usually requires identifi- alized in clinical practice. Therefore, there is a
cation and targeted treatment of reversible need for physicians to better understand the dis-
underlying causes, general supporting man- orders that can arise in individuals with kidney
agement of CKD, and consultation with spe- diseases and improve the comprehensive man-
cialist in relevant areas. agement of CKD, as doing so would be benefi-
cial for improving patients’ quality of life and
prognosis.
In this chapter, we focus on three key com-
13.1 Introduction ponents of nervous system disorders: neurocog-
nitive dysfunction, depression, and sleep
Chronic kidney disease (CKD) is associated disorder. Considering that the development of
with an accelerated process of aging that cerebrovascular disease in the context of renal
involves several organs and systems of the dysfunction is mainly due to increased cardio-
vascular injury stimuli, we do not discuss it
W. Liu (*) here. Readers interested in cerebrovascular
Centre for Kidney Disease, Second Affiliated complications can refer to Chap. 9 for a detailed
Hospital, Nanjing Medical University, discussion.
e-mail: liuwenjin@njmu.edu.cn

162 W. Liu
13.2 Neurocognitive Dysfunction aged 20–59 years, moderate CKD (eGFR

30–59 mL/min/1.73 m2) was associated with
13.2.1 Prevalence poorer performance in visual attention and learn-
ing/concentration tests [7]. This finding is sup-
Cognitive impairment has long been a neglected ported by data from a longitudinal study in which
problem in patients with CKD. Only in the past the authors found that moderate CKD, defined as
decade has this issue drawn increasing attention. serum creatinine ≥1.3 mg/dL for women and
Kidney disease has been shown to be an indepen- 1.5 mg/dL for men, was associated with a 37%
dent risk factor for cognitive impairment and increase in the risk of incident dementia [8]. The
dementia [1, 2]. In a recent study that adminis- association has also been validated in patients
tered cognitive tests over a number of years, with preserved renal function [9]. Moreover, the
patients with impaired renal function (defined as association between cognitive impairment and
an estimated glomerular filtration rate renal dysfunction seems to be “dose-dependent,”
(eGFR) < 60 mL/min/1.73 m2) had fewer cogni- as the risk of cognitive impairment was more pro-
tive impairment-free life-years than those with an nounced in patients with more severe renal dys-
eGFR ≥ 90 mL/min/1.73 m2 [3]. function [10].
Given the significant link between CKD and However, despite a great number of studies
the development of cognitive dysfunction, a supporting the link between cognitive impair-
number of studies have reported the prevalence ment and renal dysfunction, there are also lines
of cognitive impairment in various CKD stages. of evidence indicating that such an association
It is established that cognitive impairment does not exist. In the study by Freedman et al.,
becomes more prevalent as renal function the authors found no association between eGFR
decreases. In patients with end-stage renal dis- and cognitive test performance despite finding an
ease (ESRD) receiving renal replacement ther- association between the urine albumin–creatinine
apy, the estimated prevalence of cognitive ratio and digit symbol coding performance [11].
impairment ranges from 30% to 87%. In the A possible explanation for the lack of association
study by Murray et al., the prevalence of mild, between eGFR and cognitive performance may
moderate, and severe cognitive impairment was be that the Mini-Mental State Examination test
13.9%, 36.1%, and 37.3%, respectively, in a that was used for global cognitive evaluation in
group of 338 hemodialysis patients. It should be the study is not sensitive to mild cognitive impair-
noted that the choice of cognitive evaluation test, ment, which is the predominant type of cognitive
cut-off value for defining cognitive impairment, dysfunction found in CKD patients.
variation in patient characteristics, and possible
temporal changes due to the improvement of dis-
ease management over time might all contribute 13.2.2 Awareness
to the varied prevalence found in different studies
[4]. There is also evidence implying that perito- In addition to the high prevalence of cognitive
neal dialysis is associated with better cognitive impairment in CKD patients, cognitive impair-
outcome than hemodialysis [5, 6]. However, this ment is often poorly recognized by physicians
discrepancy in dialysis modality needs to be eval- and patients. In the DOPPS (Dialysis Outcomes
uated more carefully due to the possibility of and Practice Patterns Study) study, a previous
selection bias. record of a diagnosis of dementia was only found
In addition to the data from patients with in 4% of patients on maintenance hemodialysis
ESRD, some studies have also noted the develop- [12]. The low prevalence of dementia found in
ment of cognitive dysfunction in earlier stages of this study was an underestimation given the
CKD. In the National Health and Nutrition aforementioned epidemiologic data. Poor recog-
Examination Survey (NHANES) III study, nition leads directly to insufficient or even a lack
Hailpern et al. found that in nearly 5000 subjects of intervention and can be associated with
13 Nervous System Disorders in Chronic Kidney Disease: Neurocognitive Dysfunction, Depression… 163
treatment noncompliance by patients. Therefore, vascular bed share several features, which has led
it is of great importance to increase the awareness to the speculation that cognitive impairment in
of the importance of periodic cognitive assess- CKD is a manifestation of systemic vascular
ment for both physicians and patients. injury. Hypertension, chronic inflammation, and
oxidative stress, as well as many other cardiovas-
cular risk factors, are more prevalent and severe
13.2.3 Impact on Quality of Life in CKD patients than in the general population.
and Outcome In addition to the increased prevalence of stroke
in CKD patients, silent cerebrovascular disease,
It is apparent that cognitive impairment, either of which the severity increases as renal function
dementia or mild cognitive impairment, poses a declines, is also highly prevalent in these patients.
significant detriment to patients’ quality of life. However, although data from previous studies
Impairment of certain cognitive domains, includ- suggest a link between these subclinical cerebro-
ing executive function, orientation, working vascular changes in cognitive impairment in the
memory, language, and attention, is a major com- general population, there are few data regarding
plaint from patients (especially those with ESRD) CKD patients that have confirmed these
and their family members, as well as caregivers. associations.
Cognitive impairment can also affect patients’ Previous studies have shown that CKD is a
adherence to treatment regimens and impair risk factor for cognitive decline and dementia
decision-making. independent of cardiovascular risk factors, includ-
Multiple lines of evidence have demonstrated ing age, hypertension, and diabetes, which sug-
that dementia in dialysis patients is associated gests that factors other than those of cardiovascular
with mortality [12–14]. The association between origin contribute to cognitive impairment in kid-
mild cognitive impairment and a hard outcome ney disease. It has been speculated that the neuro-
has not been fully elucidated. Griva et al. defined logic toxicity of uremic toxins also contributes to
cognitive impairment as performance one stan- CKD-associated cognitive impairment. Various
dard deviation less than normative values on two uremic toxins, from small molecules (e.g., creati-
or more cognitive tests in a group of 145 dialysis nine) to large molecules (e.g., protein-bound ure-
patients and found that it was an independent risk mic toxin), have been implicated as being
factor for mortality in these patents [15]. In a involved in the pathogenesis of cognitive impair-
more recent study, Drew et al. found that worse ment. For example, cystatin-C, which is an inhib-
executive function and memory deficit were itor of cysteine proteases that co-localize with
independently associated with a risk of mortality b-amyloid in the brain of patients with Alzheimer’s
in 292 hemodialysis patients (excluding those disease, was found to be associated with lower
with dementia) [16]. However, the associations cognitive test scores and predictive of future cog-
became nonsignificant after further extensive nitive decline in a community-dwelling popula-
adjustment. tion [17]. In the study by Yeh et al., the authors
explored the cross-sectional association of two
protein-bound uremic toxins with cognition in a
13.2.4 Pathophysiology group of CKD patients and found that indoxyl
sulfate, but not p-cresyl sulfate, was associated
The exact mechanisms underlying cognitive with cognitive impairment [18].
impairment and dementia in the context of CKD In addition to cardiovascular and uremic fac-
remains to be fully elucidated. Cardiovascular tors, there are reports indicating that other fac-
risk factors and diseases emerging with renal tors are involved in the development of cognitive
function decline are considered the predominant impairment in CKD. These factors include
contributing factors to impaired cognition in sleep disturbance, depression, anemia, and
CKD patients. Cerebral circulation and the renal hyperparathyroidism.
164 W. Liu
Table 13.1 Common instruments for the assessment of The MoCA overcomes the above limitations
cognitive function
and therefore may be more suitable for screening
Domains Tests cognitive impairment in the context of
Global Mini-Mental State Exam (MMSE) CKD. However, one should bear in mind that
cognition The Modified Mini-Mental State (3MS)
these screening tests are generally influenced by
Montreal Cognitive Assessment
(MoCA) education level and language fluency. Hence, it is
The Kidney Disease Quality of Life very important to consider these factors when
(KDQOL) cognitive function subscale interpreting the scores. Specific cut-off values are
(KDOQL-SF) needed for varying education levels as well as for
Mini-cog application in different language areas.
Memory Wechsler Memory Scale-Third Edition
The Kidney Disease Quality of Life (KDQOL)
(WMS-III)
Auditory Verbal Learning Test (AVLT)
cognitive function subscale is specifically
Delayed Story Recall Test designed for the CKD population and has the
Attention Trail Making Test advantage of being self-reported. However,
Paced Auditory Serial Addition Test despite its validation against the Modified Mini-
(PASAT) Mental State (3MS), its value has been ques-
Digit Span tests from the Wechsler tioned due to its low sensitivity.
Adult Intelligence Scale-III (WAIS III)
It is natural to perform these tests when there
Executive Tower of London Test (TLT)
function The Picture Arrangement sub-test of
is a clinical need to do so (e.g., when a patient’s
the Wechsler Adult Intelligence Scales family member complains about the patient’s
(WAIS-R) symptoms). However, no general recommenda-
Wisconsin Card Sorting Test (WCST) tions or guidelines exist regarding the frequency
Verbal skill Boston Naming Test of performing the tests in CKD patients. In light
Sentence Repetition of the high prevalence of cognitive impairment in
CKD patients, we recommend performing a
screening test (e.g., MoCA) at least once every
13.2.5 Diagnosis 2 years in patients with an eGFR ≤ 60 mL/
min/1.73 m2 who are not on dialysis and annually
A variety of tools are available for the assessment in ESRD patients on dialysis. If the test results
of cognitive function, some of which were spe- indicate the existence of cognitive impairment,
cifically designed for the CKD population. referral to a neurologist is recommended for
Table 13.1 lists some of the most common tests more thorough neuropsychological evaluation
used in research and clinical practice. and management.
For global cognition, the two most widely
used and studied tests are the Mini-Mental State
Exam (MMSE) and the Montreal Cognitive 13.2.6 Management
Assessment (MoCA). Both tests have a maxi-
mum score of 30 and can be administered in The general management strategy for dementia
10 min. MMSE has some limitations in its appli- in patients with CKD should follow the same cri-
cation to the CKD population. First, it is most teria used for the treatment of Alzheimer’s dis-
useful for diagnosing dementia and less sensitive ease and should involve consultation from a
for mild cognitive impairment, which the major specialist in neurology. Cholinesterase inhibitors
form of cognitive deficit found in CKD patients. and N-methyl d-aspartate receptor antagonists
Second, there is a lack of evaluation of executive could be beneficial in slowing cognitive func-
function in the MMSE, and executive deficit is a tional decline, but their effect on long-term
prominent feature of cognitive impairment from outcome is uncertain. Additionally, there are lim-
vascular causes that is common among CKD ited data on the use of these drugs in CKD
patients. patients. For a detailed description of their use in
the CKD population, please refer to the review by study involving 194 dialysis patients, depressive
Kurella et al. [19]. symptoms were strongly associated with the
The management of mild cognitive impair- Kidney Disease Quality of Life Short-Form, a
ment in CKD is an area of uncertainty. Although measure of health-related quality of life [27].
vascular injury is considered to be the most The link between depression and impaired qual-
important contributor to cognitive impairment in ity of life among patients with renal dysfunction
CKD, it is unknown whether cardiovascular risk has also been confirmed in several other studies
factor modification will prevent cognitive impair- [28, 29].
ment/dementia. Even in the general population, There is a lack of significant evidence of an
there is conflicting evidence regarding the role of association between depression and mortality
antihypertensive therapy in cognitive decline. in CKD patients in previous studies. For exam-
Erythropoietin has been suggested to exhibit a ple, in the study by Kimmel et al., the authors
protective effect on cognitive function [20, 21]. found that depression (as assessed by the Beck
However, such evidence has generally come from Depression Inventory) was not a predictor of
observational studies and needs to be confirmed mortality in 295 dialysis patients [30]. Similar
in randomized clinical trials. results were also noted by Devins et al. [31].
Transplantation has been shown to be consis- However, these studies are limited by their rela-
tently beneficial for cognitive function in various tively small sample size. In the Dialysis
studies, whereas increasing the frequency and Outcomes and Practice Patterns Study
intensity of hemodialysis is not [22–24]. (DOPPS), self-reported depression was associ-
ated with an increased risk of mortality and
hospitalization in over 5000 patients on hemo-
13.3 Depression dialysis [32].
13.3.1 Prevalence
13.3.3 Risk Factors
Depression is not uncommon in the CKD popula-
tion. However, the exact estimate of its preva- Various factors could contribute to depressive
lence in patients with CKD is unknown and symptoms in the context of CKD. The possible
varies widely in the existing literature. Palmer pathophysiological factors include chronic
et al. performed a systematic review of previous inflammation, oxidative stress, and activation of
observational studies and found that the preva- the hypothalamus-pituitary-adrenal (HPA) axis.
lence of interview-based depression in the dialy- Psychological factors could also play a critical
sis population was 22.8% [25]. For patients with role in inducing depression in the CKD popula-
non-dialysis-dependent CKD, a study by Tsai tion. The anxiety induced by suffering from a
et al. demonstrated that self-reported depressive chronic disease, lifestyle disruption caused by
symptoms are found in 37% patients [26]. It hemodialysis or peritoneal dialysis, disease-
should be noted that self-report scales may over- related financial challenges, and impatience of
estimate the presence of depression [25]. being on a transplantation waiting list are consid-
ered to be contributing factors of depression in
CKD [33].
13.3.2 Impact on Quality of Life
and Outcome
13.3.4 Diagnosis
The high burden of depressive symptoms in CKD
can lead to significant impairment of a patient’s Major depressive episodes are defined as the pres-
quality of life. In a multicenter cross-sectional ence of five or more of the following symptoms
166 W. Liu
during the same 2-week period that represent a 13.3.5 Management

change from previous functioning (either
depressed mood or loss of interest or pleasure is It is of critical importance to initiate intervention
essential): (1) depressed mood; (2) markedly for those with depression as early as possible
diminished interest or pleasure in (almost) all since depression is usually a recurrent disorder
activities; (3) significant weight loss when not and complete remission is associated with a
dieting, weight gain, or decrease or increase in lower risk of relapse. Psychotherapy and pharma-
appetite; (4) insomnia or hypersomnia; (5) psy- cotherapy are both essential for the management
chomotor agitation or retardation; (6) fatigue or of depression.
loss of energy; (7) feelings of worthlessness or The most widely used type of psychotherapy
excessive or inappropriate guilt; (8) diminished for depression is cognitive behavioral therapy
ability to think or concentrate, or indecisiveness; (CBT). This evidence-based therapy is generally
and (9) recurrent thoughts of death, recurrent sui- short-term and aims to teach people to understand
cidal ideation, or a suicide attempt. the thoughts and feelings that influence their
While a psychologist should make the formal behavior, thereby allowing them to alter their dis-
diagnosis of depression, screening could be perturbing thoughts. Some previous studies have sug-
formed by a nephrologist or trained staff using a gested that CBT is helpful for alleviating depressive
variety of tools as part of routine clinical practice symptoms in both CKD and ESRD patients,
or in the dialysis unit. A summary of the most though these studies were limited in sample size.
widely used assessment tools is presented in Very few studies have assessed the effective-
Table 13.2. ness of pharmacotherapy for depression in the
CKD population. From the pharmacokinetic
point of view, the classical antidepressants fluox-
Table 13.2 Instruments for the screening of depression etine and sertraline do not need dosage adjust-
Number ment in patients with reduced eGFR. However,
Tests of items Notes caution should be taken with transplant recipients
Beck Depression 21 Three versions since fluoxetine and sertraline may increase the
Inventory available: BDI-I,
serum level of calcineurin inhibitors.
BDI-IA, BDI-II
Patient Health 9 More data regarding the efficacy and safety of
Questionnaire-9 antidepressants are needed, especially from ran-
Patient Health 2 PHQ-2 serves as a domized clinical trials. However, even with lim-
Questionnaire-2 “first-step” approach ited available evidence, intervention, either
in screening for
psychotherapy or pharmacotherapy, should be
depression. It consists
of the first two items implemented as soon as possible once depression
of the PHQ-9 is diagnosed. Cooperation between nephrologists
Hamilton Rating 17 The original HRSD and psychologists is encouraged.
Scale for consisted of 17 items.
Depression Other versions include
more (up to 29)
Zung Self-Rating 30 13.4 Sleep Disorder
Depression Scale
Geriatric 30 For use in the elderly 13.4.1 Prevalence
Depression Scale
Major Depression 10 Can be used to Sleep disorder refers to a group of conditions that
Inventory generate a diagnosis
Center for 20 A modified version for
affect the normal sleep pattern. There are multi-
Epidemiologic use in children is ple types of sleep disorder, including insomnia,
Studies available sleep apnea, restless legs syndrome, periodic leg
Depression Scale movement, excessive daytime sleepiness, and
nightmares, among others. While some types of sleep diary are generally sufficient for screen-
sleep disorder can be occasional and have a minor ing. Sometimes physicians may use question-
impact on an individual’s overall emotional state naires, such as the Pittsburgh Sleep Quality
and health, others can be persistent and signifi- Index (PSQI), to evaluate sleep quality and
cantly affect physical, social, emotional, and sleep pattern. However, the value of these
mental functioning. questionnaires is limited since they are
Sleep disorders are becoming increasingly subjective. Objective validated measures are

prevalent in the general population and the CKD available in some sleep laboratories.
population. Among 883 patients on maintenance Polysomnography is used to record the bio-
dialysis, the prevalence of insomnia, restless legs physiological changes (e.g., brain activity, eye
syndrome, obstructive sleep apnea syndrome, and movement, muscle activity, and heart rate) dur-
excessive daytime sleepiness was 69.1%, 18.4%, ing sleep. The Multiple Sleep Latency Test
23.6%, and 11.8%, respectively. Eighty percent (MSLT) measures the time elapsed from the
of the patients had at least one type of sleep disor- start of a daytime nap period to the first signs
der [34]. In a study involving 52 patients with of sleep (sleep latency) and is especially useful
early-stage CKD, the author found that sleep dis- for the diagnosis of narcolepsy (excessive day-
orders were present in 80.7% of the patients [35]. time sleepiness).
Despite the high prevalence of sleep disorders
in patients with CKD, there is evidence suggest-
ing that these disorders are largely under- 13.4.4 Management
recognized by healthcare providers [36].
Determination of the exact type of sleep disorder
is the first step toward treatment. Exploring the
13.4.2 Pathophysiology possible underlying cause of a sleep disorder is
of critical importance. For example, depression
The exact pathophysiological mechanism underly- is a common cause of sleep disorder in CKD
ing sleep disorders in the context of CKD is patients, especially in those on maintenance
unknown. Given the systemic nature of CKD and dialysis. In this situation, treating depression
the varied manifestation of sleep disorder, multiple should be the key component of the management
contributing factors may be involved. The possible strategy.
factors contributing to sleep disorders in CKD are: Sleep apnea: When symptoms (fragmented
sleep or daytime sleepiness) are present, or the
• Anemia apnea-hypopnea index exceeds 30, sleep apnea
• Presence of uremic toxins should be treated. Treatment options include
• Volume overload weight loss, avoidance of the supine position dur-
• Iron deficiency ing sleep, and the use of a dental appliance,
• Chronic inflammation continuous positive airway pressure, or surgical
• Depression correction of the upper airway.
• CKD-related chronic pain Insomnia: cognitive behavioral therapy and
• Stress and anxiety medication therapy can be considered.
Excessive daytime sleepiness: If the underly-
ing cause cannot be determined and the symp-
13.4.3 Diagnosis toms are severe enough to affect the patient’s
daily activities, stimulant medications (e.g.,
Patients with sleep disorder usually present with modafinil or methylphenidate) may be
typical symptoms. A detailed sleep history and a considered.
168 W. Liu
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Kurella M, Mapes DL, Port FK, Chertow
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Part III
Management of Chronic Kidney Disease
Nutritional Management
of Chronic Kidney Disease 14
Li Fang
Abstract increasing epidemic proportion worldwide.

Since chronic kidney disease (CKD) may lead Moreover, the increasing incidence of diabetes
to a unique constellation of nutritional and met- suggests that the frequency of CKD will continue
abolic abnormalities, a suboptimal nutritional to grow in the near future. With a gradual loss in
status among the population with CKD is com- kidney function, CKD might lead to a unique
mon, and this poses a direct risk for protein- constellation of nutritional and metabolic abnor-
energy wasting, disease progression, and malities. Altered protein and energy homeostasis,
increased mortality. Therefore, given the high abnormal protein catabolism, acid–base derange-
incidence and prevalence of CKD and the urgent ments, bowel flora alteration, and hormonal dys-
need for alternative disease management strate- function usually ensue. Hence, a suboptimal
gies, the patient-centered and cost- effective nutritional status among the population with
nutritional management with disease-specific CKD is common, and this poses a direct risk for
dietary ranges may be a cornerstone required protein-energy wasting (PEW), disease progres-
not only to simply adjust suboptimal nutritional sion, and increased mortality [1–3]. Therefore,
status but also to help manage uremia and other nutritional intervention is a cornerstone required
complications. Moreover, it may help increase not only to simply adjust suboptimal nutritional
longevity and prolong the dialysis-free interval status but also to help manage uremia and other
for millions of people worldwide. Nutritional complications such as electrolyte and acid–base
interventions may be increasingly chosen as an imbalances, water and salt retention, mineral and
effective management strategy for CKD. bone disorders, and failure to thrive [1, 2, 4]. In
this chapter, we mainly focus on nutritional inter-
ventions as an important management strategy
for CKD.
14.1 Introduction
With an occurrence rate of approximately 14.2 Nutritional Assessment

10–15%, chronic kidney disease (CKD) has
become a major noncommunicable disease with As renal failure advances in patients with CKD,
nitrogen-containing products accumulated from
dietary and intrinsic protein catabolism might
L. Fang (*) distort taste and blunt appetite. Additionally,
Department of Nephrology, Affiliated Hospital of since uremia status might affect the gut microbi-
Nantong University, Nantong, Jiangsu, China
e-mail: fangli@njmu.edu.cn ome and disrupt the intestinal barrier function,

174 L. Fang
gastrointestinal nutrient absorption may also spaces, as well as losses and wasting from the
become abnormal. Hence, poor nutritional status, body. In patients with CKD, hypoalbuminemia
defined as PEW and manifested as decreased can be the result of factors such as fluid overload,
body storage of protein and energy fuels, is com- proteinuria, and losses to the dialysate. Counter-
mon in patients with renal insufficiency. regulatory mechanisms may also influence the
Although a consensus on the importance of serum albumin concentration. In the short term,
identifying and treating malnutrition in patients protein deficiency might reduce the hepatic
with CKD existed for decades until now, a well- albumin- synthesizing activity; however, in the
established assessment system to accurately long term, compensation might occur through a
reflect the nutritional status remains unclear and decreased albumin breakdown and a shift of albu-
not well-used in the clinical setting [1–3]. Several min from the extravascular to the intravascular
biochemicals, clinical, anthropometric, and nutri- space. Furthermore, because albumin has an
tional parameters are associated with and fre- extraordinarily long circulatory half-life of about
quently indicative of PEW in patients with 20 days and is present in large quantities, the
CKD. However, the National Kidney Foundation impact of reduced dietary protein intake on serum
K/DOQI Clinical Practice Guidelines for albumin levels is limited. Hence, even in extreme
Nutrition in Chronic Renal Failure recommends cases of malnutrition, such as marasmus and
that nutritional status should not be evaluated anorexia nervosa, serum albumin concentrations
with only a single parameter alone but instead could remain normal or only slightly reduced.
using a combination of valid and complementary Numerous studies have shown that serum albu-
parameters. According to an expert panel directed min levels in CKD patients and dialysis patients
by the International Society of Renal Nutrition are usually low. However, it is important to con-
and Metabolism, the current procedure for the sider that patients with CKD commonly have
diagnosis of PEW recommends the analysis of comorbid conditions, such as insufficient food
serum chemistry (s-albumin, s-prealbumin, and intake, fluid overload, and chronic inflammation,
s-cholesterol), body mass (body mass index, all of which are known to affect serum albumin
body weight variation, and percent of body fat), levels. Hypoalbuminemia in patients with CKD
signs of muscle wasting over time (reduced mid- seems to be associated with a chronic inflamma-
arm muscle circumference and creatinine appear- tion rather than with malnutrition. Despite the
ance), as well as unintentional low dietary intake wide use of albumin as a nutritional status bio-
for at least 2 months [5–8]. Overall, the data for marker in CKD in many researches, serum albu-
nutritional evaluation could be classified into min levels might actually be a marker of disease
four categories four categories—biochemical, severity rather than nutrition and may be a poor
anthropometric, clinical, and dietary—discussed parameter of nutritional status in patients with
in detail as follows: CKD [9, 10].
14.2.1.2 Prealbumin
14.2.1 Biomarkers of Nutritional Prealbumin, which is also primarily synthesized
Status by the liver, is a 55-kD homotetrameric protein in
blood that plays a role in carrying thyroxine and
14.2.1.1 Serum Albumin retinol throughout the body. Prealbumin has a
Serum albumin is an important nutrient manufac- half-life in plasma of ∼2 days, much shorter than
tured by the liver that helps support muscle that of albumin. It is catabolized partly in the kid-
growth, repair damaged tissue, and defense neys, and consequently any renal dysfunction
against pathogen infection. Its concentration is causes an increase in its serum levels. Generally,
influenced by many factors, such as rates of syn- prealbumin correlates with the level of nutrition
thesis and breakdown, volume of distribution, support, increasing with sufficient dietary intake
exchange between intra- and extravascular and decreasing when dietary intake is declining.
14 Nutritional Management of Chronic Kidney Disease 175
In patients with CKD, the levels of prealbumin intake or protein depletion [9]. Thus, both in the
show a linear relationship to the degree of clinical and research settings, it is recommended
protein-energy malnutrition in patients with to check CRP levels in conjunction with other
CKD, which are restored by refeeding. However, nutritional markers and when deciding possible
as with serum albumin, prealbumin decline sensi- nutritional intervention as well as interventions
tively in response not only to inadequate protein against factors causing increased CRP levels.
intake but also to acute or chronic inflammation
(i.e., “acute-phase reactant”), limiting its speci- 14.2.1.5 Cholesterol
ficity as a marker of nutritional status. Therefore, Cholesterol is a lipoprotein that functions as a
although prealbumin is more sensitive in assess- precursor for the synthesis of steroid hormones,
ing changes of nutritional status than serum albu- bile acids, and vitamin D. Serum cholesterol and
min, however, since it could be influenced by several other blood lipids and lipoproteins such
many non-nutritional factors, serum prealbumin as total cholesterol, triglycerides, low-density
is not considered to be a valid indicator of nutri- lipoprotein [LDL] cholesterol, high-density lipo-
tional status in patients with CKD. protein [HDL] cholesterol, and non-HDL choles-
terol are indicators of patients’ nutritional status.
14.2.1.3 Creatinine Height Index Indeed, s-cholesterol has been proposed as an
Creatinine is a waste product that comes from assessment criterion for malnutrition and
continuous creatine phosphate breakdown in PEW. Contrary to the general population, a high
muscle. Since almost all creatinine is filtered s-cholesterol level in the CKD and dialysis popu-
from the blood into the urine by kidneys, serum lation is associated with improved survival [1, 2].
creatinine level is usually a good indicator of kid- However, this association seems to only be true
ney functions. Under normal renal function, cre- in patients with inflammation and/or malnourish-
atinine is typically produced by the body at a ment, which suggest that low levels of
relatively constant rate at a level proportional to s-
cholesterol may be a surrogate marker of
total muscle mass. Urinary creatinine excretion inflammation and/or malnutrition.
rate is generally related to muscle mass [11].
Normalized for height, the measurement of 24-h
creatinine excretion is an indicator of muscle 14.2.2 Clinical and Anthropometric
mass, particularly in young males. However, it is Markers of Nutritional Status
dependent on complete 24-h urine collections
and urinary excretion; low excretions of urinary 14.2.2.1 Subjective Global
creatinine may result in an inappropriate diagno- Assessment (SGA)
sis of malnutrition. Therefore, the creatinine Subjective Global Assessment (SGA) is a simple
height index might be an inaccurate indicator of and reliable nutritional assessment tool. It is
malnutrition in patients with CKD. composed of five components of a medical
history (recent dietary intake, gastrointestinal

14.2.1.4 C-Reactive Protein (CRP) symptoms, weight change, functional capacity,
C-reactive protein is an inflammation marker and disease, and its relationship to nutritional require-
not a direct nutritional marker. However, it also ments) and three components of a physical exam-
plays an important role in the overall assessment ination (signs of fat and muscle wasting,
of nutritional status in patients with CKD because nutrition-associated alternations in fluid balance)
it is an acute-phase reactant that is inversely cor- to predict nutrition-associated complications.
related with the concentrations of visceral pro- Since SGA evaluations could effectively demon-
teins. In clinical practice, one should remember strate the changes of nutritional status occurring
that very low levels of visceral proteins, for throughout the course of the disease, it was found
instance, serum albumin, are often due to the pres- to be highly predictive of malnutrition and out-
ence of inflammation rather than the low protein come in those who are nutritionally compromised
176 L. Fang
in any stage of CKD or in danger of becoming 14.2.2.3 O ther Nutritional Scoring

malnourished [12]. Using the SGA, many studies Systems
reported that patients with CKD, whether or not In addition to the SGA and MIS, alternative scor-
on dialysis, met only 50–70% of their energy ing systems have also been developed to assess
needs and only about 50% of their protein needs. nutritional status. Among those, Mini Nutritional
The SGA has been used as a surrogate for PEW Assessment (MNA) has been originally devel-
in many studies [13–15]. The Academy recom- oped as nutritional assessment tools for the geri-
mends that SGA be performed in patients with atric population [18]. It is made up of a screening
CKD at the initial visit and quarterly to determine section (six questions), known as Mini Nutritional
the patients’ nutrition status. These numbers and Assessment-Short Form (MNA-SF), which can
SGA scores improve if the dietitians followed be further complemented by 11 questions in
their patients monthly. order to gain a malnutrition indicator score scale
Although SGA has recently been recom- (full-MNA form). In addition, these tools have
mended by the National Kidney Foundation also been used in CKD and dialysis patients;
(NKF) Kidney Disease/Dialysis Outcomes and however, the usefulness of the MNA-SF remains
Quality Initiative (K/DOQI) for assessing the questionable.
nutritional status in the adult dialysis population,
it is a subjective score that may be biased by 14.2.2.4 Body Mass Index (BMI)
inter- and intrapersonal differences. Therefore, a Body mass index (BMI), which is calculated as
longitudinal research study conducted by the body weight in kilograms divided by the square
well-trained investigator following patients over of height in meters, is an indicator of body fat.
time might be necessary. According to the World Health Organization
(WHO) guidelines, the healthy range for BMI is
14.2.2.2 Malnutrition Inflammation between 18.5 and 24.9 kg/m2 for adults. Obesity
Score (MIS) is defined as a BMI ≥30.0 kg/m2, overweight as a
Stemming from the original SGA, a new com- BMI of ≥25.0 kg/m2, and underweight as a BMI
prehensive nutritional assessment tool called the <18.5 kg/m2. In patients with CKD, the BMI may
MIS which involves seven components from the not reflect the real nutritional status, as a gross
SGA questionnaire (weight change, dietary imbalance in fluid status in these patients may
intake, gastrointestinal symptoms, functional cloud the results. Furthermore, loss of muscle
capacity, comorbidity, subcutaneous fat, and mass is characteristic of PEW; however, a rela-
signs of muscle wasting) and the three additional tively well-preserved fat mass usually remains,
biochemical parameters influenced by inflam- resulting in small changes in BMI that can be dis-
mation status (body mass index, serum albumin, guised by imbalances in fluid homeostasis.
and total iron-binding capacity (TIBC)) was pro- Finally, overweight patients with end-stage renal
posed by Kalantar-Zadeh et al. [16]. In total, disease (ESRD) may also suffer from PEW. For
MIS system comprises ten parameters, each these reasons, BMI alone does not accurately
including four degrees of severity (where reflect the nutritional or PEW status in patients
0 = normal and 3 = severely abnormal) and sum- with CKD.
ming each component to produce a final score
(0 = normal nutritional status and 30 = severely 14.2.2.5 Hand Grip Strength (HGS)
malnourished). Numerous studies have demon- Muscle strength in patients with CKD is often
strated that higher MIS scores were associated evaluated by muscle dynamometry such as hand
with worse nutritional status, poorer health- grip strength (HGS) [19], which associates with
related quality of life, as well as higher hospital- lean body mass as assessed by anthropometry,
ization and mortality rates in maintenance dual-energy X-ray absorptiometry (DEXA, see
hemodialysis patients [17]. below), and creatinine kinetics and with nutritional
status as assessed by SGA score. In addition, the the body at various frequencies and the conduc-
combined assessment of body composition (lean tance is measured. The current standard BIA
body mass) and muscle function has become more models used in CKD view the body as five inter-
prevalent as a composite marker of nutritional sta- connecting cylinders: two each for the arms and
tus. Indeed, a dynamometric HGS measurement legs and one for the trunk, instead of the more
standardized to age and gender has emerged as an common previous assumption that the whole
easily performed bedside test that is considered to body can be visualized as a single cylinder. BIA
be a reliable and available marker of both nutri- models are prone to errors of simplification
tional status and future mortality risk. which depend on body size, shape, and regional
fluid accumulation.
14.2.3 Dietary Intake Information 14.2.4.2 Dual-Energy X-Ray

Absorptiometry
There are many methods to estimate dietary Dual energy X-ray absorptiometry (DEXA),
intake; however, the accuracy of document is fre- which was primarily used for assessing bone
quently fluctuating. In general, during a nutrition mineral density, has become another more reli-
interview, the clinical dietitian may ask what the able tool to estimate body composition [20].
individual ate during the previous 24 h, begin- When DEXA passes low-energy X-rays through
ning with the last item eaten prior to the inter- the body, a low-resolution image could be gener-
view. Alternatively, practitioners can also train ated to measure fat distribution throughout the
individuals on completing a food record typically body [22]. However, although DEXA could
obtained for 3–7 days. The documentation should accurately measure fat mass with high-precision,
include portion sizes and how the food was pre- low X-ray exposure, and short scanning time, it is
pared. However, documenting portion sizes is hardly feasible in routine clinical practice due to
usually difficult, and requesting that every food its high cost and its inaccuracy in severely over-
be measured or weighed is usually very difficult hydrated patients. Furthermore, the amount of
to implement and time-consuming. Therefore, radiation used during repeated DEXA scans,
nutrition interviews are not commonly used in although small, may be of concern in patients.
practice.
14.2.4.3 Magnetic Resonance
Imaging (MRI)
14.2.4 Other Methods to Assess Magnetic resonance imaging is a noninvasive
Nutritional Status medical imaging technique measuring nuclear
relaxation times from nuclei of atoms with mag-
14.2.4.1 Bioelectrical Impedance netic moments that are aligned within a powerful
and Conductance magnetic field. Magnetic resonance imaging can
Bioelectrical impedance analysis (BIA) has been be used to quantify components at the tissue-
proposed as a noninvasive and simple technique system levels of body composition, including
to measure body hydration status of patients, skeletal muscle, adipose tissue, visceral organs,
especially with regard to the determination of and the brain. Clinical systems are based on
“dry” body weight in hemodialysis patients [20, hydrogen, although it is possible to create images
21]. BIA has also been suggested as a valuable and spectrographs from phosphorus, sodium, and
tool in subjects undergoing peritoneal dialysis. carbon. The collected data are transformed into
BIA assumes that the human body may be high-resolution images, which allow the quantifi-
viewed as a number of parallel connected resis- cation of whole-body or regional-body composi-
tors. By connecting electrodes to various body tions. However, to our knowledge, no high-quality
parts (typically the arms and legs) with a con- clinical studies have assessed imaging methods
ductive gel, an electric current passes through in relation to outcome.
178 L. Fang
14.3 Nutritional Management The current evidence has suggested that reducing
protein intake could decrease proteinuria as effi-
14.3.1 Energy Intake ciently as angiotensin-converting enzyme inhibi-
tors, mainly because that a low-protein diet has a
Designing a diet for the patients with CKD to preglomerular effect that may enhance the post-
receive enough calories is of most importance. glomerular effect of angiotensin pathway modu-
However, in clinical practice, it is really a chal- lators that dilate the efferent arterioles and
lenge to estimate accurate energy requirements in consequently lower the intraglomerular pressure
patients with CKD, since the daily energy [1, 2, 4].
requirements are influenced by many variable Besides, limiting protein intake also results in
factors, such as resting energy expenditure, ther- an instant reduction in urea generation. After pro-
mic effect of meals, physical activity level, and so tein breakdown, individual amino acids are
on. Many previous studies have shown that the deaminated by the removal of an α-amino group,
energy requirements of patients with CKD were leaving a carbon skeleton of ketoacids, which can
similar to those of normal adults. Therefore, in be recycled to form other amino acids and pro-
CKD stages 1–3, the Kidney Disease Outcomes teins or can be used for energy generation through
Quality Initiative (KDOQI) recommends that the tricarboxylic acid cycle, while urea is gener-
energy intake levels support a balanced diet and ated through the urea cycle. A persistently high
maintain desirable body weight but does not rec- blood urea level, termed azotemia, which is a
ommend specific energy intake amounts. commonly used marker for uremia, may enhance
However, in CKD stages 4 through 5 (GFR protein carbamylation and generate reactive oxy-
<30 mL/min/1.73 m2), specific energy intake gen species, leading to oxidative stress, inflam-
amounts are recommended: 35 kcal/kg/day for mation, endothelial dysfunction, and ultimately,
those younger than 60 years and 30–35 kcal/kg/ cardiovascular disease. Reducing protein intake
day for those older than 60 years. If the patients could effectively decrease the production of
were overweight and obese, calories should be wasted products and uremic toxins which in turn
restricted because calories intake in excess of diminishes the uremic symptoms. Metabolic
requirements might cause obesity, and obesity consequences of low protein diet have also been
might in turn engender insulin resistance and extensively researched in recent years: reduced
impaired glucose disposal [1, 2, 4]. oxidative stress, improved insulin sensitivity, bet-
ter control of metabolic bone disorders in
response to a reduced phosphate load, and
14.3.2 Protein Intake improved anemia management.
For healthy persons, the recommended dietary
Whether the quantity or quality of ingested pro- allowance for protein is 0.8 g per kilogram per
tein is a risk factor for chronic kidney disease day, whereas the estimated average requirement
progression has been debated for nearly a cen- for adults with CKD who are otherwise healthy
tury. Now, there are mounting evidences that the is 0.66 g per kilogram per day. Hence, of the
western-type diet, which contains exceeding various ranges of low protein intakes, 0.6–0.8 g
1.5 g per kilogram of ideal body weight per day, per kilogram of body weight per day is the most
may cause glomerular hyperfiltration and proin- frequently recommended target for adults with
flammatory gene expression, which are known moderate-to-advanced kidney disease (estimated
risk factors for CKD progression. Experimental GFR <45 mL/min/1.73 m2) and for the manage-
evidence in animal models has also shown that a ment of substantial proteinuria (urinary protein
high-protein diet dilates the glomerular afferent excretion, >0.3 g per day), especially if half of
arterioles and increases glomerular filtration, the protein is of “high biologic value” (e.g., dairy
whereas low protein intake constricts the afferent products). However, the so-called very-low-
arterioles and lowers intraglomerular pressure. protein diet (<0.6 g of protein per kilogram per
day), supplemented with essential amino acids function remains less well investigated and con-
or their ketoacids, is also used. People at founding. Several studies have demonstrated that
increased risk for kidney disease, such as those a reduced sodium intake could enhance the effects
who have undergone nephrectomy for kidney of a low-protein diet and angiotensin-modulation
donation or for cancer treatment or who have therapy in decreasing intraglomerular pressure
diabetes mellitus, hypertension, or polycystic and might also decrease proteinuria and slow the
kidneys, may benefit from a modest protein progression of kidney disease. However, some
intake (<1 g per kilogram per day) in order to other studies reported that strict sodium restriction
maintain a moderately low intraglomerular pres- might also activate the renin-angiotensin-aldoste-
sure [1, 2, 4, 23, 24]. rone system, sympathetic nervous system, and
As mentioned previously, protein-energy insulin resistance.
wasting (PEW) is commonly seen in patients As ingested sodium is primarily excreted via
with chronic kidney disease (CKD); the safety the kidneys, a 24-h urinary sodium excretion is a
and feasibility of long-term dietary modification good indicator of sodium intake. Observational
are among the main concerns. From a basic point studies using urinary sodium excretion as a sur-
of view, the direct relationship between low pro- rogate for sodium chloride intake have yielded
tein intake and muscle wasting should be discov- inconsistent data, with some studies showing no
ered. Unfortunately, this approach is not clinically association between dietary sodium intake and
relevant: muscle wasting in chronic kidney dis- renal disease progression and others showing a
eases seems to be caused by the imbalance toward positive association. A longitudinal study pub-
a catabolic state (more protein degradation than lished in 2016, which involved serial 24-h urine
synthesis) and is further deteriorated by the lack collections from 3939 patients with CKD, sug-
of physical activity. Additionally, metabolic aci- gested that the highest quartile of urinary sodium
dosis closely related to inflammation and insulin excretion (≥4.5 g per day), as compared with the
resistance is also an important reason. Restrained lowest quartile (<2.7 g per day), was associated
protein intake has been proven to improve all with a 45% higher mortality and a 54% higher
these catabolic conditions. Therefore, the safety risk of disease progression. Incrementally worse
of and adherence to a low-protein diet might be cardiovascular outcomes were observed when
improved by providing adequate energy (30– dietary sodium intake exceeded 4 g per day.
35 kcal per kilogram per day), ongoing nutri- Observations in the general population suggest a
tional education, and surveillance. J-shaped association; dietary sodium intake that
is higher than 5 g per day and intake that is lower
than 3 g per day are each associated with an
14.3.3 Sodium Intake increased risk of cardiovascular disease and
death. Although a daily dietary allowance of less
Patients with hypertension and CKD are usually than 2.3 g of sodium (<100 mmol) is often rec-
salt-sensitive. The available evidence, detected as ommended for patients with cardiovascular dis-
an increase in blood pressure of more than 10% ease, there is no evidence that patients with
when a low salt diet is switched to a high salt kidney disease will benefit from this sodium
intake, demonstrated that a high-sodium diet restriction. Therefore, a daily dietary sodium
(>4 g of sodium per day) in CKD has an influence intake of less than 4 g (<174 mmol) is recom-
on hypertension, cardiovascular risk factors, and mended for the overall management of CKD and
outcomes. In patients with established CKD, its associated risks, with a sodium intake of less
dietary sodium restriction is invariably recom- than 3 g (<131 mmol) for the specific manage-
mended to control fluid retention and hyperten- ment of symptomatic fluid retention or protein-
sion and to improve the cardiovascular risk profile. uria. Evidence supporting a sodium intake of less
However, the association between salt intake and than 1.5 g per day (<87 mmol per day) for patients
renal outcome in subjects with preserved kidney with renal insufficiency is lacking, given the risk
180 L. Fang
of hyponatremia and adverse outcomes. Once careful search for other causes of hyperkalemia
sodium excretion is excessive and blood pressure should be undertaken before restricting dietary
elevates, the nutrition consultation and repeating potassium. Particularly, drugs that reduce potas-
24-h urine measurements of sodium are recom- sium excretion should be eliminated, acidosis
mend to make dietary planning more easily [1, 2, should be corrected, and constipation should be
4, 23–25]. relieved. Undoubtedly, more studies are further
Whereas adequate fluid intake may mitigate needed to investigate the advantage and dangers
the risk of kidney disease, patients with renal of increasing (or limiting) dietary potassium in
insufficiency generally have isosthenuria. This patients with CKD.
is the basis for the recommendation that patients A higher dietary potassium intake may be
with stage 3 CKD limit fluid intake to less than associated with a higher risk of kidney disease
1.5 L per day in order to avoid hyponatremia; progression. Among patients with very advanced
adjustment of that limit for a hot climate and CKD, the highest quartile of dietary potassium
other conditions associated with high insensi- intake, as compared with the lowest quartile, is
ble fluid losses is imperative. Adjunctive ther- associated with an increase in the risk of death by
apy with loop diuretics is often prescribed, a factor of 2.4; the association is independent of
particularly for patients who tend to have the plasma potassium level and other nutritional
symptomatic fluid retention or hyponatremia, measures. Therefore, the National Kidney
given the association of such conditions with Foundation’s expert panel recommended potas-
poor outcomes in CKD. It should also be noted sium restriction for individuals with advanced
that diuretics alone might fail because an unre- CKD (e.g., stage 4 CKD and an estimated GFR
stricted salt intake will overcome the effective- <30 mL/min/1.73 m2). In other epidemiologic
ness of diuretic. studies, both moderately low (<4.0 mmol per
liter) and high plasma potassium levels
(>5.5 mmol per liter) are associated with more
14.3.4 Potassium Intake rapid kidney disease progression. Dietary potas-
sium restriction is often recommended in patients
Substantial evidence has supported that with hyperkalemia, especially those with more
potassium-rich foods could reduce the possibility advanced stages of kidney disease. However,
of developing chronic diseases, such as hyperten- excessive dietary restrictions can expose patients
sion, diabetes, and coronary heart disease. Thus, to less heart-healthy and more atherogenic diets
given the well-established association of higher and worsen constipation, which may actually
dietary potassium with lower sodium intake and result in higher gut potassium absorption. Despite
lower incidences of hypertension, stroke, and the higher risk of hyperkalemia with the progres-
kidney disease, a relatively high daily intake of sion of kidney disease, few studies have exam-
potassium of 4.7 g (120 mmol) was recom- ined the effects of dietary potassium restriction or
mended in the general population by guidelines methods of extracting potassium during food
from the Institute of Medicine. However, the preparation and cooking. It is not clear whether
causal relationship between dietary potassium potassium-binding agents can allow the liberal-
and hypertension in patients with CKD was less ization of dietary potassium intake with the inclu-
studied in the previous researches. sion of healthier potassium-rich foods. In patients
Accompanied by renal insufficiency, the kid- with a tendency toward hyperkalemia (>5.5 mmol
neys’ ability to excrete excess potassium might of potassium per liter), a dietary potassium intake
be impaired. Besides, the impairment in the of less than 3 g per day (<77 mmol per day) is
action of protective hormones (e.g., aldoste- recommended, with the stipulation that the bal-
rone) or use of ACEIs, ARBs, or nonsteroidal anced intake of fresh fruits and vegetables with
anti-inflammatory drugs may also result in the high fiber should not be compromised [1, 2, 4,
impaired potassium excretion. Therefore, a 23, 24, 26, 27].
14.3.5 Phosphorus Intake phosphorus-to-protein ratio should be mini-

mized. However, in patients with stage 5 CKD
Numerous studies have determined positive who receive dialysis therapy or who are at
phosphate balance and hyperphosphatemia to be increased risk for PEW, excessively stringent
the risk factors for vascular calcification, cardio- restriction of protein intake to control hyperphos-
vascular mortality, and left ventricular hypertro- phatemia may be associated with poor outcomes.
phym in chronic kidney disease. Daily dietary Thus, an individualized dietary approach that
phosphorus intake is approximately 1000– incorporates ample use of phosphorus binders is
1200 mg, of which approximately 950 mg is optimal [1, 2, 4, 23, 24, 28].
absorbed. Phosphorus could be removed by two
systems, the gastrointestinal tract (150 mg/day)
and the urine (800 mg/day). However, as kidney 14.3.6 Calcium and Vitamin D
function declines, renal phosphorus excretion
might be progressively impaired. Decreased glo- Vitamin D insufficiency and deficiency is widely
merular filtration of phosphorus is initially com- prevalent in the patients with CKD, which is fur-
pensated by decreased tubular reabsorption ther exacerbated by the reduced ability to convert
regulated by parathyroid hormone and fibroblast 25-(OH) vitamin D into the active form, 1,25
growth factor 23 (FGF-23). Elevated parathyroid dihydroxy-vitamin D. The associated decline in
hormone and FGF-23 levels can cause renal bone 1,25-dihydroxy vitamin D may further diminish
disease, left ventricular hypertrophy, vascular gastrointestinal absorption of calcium; however,
calcification, and accelerated progression of kid- passive diffusion of ionized calcium continues
ney disease from vascular and tubulointerstitial and may lead to a positive calcium balance,
injury, highlighting the importance of dietary which is aggravated by diminished urinary
phosphorus management, even in patients with- calcium excretion due to secondary hyperpara-
out apparent hyperphosphatemia. There is a close thyroidism. Increased calcium release from bone
relationship between protein and phosphorus in hyperactive renal bone disease (increased bone
intake: 1 g protein brings 13–15 mg phosphate, resorption because of secondary hyperparathy-
of which 30–70% is absorbed through the intesti- roidism) enhances the positive calcium balance
nal lumen. High-protein diet may aggravate ure- and may worsen vascular calcification. Gut cal-
mic symptoms and hyperphosphatemia; however, cium absorption varies because of differences in
although a low-protein diet also decreases phos- dissociation and bioavailability from one type of
phorus intake, the quantity and bioavailability of elemental calcium to another; for instance, cal-
phosphorus differ according to the type of pro- cium citrate is more readily absorbable than cal-
tein. For example, the phosphorus-to-protein cium acetate. Two studies suggested that an
ratios of egg whites and egg yolks (which have intake of 800–1000 mg of elemental calcium per
3.6 and 2.7 g of protein per egg, respectively) are day (20–25 mmol per day) can result in a stable
1–2 mg per gram and 20–30 mg per gram, respec- calcium balance in people with stage 3 or 4
tively. The gastrointestinal absorption of phos- CKD. Hence, whereas the suggested calcium
phorus, mostly in the form of phytates, is lower intake for persons without kidney disease is
from plants (along with fibers) than that from 1000–1300 mg per day (25–32 mmol per day),
meat (30–50% vs. 50–70%). Since food additives 800–1000 mg of elemental calcium from all
include readily absorbable inorganic phosphorus, sources per day should suffice in patients with
ingestion of processed foods results in an even moderate-to-advanced CKD [1, 2, 4, 23].
higher phosphorus burden. Restricting dietary Native vitamin D supplementation (cholecal-
phosphorus intake to less than 800 mg per day ciferol or ergocalciferol) may be offered to
(26 mmol per day) is recommended for patients patients with CKD and low levels of circulating
with moderate-to-advanced kidney disease, and vitamin D. In some studies, vitamin D analogs
the consumption of processed foods with a high have been associated with decreased proteinuria
182 L. Fang
in addition to the healing of renal osteodystrophy. Uremia itself, as well as dietary restrictions
Notwithstanding inconsistent data on the require- and pharmacotherapy, including antibiotics, may
ment for and the effect of vitamin D in certain alter the gut microbiome; this change may affect
subpopulations of patients with CKD, including the symptoms and progression of kidney disease.
black Americans, who have lower total vitamin D Gut dysbiosis, which is manifested by qualitative
levels and higher parathyroid hormone levels and quantitative changes in host microbiome pro-
than those in white Americans, hydroxylated file and disruption of gut barrier function, was
vitamin D agents may be needed in addition to commonly seen in patients with CKD. Endotoxin
native vitamin D to control progressive second- derived from gut bacteria can incite a powerful
ary hyperparathyroidism. chronic inflammation in the host organism.
Furthermore, disruption of gut barrier function in
CKD may allow translocation of endotoxin and
14.3.7 Vegetarian Diet, Fiber, bacterial metabolites to the systemic circulation,
and the Microbiome which contributes to uremic toxicity, inflamma-
tion, progression of CKD, and associated cardio-
Plant-based diets, despite containing low amounts vascular disease. Therefore, targeted microbiome
of protein, are also rich in potassium and phos- modulation through nutritional interventions,
phorus, and therefore vegetarianism is believed such as consumption of probiotics, may help to
to be unsuitable for CKD patients. However, control the production, degradation, and absorp-
numerous clinical studies have recently demon- tion of certain uremic toxins that are fermenta-
strated that such a plant-based diet could be ben- tion by-products of gut microbial activities,
eficial for the patients when they learn how to use including indoxyl sulfate, p-cresol, and trimeth-
it wisely. Plant-based foods are recommended as ylamine [1, 2, 4, 23, 29]. For example, in a study
part of many strategies for the prevention and involving 40 patients with moderate-to-advanced
management of kidney disease because these CKD, a lower ratio of dietary fiber to protein was
foods contain smaller amounts of saturated fatty associated with higher blood levels of indoxyl
acids, protein, and absorbable phosphorus than sulfate and p-cresol. Nutritional and pharmaco-
meat; they also generate less acid and are rich in logic interventions, including the use of absor-
fibers, polyunsaturated and monounsaturated bent ingestible agents and high-fiber or vegetarian
fatty acids, magnesium, potassium, and iron. diets, are being tested as a means of reducing gut
Besides, according to several studies, a plant- absorption of uremic toxins to control uremic
based diet was found to delay the progression of symptoms and slow disease progression.
CKD, help to control high blood pressure, and
decrease proteinuria, while others indicated that
high plant protein intake is likely to accelerate 14.3.8 Carbohydrate and Fat Intake
CKD progression when compared to animal pro-
teins. Therefore, the National Kidney Foundation National dietary recommendations have pro-
recommends vegetarianism, or part-time vegetar- moted high-carbohydrate, low-fat diets to reduce
ian diet as being beneficial to CKD patients. cardiovascular disease risk. These recommenda-
Besides, constipation can lead to higher reten- tions were based on observational studies in
tion of uremic toxins and hyperkalemia, whereas which low fat intake was associated with a low
loosening stools may enhance fluid loss and risk for cardiovascular disease, presumably by
removal of nitrogenous products. The protein in a lowering LDL cholesterol levels. Unrefined car-
vegetarian diet is less fermentable, and has high bohydrates account for half the usual daily energy
fiber content, increasing peristalsis, and the num- intake, and the proportion may be even higher in
ber of bowel movements, and is associated with a low-protein diet. In patients with kidney dis-
less uremic toxin production, exposure, and ease, carbohydrates should be complexed with
absorption. high fiber content (e.g., whole-wheat breads,
multigrain cereal, oatmeal, and mixed fruits and more than 90% of the daily energy intake require-
vegetables) to help reduce dietary phosphorus ment of 30–35 kcal per kilogram to avoid
and protein as well as urea and creatinine genera- PEW. Obviously, in patients with diabetic kidney
tion. Such a diet may promote a more favorable disease, proper glycemic control should be main-
microbiome with less constipation. tained, but adequate energy intake is needed to
Reducing fat as part of a low-calorie diet is a mitigate the risk of PEW and hypoglycemia,
practical way to reduce energy intake. However, which increases with worsening kidney function
clinical trials of diet therapy to reduce lipids and [1, 2, 4, 23].
slow progression of CKD have not been con-
ducted. Dietary fat recommendations for obese
patients with CKD should be in accordance with 14.3.9 Dietary Management
the National Cholesterol Education Program/ of Acidosis in Chronic Kidney
Adult Treatment Panel III (NCEP/ATPIII) guide- Disease
lines (2001) developed for cardiovascular risk
reduction. In CKD stages 1 through 4, the Daily acid production results from bicarbonate
KDOQI recommends that 25–35% of the total losses in the gut (20–30 mmol of bicarbonate per
energy intake comes from fat, with 10% of the day), breakdown of amino and nucleic acids from
total from saturated fat. The recommended cho- proteins (20–30 mmol per day), and oxidation of
lesterol intake is 200 mg/day. The objective of carbohydrates and fats to lactic acid and ketoac-
these guidelines is to control blood lipid levels, ids (10–20 mmol per day). The kidney plays an
minimizing elevated blood glucose and triglycer- important role in regulating of the acid–base bal-
ide levels. Because diets for patients with CKD ance. The kidneys regenerate the bicarbonate
are sometimes mildly restricted in protein, it may used for buffering by the excretion of both net
be difficult to provide sufficient energy without acid and acid buffers, including phosphate, and
resorting to a large intake of high-glycemic index by ammoniagenesis through the deamination of
carbohydrates that may increase triglyceride pro- glutamine in the proximal tubule and its syntheti-
duction. Another challenge when addressing fat zation to ammonium in the collecting ducts, with
intake is maintaining recommended macronutri- subsequent urinary excretion. Hence, chronic
ent balances when lowering saturated fat in the kidney disease and reduced glomerular filtration
diet. When saturated fat is reduced in the diet, it rate may contribute to the development of chronic
can be replaced with unsaturated fat, protein, or metabolic acidosis. Kidney disorders, including
carbohydrates. The optimal means of replace- renal tubular defects, are often associated with
ment of saturated fats is not known. Data from chronic metabolic acidosis. Metabolic acidosis is
dietary intervention trials suggest that a diet low a relatively common complication in patients
in saturated fat that uses either protein or unsatu- with renal failure, particularly in those with GFR
rated fats to replace carbohydrates can have falls below 30 mL/min/1.73 m2. Also, a large
favorable effects on lipids. Unsaturated fat is the amount of evidence identifies acidosis not only as
preferred lipid in the diet. Replacement of butter a consequence of, but as a contributor to, kidney
with flaxseed, canola, or olive oil, all of which disease progression.
are rich in unsaturated fatty acids, may be worth- Diet plays an important role in acid–base
while. For example, a recent study suggested that balance. The modern high-protein diets may
dietary unsaturated fatty acid supplementation in yield about 1 mmol/kg body weight/day of net
patients with diabetes and hypertriglyceridemia endogenous H+ production, while the fruits and
may reduce albuminuria and preserve renal func- vegetables may generate base from the metabo-
tion. There is currently no evidence that low-fat lism of organic anions such as citrate and
diets, recommended by some guidelines, improve malate. The 24-h urinary excretion of ammo-
kidney disease outcomes. In a low-protein diet, nium and titratable acid minus bicarbonate
fat and carbohydrates should together account for could be used as an indicator of total net acid
184 L. Fang
excretion (NAE). A well-controlled clinical CKD. Deficiencies of zinc, copper, and selenium

trial in healthy adults consuming various diets may occur, whereas aluminum and magnesium
has revealed that pH value in 24-h urine was levels may increase. A recent study showed that
closely related to the total renal NAE. Moreover, 800 μg of folic acid per day, when added to enala-
the total urinary NAE can be reasonably esti- pril, led to slower disease progression than that
mated from dietary intake, intestinal absorp- with enalapril alone. Experimental models of
tion, and the metabolism of most important CKD suggest that vitamin K supplementation
inorganic anions and cations in urine. On the may blunt the development of vascular calcifica-
basis of these factors, the potential renal acid tion. Daily intake of other vitamins and trace ele-
load (PRAL) can be calculated directly from ments at conventional doses is often recommended
dietary intakes. While protein-rich foods such both for persons at high risk for kidney disease
as meat, fish, and cheese are the food groups and for those with established renal insufficiency
with the highest acid loads, fruits, vegetables, [1, 2, 4].
salads, and fruit juices have a high alkalizing
potential. An increase in the dietary acid load
may be associated with glomerular hyperfiltra- 14.3.11 Practice Strategies
tion. Metabolic acidosis is associated with more
rapid kidney disease progression and an Dietary protein, energy, and micronutrient intakes
increase in the overall risk of death. should be assessed regularly. In addition, 24-h
Hyperparathyroidism, along with chronic buff- urine collection should be performed to estimate
ering of acid by bone, leads to progressive loss the dietary intakes of protein (based on urinary
of bone minerals and worsening renal osteodys- urea nitrogen), sodium, and potassium; to mea-
trophy. Hence, reduced protein intake with a sure creatinine clearance and proteinuria; and to
greater proportion of diet from plant-based evaluate adherence to dietary recommendations,
foods to correct acidosis improves bone miner- with suggestions for improving adherence if nec-
alization and may slow protein breakdown and essary. Excessive restrictions may be harmful
disease progression. Adjunctive alkali therapy and should be avoided [4].
can also be considered to mitigate acidosis in
patients with CKD [1, 2, 4, 30].
14.4 Conclusions
14.3.10 Trace Elements and Vitamins Given the high incidence and prevalence of CKD
and the urgent need for alternative disease man-
PEW has the potential to impact not only macro- agement strategies, patient-centered and cost-
nutrient metabolism but also vitamin and trace effective nutritional interventions with
element status in patients with CKD. Inadequate disease-specific dietary ranges help delay pro-
food intake may result in an insufficient ingestion gression of CKD, prolong the dialysis-free inter-
of antioxidant vitamins, including vitamins C val, improve quality of life, and increase
and E and carotenoids; in addition, patients with longevity for millions of people worldwide.
advanced renal disease often become deficient in Nutritional management for renal failure is
folate, vitamin K, and calcitriol. A micronutrient structured to achieve a lower protein, phosphate,
imbalance in patients with kidney disease may and sodium intake, while supplying with enough
contribute to a higher burden of oxidative stress, energy. In general, the purpose of nutritional
inflammation, and cardiovascular disease. management is to improve signs, symptoms, and
Among the trace elements, iron deficiency is complications of renal insufficiency, delay the
most problematic given the high frequency of progression of disease, and preserve good nutri-
gastrointestinal blood loss in patients with tional status.
9. Stoffel LMB, Muniz F, Colussi PRG, Rosing CK,

Key Messages Colussi EL. Nutritional assessment and associated
factors in the elderly: a population-based cross-
• Nutritional status in patients with CKD sectional study. Nutrition. 2018;55–56:104–10.
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gle parameter but with the combined use Barany P, Lindholm B, Qureshi AR. Serum albu-
of valid and complementary min as predictor of nutritional status in patients
with ESRD. Clin J Am Soc Nephrol. 2012;7(9):
parameters. 1446–53.
• Nephrologists, nutritionists, and other 11. Hsu J, Johansen KL, Hsu CY, Kaysen GA, Chertow
interested physicians have a common GM. Higher serum creatinine concentrations in black
principle of discussing the underlying patients with chronic kidney disease: beyond nutri-
tional status and body composition. Clin J Am Soc
research and translation of best prac- Nephrol. 2008;3(4):992–7.
tices for the nutritional management and 12. Steiber AL, Kalantar-Zadeh K, Secker D, McCarthy
prevention of renal disease. M, Sehgal A, McCann L. Subjective Global
• The purpose of nutritional management Assessment in chronic kidney disease: a review. J Ren
Nutr. 2004;14(4):191–200.
for CKD is to maintain good nutritional 13. Cuppari L, Meireles MS, Ramos CI, Kamimura

status, slow progression, and reduce MA. Subjective global assessment for the diagnosis
complications. of protein-energy wasting in nondialysis-dependent
chronic kidney disease patients. J Ren Nutr.
2014;24(6):385–9.
14. Windahl K, Faxen Irving G, Almquist T, et al.

Prevalence and risk of protein-energy wasting assessed
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Medication in Chronic Kidney
Disease 15
Hongdi Cao

Chronic kidney disease (CKD) is a common
disorder that is associated with multiple Up to 10–15% of the global population is esti-
comorbidities and complications. The evi- mated to have some degree of chronic kidney dis-
dence for medications in patients with CKD is ease (CKD). End-stage renal disease (ESRD)
still insufficient. Several factors should be represents the final stage of CKD and ultimately
considered when different medications were leads to the initiation of renal replacement ther-
selected in patients with CKD, such as the apy to treat kidney failure. However, the evidence
altered drug absorption and distribution. for medications in patients with CKD is still
Because most pharmacokinetic data are col- insufficient, including those with CKD not
lected from the trials which usually do not requiring renal replacement therapy, the patients
include patients with CKD, the evidence and undergoing hemodialysis or peritoneal dialysis,
the guidelines for the treatment of a general and those receiving kidney transplants. CKD
population might not be suitable for patients patients and ESRD patients on dialysis have sev-
with CKD. Commonly used medicines in eral comorbidities and complications that require
patients with CKD such as adrenal glucocorti- pharmacological management, including diabe-
coids, immunosuppressants, diuretics, inhibi- tes, hypertension, and anemia. To control these
tors of the renin-angiotensin-aldosterone comorbidities, CKD or ESRD patients take an
system, anticoagulation agents, antibacterial average of 12 different medications. The risk of
agents, and traditional Chinese medicines are medication-related problems is heightened due to
described. Patients with CKD often need mul- the polypharmacy experienced by CKD patients.
tiple medications for treatment of complica- In practice, patients with CKD, ESRD, or kidney
tions, and most drugs are excreted through the transplants have often been excluded from most
kidneys of a prototype or metabolite, thus randomized controlled trials (RCTs) testing for
most therapies should be adjusted according drug efficacy. In addition, the relatively few trials
to renal function to avoid side effects of drug that enrolled and were restricted to patients with
accumulation. CKD or ESRD were often negative or
inconclusive.
The kidney plays a vital role in metabolism
H. Cao (*) and clearance of drugs. Due to the pharmacoki-
Centre for Kidney Disease, Second Affiliated netics changes in CKD, the pharmacological
Hospital, Nanjing Medical University, action intensity and the maintenance time of
e-mail: caohongdi@njmu.edu.cn drugs are also altered. Two main factors must be

188 H. Cao
considered when selecting medications for treat- Table 15.1 Summary of pharmacokinetic changes in
hemodialysis patients
ing patients with CKD: one is the glomerular fil-
tration of drugs which mainly depends on the Pharmacokinetic
process Changes in hemodialysis
concentration of free drugs in serum and the glo-
Absorption Increased absorption mediated by:
merular filtration rate, the other one is the meta- • Paracellular leakage
bolic changes of drugs, such as digestion, • Decreased efflux transporter
absorption, distribution, and excretion. For those activity
patients undergoing dialysis, the effect of dialysis • Decreased P450 activity
Distribution Increased free drug concentration
itself on the clearance of drugs could not be
mediated by:
ignored. Furthermore, multidrug use naturally • Decreased albumin concentration
leads to an increased risk of drug–drug interac- • Uremic toxin-mediated decreases
tions. This chapter discusses in detail in these in protein binding
issues and the commonly used medicines in CKD Metabolism • Decreased Phase I metabolism
• Decreased Phase II metabolism
or ESRD patients.
Excretion • Decreased renal drug excretion
• Decreased biliary drug excretion
Hemodialysis • Dialytic drug clearance leading to
15.2 Pharmacokinetic Changes decreased plasma concentration
in CKD • Normalization of non-renal drug
clearance pathways
The kidney plays an important role in the metab-

olism and clearance of drugs and their metabo- patients with CKD. (4) Drug excretion: drug
lites. It is widely known that the medicines which excretion rate slows down and half-life is pro-
are predominantly excreted by the kidney should longed accompanied with the decrease of creati-
be adjusted in patients with CKD. How the nine clearance rate. Therefore, the dosage of
decrease of renal function alters the aspects of the drugs should be adjusted according to the degree
pharmacokinetics and pharmacodynamics of sev- of renal dysfunction to avoid drug accumulation
eral drugs has caused for concern; the rate and and poisoning in patients with CKD [2]. A sum-
extent of drug absorption, distribution among mary of the pharmacokinetic changes in patients
kidney, metabolism, and excretion of pro-drugs, with hemodialysis is shown in Table 15.1.
drugs, and their active or toxic metabolites must The medication in patients with CKD needs
be considered [1]. to be made according to the characteristics of the
Pharmacokinetics in patients with CKD is dif- specific drugs and their metabolites, as well as
ferent from that in general population, which is the degree of renal function. Drugs in patients
mainly reflected in the following aspects: (1) with CKD should be selected and adjusted
Drug absorption: in patients with CKD, the appropriately. Drug adjustments could be car-
increase of ammonia leading to a relatively alka- ried out through the following common ways:
linized milieu which might affect the dissolution (1) Dosing adjustment: the initial dose of the
of certain drugs, thus leading to reduced absorp- drug and the drug interval remain unchanged,
tion. Phosphate binders are a classic example of while the maintenance amount is reduced. (2)
pH-dependent effectiveness. (2) Drug distribu- Interphase extension: the dosage of the drug
tion: CKD may cause the loss of protein from remains unchanged, but the interphase is pro-
urine or the change of protein structure in serum longed. Individualized medication regimens are
to reduce the affinity with drugs, thus affecting implemented according to the specific condi-
the distribution of the drugs. Edema and fluid tions of patients. For special drugs, the regimen
overload, especially the cyclic hydration changes needs to be adjusted by monitoring the serum
in hemodialysis patients may change the volume drug concentration. It should be emphasized that
of distribution for certain drugs. (3) Drug catabo- drugs with a high risk of renal damage might be
lism: the oxidation rate is usually enhanced in banned or used with caution in patients with
15 Medication in Chronic Kidney Disease 189
CKD. Several publications have focused specifi- 15.4 M

edication Use in Patients
cally on recommendations for drug dosing and with CKD
monitoring of patients with CKD, patients with
ESRD who are on renal replacement therapy, Commonly used medicines in CKD or ESRD are
and patients on continuous renal replacement described in detail below, according to the thera-
therapy. peutic types [4].
15.3 Challenge of Evidence-Based 15.4.1 Adrenal Glucocorticoids

Prescribing in CKD
Adrenal glucocorticoids are commonly used in
Increasingly, more and more evidence concern- CKD, especially in primary membranous
ing medication in general populations has accu- nephropathy, lupus nephritis, and other immuno-
mulated and may guide the treatment decisions. logical nephropathies. The absorption, distribu-
The types of patients selected for experimental tion, metabolism, and excretion of glucocorticoids
treatments in clinical trials must be considered. It are different, and there are differences in efficacy
is worth noting that CKD, especially ESRD, is and adverse drug reactions. When oral glucocor-
often an important clinical feature excluded by ticoids enter the blood, most bind with cortisol-
clinical trials [3]. For example, CKD patients binding globulin (CBG). Glucocorticoids are
were definitely excluded from approximately mainly metabolized by the liver and excreted by
50% of RCTs of interventions in chronic heart the kidneys with a variety of inactive metabolites,
failure or acute coronary syndrome. Exclusions such as tetrahydroxy cortisol. Different glucocor-
of patients with CKD were usually common in ticoids have different anti-inflammatory proper-
the clinical trials of inhibitors of the renin angio- ties, drug removal half-lives, and durations of
tensin-aldosterone system and anticoagulants. efficacy (Table 15.2).
Thus, because most evidence is derived from Indications and contraindications should be
the trials in the general population, whether strictly evaluated before using a glucocorticoid.
such evidence and the resulting guidelines for The dosage, duration, and adverse drug reactions
therapies could be used to guide treatment of must be closely monitored. Glucocorticoid resis-
patients with CKD or ESRD still need to be tance is defined as a nephrotic syndrome without
confirmed. Whether such extrapolations are improvement following sufficient glucocorticoid
appropriate is unclear, and in some instances treatment (e.g. prednisone 1 mg/kg/day) for more
extrapolation is appropriate, whereas in others than 3 months. The common reasons for gluco-
it is not. More RCT studies are needed to sup- corticoid resistance are as follows: co-existing
port medication use in patients with CKD or complications, such as infections, thrombosis, and
ESRD. embolism; severe edema leading to abnormalities
Table 15.2 Characteristics of glucocorticoids used in CKD

Equivalent Anti-inflammatory Water sodium Plasma binding Duration of
dose (mg) properties retention T1/2 (h) protein efficacy (h)
Cortisone acetate 25 0.8 2 0.5 CBG/Alb 8–12
Hydrocortisone 20 1 2 1.7–2.1 CBG/Alb 8–12
Prednisone 5 4 1 2.9–4.1 CBG/Alb 18–36
Prednisolone 5 4 1 2.7–4.1 CBG/Alb 18–36
Methyl 4 5 0 1.6–3.4 Alb 18–36
prednisolone
Dexamethasone 0.75 27 0 4.1–5.4 Alb 36–54
Abbreviations: CBG cortisol-binding-globulin, Alb albumin
190 H. Cao
of the digestive and absorptive functions of the Table 15.3 Characteristics and therapeutic principles of
cyclophosphamide
gastrointestinal tract; concurrent drug use that
reduces glucocorticoid concentrations; and pri- Cyclophosphamide
mary kidney disease types which have poor • Alkylating agent
• Gonadal toxicity depends on cumulative doses and
responsiveness to glucocorticoids.
increased age
Adverse reactions to glucocorticoids are • Gastrointestinal and hematological system toxicities
closely related to dosage and treatment duration. are common
Common adverse reactions include infection; • Increases the risk of malignancy in the
adverse reactions of the skin and soft tissues, hematological system
such as acne; water and sodium retention; adverse • Due to the risk of hemorrhagic cystitis and bladder
neoplasms, patients should be hydrated during
reactions of the cardiovascular system, such as treatment
hypertension; adverse reactions of the digestive • Oral dose: 1–2 mg/kg/day
system, such as peptic ulcers and gastrointestinal • Impact intravenous doses: 0.5–1.0 g/m2 surface area
bleeding; osteoporosis; elevated blood sugar; • Routine blood and liver function should be monitored
adverse reactions of the central nervous system, and routine urine output monitored for life
such as insomnia and euphoria; adverse reactions • Cystoscopy is required for non-glomerular-derived
hematuria
of the reproductive system, such as menstrual
disorders and decreased fertility; and adrenocor-
Table 15.4 Characteristics and treatment principles of
tical insufficiency such as that seen in patients azathioprine
upon withdrawal of long-term use of
Azathioprine
glucocorticoids.
• Purine analog
• Digestive and hematological system toxicity is
common
15.4.2 Immunosuppressants • Dose for kidney transplantation: 3–5 mg/kg/day
• Dose for autoimmune disease: 1–2.5 mg/kg/day
Immunosuppressants and immune regulators have • Contraindicated with allopurinol and febuxostat
been rapidly developed recently, with research • Routine blood and urine analyses and liver function
should be monitored
focusing on new drugs and combinations of differ- • Use with glucocorticoids to reduce glucocorticoid
ent types of immunosuppressants to reduce adverse dosage or to maintain treatment
reactions. This chapter briefly summarizes the cur-
rent clinical applications of immunosuppressants in Table 15.5 Characteristics, treatment principles, and
primary and secondary CKD and renal transplanta- precautions of methotrexate
tion, including cyclophosphamide, azathioprine, Methotrexate
methotrexate, mycophenolate mofetil, leflunomide, • An indirect agonist of adenosine
and calcineurin inhibitors. The specific drug char- • Dihydrofolate reductase inhibitor
acteristics and treatment principles are shown in • Adverse reactions in the gastrointestinal,
Tables 15.3, 15.4, 15.5, 15.6, 15.7, and 15.8. hematological system, and skin mucosa are common
• The liver, hematological system, and lung can have
rare but serious adverse reactions
• Dose: 5–30 mg per week
15.4.3 Diuretics • Daily use of 1–2 mg of folic acid can partially
reduce the incidence of adverse reactions or
Diuretics are one of the most common medicines decrease their severity
used for treating CKD in patients with decreased • Patients with decreased glomerular filtration rate
(GFR) or concurrent alcohol use should receive a
urine output. Commonly used diuretics include reduced dose
loop diuretics, thiazide diuretics, and potassium- • White blood cell counts and liver and kidney
sparing diuretics. The classification and charac- function should be measured every 4–8 weeks
teristics of the main diuretics are shown in • Chest radiographs should be obtained before
Table 15.9. treatment
Table 15.6 Characteristics, treatment principles, and the use of diuretics, such medications are suitable
precautions of mycophenolate mofetil (MMF)
for use in heart or respiratory function insuffi-
MMF ciency, obvious ascites, or in patients with edema
• Inositol monophosphate dehydrogenase (IMPDH) who cannot accept a strict salt restriction. A strong
inhibitors
diuresis is necessary only in patients with acute
• Gastrointestinal and hemotological system toxicities
are common pulmonary edema and acute renal failure, while
• Dosage: 1–2 g/day, taken on a separate basis other conditions should adhere to the principle of
• Doses should be reduced according to renal function slow diuresis. Adverse reactions should be closely
• Routine blood analyses should be monitored after monitored during diuresis, especially abnormal
administration blood volume, and electrolyte disturbances.
• The efficacy of this class of drugs is superior to
azathioprine in organ transplantation
15.4.3.2 Indications of Diuretics
Table 15.7 Characteristics, treatment principles and pre-
cautions of leflunomide Nephrotic Syndrome
Leflunomide Diuretic treatment in nephrotic syndrome can
• Isoxazole derivatives improve the pathophysiological changes caused
• May be used in kidney transplantation, autoimmune by H2O storage by the kidney, which is one of the
disease, and primary renal disease basic steps in the treatment of nephrotic syn-
• Active metabolites can inhibit dihydroorotate drome. However, there are two pathophysiologi-
dehydrogenase (DHODH)
cal conditions associated with the occurrence of
• Gastrointestinal toxicity is common
• Dosage: 50–100 mg/day for 3 days, 20–30 mg/day
edema in nephrotic syndrome: insufficient circu-
for maintenance lating blood volume caused by fluid flow to the
• Dosage does not require adjustment in impaired interstitial fluid, or due to excessive capacity due
renal function to kidney sodium. The former may exacerbate pri-
• Liver function should be monitored mary kidney damage by the use of diuretics.
Therefore, it is necessary to carry out a careful
Table 15.8 Treatment principles and precautions for cal- assessment of the condition to give correct diuretic
cineurin inhibitors
treatment.
Calcineurin inhibitors
• Cyclosporine A and tacrolimus (FK506) are Acute Kidney Injury (AKI)
commonly used
• May be used in kidney transplantation, autoimmune
A large number of RCTs showed no clinical ben-
disease, and primary renal disease efit in the incidence of inpatient mortality and
• Inhibition of calcineurin renal replacement therapy for AKI patients.
• Nephrotoxicity and neurotoxicity are most common Therefore, diuretics should not be used as pre-
• Because the effective treatment concentration range ventive or therapeutic drugs when AKI occurs.
is narrow, blood drug concentrations should be
monitored during treatment
Chronic Renal Failure (CRF)
• Liver function should be monitored
Diuretics can be helpful for the regulation of the
total body water, electrolyte disorders, and hyper-
15.4.3.1 Clinical Application tension in CRF patients.
Principles for Diuretics
First, the uses of diuretics must be based on Renal Tubular Acidosis
dietary controls that limit Na+ intake and control Loop diuretics can increase H2O and NaCl in the
of salt intake. Patients with mild and moderate downstream nephron and stimulate the secretion
edema require a low-salt diet, and patients with of aldosterone and phosphorus excretion.
severe refractory edema require a salt-free diet. Therefore, loop diuretics increase the discharge
While edema is not the preferred indication for of acid.
192 H. Cao
Table 15.9 Common diuretics and their functional characteristics

Classification Representative drugs Characteristics
Loop diuretics • Furosemide • Inhibits the active reabsorption of NaCl in the loop
• Bumetanide • Destruction of the intramedullary mass
• Butyric acid concentration gradient
• Tolasemi • Damage of renal dilution function
• Damage of renal concentration function
• Maximum diuretic effect can reach 20–50% of total
Na+ filtration
• Increases urinary potassium excretion
• Dilated renal cortical vessels
Thiazide diuretics • Chlorothiazide • Inhibition of cortical distal convoluted tubule Na+
• Hydrochlorothiazide reabsorption
• Indapamide • Poor function when creatinine clearance is decreased
• Limited renal dilution function
• Does not affect the concentration function
• Increases urinary potassium excretion
• Constricts blood vessels
Potassium-sparing • Aldosterone antagonist: • Potassium-sparing
diuretics spironolactone • The diuretic effect is weak and is not used alone
• Inhibition of potassium extraction:
amiloride, aminobenzene
Heart and Liver Diseases terms of their protective effects in CKD. Both

Diuretics can be helpful for improvement of angiotensin-converting enzyme (ACE) inhibitors
CKD with heart and liver disease, such as acute and angiotensin receptor blockers are recom-
left heart failure and chronic cirrhosis. mended in CKD patients with hypertension and
proteinuria, especially in those with diabetic
Hypertension nephropathy. Underuse of these drugs in CKD
Diuretics can be effective for controlling blood population seems to be especially common
pressure by reducing the circulating blood vol- among the elderly and the patients with heart fail-
ume. Thiazide diuretics might be beneficial in the ure. Another topic often be discussed is the lower
treatment of hypertension; however, the meta- use of inhibitors of RAAS for secondary preven-
bolic side effects of thiazides are gradually tion after myocardial infarction. Patients dis-
attracting attention. charged from hospitalization for myocardial
infarction usually experienced a lower mainte-
15.4.3.3 Adverse Reactions nance treatment of beta blockers, statins, and
of Diuretics RAAS inhibitors in CKD patients. It is vital to
Adverse reactions of diuretics, especially loop point out that in patients with CKD who receive
diuretics and thiazide diuretics, include metabolic RAAS inhibitors, serum creatinine, and creati-
abnormalities and allergic reactions. Blood vol- nine potassium should be monitored closely. If
ume, hyponatremia, and hypokalemia are the most the level of serum creatinine exceeds more than
significant adverse reactions. Therefore, the ensu- 30% over the base value or hyperkalemia is
ing changes in volume and electrolytes should be detected, the use of RAAS inhibitors needed to
closely monitored during treatment with diuretics. be reassessed or discontinued if necessary.
15.4.4 Inhibitors of the Renin- 15.4.5 Anticoagulation Agents

Angiotensin-Aldosterone
System (RAAS) Patients with CKD often need anticoagulation,
especially for those patients undergoing hemodialy-
Among all oral prescription medications, inhibi- sis. The most widely used anticoagulant therapy for
tors of RAAS have received the most attention in hemodialysis includes heparin and low-molecular
weight heparin. In patients with ESRD, antiplatelet 15.5 A

djustment of Drug Dosage
agents such as aspirin and clopidogrel together with in CKD or ESRD
thrombolytics do not require dose adjustment.
Warfarin could be used for atrial fibrillation or Patients with CKD often require multiple med-
venous thromboembolism in patients with CKD or ications to treat complications. Because most
ESRD, which needed to be dose adjusted according drugs are excreted by the kidneys in the form
to the international normalized ratio (INR). of a prototype or metabolite, most drugs need
However, it is important to emphasize that patients to be adjusted according to the renal function
with CKD or ESRD might display a greater risk of of the patient to avoid side effects of drug
bleeding with anticoagulation treatment. However, accumulation [6].
the direct oral anticoagulants still require more
study to support their use in patients with CKD or
ESRD, which are currently not recommended 15.5.1 Clinical Manifestations
among such population. of Drug Accumulation
in CKD or ESRD
15.4.6 Antibacterial Agents 15.5.1.1 Abnormalities of the Central

Nervous System
As similar to antibacterial therapy in the general Antibiotic encephalopathy is the most common
population, the choice of antibacterial agents is drug accumulation response in patients with
mainly based on the likely source of infection, CKD or ESRD, which is referred to as a brain
the types of organism, and the local antibiotic dysfunction caused by antibiotics poisoning,
resistance patterns. If sepsis is suspected, broad- showing a series of nervous system symptoms,
spectrum antibiotics should be needed. The most which usually occur 3–10 days after the start of
two common infections in patients with CKD or antibiotics. Clinically, cephalosporins and car-
ESRD are catheter-associated infections and bapenems are commonly associated with antibi-
lower respiratory tract infections. For catheter- otic encephalopathy.
associated infections, for example, for catheter-
associated infections in patients undergoing 15.5.1.2 Liver Function and Kidney
hemodialysis, vancomycin might be selected in Function Injury
combination with another agent. However, due to The capacity of drug metabolism and excretion
its nephrotoxicity, vancomycin might be avoided often decreases following renal function impair-
in patients with CKD who are not on dialysis. If ment. The accumulation of drugs might increase
methicillin-sensitive S. aureusis is present, the burden of the liver and the kidneys, leading to
cefazolin could be selected. Trimethoprim should the dysfunctions of these organs. When patients
be avoided due to the high risk of hyperkalemia with CKD or ESRD have unexpected clinical
in patients with CKD or ESRD. Dose adjust- manifestations, in addition to the factors of pri-
ments of antibacterial agents in CKD are summary morbidity and complications, the possibil-
marized in Table 15.10 [5]. ity of drug accumulation should be considered.
15.4.7 Traditional Chinese Medicines 15.5.2 The Main Principles of Dose

Adjustment for CKD
There is an increasing evidence supporting the
application of traditional Chinese medicines in Adjustment of the dosage and dosing intervals of
CKD. Table 15.11 summarizes the primary mech- drugs in CKD or ESRD patients is vital to avoid
anisms and indications for the use of several com- drug accumulation and related adverse reactions.
monly used traditional Chinese medicines in CKD. These principles should be followed:
Table 15.10 Dose adjustment of antibacterial agents in CKD
194
Antibacterial Dose in general 50 < GFR < 90 10 < GFR < 50 GFR < 10 (mL/

agents T1/2 (h) population (mL/min/1.73 m2) (mL/min/1.73 m2) min/1.73 m2) HD PD CRRT
Ertapenem 4 1.0 qd 100% 50% (GFR < 30) 0.5 qd 0.5 qd after HD
Imipenem 1 0.5 q6h 0.25–0.5 q6–8h 0.25 q6–12h 0.125–0.25 q12h After HD 0.125–0.25 q12h 0.5–1.0 bid
Meropenem 1 1.0 q8h 100% 1.0 q12h 0.5 qd After HD 0.5 qd
Cefuroxime 1.2 0.75–1.5 q8h 100% 0.75–1.5 q8–12h 0.75–1.5 qd After HD 0.75–1.5 qd 0.75–1.5
q8–12h
Ceftazidime 1.2 2.0 q8h 2.0 q8–12h 2.0 q12–24h 2.0 q24–48h Additional 1 g 0.5 qd 2.0 q12–24h
after HD
Cefaclor 1 0.375 po 100% 50% 50%
sustained q12h
release tablets
Cefoperazone/ 1.7/1 1/0.5–2.0/1.0 100% 100% Sulbactam Additional 1.5 g
sulbactam q12h 0.5 q12h after HD
Cefepime 2.2 2.0 q8h 100% 2.0 q12–24h 1.0 qd Additional 1 g 1.0–2.0 q48h 2.0 q12–24h
after HD
Penicillin G 0.5 0.5–4 million U 100% 75% 20–50% After HD 20–50% 75%
q4h
Amoxicillin 1 0.25–0.5 q8h 100% 0.25–0.5 q8–12h 0.25–0.5 qd After HD 0.25 q12h 0.25–0.5
q8–12h
Ampicillin 1 0.25–2.0 q6h 0.25–2.0 q6h 100% 0.25–2.0 q6–12h After HD 0.25 q12h 0.25–0.5
q8–12h
Amoxicillin/ 1.3/1 0.5/0.125 q8h 0.5/0.125 q8h 100% Amoxicillin Additional
clavulanate 0.25–0.5 q 12h 0.25–0.5 after
potassium HD
Ampicillin/ 1/1 2.0/1.0 q6h 2.0/1.0 q6h 100% 2.0/1.0 q8–12h After HD 2.0/1.0 qd 1.5/0.75
sulbactam q12h
Piperacillin/ 0.7–1.2 4.0/0.5 q6–8h 4.0/0.5 q6–8h 100% 2.0/0.25 q6h 2.0/0.25 q8h, 4.0/0.5 q12h 4.0/0.5 q48h
tazobactam (<20:q8h) additional 2.25
after HD
Aztreonam 2 2.0 q8h 100% 50–75% 25% Additional 0.5 g 25% 50–75%
after HD
Ciprofloxacin 3–6 0.5–0.75 po or 100% 50–75% 50% 0.25 po or 0.2 iv 0.25 po or 0.2 iv
0.4 iv q12h q12h q8h
H. Cao
Levofloxacin 6–8 0.75 qd 100% 20–49: 0.75 q48h <20: Loading 0.75, Loading 0.75, Loading
Loading 0.75, following 0.5 following 0.5 0.75,
following 0.5 q48h q48h following
q48h 0.5 q48h
Rifampicin 1.5–5 0.6 po qd 100% 0.3–0.6 po qd 0.3–0.6 po qd 0.3–0.6 po qd 0.3–0.6 po qd 0.3–0.6 po
qd
Ethambutol 4 15–25 mg/kg 100% 15–25 mg/kg 15–25 mg/kg After HD 15–25 mg/kg 15–25 mg/
qd q24–36h q48h q48h kg q24–36h
Pyrazinamide 9 25 mg/kg qd 100% 25 mg/kg qd 12–25 mg/kg qd 40 mg/kg, 24 h 25 mg/kg qd 25 mg/kg qd
before dialysis
Vancomycin 6 1.0 q12h 100% 1.0 q24–96h 1.0 q4–7d 1.0 q4–7d 1.0 q4–7d 0.5 q24–48h
Teicoplanin 45 6 mg/(kg d) qd q 48h q 72h q72h q 72h q 48h
TMP-SMZ 11/10 TMP: 5–20 mg/ 100% 30–50: 5–7.5 mg/ Not Not Not 5–7.5 mg/kg
(kg d) q6–12h kg q8h; 10–29: recommended, if recommended, if recommended, if q8h
15 Medication in Chronic Kidney Disease
5–10 mg/kg q12h used: 5–10 mg/ used: 5–10 mg/ used: 5–10 mg/kg

kg qd kg qd qd
Amphotericin B 24 0.4–1.5 mg/ qd qd q24–48h No adjustment
(kg d)
Fluconazole 37 0.1–0.4 qd 100% 50% 50% After HD 50% 0.2–0.4 qd
Itraconazole iv 21 0.2 q12h 100% Ccr <30mL/min is contraindicated
Voriconazole iv Pharmacokinetic 6 mg/kg 100% Po or be forbidden 4 mg/kg po
nonlinearity q12h∗twice to q12h
4 mg q12h
Ganciclovir iv 3.6 5 mg/kg 50–100% 0.625–2.5 mg/kg 0.625–1.25 mg/ After HD 0.625–1.25 mg/kg
q12–24h qd kg tiw tiw
Ganciclovir po 3.6 1.0 po tid 50–100% 0.5–1.0 po qd 0.5 po tiw 0.5 g after HD
Acyclovir po 2.5 0.2–0.8 q4–12h 100% 75% 0.2 q12h
Acyclovir iv 2–4 5–10 mg/kg 100% 5–10 mg/kg 50% reduced qd After HD 50% qd 5–10 mg/kg
q8h q12–24h qd
Lamivudine 5–7 0.3 po qd 100% 0.05–0.15 qd 0.025–0.05 qd After HD 0.025–0.05 qd 0.1∗1d to
0.05 qd
Abbreviation: HD hemodialysis, PD peritoneal dialysis, tiw three times per week, qd once per day, TMP-SMZ trimethoprim-sulfamethoxazole
195
196 H. Cao
Table 15.11 Traditional Chinese medicines in CKD

Main mechanism Indications
Emodin • Anti-inflammatory • Various chronic kidney diseases
• Immunosuppressant
• Anti-oxidant
• Anti-fibrosis
Cordyceps and its • Decreases proteinuria • Various chronic kidney diseases
preparations • Improves renal fibrosis
• Delays progression of
renal function
Tripterygium • Suppresses immunity and • Various primary and secondary nephropathies, such as
wilfordii tablet inflammation chronic glomerulonephritis, lupus nephritis, nephrotic
syndrome, and diabetic nephropathy
1. A familiarity with the pharmacokinetic char- removal remains dependent on the molecular
acteristics of commonly used drugs weight of the drug, the degree of protein binding,
2. A correct determination of the degree of renal drug water solubility, the volume of drug distri-
impairment, nutritional metabolism, and bution and the elimination pathway. For example,
internal environmental stability larger apparent distribution volumes (>250 L)
3. Defined indications for drug administration render drug dialysis more difficult. Drugs with
4. Selection of drugs with relatively low renal poor water solubility are usually distributed
toxicity as the first line of treatment between tissues and cannot be easily dialyzed. In
5. The adjustment of the dosage regimen accord- summary, hydrophilic or low-molecular weight
ing to the degree of renal impairment if drugs drugs which weakly bind plasma proteins can be
with nephrotoxicity are unavoidable readily dialyzed, while lipophilic or high-
6. The close monitoring of clinical efficacy and molecular weight drugs which significantly bind
toxicity of drug reactions plasma proteins cannot be easily cleared by dial-
ysis. Furthermore, the characteristics of the dial-
For those patients undergoing HD or PD, dialysis membrane or the dialysis mode might have
ysis membrane-permeable drugs must be replen- different degrees of influence on drugs, such as
ished. Dispersion is the basic principle of solute high-flux dialysis [7].
removal in hemodialysis. Because there is no
drug in the dialysate, there is a large concentra-
tion gradient between the blood and the dialysate. 15.6 Summary
Therefore, free drugs in the blood can easily be
removed by dialysis. In ESRD patients, toxin CKD is a complex disorder that is associated
molecules may replace a highly protein-bound with multiple comorbidities and complications.
drug at its adhesion site to increase the plasma Patients with CKD are often prescribed several
concentration of free drug. In this case, a large medications to treat these comorbidities and
amount of free drug can be removed by dialysis. complications and attempt to improve the quality
In general, drugs with lower molecular weights of life and life expectancy, which increase the
(<500 Da) are more easily dialyzed than those risk of drug–drug interactions. Significant drug
with higher molecular weights. Drugs with a accumulation occurs in CKD or ESRD patients,
molecular weight ranging between 500 and which also places patients at an increased risk of
20,000 Da can be removed by peritoneal dialysis adverse medication reactions.
or high-flux dialysis. Those drugs exhibiting a This chapter has summarized the characteris-
high degree of protein binding are less suscepti- tics and principles of commonly used medicines in
ble to dialysis. Therefore, influencing the perme- CKD. Although it has long been appreciated that
ability of drugs is complex. The extent of drug ESRD patients do not have renal drug excretion
capacity, emerging studies have clearly docu- When encountering a CKD or ESRD patient,
mented that hepatic clearance of many drugs is clinicians should first search for evidence of drug
decreased in CKD. Studies in both animal models dosing recommendations in these populations.
and clinical pharmacokinetic studies in dialysis Indeed, dosage adjustments in CKD may be
patients have suggested that kidney disease found in the product monograph. When specific
decreases hepatic metabolism. Unfortunately, pharmacokinetic data in CKD are not available,
these studies have not yet clarified specific meta- the clinician must evaluate all known information
bolic pathways that are altered in patients with on the pharmacokinetics and pharmacodynamics
CKD. In the past 15 years, there is an abundance of of the drug, as well as what processes are likely
evidence affirming that drug transporters play a to be altered in CKD or ESRD, and prescribe a
critical role in determining the disposition of many dosage that is supported by available evidence.
medications. Much like metabolism, several clini-
cal pharmacokinetic studies in ESRD patients
have demonstrated that drug transport is impaired Key Messages
in ESRD patients. Unlike metabolism, which has • Several factors should be considered
many well-established, specific in vivo probe sub- when different medications were
strates, transporter probes used in vivo in clinical selected in patients with CKD, such as
pharmacokinetic studies are nonspecific. Although altered drug absorption and distribution.
animal models of CKD have been helpful in this • Commonly used medicines such as
regard, we must be cautioned that there are known adrenal glucocorticoids, immunosup-
differences in the regulation of drug metabolizing pressants, diuretics, inhibitors of RAAS,
enzymes and transporters between rodents and anticoagulation agents, antibacterial
humans. Accordingly, humanized mouse models agents, and traditional Chinese medi-
may provide a useful tool for evaluating the impact cines in CKD or ESRD are described in
of CKD on specific transporter expression and detail in this chapter according to the
activity. Even with the use of these models, drugs medicine types.
that may be used in patients with CKD should • Patients with CKD often need multiple
have clinical pharmacokinetic studies prior to use medications for complications. Because
in this patient population [8]. most drugs are excreted from kidneys in
The hemodialysis process itself can have a the form of a prototype or metabolite,
profound impact on the pharmacokinetics of most therapies should be adjusted
drugs. The changes in dialysis prescription from according to renal function to avoid
low-flux to high-flux dialysis means that we do side-effects of drug accumulation.
not have good evidence for the dialytic clearance
off or many drugs that are commonly in use
today. In general, the implementation of high-
flux dialyzers would be expected to increase the
dialytic clearance of drugs. It is likely that many References
drugs are eliminated by dialysis and may not be
1. Velenosi TJ, Urquhart BL. Pharmacokinetic con-
present at concentrations required to generate
siderations in chronic kidney disease and patients
therapeutic efficacy. Multiple studies have shown requiring dialysis. Expert Opin Drug Metab Toxicol.
that the hemodialysis process itself can impact 2014;10(8):1131–43.
the intradialytic pharmacokinetics of drugs. 2. Long B, Koyfman A, Lee CM. Emergency medi-
cine evaluation and management of the end
Accordingly, clinical pharmacokinetic studies
stage renal disease patient. Am J Emerg Med.
should be used to determine optimal dosing for 2017;35(12):1946–55.
patients across the spectrum of CKD and those in 3. Weir MR, Fink JC. Safety of medical therapy in
ESRD who require hemodialysis. patients with chronic kidney disease and end-
198 H. Cao
stage renal disease. Curr Opin Nephrol Hypertens. 6. Fink JC, Chertow GM. Medication errors in chronic
2014;23(3):306–13. kidney disease: one piece in the patient safety puzzle.
4. Coca SG, Krumholz HM, Garg AX, Parikh Kidney Int. 2009;76(11):1123–5.
CR. Underrepresentation of renal disease in ran- 7. Dreisbach AW. The influence of chronic renal failure
domized controlled trials of cardiovascular disease. on drug metabolism and transport. Clin Pharmacol
JAMA. 2006;296(11):1377–84. Ther. 2009;86(5):553–6.
5. Kuang D, Verbine A, Ronco C. Pharmacokinetics 8. Liles AM. Medication considerations for patients with
and antimicrobial dosing adjustment in critically ill chronic kidney disease who are not yet on dialysis.
patients during continuous renal replacement therapy. Nephrol Nurs J. 2011;38(3):263–70.
Clin Nephrol. 2007;67(5):267–84.
Initiation Timing and Modality
Option for Renal Replacement 16
Therapy
Ping Wen
Abstract toneal dialysis (PD), and renal transplantation.

The decision of the initiation timing of dialy- Every approach to renal replacement therapy
sis is not only due to the stage of chronic kid- (RRT) has its unique risks and benefits. The cur-
ney disease but also due to the uremic rent prevalence rate of chronic kidney disease
symptoms. The uremic syndrome is a cluster (CKD) in China is 10.8%. The incidence and
of clinical and metabolic characteristics asso- prevalence of ESRD are predicted to continu-
ciated with fluid, electrolyte, hormonal, and ously increase, and ESRD will affect an esti-
metabolic abnormalities that progress as kid- mated 750,000 individuals by 2020 [1, 2].
ney function aggravates. Current KDOQI rec- Furthermore, ESRD care is costly. According to
ommendations on indexes of the initiation of statistical data from Western countries, approxi-
dialysis include Kt/V and malnutrition. If the mately 2% of patients with CKD will progress to
symptoms (anorexia, nausea, vomiting, fatiga- ESRD and require RRT [2]. If every patient
bility, and diminished sensorium) and signs receiving dialysis therapy would cost 100,000
(refractory pulmonary edema, metabolic aci- RMB per year, all patients would cost 240 billion
dosis, foot or wrist drop, and asterixis) of ure- RMB annually. It should be recognized by physi-
mia are present, dialysis treatments are cians and patients that these treatment options
emergently indicated. Decisions on modalities can also be complementary, thereby allowing to
of renal replacement therapy depend on not choose different modality under different clinical
only physical conditions but also lifestyle and conditions. Patients with progressive renal failure
psychological conditions of patients. should be identified to enable them to make an
educated choice that suits their medical situation
and lifestyle. Emergency hospitalizations, com-
plications, and costs can be decreased by careful
16.1 Introduction planning. Moreover, early assessment enables the
identification of potential living donors, so that
Therapeutic modalities for irreversible end-stage preemptive transplantation can be performed.
renal disease (ESRD) include hemodialysis, peri-
16.2 Indications for RRT

P. Wen (*)
Centre for Kidney Disease, Second Affiliated Other than serum blood urea nitrogen or creati-
Hospital, Nanjing Medical University, nine level, the symptoms and signs of patients
e-mail: wenping@njmu.edu.cn contribute more to the decision as to when dialy-

200 P. Wen
sis should be performed [3]. The good points of culating. The urea distribution volume is calcu-
early initiation of dialysis include the avoidance lated based on weight and/or total body water
of fluid retention, malnutrition, and harmful estimate or according to standard formulas. A
effects of prolonged exposure to high concentra- weekly Kt/V of 2 is approximately equal to a urea
tions of phosphorus, β2-microglobulin, and other clearance of 7 mL/min and creatinine clearance
uremic toxins. Nevertheless, there is no signifi- between 9 and 14 mL/min/1.73 m2 [7]. An exam-
cant benefit of early initiation of dialysis comple of weekly Kt/V calculation for a nondialysis
pared with standard care [4, 5]. The absolute individual is shown in Table 16.1 [8].
indication for dialysis is hyperkalemia unrespon- A stage-based paradigm that utilizes either
sive to medications and dietary restriction accom- eGFR calculated using the Modification of Diet
panied with electrocardiographic changes. in Renal Disease (MDRD) study equation or an
Dialysis should be performed to avoid life- actual measurement of glomerular filtration rate
threatening arrhythmias. The clinical manifesta- (GFR) have been suggested to apply for the deci-
tions of uremic syndrome requiring dialysis sion of the initiation time of dialysis by the cur-
treatment include fluid overload refractory to rent KDOQI guidelines [9]. These guidelines
intravenous diuretics, nausea, anorexia, increas- specifically interpret that patients at stage 4 CKD
ing lethargy, and difficulty in concentrating. should be educated about dialysis and that refer-
Complications of brain and heart such as uremic ral for dialysis should be considered after the
encephalopathy, seizures, coma or pericarditis, GFR declines to 15 mL/min/1.73 m2 (see
and pericardial tamponade should be prevented Table 16.1) [2]. According to these guidelines, it
by prior interventions. Emergency hemodialysis
is more costly because of the lack of vascular
access and the requirement of prolonged Table 16.1 Calculation of weekly Kt/V
hospitalization. Steps in calculation Example of calculation or formula
Calculate the urea Urea clearance = Uurea/Purea ∗
clearance for a urine volume/1440 = Urea mL/
24-h period min
16.3 C
urrent Kidney Disease Determine urea L/week = Urea mL/min ∗
Outcomes Quality Initiative clearance in liters, number of minutes in week
(KDOQI) Recommendations which is (10,080)/1000 mL/1 L
for the Initiation of Dialysis equivalent to Kt
Determine the V (L) men = 2.5 + 0.34 ∗ Wt
urea distribution (kg) + 0.118 ∗ ht (cm) − 0.095 ∗
16.3.1 Krt/Vurea (Kt/V) volume (V) in age (years)
liters (L) V (L) women = −35.3 + 0.18 ∗
The weekly renal urea clearance, calculated as W + 0.34 ∗ H or
Krt/Vurea (r, residual) although not discussed in the V (L) men = 0.6 ∗ (Wt in kg)
V (L) women = 0.5 ∗ (Wt in kg)
2006 KDOQI clinical practice guidelines [6], Calculate the Kt/Vweek = Urea (mL/min) ∗
was the primary criterion applied to determine weekly Kt/V number of minutes in week
the initiation timing of dialysis in the 2000 (Kt/Vweek) week/V (10,080)/1000 mL/1 L/V (L)
KDOQI guideline recommendations. Based on (L)
viewpoint, an actual weekly Kt/V < 2 approxi- Example: a 70-kg Uurea/Purea ∗ urine volume = Urea
man with 24-h mL/min = 10 mL/min
mates an estimated glomerular filtration rate urea clearance of 10 mL/min ∗ 10,080 min/week ∗
(eGFR) of 10.5 mL/min/1.73 m2 when corrected 10 mL/min 1 L/1000 mL = 100.8 Urea
to total body water. The weekly Kt/V can be cal- clearance
culated to provide an objective functional detec- Assess total body water (V)
(approx. 0.6 ∗ Wt) = 42 L
tion therefore helping to determine the timing for Kt/Vweek = 100.8/42 = 2.4
the initiation of dialysis based on urea clearance
Abbreviations: Wt weight, ht height (Reproduced with
instead of eGFR, which is creatinine-based. The permission from Bessie Ann Young [8])
24 h urea clearance is used for weekly Kt/V cal-
16 Initiation Timing and Modality Option for Renal Replacement Therapy 201
was shown that dialysis was initiated at a higher University First Hospital in 2000 and reported
mean GFR in 2006 than that in 1994, occurring at that the average creatinine clearance upon initia-
a conspicuous cost and also with early loss of tion of dialysis was 4.2 mL/min. In addition,
residual renal function. Study of the Initiating many patients had complications such as hyper-
Dialysis Early and Late randomized trial showed kalemia and acute pulmonary edema when they
that there was no evident difference in mortality started dialysis. Liu et al. compared the timing
between early initiation of dialysis (eGFR, for the initiation of dialysis in 2000 and 2006 in
10–14 mL/min/1.73 m2) and late initiation of the same hospital and showed that dialysis was
dialysis (eGFR, 5–7 mL/min/1.73 m2). Current initiated earlier in 2006; however, complications
formulas for the calculation of eGFR are listed in were present.
the KDOQI guidelines for CKD, and most labo- Controversy exists as to whether earlier dialy-
ratories currently include serum creatinine-based sis can improve the quality of life and prolonged
eGFR calculated using the four-variable MDRD the lifespan. Kazmi et al. analyzed the US
study equation proposed by Levey et al. Medicare data and showed that a higher eGFR at
(Table 16.2). Table 16.3 shows the KDOQI rec-
ommendations for the initiation of dialysis.
Table 16.3 Kidney Disease Outcomes Quality Initiative
Therefore, even if the weekly Kt/V decreases recommendations for the initiation of dialysis
to 2.0, it is not necessary to immediately start CKD
dialysis if the following conditions exist: stage Recommendation
Stages 1 • Diagnosis of CKD and initiation of risk
1 . Absence of edema and no weight gain and 2 factor reduction
2. Nutrition indexes indicating no need for
Stage 3 • Referral from PCP to nephrologist for
the evaluation of CKD and assessment
dialysis of risk factors for progression
3. Absence of clinical symptoms and signs of Stage 4 • CKD education, including education
uremia about transplant and dialysis
• Referral to vascular surgery for AV fistula
However, the initiation of dialysis in patients once estimated GFR <20 mL/min/m2
• Preemptive transplantation
with CKD in practical works is always later than
Stage 5 • Cadaveric transplant wait-listing
the KDOQI recommendation. The Netherlands • PD catheter placement
Cooperative Study on the Adequacy of Dialysis • AV graft placement
investigated the average Kt/V upon initiation of • Initiation of hemodialysis if uremic
symptoms exist
dialysis in the Netherlands from 1993 to 2000
and reported that the average Kt/V was 0.5 in Abbreviations: CKD chronic kidney disease, PCP pri-
mary care provider, AV arteriovenous, GFR glomerular
1993 and 0.8 in 2000 [10]. In China, Yang et al. filtration rate, PD peritoneal dialysis (Reproduced with
surveyed the conditions of patients in Peking permission from Bessie Ann Young [8])
Table 16.2 Chronic Kidney Disease Epidemiology Collaboration equation for estimating GFR
Race Sex Serum creatinine level, μmol/L Equation
Black Female ≤62 μmol/L (≤0.7 mg/dL) GFR = 166 ∗ (SCr/0.7)−0.329 ∗ (0.993)Age
Female >62 μmol/L (>0.7 mg/dL) GFR = 166 ∗ (SCr/0.7)−1.209 ∗ (0.993)Age
Black Male ≤80 μmol/L (≤0.9 mg/dL) GFR = 163 ∗ (SCr/0.7)−0.411 ∗ (0.993)Age
Male >80 μmol/L (>0.9 mg/dL) GFR = 163 ∗ (SCr/0.7)−1.209 ∗ (0.993)Age
White Female ≤62 μmol/L (≤0.7 mg/dL) GFR = 144 ∗ (SCr/0.7)−0.329 ∗ (0.993)Age
or other Female >62 μmol/L (>0.7 mg/dL) GFR = 144 ∗ (SCr/0.7)−1.209 ∗ (0.993)Age
Male ≤80 μmol/L (≤0.9 mg/dL) GFR =141 ∗ (SCr/0.7)−0.411 ∗ (0.993)Age
Male >80 μmol/L (>0.9 mg/dL) GFR = 141 ∗(SCr/0.7)−1.209 ∗ (0.993)Age
Abbreviations: GFR glomerular filtration rate, SCr serum creatinine (Reproduced with permission from Bessie Ann
Young [8])
202 P. Wen
the initiation of dialysis indicated a higher risk of level and survival rate of patients starting on
death, possibly implying that patients had much hemodialysis. However, the sample size was
more serious complications. However, Beddhu small (n = 139), and 94% were black (83%) or
et al. examined the risk of death adjusted for Hispanic (11%) in this study.
complications and obtained the same results [11]. Despite controversial conclusions, there was
Current clinical practice guidelines have sug- evidence showing that nutritional status improved
gested the timing for the initiation of dialysis after dialysis treatment in malnourished patients;
according to renal function, nutritional status, however, the improvement in nutritional status
and symptoms and signs of uremia. However, the did not improve the prognosis. Conversely, in
key factor to determine when to institute dialysis patients with good nutritional status, their nutri-
is the existence of complications in clinical prac- tional status remained unchanged after dialysis.
tice, especially in patients with diabetes. The Accordingly, despite the absence of evidence, the
measurement of residual renal function is helpful KDOQI guidelines suggest that maintaining
for doctors to evaluate the complications of good nutrition before dialysis could be helpful
patients and to determine the timing for the initia- for the prognosis of patients.
tion of dialysis. More studies are required to con- Patients with CKD are usually prescribed with
firm the advantages of earlier-onset dialysis. a “low-protein diet.” An inappropriate low-
protein diet could result in malnutrition and poor
prognosis. Hence, if the nutritional status of
16.3.2 Malnutrition patients with CKD (GFR <20 mL/min/1.73 m2)
is aggravated with no firm causes and cannot be
RRT should be considered if malnutrition cannot corrected by interventions, RRT should be con-
be corrected using standard non-dialysis treatment. sidered even though pericarditis or hyperkalemia
According to the KDOQI guidelines, maintenance is absent.
dialysis or kidney transplantation is recommended
for non-dialysis patients with CKD (GFR <15 mL/
min/1.73 m2) if protein–energy malnutrition is per- 16.3.3 Indications for Emergency
sistent or progresses despite treatment in which Dialysis
reasons for malnutrition are absent (viewpoint).
Extensive data showed that mortality and the Severe hyperkalemia, acidosis, and acute pulmo-
incidence of complications were significantly nary edema are indications for emergency
increased in patients with protein–energy malnu- dialysis.
trition at the initiation of dialysis [12, 13].
Supplementary evidence indicated that the sur-
vival rate of patients with ESRD closely correlated 16.4 Modality Option for RRT
with nutritional status. This is true not only in
patients on maintenance dialysis but also in 16.4.1 Medical Consultations
patients who are to undergo dialysis. A study for Patients and Relatives
investigating 683 patients undergoing dialysis
between 1970 and 1989 showed that hypertension, The purpose of management of patients with
coronary artery disease, and hypoalbuminemia CKD in different stages is distinct. Stage 3 CKD
preexisting before dialysis were independent risk is followed by renal anemia, renal osteopathy,
factors for mortality. Another study that included electrolyte disturbance, acidosis, cardiovascular
1982 hemodialysis patients indicated that hypoal- disease, and malnutrition. Patients with these
buminemia at the start of dialysis was correlated must be intensively monitored by renal physi-
with the risk of death. A study that included 680 cians. Moreover, endocrine and cardiovascular
PD patients also reported similar results. specialists are involved in the management of
Moreover, one study reported the opposite and patients. Dietitians are required to evaluate the
observed no correlation between serum albumin nutritional status and institute a low-protein diet
plan to delay the progression of kidney disease. tus of patients should be considered when modal-
As kidney disease progresses, mental disorders ity selection is decided. Therefore, patients are
are always accompanied by physical conditions. suggested to consult with a financial specialist
Therefore, psychologists and social workers are who can evaluate current health insurance dialysis
required to participate in the management of coverage and help patients decide which modality
patients. Treatments for stage 4 CKD include is suitable for them. In China, although majority
retardation of progression, management of com- of dialysis-related healthcare is paid by the China
plications, and physical and psychological prepa- Health Care, it may not cover all care, which may
rations for RRT. Studies have shown that quality be province-dependent. Transplantation is still the
of life and survival rates were better in patients best therapy for irreversible kidney failure, so
undergoing appropriate management before dial- evaluation for preemptive transplantation before
ysis than in those without rational treatment by initiating dialysis should be considered for all
nephrologist [14–16]. patients, as should registering for transplantation
The physical preparations for RRT include cor- as soon as possible or simultaneously as patients
rection of anemia, treatment of bone disease, are being prepared for dialysis.
maintenance of electrolyte and acid–base balance,
and preservation of good nutritional status [17]. 16.4.2.1 Hemodialysis
Patients with stage 4 CKD should be followed up Dialysis substitutes two major kidney functions:
every 2 or 3 months if diagnosed with diabetic or solute removal and fluid removal. The passive
nondiabetic nephropathy, respectively. movement of solutes from the blood compartment
With respect to psychological preparations for to the dialysate compartment across a semiperme-
RRT, first of all, doctors should assist patients in able membrane, called diffuse, is the predominant
eliminating their fear, depression, and anxiety mode by which the solute is removed in hemodi-
about RRT, and information on CKD, renal fail- alysis. The rate of diffusion depends on several
ure, and modalities of RRT should be subse- coefficients, such as molecular weight of solutes,
quently introduced to them. In addition, patients membrane permeability, blood flow rate, concen-
could be introduced to the hemodialysis or PD tration gradient of the solutes between the blood
settings to help eliminate RRT rejection. and dialysate, membrane permeability, and flow
Unhealthy mental condition before dialysis cor- rate. The clearance of smaller molecules is higher.
relates with poor prognosis of patients. The greater the concentration gradient between
the blood and the dialysate, the more rapidly dif-
fusion occurs. Membrane permeability is deter-
16.4.2 Modalities of RRT mined by several specific membrane
characteristics, such as pore size, charge, and qua-
Patients at stage 4 CKD should make a decision of ternary conformation. Higher flow rates facilitate
dialysis modality with respect to RRT, which is greater solute removal, and the countercurrent of
expected to be made during a relatively short dialysate flow to blood flow will maxim the gradi-
period of time, such as during a clinic visit. Many ent across the dialysis membrane [18].
educational facilities such as DVDs, videos, or Another principle of hemodialysis is convec-
Internet programs can be used to assist patients tion, which means the spontaneous transport of
and their families in considering which modality solutes across the dialysis membrane. Although
best fits their lifestyle and needs. Moreover, to the convective mass transfer of solutes may not
acquire sufficient exposure to diverse available play a dominant role in conventional hemodialy-
dialysis options, patients are advised to discuss sis, convection is mainly responsible for scaveng-
dialysis option selection with a patient peer who ing macromolecules and plays an important role
is on dialysis or has a transplant and with a trained predominantly in high-flux dialysis and continu-
dialysis social worker who is familiar with all ous venovenous hemofiltration.
aspects of RRT (transplant, hemodialysis, and Solvent such as water removal in hemodialysis
peritoneal dialysis). In addition, the economic sta- occurs by the process of ultrafiltration. Fluid can
204 P. Wen
be forced across a semipermeable membrane on a Approximately 10% of patients with ESRD in

pressure gradient from higher to lower pressures, the United States and more than 50% of those in
and the pressure could result from the mechanical the United Kingdom, Mexico, Canada, and
hydrostatic pressure or osmotic force. When posi- Australia receive CAPD. Compared with hemo-
tive pressure is applied to the blood compartment dialysis, PD obviates the need for vascular
or negative pressure is applied to the dialysate access, which is a predominant challenge in
side of the membrane, ultrafiltration will multiply. patients with diabetes, young children, elders,
The ultrafiltration rate is adjusted to obtain the and patients with severe vascular disease.
desired fluid removal during dialysis. Furthermore, anticoagulation is not needed in
The hemodialysis machine has three main com- PD so the risk of bleeding decreases. Patients
ponents: (1) the dialyzer (i.e., dialysis membrane); with PD has more stable hemodynamic status as
(2) a pump that regulates blood flow; and (3) a PD is a slow and continuous process compared
dialysate solution delivery system at a constant rate with hemodialysis, thereby reducing the risk of
up to approximately 500 mL/min. In addition, the cardiovascular complications and protecting the
machine has many safety devices to ensure the residual renal function. PD can be performed by
proper, safe, and reliable delivery of blood and patients at home, thereby giving patients a sense
dialysate to the filter where exchange of water and of control and independence. In addition, the
solutes takes place. These devices include monitors diet restriction for salt, potassium, protein, and
to ensure that the pressures inside the extracorpo- fluid is not so strict in PD. For children with
real circuit are not excessive, a detector for leakage ESRD, PD is the option of choice because it
of red blood cells from the blood compartment into avoids frequent vascular punctures and, most
the dialysate compartment, an air detector and importantly, allows children to grow. Despite the
shut-off device to prevent air embolism, a pump to advantages of PD, there is still controversy about
deliver dialysate, a proportioning system to prop- its outcomes compared with those of hemodialy-
erly dilute the dialysate concentrate, a heater to sis. PD has been represented with worse, similar,
warm the dialysate to body temperature, an ultrafil- and better mortality compared with hemodialy-
tration controller to precisely regulate fluid sis, depending on the study design and statistical
removal, and conductivity monitors to check the analysis.
ionic strength of the dialysate. Hemodialysis, PD, and transplantation are the
Under most conditions, solute removal and cornerstones of modern renal replacement ther-
fluid removal occur simultaneously. However, if apy. It is crucial to understand that these modali-
vigorous ultrafiltration is attempted during con- ties are not mutually exclusive, because patients
ventional hemodialysis, patients frequently com- may transfer from one to another during the
plain of nausea, muscle cramping, and vomiting. course of their treatment. Thus, PD is an excellent
At the same time, systemic vascular resistance option for initial dialysis treatment if a patient will
may decrease, thereby hypotension develops. have a transplant within a short period of time.
Osmotic changes are minimized with isolated Also, for patients who would like to be in more
fluid removal in the absence of solute removal. control of their dialysis, or who intend to do dialy-
Separating ultrafiltration will produce greater sis at home, PD is a good choice.
hemodynamic stability. For PD therapy, the peritoneal membrane is
used as the dialyzing surface. Therefore, the
16.4.2.2 Peritoneal Dialysis function of peritoneal membrane should be eval-
In the 1950s and 1960s, peritoneal dialysis (PD) uated regularly to avoid insufficient dialysis.
was utilized mainly to treat acute kidney injury. Unless there is a major contraindication, PD
Patients with ESRD were treated almost exclu- should be considered as the first-line therapy for
sively by hemodialysis and occasionally by inter- all patients undergoing preemptive kidney trans-
mittent peritoneal dialysis (IPD). In 1976, the plantation and other home dialysis therapies.
introduction of continuous ambulatory peritoneal Table 16.4 lists some recommendations for
dialysis (CAPD) transformed this situation. modality selections (hemodialysis or PD).
Table 16.4 Recommendations for modality selections 16.4.2.3 Renal Transplantation

Recommended Patients can gain best quality of life while suc-
Conditions of patients modality cessful renal transplantation is performed. After
Cannot establish vascular PD is strongly transplantation, because of the restoration of nor-
access recommended
Refractory heart failure mal renal function, they are free from diet and
Postoperative valve repair fluid restrictions, are free to work and travel, and
Intolerant to HD (severe achieve correction of metabolic disturbances and
headache) anemia. Moreover, the long-term survival of
0–5 years old
Patients’ strong wish to renal transplantation patients is better than that of
undergo PD hemodialysis patients.
Cardiovascular diseases PD is recommended Even though the kidney survival has been
Chronic diseases improved dramatically nowadays, complications
Hemorrhagic diseases
after transplantation and long-term survival are
Myeloma
Unstable diabetes still challenges for surgeons and nephrologists.
HIV infection There are a lot of factors influencing the progno-
Hepatitis B or C sis of transplantation including ages of donor and
Preparation for kidney
recipient, race and sex, major histocompatibility
transplantation
Fainting during acupuncture complex (MHC), pre-sensitization to human leu-
Diabetes mellitus PD or HD, HD is kocyte antigen (HLA), kidney disease of recipi-
Peripheral vascular diseases preferred ent, condition and complication before
Polycystic kidney transplantation, compliance of recipient, cold
Scleroderma
Chronic glomerulonephritis ischemia time, number of nephrons of donor, and
Overweight immunosuppressive strategy.
Chronic diverticulitis For kidney transplantation, the identification
Severe back pain of potential candidates is very important. Patients
Hernia
Multiple abdominal with transplantation aspiration should be added
operations to the list while dialysis initiated. To offer patients
Poor operational capacity with the best quality and quantity of life, it is
Blind essential to assess candidates early and, if possi-
Diaphragmatic hernia PD is relatively
ble, proceed directly to preemptive transplanta-
(diaphragmatocele) contraindicated
Malnutrition tion if a living donor can be identified [19, 20].
Abdominal adhesions The evaluations of the recipients include the
Urine protein >10 g/day general condition such as age, body mass index
Severe diabetic gastroplegia
(BMI), primary kidney disease, and immune
Severe hypertriglyceridemia
Severe COPD state of particularly the panel reactive antibodies
Ascites (PRAs). Additionally, identification of the latent
Upper amputation infective diseases like tuberculosis, hepatitis B,
Poor sanitation
and C is also necessary.
Poor home environment
Infective abdominal diseases Owing to the stage-based approach to the ini-
Acute diverticulitis PD is absolutely tiation of RRT in patients with stage 5 CKD,
Acute ischemic enteropathy contraindicated opinions on RRT initiation timing have changed
Abdominal abscess significantly over the last decade. Preemptive
Pregnancy
transplantation is the preferred choice for RRT;
Abbreviations: PD peritoneal dialysis, HD hemodialysis,
HIV human immunodeficiency virus, COPD chronic
even though due to the enlarged number of
obstructive pulmonary disease patients with kidney disease and who will receive
206 P. Wen
RRT, adequate transplants are not available, and References

other modalities for RRT are still needed.
Besides conventional hemodialysis, other home 1. Coresh J, Selvin E, Stevens LA, et al. Prevalence of
chronic kidney disease in the United States. JAMA.
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home hemodialysis modalities may approximate the United States. Bethesda; 2008.
3. Klaric D. End-stage renal disease, dialysis treatment
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RRT when transplantation is not available. The 4. Rosansky SJ, Clark WF, Eggers P, et al. Initiation of
RRT modalities are not inflexible for one patient, dialysis at higher GFRs: is the apparent rising tide
of early dialysis harmful or helpful? Kidney Int.
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and life quality for ESRD patients [22]. Home cardiovascular events? Kidney Int. 2015;88(5):942–4.
dialysis treatments including PD should be 6. NKF-K/DOQI clinical practice guidelines for peri-
toneal dialysis adequacy: update 2000. Am J Kidney
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or have an impending living donor transplant. ized controlled trial of early versus late initiation of
Finally, newer home hemodialysis modalities dialysis. N Engl J Med. 2010;363:609–19.
8. Himmelfarb J. Chronic kidney disease, dialysis, and
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ate transplant candidates. tice guidelines for chronic kidney disease: evaluation,
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10. Termorshuizen F, Korevaar JC, Dekker FW, et al.
Time trends in initiation and dose of dialysis in
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and symptoms rather than absolute Nephrol. 2003;14:2305–12.
12. Liu Y, Coresh J, Eustace JA, et al. Association

blood urea nitrogen or serum creatinine between cholesterol level and mortality in dialy-
level. sis patients: role of inflammation and malnutrition.
• Current KDOQI recommendations on JAMA. 2004;291:451–9.
indexes of initiation of dialysis include 13. Chung SH, Lindholm B, Lee HB. Is malnutrition

an independent predictor of mortality in perito-
Kt/V and malnutrition. neal dialysis patients? Nephrol Dial Transplant.
• Severe hyperkalemia, acidosis, and 2003;18:2134–40.
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for emergency dialysis. nephrology referral and mortality among patients
with end-stage renal disease: a propensity score anal-
• Decisions on modalities of RRT depend ysis. Nephrol Dial Transplant. 2004;19:1808–14.
on not only physical conditions but also 15. Sprangers B, Evenepoel P, Vanrenterghem Y. Late

lifestyle and psychological conditions referral of patients with chronic kidney disease: no
of patients. time to waste. Mayo Clin Proc. 2006;81(11):1487–94.
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• To offer patients with the best quality predialysis education decreases the incidence of dial-
and quantity of life, it is essential to ysis and reduces mortality—a controlled cohort study
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proceed directly to preemptive trans- Transplant. 2009;24(11):3426–33.
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identified. eral metabolic control among chronic hemodialysis
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Hemodialysis
17
Hong Ye, Hao Ding, Wei Gan, Ping Wen,
Yang Zhou, Hongdi Cao, and Weichun He
Abstract descriptions of other replacement therapies,

Hemodialysis (HD) sustains life for more than such as transplantation and peritoneal dialysis,
millions of people worldwide, without which are reviewed in the following chapters.
most would die within a few weeks. The life-
sustaining treatment depends on an extracorpo-
real blood device and requires caregivers to
in-depth process detailed aspects of dialysis 17.1 Introduction
procedure in addition to an understanding of
the pathophysiology of the uremic state. More than a million patients worldwide would
Patients with end-stage kidney disease rou- die within a couple of weeks without hemodialy-
tinely relies on HD to preserve life since half a sis (HD). Several early pioneers laid the founda-
century ago. Several early pioneers deserve to tion for the life-sustaining therapeutic dialysis.
be remembered for laying the foundation for Claude Bernard and Milieu Intérieur introduced
HD, which had become technically feasible and described the concept of HD. Thomas
nowadays. The government approval of public Graham (1805–1869) is named the “father of
funding for HD made the life-sustaining kidney dialysis” because of his discovery of the funda-
replacement available for virtually all patients. mental process using semipermeable membranes
In this chapter, we review the physical, chemi- to separate solutes in vitro. John Jacob Abel was
cal, and clinical principles of HD as they relate the first to present the idea of passing the blood of
closely to the treatment of uremia patients and a living rabbit and dogs over a dialysis membrane
the complications associated with HD. The and using hirudin extracted from a leech for anti-
coagulation. Georg Haas started the use of an
artificial kidney for dialysis in humans in 1924.
In 1944, Willem Kolff successfully used extra-
corporeal dialysis as a human life-saving
treatment for patients with kidney failure; hence,
H. Ye · H. Ding · W. Gan · P. Wen (*) he is often referred to as the “father of artificial
Y. Zhou · H. Cao · W. He
Centre for Kidney Disease, Second Affiliated organs.” In 1960, a blood access device applying
Hospital, Nanjing Medical University, plastic tubes inserted into the vein and artery was
Nanjing, Jiangsu, China developed by Belding Scribner, collaborating
e-mail: yehong@njmu.edu.cn; dinghao@njmu.edu. with Quinton and Dillard at the University of
cn; ganwei@njmu.edu.cn; wenping@njmu.edu.cn;
zhouyang@njmu.edu.cn; caohongdi@njmu.edu.cn; Washington. Subsequently, Brescia and Cimino
heweichun@njmu.edu.cn introduced the more permanent arteriovenous fis-

210 H. Ye et al.
tula (AVF). Kolff and Scribner were granted the Adsorption: Adsorption is a method for
prestigious Albert Lasker Award for Clinical removing molecules from the blood or plasma by
Medical Research in 2002 for their pioneering attachment to a surface incorporated in a module
work in the field of artificial organs [1, 2]. within an extracorporeal circuit. Adsorption
occurs fundamentally because of the hydropho-
bic properties of sorbents. In this group, the sor-
17.2 Principles bents used in different dialysis techniques are
charcoal and nonionic macroporous resins.
Diffusion: The spontaneous passive movement of Adsorption occurs by chemical affinity, such as
solutes across the dialysis membrane is called ion-exchange resins and chemisorbents.
diffusion (Fig. 17.1). The rate of diffusion Ultrafiltration: A solvent such as water can be
depends on several coefficients, such as molecu- forced across a semipermeable membrane on a
lar weight of solutes, membrane permeability, pressure gradient from higher to lower pressures,
blood flow rate, concentration gradient of the sol- and the pressure could result from the mechani-
utes between the blood and dialysate, dialysate cal hydrostatic pressure or osmotic force. The
temperature, and flow rate. solvent carries with it the dissolved solute mole-
Convection: The spontaneous transport of sol- cules that are small enough to pass through the
utes across the dialysis membrane is called con- membrane pores. This movement of molecules
vection. Convection is mainly responsible for across a semipermeable membrane due to a pres-
scavenging macromolecules. Factors affecting sure difference is called ultrafiltration (UF)
convection include the screening coefficient of (Fig. 17.2). If the pressure is hydrostatic, the pro-
dialysis membrane and membrane pore size, the cess is called hydrostatic UF. Conversely, UF due
size and configuration of solute molecules, and to osmotic pressure is called osmotic UF. For sol-
the charge of membrane and solute. utes with a sieving coefficient close to diffusion,
Fig. 17.1 Diffusion
across a semipermeable Blood Dialysate
membrane. The driving
force for solute diffusion
is the transmembrane
concentration gradient.
Small solutes with
higher concentrations in
the blood compartment,
such as potassium, urea,
and small uremic toxins,
diffuse through the
membrane into the
dialysate compartment.
Dialysis dissipates this
concentration gradient
(i.e., the molecular
concentration gradient
decreases with dialysis).
Larger solutes and
low-molecular-weight
proteins such as albumin
diffuse poorly across the
semipermeable
membrane
Urea
Low-molecular-weight protein
17 Hemodialysis 211
Fig. 17.2 Ultrafiltration
across a semipermeable Adjustable pressure Blood Ultrafiltrate
membrane. The driving
force for ultrafiltration is
the transmembrane
hydrostatic pressure.
When applied to the
blood compartment,
solvent flows across the
membrane into the
dialysate compartment,
bringing along solutes
the concentrations of solvent molecules do not are two basic flow path geometries: (1) rectangu-
change with time. lar cross section, seen in parallel plate dialyzers,
and (2) circular cross section, seen in hollow-
fiber dialyzers. Virtually all hemodialyzers in
17.3 Dialysis System clinical use today are the hollow-fiber type. The
hollow-fiber artificial kidneys are by far the most
The purpose of HD is to effectively remove ure- commonly used dialyzers and are available in a
mic toxins and extra fluid from the blood. The wide variety of sizes and membranes. Cellulosic
dialysis systems are mainly composed by the dia- or synthetic tiny hollow fibers are approximately
lyzer, dialysis machine, extracorporeal blood cir- 150–250 μm in diameter. Wall thickness may be
cuit, and water purification system [3]. The as thin as 7 μm, although some synthetics have
dialysis machine has a blood and dialysate walls with thickness of 50 μm or more. The blood
pumps, dialysate mixing and degassing unit, flows through these tens of thousands of hollow
heating system, UF balancing system, as well as fibers. The contained blood volume is very low in
monitoring and safety system. Contaminants relation to the dialyzer’s surface area because of
must be purified from the water for dialysis prior the dialyzer’s flow geometry. Resistance to blood
to its use. The final dialysate is produce by the flow is low because of the large number of blood
proportioning water purification system. passages. Hollow-fiber dialyzers are not compli-
ant; therefore, they do not increase in shape or in
the volume that they hold under high transmem-
17.3.1 Dialyzer brane pressure. UF can be precisely controlled.
Hollow-fiber dialyzers can be effectively steril-
The dialyzer controls the transfer of water and ized using ethylene oxide (ETO), gamma irradia-
solutes across the semipermeable membrane tion, or steam. Electron beam (e-beam) is a newly
(Fig. 17.3). All dialyzers consist of a series of discovered method applied in factory steriliza-
parallel flow paths designed to provide a large tion. As e-beam sterilization does not use chemi-
surface area between the blood and membrane cals or radioactive materials, it may be an
and between the membrane and dialysate. There alternative for patients sensitive to ETO.
212 H. Ye et al.
Fig. 17.3 Membrane
fluxes in dialysis.
Dialysis is the process of
separating elements in a Blood Membrane Dialysate
solution by diffusion
across a semipermeable
membrane (diffusive
solute transport) down a Na+ Na+
concentration gradient.
This is the principal
process for removing the
end-products of nitrogen K+ K+
metabolism (urea,
creatinine, and uric acid)
and for repletion of the Ca2+ Ca2+
bicarbonate deficit of the
metabolic acidosis
associated with renal HCO3- HCO3-
failure in humans. The
preponderance of
diffusion as the result of Creatinine Creatinine
gradient is shown by the
displacement of the
arrow Urea Urea
17.3.2 Dialysis Membrane Table 17.1 Examples of dialyzer

Material (abbreviation) Membrane type
Membranes vary with respect to biophysical Cellulose triacetate (CTA) Hollow fiber
properties such as transport characteristics, chem- Polysulfone (PS) Hollow fiber
Polyethersulfone (PES) Hollow fiber
ical structure, and biocompatibility. Cellulose
Polymethylmethacrylate (PMMA) Hollow fiber
(C6H10O5) is a complex carbohydrate polymer that Polyester polymer alloy (PEPA) Hollow fiber
is the structural material of plants. Cuprophan has Ethylene vinyl alcohol copolymer Hollow fiber
been widely used. The cellulose is treated with (EVAL)
ammonia and copper oxide during manufacture; Polyacrylonitrile (PAN) Hollow fiber,
cuprammonium rayon and Hemophan are modifi- laminated
cations. Saponified cellulose ester, cellulose ace-
tate, and triacetate are other widely used cellulose
materials. One distinct advantage of cellulosic their overall mass transport. These membranes
membranes is the fact that they have been used for mainly remove “middle” and large molecules. All
many years; therefore, their transport characteris- have UF coefficients of 20–70 mL/h/mmHg or
tics are well known. They are also relatively inex- more and are well adapted for reuse. Synthetic
pensive. However, all cellulosic membranes have membranes have much fewer bioincompatibility
some degree of bioincompatibility with blood. problems than cellulosic membranes.
The synthetic membranes are thermoplastics. Dialyzer performance indices include the
They have a thin, smooth luminal surface sup- following:
ported by a sponge-like wall structure. Those used
for HD include polyacrylonitrile, polysulfone, 1. Biocompatibility of membrane: The biocom-
polyamide, polymethyl methacrylate, and others patibility of synthetic membrane is superior to
(Table 17.1). Convective transfer accounts for that of fiber membrane. After contact with the
17 Hemodialysis 213
blood, the dialysis membrane may produce Table 17.2 Association for the Advancement of Medical
Instrumentation water quality standard for dialysis
various reactions, including the activation of
complement, slow excitation peptide, white Maximum allowable concentration
Substance (mg/L)
blood cells, platelets, and blood coagulation
Aluminum 0.01
factor. Membranes with better biocompatibil-
Chloramines 0.1
ity produce less reaction. Improvement in bio- Copper 0.1
compatibility can reduce the deposition of Fluoride 0.2
amyloidosis, which can be characterized by Nitrate 2.0
joint disease, bone lesions and pathological Sulfate 100.0
fracture, soft tissue swelling, and carpal tunnel Zinc 0.1
syndrome. In addition, it can reduce allergic Arsenic 0.005
reactions, reduce the occurrence of dialysis Barium 0.1
hypotension, improve nutrition, preserve Cadmium 0.001
Chromium 0.014
residual renal function, reduce the incidence of
Lead 0.005
cardiovascular disease, and reduce mortality. Mercury 0.0002
2.
Permeability of dialysis membrane: Selenium 0.09
Permeability of water is expressed as UF Silver 0.005
coefficient Kuf, which refers to the UF of unit Calcium 2.0 (0.1 mEq/L)
pressure in unit time. According to Kuf, dia- Magnesium 4.0a (0.3 mEq/L)
lyzers can be divided into three groups: low- Potassium 8.0a (0.2 mEq/L)
flux dialyzer (Kuf <6 mL/mmHg·h) is used in Sodium 70.0a (3.0 mEq/L)
ordinary dialysis; Kuf 7–20 mL/mmHg·h is in Antimony 0.003
Free chlorine 0.50
flux, the parser that can be used for efficient
Thallium 0.002
dialysis; and high-flux dialyzer (Kuf >20 mL/
Maximum allowable error
a
mmHg·h) is used for the removal of water and
macromolecules. It is suitable for high-flux
HD and hemofiltration (HF). be <200 colony-forming units (CFU)/mL, endo-
3. Dialysis membrane solute sieving coefficient: toxin concentration should be <2 endotoxin units
The ability of the dialysis membrane to filter (EU)/mL, and respective action levels should be
the solute in the convection is related to the 50 CFU/mL and 1 EU/mL (Table 17.2).
molecular weight of the solute. The dialysate carries away the waste materi-
als and fluid removed from the blood by the dial-
ysis procedure, prevents the removal of essential
17.3.3 Water Treatment electrolytes, normalizes electrolyte levels, and
and Dialysate averts excess water removal during the proce-
dure. Furthermore, the dialysate corrects the
A standard 4-h HD session, with a dialysate flow acid–base balance in the patient. These functions
of 500 mL/min, exposes the patient to 120 L of are achieved by modulating the chemical com-
water [3]. Therefore, water quality is of para- position in the dialysate close to that in normal
mount importance for the patient’s well-being. blood.
Water treatment includes filtration, adsorption There are five major components in the dialy-
(activated carbon filters), softening, reverse sate (Table 17.3): sodium chloride, sodium bicar-
osmosis, deionization, and ultraviolet light expo- bonate or sodium acetate, calcium chloride,
sure. The dialysate water must meet the potassium chloride, and magnesium chloride.
Association for the Advancement of Medical Glucose is usually included to prevent intradialytic
Instrumentation (AAMI) standards for chemical, hypoglycemia. Dialysate is currently produced by
bacterial, and pyrogen content. Current AAMI mixing bicarbonate and acid components, which
standards suggest that the microbial count should are provided as liquid or dry (powder) concen-
214 H. Ye et al.
Table 17.3 Solute concentrations present in the dialysate membrane. For example, urea diffuses from the
Solutes Concentration (mEq/L) blood to the dialysate compartment, thereby
Sodium 135–145 decreasing the total urea mass in the body and the
Chloride 102–106 urea concentration in the plasma. Conversely, the
Bicarbonate 30–39 concentration gradient of bicarbonate usually
Dextrose 11
favors diffusion of this ion from the dialysate to
Acetate 2–4
the blood compartment. Movement of water-
Magnesium 0.5–1
Potassium 0–4
carrying solutes across the dialysis membrane is
Calcium 0–3.5 not necessary for solute transport in this modal-
pH 7.1–7.3 ity, although removal of fluid from the patient’s
plasma is often desirable because dialysis patients
are usually fluid-overloaded. High efficiency in
trates. The bicarbonate component contains HD refers to a high rate of removal by diffusion
sodium bicarbonate and sodium chloride, whereas of small-sized solutes; high flux in HD refers to a
the acid component contains chloride salts of Na, high rate of removal by diffusion of “middle mol-
K, Ca, Mg, acetate (or citrate), and glucose ecules” that are substantially larger than urea. A
(optional). The potassium concentration in the membrane can be a high-efficiency/high-flux,
dialysate may be modulated between 0 and high-efficiency/low-flux, low-efficiency/high-
4 mmol/L according to the predialysis plasma flux, or low-efficiency/low-flux membrane. The
potassium concentration. The calcium concentra- term “conventional dialysis membrane” usually
tion in the dialysate in China is 1.5 mmol/L. Higher refers to a low-efficiency/low-flux membrane.
dialysate calcium concentrations may be used in
patients with hypocalcemia associated with sec-
ondary hyperparathyroidism or following parathy- 17.4.2 Hemofiltration
roidectomy. The usual sodium concentration in the
dialysate is 135–140 mmol/L. Lower dialysate HF, another form of extracorporeal therapy,
sodium concentration is associated with a higher removes fluid by convection (i.e., water move-
frequency of hypotension, cramping, vomiting, ment across the large-pore HF membrane into the
fatigue, and dizziness. Sodium concentration in ultrafiltrate compartment drags along the solutes
the dialysate is gradually changed from 145– dissolved in the water). A crucial distinction
155 mmol/L to 140 mmol/L (isotonic concentra- between HD and HF is that fluid removal, but not
tions) at the end of dialysis treatment and is the concentration gradient of the solute, is
typically reduced either in steps or in a linear or required for solute removal in HF. Removal of
exponential fashion. fluid with its accompanying solutes results in a
loss of the total body mass of the solute, but not
necessarily a decrease in the plasma concentra-
17.4 HD Techniques tion. In order to achieve a substantial decrease in
concentration, “clean” replacement fluid devoid
Here, HD techniques refer to common blood of that solute is intravenously infused to replace
purification techniques, which include HD, HF, nearly the large volume of plasma fluid removed
and hemoperfusion (HP) [4–6]. in the hemofilter. This modality is analogous to
glomerular filtration, in which plasma solutes are
removed by convection. In the case of the glom-
17.4.1 Hemodialysis erulus, however, the replacement fluid is water
and electrolytes that are selectively reabsorbed
HD removes solutes by diffusion based on the from the renal tubules. The term hemodiafiltra-
concentration gradients of solutes between the tion (HDF) refers to the combination of HD and
blood and dialysate across the semipermeable HF operating simultaneously using a large-pore
17 Hemodialysis 215
membrane (i.e., solutes are removed by both dif- diseases are at risk of disequilibrium syndrome.
fusion and convection). As the water flows to higher urea concentration,
When HD, HF, and HDF are continuously the brain cells begin to swell, causing neurologi-
applied for days to weeks in the presence of acute cal symptoms that range from headache, nausea,
kidney injury (AKI), they are referred to as con- vomiting, restlessness, and twitching to the more
tinuous renal replacement therapy (CRRT). The severe tremors, disorientation, and convulsions.
terms are further qualified by the forms of vascu- Treatment includes the administration of a hyper-
lar access used. For example, continuous HF tonic solution, such as hypertonic saline, 50%
using an artery for blood supply and a vein for dextrose, or mannitol. The patients’ symptoms
blood return in the extracorporeal circuit is called should be treated. Delivering a less effective
continuous arteriovenous hemofiltration. treatment using lower blood and dialysate flow
Continuous HDF exclusively using veins for vas- rates, decreasing treatment time, or running the
cular access is called continuous venovenous patient with a concurrent flow will help minimize
HDF. A rather common form of CRRT is slow (or these symptoms until the blood urea nitrogen lev-
sustained) low-efficiency HD. els stabilize [7, 8].
17.5.1.2 Muscle Cramps

17.4.3 Hemoperfusion Persistent involuntary skeletal muscle contrac-
tions with pain is a common complication during
HP is the removal of solutes (usually toxins) from dialysis. It usually occurs near the end of dialysis,
the blood by adsorption onto materials, such as may be associated with low blood pressure, and
charcoal or resins, in the extracorporeal circuit. is responsive to treatment with plasma volume
HP is primarily used as treatment for acute poi- expanders. However, cramps do not always rely
soning. Adsorbents designed to remove specific on significant volume reduction and hypotension
molecules, such as β2-microglobulin, are not and have a positive response to hypertonic saline,
used in routine clinical renal replacement thera- mannitol, and hypertonic glucose solutions,
pies (RRTs). which may suggest a role for low osmotic pres-
sure in the pathogenesis of muscle contraction.
Muscle cramps is often associated with periph-
17.5 Acute Complications of HD eral vascular disease and the management for
symptom includes the following aspects which
17.5.1 Neurological Complications are aimed at increasing plasma osmotic pressure.
It has been shown that parenteral infusion of 25%
17.5.1.1 Disequilibrium Syndrome mannitol (50–100 mL), 23.5% hypertonic saline
Disequilibrium syndrome is a situation that pro- (15–20 mL), or 50% hypertonic glucose solu-
duces neurological and other symptoms soon tions (25–50 mL) is equally effective. Applied
after a patient begins dialysis treatment. Urea is before hemodialysis, midodrine hydrochloride
able to move freely between the cells and serum. tablet may be effective in reducing muscle con-
Theories suggest that when a severely uremic traction in patients with symptomatic hypoten-
patient is dialyzed for the first time, as the urea is sion during dialysis. Precautions include reducing
removed, the plasma becomes more hypotonic, excessive weight gain between dialysis to avoid
causing water to shift from the plasma into the rapid UF. Increasing the dry weight may be sug-
brain tissue, which is less hypotonic and contains gested if interdialytic weight gain is appropriate.
higher amounts of urea. Patients who (1) are It has been found that the use of quinine sulfate
treated with HD, (2) have very high blood urea (oral, 325 mg) at the onset of HD may signifi-
nitrogen levels (usually >60 mmol/L), (3) have cantly reduce the incidence of muscle contrac-
severe acidosis, (4) are elderly individuals or tion. Using different sodium modeling strategies
children, and (5) have a history of neurological (exponential or stepwise), for example, starting
216 H. Ye et al.
from a dialysate sodium concentration of 145– allergy to disinfectants, or release of noxious

155 mEq/L and linearly decreasing to 135– substances that have contaminated the dialyzers
140 mEq/L, has led to similar clinical results. during the manufacturing or sterilization process.
The use of internal blood volume UF feedback Another cause is the accumulation of vasoactive
control system is associated with a lower inci- kinins as a result of enhanced activation of kinin-
dence of muscle contraction. Finally, stretching ogen by dialysis membranes made of copolymers
exercises for affected muscle groups during dial- of acrylonitrile and methallyl sulfonate and
ysis may be beneficial [9–11]. decreased kinin degradation due to the simulta-
neous administration of angiotensin-converting
17.5.1.3 Convulsion enzyme inhibitors, which are also kininase
Convulsion occurs in <10% of patients and more inhibitors. Type A reactions are usually due to the
frequently in patients starting HD. Cerebral hem- factory sterilant ETO. This type of reaction is
orrhage should be considered when focal neuro- currently less common because some dialyzer
logical signs are positive. Other reasons include manufacturers are using alternative sterilization
hypertensive encephalopathy, disequilibrium methods such as gamma irradiation as a sterilant,
syndrome, uremic encephalopathy, acute alumi- e-beam sterilization, or steam sterilization. For
num poisoning, hypoglycemia, and alcohol with- those using dialyzers sterilized with ETO, proper
drawal. Termination of HD should be immediately priming of the dialyzer may help prevent pockets
performed when convulsion occurs, the respira- of ETO from remaining in the fibers to be released
tory tract should be kept unblocked, and the cir- during the patient’s dialysis treatment. Type B
culation should be maintained stable. Electrolyte reactions are less threatening but more com-
and blood glucose levels should be immediately monly seen. The symptoms usually occur as
measured, and sedatives should be administrated soon as the patient’s blood is exposed to the dia-
to stop convulsion. Subsequent treatment needs lyzer and returned to the patient. Symptoms
to be decided according to the process of attack, include chest pain, hypotension, and occasionally
signs, and results of blood tests. back pain. The treatment for both types of reac-
tions is based on symptoms. Dialysis treatment
should be discontinued until the cause of symp-
17.5.2 Allergic Reactions toms is determined and the physician is notified.
Oxygen is generally administered for difficulty
17.5.2.1 Dialyzer Reactions in breathing. Intravenous antihistamines or epi-
Dialyzer reactions are sometimes referred to as nephrine may be ordered for anaphylaxis. Blood
“first-use syndrome” because some patients, pressure support may also be necessary for hypo-
upon exposure to the dialyzer membrane for the tension [12].
first time, develop allergic-type symptoms.
Dialyzer reactions are at present more commonly 17.5.2.2 Reuse Syndromes
referred to as type A and B reactions, with type A The reuse reaction is more likely due to other
reactions being more severe and often presenting agents such as germicides for re-treatment of dia-
with anaphylactic-type symptoms. These reac- lyzers because most of the remaining ETO is
tions usually occur within the first 5 min of treat- washed out of the dialyzer at “first use.”
ment, with patients experiencing the following Commonly used germicides include glutaralde-
symptoms: dyspnea, chest and back pain, feeling hyde, peracetic acid/hydrogen peroxide, and
of warmth, sense of impending doom, and car- formaldehyde. Formaldehyde is a known aller-
diac arrest. Less threatening symptoms include gen and a life-threatening response is observed in
itching, urticaria, coughing, sneezing, watery HD patients who are positive for the radioactive
eyes, and abdominal cramping. The causes are sorbent formaldehyde test. Disinfection of the
probably multifactorial and may involve the acti- water supply system may also result in exposure
vation of plasma proteins by dialysis membranes, to residual formaldehyde.
17 Hemodialysis 217
17.5.2.3 Drug-Induced Reactions asymptomatic, it may be accompanied by a

severe decrease in blood perfusion in vital organ,
Intravenous Iron Dextran leading to loss of consciousness, seizures, and
Iron dextran is a mixture of synthetic glucose even death. There are a lot of reasons for intradia-
polymers that is involved in systemic reactions. lytic hypotension. First, blood volume may
The allergic reaction to iron dextran is due to this decrease excessively. Excessive weight gain
compound, which occurs at 0.6–1% of the recipi- between two dialysis sessions or inappropriate
ents. Clinical practice guidelines of the National dry weight may lead to plasma refilling failure
Kidney Foundation’s recommend that resuscita- during dialysis, which is a crucial reason that
tion equipment and healthcare personnel should accounts for hypotension. The rapid clearance of
be available whenever iron dextran is used. High uremic toxins results in a low osmotic pressure of
and low molecular weight dextran iron prepara- interstitial fluid and blood leading to the shift of
tions differ in the frequency of allergic reactions, water into the cells and eventually causes a
which latter appear to be safer. The exact mecha- decrease in blood volume. Second, there may be
nism of dextran-induced allergic reactions is a decrease in vascular tone. The inability of the
unclear, but dose-dependent histamine releases body to make a normal compensatory response to
from basophils, which may be the cause of car- hypovolemia, characterized by a central redistri-
diovascular failure, seems to occur. Due to this bution of blood volume and an increase in periph-
dose-related toxicity, 0.5–1 mg of iron dextran eral vascular resistance, is a common mechanism
should always be used as a starting test dose so of hypotension. Several patient-related factors
that staff could deal with the reaction in time. If are involved in the mechanism of the failed com-
the test dose is safe, a course of treatment with pensatory response, which include arrhythmia,
ten doses of 100–200 mg per session of dialysis taking antihypertensive drugs, structural heart
can be safely provided. An alternative to iron disease, bleeding, anemia, autonomic neurologi-
dextran including intravenous administration of cal dysfunction (especially in patients with dia-
iron gluconate and saccharin may cause less betes and elderly), food intake during dialysis,
allergic reactions, but it has been recognized that venous stasis during dialysis, fervescence, and
free iron released from these drugs can lead to sepsis. Reduced sensitivity to renin-angiotensin,
inflammatory reactions. adrenergic, and arginine vasopressin systems
may also result in insufficient vasoactive response
Heparin to hypovolemia induced by HD. Third, a distur-
Patients are rarely highly sensitive to heparin bance in cardiac constructive and dilated function
preparations, and allergic reaction usually occurs can also contribute to intradialytic hypotension.
only when beef heparin and porcine heparin are Hypotension during dialysis should be treated
exchanged. immediately. The rescue measures include plac-
ing the patient in Trendelenburg position to facil-
Desferrioxamine itate the recovery of perfusion of important
Desferrioxamine or iron chelation in the treat- organs, preventing accidental inhalation, increas-
ment of aluminum poisoning can lead to hypo- ing circulating blood volume by infusion of iso-
tension during dialysis, hearing toxicity, bone tonic saline or hypertonic agents, and reducing or
pain, gastrointestinal disorders, visual loss, or stopping UF. Additional treatments such as use
even rare allergic reactions or aggravation of alu- of bicarbonate dialysate, UF volume control,
minum encephalopathy. increase of sodium concentration in dialysate,
more accurate assessment of dry weight of
17.5.2.4 Intradialytic Hypotension patients by bioimpedance or vena cava ultra-
Hypotension during dialysis requiring drug inter- sound, and decrease of dialysate temperature
vention occurs in 10–30% of treatments. may improve cardiovascular stability and reduce
Although intradialytic hypotension can often be occurrence of hypotension during dialysis.
218 H. Ye et al.
Table 17.4 Strategies for intradialytic hypotension lar of blood pressure (BP) management in
Proposed physiologic patients with HD, as many as 50% of patients have
Management strategies mechanisms not achieved the ideal BP control. Several volume-
• Lowering UFR or • Optimizes plasma indepentent factors associated with hypertension
suspending UF refill/increases preload
during dialysis include activation of renin-angio-
• Trendelenburg position • Increases cerebral
perfusion/augments tensin system owing to decreased blood volume
venous return and hypokalemia, increased inotropism and vascu-
• Infusion of saline or • Restores plasma lar tone induced by hypercalcemia, and preexist-
albumin volume/augments ing hypertension. Other hypothesized mechanisms
venous return
for hypertension in dialysis include increased
• Pressor agents • Increases vascular
resistance sympathetic tone and cardiac output in response to
• Nasal catheter oxygen • Prevents or reduces fluid removal, especially in patients with cardiac
inhalation 2–4 L per organ hypoxemia dysfunction. It has been shown that long-term
minute usage of recombinant human erythropoietin
• Reduction of blood flow • Minimizes plasma
(rHuEPO) is also related to hypertension.
and dialysate flow osmotic gradients
In the absence of signs or symptoms of volume
Abbreviations: UFR ultrafiltration rate, BP blood pressure
contraction, it is reasonable to reduce dry weight
by 0.5 kg and observe the clinical response, fol-
Furthermore, sodium modeling can reduce epi- lowed by reevaluating periodically. Increased
sodes of hypotension, while the effect of low-salt dialysis or UF time and/or frequency can promote
albumin is not better than that of normal saline volume removal. Detection value of atrial natri-
and the cost is higher. The effectiveness of online uretic peptide shows that the true dry weight is not
blood volume monitoring technique is controver- achieved in most patients with refractory hyper-
sial even if it has been used to control intradia- tension during dialysis. Altering the approach of
lytic hypotensive episodes. There are other rHuEPO administration from the intravenous to
strategies for preventing intradialytic hypoten- the subcutaneous route is associated with
sion, including avoiding food ingestion before improved BP control in patients with hyperten-
and during dialysis, stopping antihypertensive sion during dialysis. Finally, consideration should
drugs before dialysis, correcting anemia and be given to the use of minimal doses of antihyper-
hypoalbuminemia, treating congestive heart fail- tensive drugs that cannot be cleared by dialysis
ure and arrhythmia, searching for other reasons such as carvedilol, clonidine, calcium channel
such as pericardial effusion, and counseling blockers, and angiotensin II receptor blockers.
patients on weight gain. Lastly, the use of
selective alpha-1-adrenergic receptor agonist
17.5.2.6 Cardiac Arrhythmias
midodrine prior to a session of dialysis can effec- Atrial and ventricular arrhythmias often occur
tively and safely reduce the severity and fre- in patients undergoing HD, while the etiology of
quency of intradialytic hypotension. l-Carnitine these arrhythmias is multivariate. Potential con-
and sertraline are also pharmacological options ditions frequently encountered include uremic
[13]. Common measures for the treatment of pericarditis, ischemic or hypertensive heart dis-
intradialytic hypotension are listed in Table 17.4. ease, silent myocardial ischemia, left ventricu-
lar hypertrophy and dysfunction, and conduction
17.5.2.5 Intradialytic Hypertension system calcification. Furthermore, rapid or
Hypertension during dialysis is one of the risk fac- slow changes in the homestasis of fluids, elec-
tors for cardiovascular disease morbidity and mor- trolyte, and acid-base during HD may aggravate
tality, which occurs in 8–30% of treatments. the arrhymogenic effects of digitalis prepara-
Although volume control remains the primary pil- tion, antiarrhythmic medications, and other
17 Hemodialysis 219
drugs. Arrhythmias may only be caused an acceptable hemoglobin level and HD adequacy
by increased transport or consumption of oxy- could help correct platelet dysfunction. For
gen in the myocardium, such as volume over- patients with severe hemorrhagic tendency, hepa-
load or intradialytic hypotension. rin-free dialysis can be considered to reduce the
Measures that can be used to prevent arrhyth- risk of anticoagulant-related bleeding. The method
mias include the use of bicarbonate dialysate and in detail is as follows: the dialysis pipeline should
tight monitoring of potassium and calcium levels be rinsed using 100–200 mL of 0.9% sodium chlo-
in dialysate. Because of the possibility arrhyth- ride every 15 or 30 min (the UF volume should be
mogenesis, zero potassium dialysate should be increased). The blood flow rate should be
banned, and an adjusted concentration of potas- increased, whereas the UF rate should be decreased
sium in dialysate may be helpful. to avoid coagulation when heparin is not used.
Regional citrate anticoagulation (RCA) is an
effective approach to reduce the risk of bleeding.
17.5.3 Hematological Complications
17.5.3.1 Hemolysis 17.5.4 HD Technique-Associated

Hemolysis (lysis of red blood cells) may be due to Complications
thermal, chemical, or mechanical events, resulting
in the release of intracellular potassium. Chemical 17.5.4.1 Air Embolism
causes of hemolysis include exposure of the blood An air embolism, also known as a gas embolism, is
to chemicals, such as sodium formaldehyde, a blood vessel blockage caused by air or a large
nitrates, hypochlorite, or copper. Thermal hemoly- amount of foam in the patient’s circulatory system.
sis is caused by exposure of the blood to over- Air embolism can occur when blood or saline infu-
heated dialysate. Dialysate temperatures >42 °C sion bags run dry or when arterial or venous lines
are considered dangerous. Mechanical causes of become disconnected. The patient may complain
hemolysis include kinking of blood lines, over- of chest pain or tightness or shortness of breath and
occluded blood pumps, excessive negative pres- may cough. If the patient is sitting upright, air may
sure from a small-gauge needle with a high blood be introduced into the cerebral venous system and
flow rate, and a poorly positioned needle. Other causes neurological symptoms, such as visual
causes of hemolysis include dialyzing the patient problems, loss of consciousness, and convulsions.
against a hypotonic bath and blood transfusions. Dialysis should be stopped immediately, and
The diagnosis of severe hemolysis is not difficult patients should be placed on their left side in a
(blood from the dialyzer appears bright red); how- head-down position (to trap air at the apex of the
ever, chronic and mild hemolysis is difficult to right ventricle) once an air embolism is suspected.
diagnose unless a diagnostic test for HD is per- After this, endotracheal intubation with oxygen
formed. Treatment consists of discontinuation of flow at high rate should be started. Swan–Ganz
dialysis and the blood in the blood circuit must not catheter may be used to aspirate air from the right
be returned. In addition, it is common to collect ventricle in some severe cases.
blood samples to detect blood potassium levels.
17.5.4.2 Loss of Blood
17.5.3.2 Acute Bleeding Loss of blood is usually due to disconnections of
Hemorrhagic tendency is aggravated by the use of needles, catheters, and junctions of the artery or
anticoagulant agents during HD in uremic patients. vein to the dialyzer along the extracorporeal cir-
Monitoring the bleeding time is the best method to culation pathways and sometimes results from
evaluate hemorrhagic tendency. Platelet dysfunc- failure characteristics of products such as rupture
tion is another cause of bleeding, and maintaining of pump tubes.
220 H. Ye et al.
17.6 Chronic Complications of HD tained system, the microbial content of water
should be well within the recommended limits.
17.6.1 HD-Associated Infections Increasing data suggest that the use of ultra-
pure water and dialysate would benefit mainte-
Infection is the second leading cause of death after nance dialysis patients, and the microbial quantity
cardiovascular diseases among patients with chronic of HD fluids acts on the alleviation of chronic
HD. Many factors contribute to the susceptibility of inflammatory response syndrome, manage-
patients to infectious agents such as impaired cel- ment of anemia, retardation of residual renal
lular immunity, defective neutrophil function, and function decline, and improvement in serum
complement activation. Infections transmit to sus- albumin level in patients with HD.
ceptible patients either from an infected healthcare
worker (professional to patient transmission) or 17.6.1.2 Vascular Access Infections
from another infected patient (patient to patient Vascular access-related infections remain a major
transmission) through contaminated equipment, cause of morbidity and mortality in this popula-
supplies, intravenous medications, environmental tion, owing to disseminated bacteremia, dysfunc-
surfaces, or hands of healthcare workers. Moreover, tion of or even loss of vascular access. Some local
intermittent hospitalizations and surgeries increase signs near the vascular access may indicate infec-
the opportunities for exposure to non-community tions such as erythema, swelling and tenderness,
acquired infections. induration, skin breakdown, warmth, loculated
fluid, and purulent exudates. As the initial reported
17.6.1.1 Microbial Contaminants by the surveillance project performed by Centers
in HD Systems for Disease Control and Prevention (CDC), the
Several microbiological parameters were frequency of bacteremia associated with vascular
neglected in the design of many dialysis machines access was 1.8 overall per 100 patient-months,
and corresponding water supply systems. Gram- and it varies among different types of access: 0.25
negative water bacteria (e.g., Burkholderia, for fistulas, 0.53 for grafts, 4.8 for permanent
Flavobacterium, Pseudomonas, Ralstonia, catheters with tunnel and cuff, and 8.7 for tempo-
Serratia, and Sphingomonas) are commonly rary catheters without tunnel and cuff. On the
detected in water supplies used for HD. Under basis of a later report from survey data collected
certain circumstances, these microorganisms can by this system between 1995 and 2005, the aver-
persist and multiply in aqueous environments age frequency of infection ranged from 10.1 for
associated with HD equipment, and they can temporary catheters to 0.6 for fistulas per 100
adhere to surfaces and form biofilms (glycocalyx), patient-months, and the total frequency was 3.1.
which are virtually impossible to eradicate. This According to the frequency of pathogens
can directly or indirectly affect patients by septi- causing vascular access infections, 32–53% of
cemia or endotoxemia. Control strategies are cases were Staphylococcus aureus, 20–32%
designed not to eradicate bacteria but to reduce coagulase-negative staphylococci, 10–18%
their concentration to relatively low levels and Gram-negative bacilli, 10–12% other Gram-
prevent their regrowth. positive cocci (including enterococci), and <1%
While the incoming tap water flows through of case were fungi infection. Staphylococcus
each component of the water treatment system in aureus infection is more common in patients with
turn, which is composed of prefilters, a water fistulas or grafts, while coagulase-negative staph-
softener, carbon adsorption tanks, a particular fil- ylococci accounts for a higher proportion of
ter for the protection of the reverse osmosis mem- patients who use catheters.
brane, and a reverse osmosis unit, it becomes The type of vascular access is the major risk
more chemically pure while avoiding high levels factor for infection associated with access, as
of microbial contamination. Under the conditions catheters, grafts, and native AVFs having the high-
of a thoroughly sterilized and regularly main- est, moderate, and the lowest risk of infection,
17 Hemodialysis 221
respectively. Other potential risk factors for vas- effect of routine antibiotic use with catheter lock
cular access infection include (1) immunosup- solutions remains unknown. In spite of promising
pression; (2) diabetes; (3) older age; (4) chronic results from these studies, a routine antimicrobial
inflammatory state; (5) access location in the lock solution use is not recommended by the
lower extremity; (6) scratching over the access CDC for fear of antimicrobial resistance.
site, dermatitis, trauma, or hematoma; (7) recent The Infectious Diseases Society of America
vascular access surgery; (8) poor needle puncture recommends a nasal mupirocin treatment for
technique; (9) poor patient hygiene; (10) intrave- documented S. aureus carriers who are suffered
nous drug use; and (11) iron overload. Based on from catheter-related bloodstream infection and
the relative risk of both infectious and noninfec- continues to require a catheter. Apart from this,
tious complications, it is recommended that native neither the CDC nor National Kidney Foundation
AVFs be more commonly used and HD catheters recommends a routine use of nasal mupirocin in
less commonly and that no more than 10% of dialysis patients with catheters.
patients should be maintained with permanent
catheter-based HD treatment. To minimize infec- 17.6.1.3 Chronic Infections
tious complications, patients should be referred
early for the creation of an implanted access, Hepatitis B Virus (HBV) Infection
thereby decreasing the time for dialysis using a HBV infection is one of the most frequent and
temporary catheter. Additionally, catheters should morbid viral infections in HD patients. In the
be used only in patients for whom a permanent early times, HBV infection spread regionally in
access is impossible. dialysis unit and outbreak frequently. Since the
To reduce infections associated with vascular introduction of vaccination and improvements in
access, several recommendations have been infection control, the incidence and prevalence of
made by the National Kidney Foundation and HBV infection rates among HD patients in the
CDC as follows: (1) avoiding preventive use of USA have sharply declined, being 0.12% and
antibiotic; (2) avoiding to replace catheter rou- 1%, respectively, in 2002. Skin (i.e., through skin
tinely; (3) following the principle of aseptic tech- puncture) or mucous membrane (direct contact
nique strictly during catheter placing; (4) with mucous membrane) exposed to infectious
restricting the service life of temporary catheter blood or body fluids containing blood is the main
to 3–4 weeks; (5) avoiding usage of catheter for route of transmission of HBV.
other purpose beyond HD; (6) allowing only HBV is resistant to the external environment
skilled staff to participate in catheter manipula- and able to stay viable for more than 7 days on
tion; (7) changing dressing on catheter-site dur- environmental surfaces at room temperature.
ing each dialysis session or if damp, lose, or HBsAg could be detected on hemostats, scissors,
soiled; (8) sterilizing the skin with a 2% dialysis machine control panels, and door knobs
chlorhexidine-based preparation before catheter in dialysis facilities. By this way, blood contami-
insertion and dressing replacement; (9) offering a nated apparatuses without routinely cleaning and
catheter-site care which is compatible with cath- sterilization could turn into a reservoir for HBV
eter material. To reduce catheter-related blood- transmission. In addition, HBV could be trans-
stream infections in HD patients, some mitted to susceptible patients from an infected
researchers adopt an antimicrobial lock strategy. health care worker.
Two meta-analyses have drawn conclusions from In most cases, HBV infection outbreaks
these studies, that is, bloodstream infections among HD patients were induced through (1)
associated with catheter could be dwindled by environmental surfaces, instruments, or equip-
this antimicrobial lock strategy, and in clinical ment without routinely cleaning and sterilizing
practice, in combination with other prevention after each use; (2) using one multiple-dose intra-
methods, this treatment strategy should be con- venous solution or vial for more than one patient;
sidered routinely. Nevertheless, the long-term (3) intravenous medications prepared close to
222 H. Ye et al.
areas where blood samples were handled; (4) Machines, equipment, and supplies for
health care workers providing medical service to HBsAg-positive patients should be dedicated and
both infected and susceptible patients simultane- placed in an isolated area. Since the transmission
ously. If there are certain factors which promote of HBV occurs via occupational contact with
HBV transmission among patients being identi- blood, and repeated use of dialyzers in HBsAg-
fied, the following measures for control are rec- positive patients increases the risk of infection
ommended: (1) serological test for screening among staff members susceptible to HBV,
HBV infection in both HD patients and health repeated use of dialyzers should be avoided.
care workers; (2) setting up an isolated area for Chronic HBV-infected patients, that is, HBsAg-
all HBsAg-positive patients; (3) avoiding assign- positive, total anti-HBc-positive, and IgM anti-
ment health care workers to HBsAg-positive HBc-negative, who are at a high risk of chronic
patients and to HBV-susceptible patients during liver diseases are major source of infection.
the same shift; (4) separating dialysis equipment Moreover, assessment based on current clinical
for HBV-susceptible patients from that for practice guidelines is preferred for HBsAg-
HBsAg-positive patients; (5) routinely assigning positive patients. The hepatitis A virus vaccine
a supply tray to each patient no matter what sero- inoculation should be considered for people with
logical status is; (6) cleaning and sterilizing of chronic liver disease to prevent further impair-
instruments that are not disposable such as ment of liver. Although routine follow-up tests in
clamps, scissors, and hemostats before they are chronic HBV-infected patients do not improve
used for another patient; (7) wearing gloves the control of infection, it is reasonable to test
regardless of touching dialysis equipment or not HBsAg annually for the small proportion of
and changing gloves between each station and HBV-infected patients whose HBsAg may shift
between each patient; (8) cleaning and sterilizing to negtive.
equipment and environmental surfaces routinely.
In the acute care setting, HD has also been HCV Infection
found associated with HBV infection among Another common viral infection in dialysis unit
patients. Other related risk factors include sexual is a single-stranded RNA virus named hepatitis C
and household exposure, multiple sexual part- virus (HCV) which belongs to the Flaviviridae
ners, male homosexual activity, drug injection, family. HCV is another efficiently transmitted
and perinatal exposure. Staff of dialysis unit blood-borne viral pathogen in the dialysis set-
should educate patients about these and inform ting. Incidence and prevalence of HCV infection
infected patient’s sexual partners and household varies greatly in different dialysis unit of the
of vaccine inoculation. world. HCV remains relatively stable when
There are three pairs of antigen–antibody sys- exposed to external environment and able to sur-
tems found associated with HBV infection, vive for more than 16 h in a dry environment at
including HBsAg and antibody to HBsAg (anti- room temperature. Direct percutaneous exposure
HBs); hepatitis B core antigen (HBcAg) and anti- to blood plays a pivotal part in HCV transmis-
body to HBcAg (anti-HBc); and hepatitis B early sion; similar to HBV, chronic infected patients
antigen (HBeAg) and antibody to HBeAg (anti- play a key role in the spread of HCV. Risk factors
HBe). These serological biomarkers can be for HCV infection among HD patients include
detected in different combinations at different blood transfusions from unscreened donors,
stages of infection. The other screening test for intravenous drug abuse, low staff-to-patient
HBV infection is qualitative or quantitative anal- ratios, and years on dialysis. The number of years
ysis for HBV DNA. Routine screening for HBV on dialysis is the major risk factor independently
infection should be performed for all HD patients, associated with higher rates of HCV infection.
and in order to ensure that the patients are prop- The prevalence rate of HCV infection increased
erly managed in a timely manner, their test results with the increase of dialysis time, and the average
should be reviewed promptly. rate of patients receiving dialysis <5 years was
17 Hemodialysis 223
12%, while that of patients receiving dialysis RIBA or NAT positivity; or a positive anti-HCV
>5 years was 37%. screening test result with NAT negativity and
There were several media identified associ- RIBA positivity) from other patients or restrict
ated with cross-infection among HD patients, them to dedicated dialysis machines. Routine test
including (1) medical instruments and supplies could both monitor virus transmission in dialysis
without sterilization after use; (2) shared drug unit and judge whether established preventive
cart for preparing and distributing medications at measures are efficiently executed or not. HCV-
patient stations; (3) contaminated multiple-dose positive patients should be evaluated (by consul-
vials after repeated use; (4) polluted priming tation or referral, if appropriate) for the presence
buckets without cleaning and sterilization; (5) or development of chronic liver disease accord-
machine surfaces that were not routinely cleaned ing to the current medical practice guidelines and
and disinfected between patients; and (6) spilled should receive information on how they can pre-
blood containing HCV. There are some other risk vent further injury to their liver and transmitting
factors for HCV infection such as intravenous HCV to others. Those with chronic liver disease
medication, blood transfusion, exposure to a should be vaccinated against hepatitis A, if sus-
HCV-infected sexual partner or household con- ceptible [14, 15].
tact, number of sexual partners, and vertical
transmission.
Recombinant immunoblot assay (RIBA) and 17.6.2 Hypertension
nucleic acid test (NAT) for HCV-RNA are the
only two methods used for the diagnosis of HCV Hypertension is one of the common complica-
infection approved by the Food and Drug tions of chronic kidney disease (CKD). With
Administration. More often than not, an initial the decline of glomerular filtration rate, the
enzyme-linked immunosorbent assay (ELISA) prevalence of hypertension increases gradually,
anti-HCV screening is used for saving cost of and more than 80–90% of patients have hyper-
detecting. Note worthily, the ELISA anti-HCV tension at the start of dialysis. There is a
test result should be interpreted with caution for U-shaped relationship between BP and cardio-
each of the following cases: (1) a false-negative vascular disease outcomes in the dialysis popu-
test result in nearly 10% of HCV-infected population, with increased cardiovascular disease
lation; (2) previous acute HCV infection; (3) in events and mortality at both markedly elevated
the acute phase of HCV infection, there may be a postdialysis systolic BP (SBP >180 mmHg)
prolonged interval between the onset of illness and lower SBP (<110 mmHg). Certainly, hyper-
and seroconversion; and (4) a high rate of false- tension does not appear entirely benign in dial-
positive in people with low infection rate. ysis patients, and it is an independent risk factor
Therefore, a positive anti-HCV screening test is for ischemic heart disease, LVH, heart failure,
not reliable to make a diagnosis of HCV and cerebral hemorrhage. Although it is gener-
infection. ally considered that UF to dry weight is an ini-
An initial ELISA-based screening test is tial treatment for hypertension, there is no
suggested as a routine test, while anti-HCV evidence to support any BP target or even the
assay using RIBA or HCV-RNA test could best method to achieve a specific BP target in
serve as a supplement for positive ones. It has this population.
been recommended that anti-HCV routine
examination be performed every 6 months in 17.6.2.1 BP Target for HD Patients
patients with HD. According to the suggestions of the Eighth Joint
It is not necessary to separate HCV-positive National Committee on Prevention, Detection,
patients (defined as a positive anti-HCV screen- Evaluation, and Treatment of High Blood
ing test result with a high signal-to-cutoff ratio; Pressure in the United States with respect to the
or a positive anti-HCV screening test result with staging and treatment of hypertension, normal
224 H. Ye et al.
BP is <120/80 mmHg. HD treatment makes BP 17.7 Vascular Access

variation more complex. Partial patients (40–
50%) have decreased BP, whereas some have Maintenance of vascular access is a major chal-
increased BP. Some studies show significant lenge in chronic HD. An adequate vascular access
associations between SBP before HD and LVH, should permit blood flow to the dialyzer at a rate of
whereas other investigations reported good cor- 200–500 mL/min in adults, depending on patient
relation between ambulatory BP monitoring and size. In the United States, there is a tendency to use
interdialytic BP. With respect to clinical practices blood pump speeds of 350–500 mL/min, whereas
for cardiovascular diseases, the Kidney Disease speeds of 200–250 mL/min are common in Asia.
Outcomes Quality Initiative (KDOQI) suggested This discrepancy is partly due to the smaller body
that the BP should be <140/90 mmHg and size in the Asian population, longer dialysis ses-
<130/80 mmHg before and after dialysis, sions in some countries, and uncertainty as regards
respectively. the clinical benefits of very high clearances of
small solutes in chronic HD. A large-diameter
17.6.2.2 Measures to Control BP venous catheter is necessary to perform acute HD
High blood volume is the main factor for hyper- in the absence of a functional permanent vascular
tension in patients undergoing maintenance HD, access. Under these circumstances, a double-lumen
and approximately 50% of patients are volume- catheter is placed, usually in the internal jugular
dependent. The Hemodialysis (HEMO) study vein or femoral vein. One lumen is used to extract
suggested that the volume affected the BP both the blood from the patient (the so-called arterial
before and after dialysis. Therefore, accurate side, even though it comes from the patient’s vein),
evaluation of dry weight is an important strategy and the other lumen is used to return the blood to
to control hypertension in HD patients. Sodium the patient (“venous” side). Femoral catheters are
and liquid intake should be restricted to avoid seldom left in place for more than one dialysis ses-
excessive weight gains. In addition, hypercalce- sion unless the patient is confined to bed, because
mia and usage of erythropoietin can contribute to catheters in this location are prone to kinking, dis-
hypertension. lodgement, and infection [17].
The usage of antihypertensive agents and
adjustment of dosages are essential for BP con-
trol. A combination of two or more a ntihypertensive 17.7.1 Arteriovenous Fistula
agents is needed to achieve BP targets for HD
patients. According to the KDOQI guidelines, Long-term vascular access for HD is usually
angiotensin-converting enzyme inhibitors and established by the creation of an AVF in an upper
angiotensin II receptor blockers are preferentially extremity, although a lower extremity or even an
selected because they can inverse LVH, reduce axillary vessel may sometimes be employed.
the excitability of sympathetic nerves, decrease After AVF is established, the venous will receive
the pulse wave velocity, improve endothelial a large flow of arterial blood so the venous seg-
function, and reduce oxidative stress. Another ment will dilate and develop a thickened wall
principle is to choose long-acting drugs. For diffi- (arterializes) over time. As the KDOQI guide-
cult-to-control hypertension in HD patients, beta lines suggested, the AVF is the best vascular
receptor blocker, calcium channel blocker, adren- access method up to now. A literature review by
ergic blocker, and vasodilator agent can be used to the KDOQI groups determined that the AVF has
control BP. Additionally, pharmacokinetics of the the “longest life with least complications” and a
antihypertensive agents should be considered in “longer intervention-free life” than any other vas-
HD patients (e.g., the clearance of drugs in HD cular access method. The radial artery and
treatment) [16]. cephalic vein at the wrist are the most commonly
17 Hemodialysis 225
used vessels for fistula (radiocephalic fistula) ing saphenous vein, bovine carotid artery, and
(Fig. 17.4). polytetrafluoroethylene (PTFE). Partly due to the
When a distal fistula has failed to creation or ease of placement and the short time required
distal vessels are unavailable, the upper arm veins from the placement of an AVG to the initiation of
can provide other options. Both the cephalic and puncture, PTFE accesses are highly prevalent. An
basilic veins can be applied to fistula creation; AVG can be placed as a straight tube or as a loop
however, it is noteworthy that the basilic vein between an artery and an appropriately matched
courses the upper arm in deep fascia, thereby an vein, and it can be created almost anywhere in the
additional procedure of transposition is required. arm (sometimes in the thigh if vessels in the arm
Fistulas should not be used for 6 weeks after their are not available) (Fig. 17.5). Usually, a mini-
creation because their use prior to the maturity of mum waiting period of 2–3 weeks is recom-
the venous wall can shorten their life. mended prior to use. However, a new material
graft with trilayer sealing properties can be used
after 24 h of implantation. Some complications
17.7.2 Arteriovenous Graft (AVG) of graft are similar to AVF, but the incidence rate
of infection, stenosis, and thrombosis is higher.
If a native AVF cannot be created, tubal material The most common cause of flow problems is inti-
can be grafted under the skin between the artery mal hyperplasia that leads to stenosis at the
and vein and be used as blood access. The use of venous anastomosis. AVGs need more monitor-
several graft materials (autogenous, heteroge- ing and intervention treatment to maintain a lon-
neous, and synthetic) has been attempted, includ- ger patency.
Fig. 17.4 Arteriovenous Arteriovenous fistula

fistula. Arteriovenous To dialysis machine
Artery
fistula is established by
surgical anastomosis of
a peripheral artery with
a larger subcutaneous
vein
Vein
From dialysis machine
Fig. 17.5 Arteriovenous Synthetic bridge graft From dialysis machine

grafts. Arteriovenous
grafts might be Vein
necessary when the
patient’s vascular status
does not support a
fistula.
Polytetrafluoroethylene
grafts are commonly
used and can be
repetitively punctured
for hemodialysis
Artery
To dialysis machine
226 H. Ye et al.
Stenosis at the outflow tract of AVFs, especially by percutaneous balloon angioplasty with or
AVGs, frequently occurs and represents the major without the placement of a stent to keep the
cause of failure of these accesses. Stenosis is lumen patent. Although angioplasty temporarily
almost exclusively due to neointimal hyperplasia, restores the flow and usefulness of the vascular
which is composed of proliferating myofibro- access, a major problem with it is that the trauma
blasts, and deposition of extracellular matrix, simi- induced by the balloon actually predisposes the
lar to that observed in coronary artery restenosis. vessel wall to further stenosis, setting up a vicious
Partial obstruction of the dialysis access impedes cycle. If left untreated, most stenotic vascular
the flow of cleansed blood from the dialyzer back accesses eventually become totally occluded by
to the central veins; as a result, the blood recircu- thrombi. The value of systemic antiplatelet agents
lates back to the “arterial” (afferent) limb of the or anticoagulants to prolong the useful life of an
fistula and decreases the amount of fresh systemic AVF or AVG is unproven. Various pharmacologic
blood delivered to the dialyzer, diminishing the and radiation strategies are being investigated to
overall efficiency of the dialysis process. prevent dialysis graft stenosis and make synthetic
Several methods can be used to detect stenosis grafts a better option. Until those strategies mate-
of AVFs and AVGs. Obstruction of the vascular rialize, the native AVF remains the preferred vas-
access outflow tract leads to an increase in pres- cular access.
sure inside the “venous” (efferent) tubing during
HD, which has been used as a clue to the pres-
ence of fistula outflow stenosis. Techniques 17.7.3 Central Venous Catheters
involving noninvasive devices and the dilution (CVCs)
principle have been developed to assess the total
blood flow through AVFs or AVGs. These moni- Despite guidelines suggesting the early place-
toring techniques are performed during HD, and ment of an AVF and restraining CVCs to no
the monitoring equipment is sometimes built-in more than 10% of all prevalent accesses, the
as a component of the dialysis machine. Gradual usage of CVC is still prevalent. Currently, 82%
decrease in blood flow rate through the fistula or of patients in the United States initiate dialysis
graft over time provides a clue and allows earlier with a CVC, and 19–25% use a CVC as their
detection of stenosis. Duplex ultrasonography is permanent access. The materials of current cath-
also useful for the diagnosis of vascular access eters include silicone, polyurethanes, or copoly-
stenosis. Nevertheless, the predominance of evi- mers. Silicone is soft and flexible, while
dence suggests that regular monitoring of blood polyurethane is more rigid than silicone and is
flow rates and prophylactic angioplasty interven- thermoplastic (i.e., more plastic when heated to
tion do not prolong the useful life of HD grafts. body temperature), making it easier to insert,
An angiogram (also called a “fistulogram” for especially for emergent HD. The most efficient
AVFs) with contrast dye injection remains the shaft design for dual- lumen catheters is the
gold standard for the confirmation and anatomic “double D.” The size of current dual-lumen cath-
definition of vascular access stenosis. The fistulo- eters ranges from 12F to 16F, and larger sizes are
gram is also helpful in searching for collateral used for tunneled catheters. Current tunneled
veins, which are impediments for the growth and catheters can be adjusted to adapt to blood flow
maturation of the native fistula. Improvement in rates of 300–400 mL/min. For acute HD, espe-
duplex ultrasonography techniques has dimin- cially unstable patients like patients with sepsis,
ished the use of contrast fistulograms, unless an the best suitable catheter is dual-lumen, non-
angioplasty procedure is being planned in con- cuffed temporary catheter. The three main ana-
junction with the fistulogram. tomical locations for catheter insertion are the
Fistula or graft stenosis can be surgically femoral, jugular, and subclavian vein. For
treated by replacing or bypassing the stenotic patients requiring extended HD or maintenance
segment. Alternatively, stenosis may be relieved HD, tunneled cuffed catheters are preferred to be
17 Hemodialysis 227
utilized. It takes longer time to insert cuffed thrombin III activity >50%, UFH might be the
catheter and fluoroscopy is often required to first choice for HD. UFH for anticoagulation dur-
ensure proper placement with the arterial port of ing HD can be monitored by monitoring the acti-
the catheter at the entrance to the right atrium. vated partial thromboplastin time (APTT). The
Compared with AVF, catheters provide more value of APTT 1.5–2.0 times above the baseline
rapid access to the circulation and can be placed during HD is recommended. UFH can reduce the
in most patients in many different locations. platelet count (<100,000/mL), called heparin-
However, it is notable that catheter placed for a induced thrombocytopenia (HIT), which is
long period could lead to stenosis and even closely related to the immune response mediated
occlusion of the placed vessel. Therefore, the by the anti-platelet factor 4–heparin complex.
internal jugular vein on the contralateral side of
the planned AVF is preferred and used to avoid
complications of central vein stenosis. Compared 17.8.2 Low-Molecular-Weight
with arteriovenous access, CVCs are associated Heparins (LMWHs)
with more hospitalizations, higher morbidity and
mortality, and higher overall annual per-person LMWH is derived from UFH via chemical or
costs. enzymatic depolymerization and is one third of
the molecular weight of UFH. LMWH acts as
an anticoagulant by inhibiting the activity of X
17.8 HD Anticoagulation factor, which has been thought to be safer in
bleeding than UFH. Intravenous injection of
As an extracorporeal circulation treatment, anti- 60–80 U/kg is administered before treatment,
coagulation is required during HD and CRRT to and no additional dosage is required for
prevent clotting in the extracorporeal circuits. HD. The European Renal Best Practice guide-
The ideal use of anticoagulants should not only lines for HD has recommended the use of
ensure sufficient anticoagulation during HD but LMWH for HD anticoagulation; nevertheless,
also avoid excessive anticoagulation leading to UFH remains the most common anticoagulant
bleeding. The usage of anticoagulation therapy for HD in China. Although cost might be the
includes the evaluation of coagulation status, main factor against the use of LMWH in HD,
individualized selection of appropriate anticoag- their safety remains a matter of concern. The
ulants, and regular monitoring of coagulation hemorrhagic risk of LMWH was not signifi-
state. Common anticoagulation methods are as cantly different compared with UFH. To date,
follows: standard heparin anticoagulation, low- LMWH has been considered to be the antico-
molecular-heparin anticoagulation, argatroban agulant as safe as UFH in HD [18].
anticoagulation, local citric acid anticoagulation,
and heparin-free anticoagulation.
17.8.3 Argatroban
17.8.1 Standard Heparin Argatroban, a new thrombin inhibitor, can be

Anticoagulation reversibly combined with thrombin, which is
mainly used in anticoagulation therapy for
Unfractionated heparin (UFH) remains the most patients with acute cerebral ischemic infarc-
commonly selected anticoagulant during tion. Argatroban is highly selective for throm-
HD. The loading dose is given at the start of HD bin. Argatroban is a direct thrombin inhibitor
and then continued to be replenished into the derived from arginine that is used for anticoag-
blood through the heparin pump until 30 min ulation of HD in patients with contraindications
before the end of HD. When there is no clinical to UFH or LMWH. Clinically, if there are obvi-
risk of hemorrhagic disease and plasma anti- ous bleeding tendencies in HD patients; or
228 H. Ye et al.
plasma APTT, prothrombin time, and interna- time, calcium solution is infused at venous to
tional normalized ratio are significantly pro- supplement ionized calcium. Due to the antico-
longed; or HIT is suspected; or antithrombin III agulant effect only in vitro, RCA is especially
activity is below 50%, argatroban might be pre- suitable for patients in high risk of bleeding. The
ferred in HD anticoagulation. It could be 2012 KDIGO clinical practice guidelines for AKI
administered as an initial dosage of 100– have recommended RCA as the preferred antico-
250 μg/kg followed by a maintenance infusion agulation modality for CRRT in patients without
of 0.5–2.0 μg/kg/min, which could be stopped contraindications for citrate. However, for
at 20–30 min before the end of HD. The dose of patients with liver insufficiency, citric acid should
argatroban should be adjusted according to the be used with caution [19].
plasma APTT.
17.8.5 Heparin-Free HD
17.8.4 Regional Citrate
Anticoagulation Heparin-free HD was developed for use in patients
at high risk of bleeding or with bleeding complica-
Hemorrhagic events have been reported in more tions. In heparin-free dialysis, preflushing the
than 30% of critically ill patients with AKI blood line with heparin saline and flushing the dia-
receiving renal replacement. Regional citrate lyzer with physiological saline every 15–30 min
anticoagulation (RCA) has been shown to pro- may help prevent clotting. Both the blood lines and
long the circuit life and reduce the incidence of the dialyzer need to be pretreated in heparin-free
hemorrhagic complications (Fig. 17.6). Citrate is HD; the cumulative volume of saline administered
infused into the proximal portion of the dialysis should be removed from the body during dialysis.
circuit, which combined with the circulatory ion- Nursing plays a vital role in heparin-free HD, with
ized calcium prevents thrombin activation to carefully monitoring of arterial and venous pres-
achieve full blood anticoagulation. At the same sure alarms to detect early clotting. With the devel-
Calcium-free dialysate and/or calcium-free or

Citrate
calcium-containing post-dilution replacement
solution
fluid
Citrate flow-rate(ml/h) according
to Qb, citrate soultion
concentration and citrate dose CVVHD
Post-filter sampling for or
Sampling for Citrate chelates ionized circuit ionized calcium, CVVHDF
systemic ionized calcium, reducing its to modulate cirtrate
calcium concentration below the flow rate CaCl2 or
intended target Ca-gluconate
(to replace calcium losses)
Arterial CITRATE DOSE Venous
Line 3 mmol/I line
Blood flow (Qb) 100-200ml/min Metabolic citrate load

CVVHD derived from citrate
or anions and calcium-
Citrate anions and calcium-citrate CVVHDF citrate complexes
complexes are partially lost in the effluent returning to the patient
effluent fluid
(40-60%, depending from CRRT dose)
RCA targets:
Systemic ionized calcium 1.1-1.25mmol/L
Post-filter circuit ionized calcium<0.3-
0.5mmol/L
Fig. 17.6 Basic principles of regional citrate anticoagu- ous venovenous hemodialysis, CVVHDF continuous
lation in continuous renal replacement therapy. CRRT venovenous hemodiafiltration, RCA regional citrate
continuous renal replacement therapy, CVVHD continu- anticoagulation
17 Hemodialysis 229
opment of RCA application for patients at high risk (NCDS), HEMO study, and Membrane
of bleeding, the clinical application of heparin-free Permeability Outcome (MPO) study. The first
dialysis is gradually decreasing. two studies evaluated the effect of increased
clearance of both water-soluble toxins and mid-
dle molecules such as β2-microglobulin. The
17.9 Adequacy of Dialysis Dose results from NCDS demonstrated that small sol-
ute clearance was an important clinical predictor
Dialysis adequacy mainly relies on the solute of HD patients. On the basis of NCDS, the urea
mass balance achieved during HD, with the kinetics as the measure of HD dose was estab-
objective of restoring the homeostasis of the lished. The MPO study showed that HD patients
patient and without sodium and water overload. appeared to gain no major benefit from a dialysis
Efficacy of dialysis refers to the delivery of treat- dose higher than that recommended by the cur-
ment which is sufficient to achieve an optimal rent guidelines. There was no other benefit from
long-term outcome. An adequately treated HD the application of high-flux membrane either. In
patient with a good quality of life is usually phys- the MPO study, it was demonstrated that the use
ically active, euvolemic, well nourished, and of high-flux membranes displayed a significant
normotensive. survival benefit among patients with hypoalbu-
Different types of uremic toxins could be used minemia [20–22].
to understand the relationship between HD pre-
scribed parameters and uremic toxin clearance.
The dose of uremic toxin clearance could be 17.9.2 Assessment of Dialysis Dose
divided into three types: (1) dose of water-soluble with Water-Soluble Toxin
toxin clearance, (2) dose of middle molecule Clearance
clearance, and (3) dose of protein-bound toxin
clearance. The dose of water-soluble toxin clear- The clearance of water-soluble toxin by HD is
ance has been identified with urea, and Kt/Vurea is primarily limited by the blood flow rate to the
the commonly used dose parameter. dialyzer, the dialysate flow rate, and the surface
β2-Microglobulin is the widely used marker sol- area of the HD membrane. In clinical practice,
ute for middle molecules, and the dose of middle dialysis dose is often expressed as Kt/V or urea
molecule clearance is related to the membrane reduction ratio (URR).
pore size. Serum urea and β2-microglobulin
could be detected routinely in clinical conditions. 17.9.2.1 Kt/V
Due to the complexity of detection methods, the Kt/V is a tool widely used to assess the delivery
clearance of protein-bound toxins is difficult to of dialysis dose. In clinical practice, Kt/V is used
be applied. P-cresol or p-cresol sulfate might be almost for urea, where K is the dialyzer urea
the most common marker used to categorize clearance (liters per hour), t is the dialysis session
protein-bound toxin clearance. Because the rela- time (hours), and V is the urea volume d istribution
tionship between long-term outcome and protein- (liters). A delivered Kt/V of 1.0 demonstrates that
bound solute clearance has not been clarified the volume of plasma cleared of urea (K × t) dur-
definitely, this specific class of toxins will not be ing a dialysis session is equal to urea distribution
further discussed here. volume (V). In daily clinical practice, single-pool
Kt/V (spKt/V) is the most widely used parameter
to assess dialysis dose.
17.9.1 Randomized Controlled
spKt / V =
Clinical Trials on HD Adequacy
- ln ( R - 0.008 ´ t ) + ( 4 - 3.5 ´ R ) ´ UF / W
So far, there has been three randomized con- where “ln” is the natural logarithm, “R” is the
trolled clinical trials (RCTs) evaluating HD ade- post-dialysis/pre-dialysis circulatory urea ratio,
quacy, the National Cooperative Dialysis Study “t” is the HD session time (hours), “UF” is the
230 H. Ye et al.
ultrafiltration volume (liters), and “W” is the target dose be 1.2. These two recommendations
patient’s post-dialysis body weight (kilograms). are similar because a target eKt/V of 1.2 is
approximately equal to a target spKt/V of 1.4.
17.9.2.2 Urea Reduction Ratio Once URR is used, average URR of 65% might
Urea reduction ratio (URR) refers to the dialysis- be equivalent to a Kt/V of 1.2. The delivered
related reduction in circulatory urea concentra- dose of HD should be monitored at least once
tion and is computed simply: URR = 1 − (Ct/C0), per month in all HD patients.
where C0 is the concentration of pre-dialysis
serum urea and Ct is the concentration of post-
dialysis serum urea. URR is a simple but an
imprecise method of quantifying dialysis dose Key Messages
because it does not consider the urea generation • Aside from renal transplantation and
during the dialysis and convective urea removal peritoneal dialysis, HD is the most pop-
by UF. Even so, URR has been the widely ular RRT for patients with end-stage
accepted method to the evaluation of dialysis renal disease. Diffusion and convection
adequacy. It has been shown that URR is corre- are its main principles. The main com-
lated well with the dialysis outcome. A minimum ponents of the dialysis system include
URR of 65–70% has been recommended for ade- the extracorporeal blood circuit, dia-
quate HD. lyzer, dialysis machine, and water puri-
fication system.
17.9.2.3 Evaluation Criteria • Acute complications of HD include
for the Adequacy of Dialysis neurological complications, allergic
Dose reactions, cardiovascular complications,
• Good well-being hematological complications, and HD
• Fewer complications of HD technique-associated complications;
• Better control of BP and extracellular fluid HD-associated infections and hyperten-
volume sion are the main chronic complications
• Electrolyte and acid–base balance maintained of HD.
in the normal range • AVF is by far the best vascular access
• Adequate nutritional status method for HD, having the “longest life
• More effective removal of solute with least complications” and a “longer
intervention-free life” than any other
vascular access method.
17.9.3 Recommendations • Anticoagulation is required during HD
for the Adequacy of Dialysis to prevent clotting in the extracorporeal
Dose circuits. Several anticoagulants have
been described, including systemic anti-
Many expert groups have proposed clinical coagulation, regional citrate anticoagu-
practice guidelines based on the three above- lation, and anticoagulation-free dialysis.
mentioned RCT studies. For example, the 2012 • Adequacy of dialysis dose refers to the
KDOQI clinical practice guidelines recom- dialysis dose considered sufficient to
mend that the dialysis dose should be moni- promote an optimal long-term outcome.
tored using spKt/V and the minimum dose be The 2012 KDOQI clinical practice
1.2 with a target dose of 1.4 was suggested. guidelines recommend that the dialysis
However, the European Renal Best Practice dose should be monitored using spKt/V
guidelines recommend that the dialysis dose and suggest with a target dose of 1.4.
might be monitored using eKt/V and that the
17 Hemodialysis 231
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end stage kidney disease: a systematic review. Lancet.
2015;385(9981):1975–82.
1. Brenner & Rector’s the kidney. Chapter 65. 9th ed.
15.
Kidney Disease: Improving Global Outcomes
2012.
(KDIGO) CKD Work Group. KDIGO 2012 clinical
2. Himmelfarb J. Chronic kidney disease, dialysis, and
practice guideline for the evaluation and management
transplantation. Chapter 20. 3rd ed. 2010.
of chronic kidney disease. Kindey Int. 2013; 3(Suppl):
3. Ahmad S. Manual of clinical dialysis. Chapter 1 and
1–150.
2. 2nd ed. 2009.
16. National Kidney Foundation. KDOQI clinical prac-
4. Larry Jameson J. Harrison’s nephrology and acid-
tice guidelines and clinical practice recommenda-
base disorders. Chapter 12. 2nd ed. 2013.
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5. Kallenbach JZ. Review of HD for nurses and dialysis
dialysis adequacy 2006, and vascular access. Am J
personnel. Chapter 18. 9th ed. 2015.
Kidney Dis. 2006;48(Suppl 1):S1–322.
6. Golper TA, et al. HD: core curriculum 2014. Am J
17. Woo K, Lok CE. New insights into dialysis vascu-
Kidney Dis. 2014;63:153–63.
lar access: what is the optimal vascular access type
7. Arieff AI. Dialysis disequilibrium syndrome: current
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concepts on pathogens is and prevention. Kidney Int.
patients? Clin J Am Soc Nephrol. 2016;11:1487–94.
1994;45:629–35.
18. Lazrak HH, René É, Elftouh N, Leblanc M, Lafrance
8. So Metz F, Mir S, Tutuncuoglu S. Potential pro-
JP. Safety of low-molecular-weight heparin com-
phylactic use of benzodiazepines for hemodialysis-
pared to unfractionated heparin in hemodialysis: a
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systematic review and meta-analysis. BMC Nephrol.
9. Canzanello VJ, Burkart JM. Hemodialysis-associated
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muscle cramps. Semin Dial. 1992;5:299–304.
19. Santo M, Valentina P, Luigi T, Enrico F. Regional
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citrate anticoagulation for RRTs in critically ill patients
et al. Comparison of 50% dextrose water, 25%
with AKI. Clin J Am Soc Nephrol. 2014;9:2173–88.
mannitol, and 23.5% saline for the treatment of
20. Lowrie EG, Laird NM, Parker TF, Sargent JA. Effect
hemodialysis-associated muscle cramps. ASAIO
of the HD prescription on patient morbidity. N Engl J
Trans. 1991;37:649–52.
Med. 1981;305:1176–81.
11.
Cruz DN, Mahnensmith RL, Perazella
21. Eknoyan G, Beck GJ, Cheung AK, et al. Effect of
MA. Intradialytic hypotension: is midodrine ben-
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22. Locatelli F, Martin-Malo A, Hannedouche T, Loureiro
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A, Papadimitriou M, Wizemann V, Jacobson SH,
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Dis. 2001;38(Suppl 4):S26–36.
Peritoneal Dialysis
18
Jia Di
Abstract function than HD. Most studies indicate the sur-

Peritoneal dialysis (PD) is an effective, conve- vival advantage of PD for individuals without
nient, and economical modality for patients diabetes and younger individuals with diabetes
with renal failure, and its characteristic is that who have no other coexisting medical conditions
the treatment of PD can be done at home. PD [1]. Therefore, PD is the first choice of stage 5
utilizes the peritoneum as a biological dialysis chronic kidney disease (CKD) for individuals
membrane to remove metabolites from the with residual renal function, children aged 2 years
body to the peritoneal cavity and to correct the or older, and adults without serious complica-
abnormality of the fluid and electrolyte by dif- tions. On the contrary, the worse overall health of
fusion and ultrafiltration simultaneously. The the patient is, the lesser survival advantage with
main components of PD system include peri- PD becomes. The health-associated quality
toneal and abdominal cavity, dialysate, perito- of life provided by PD to patients is similar to
neal catheter, and connecting devices. In this that provided by HD; however, PD patients are
chapter, we mainly introduce the principles of more satisfied with their care but are more likely
PD, indications and contraindications for PD, to switch to HD because of technique failure.
PD modalities, evaluation methods of PD, and
its applications and complications.
18.2 Peritoneal Barrier
The mechanism of PD is to remove uremic toxins

18.1 Introduction and excess fluid by using a system of biological
membranes and the dialysis fluid infused into the
For patients with acute and chronic renal failure, peritoneal cavity. Peritoneal cavity is the largest
peritoneal dialysis (PD) is one of the main moda- serosal cavity in the human body, the surface area
lites of renal replacement therapy. Overall, there of which is about 1–2 m2 [5].
exists no evidence on significant differences in There are five different resistance barriers that
critical outcomes between PD and hemodialysis are contained in the peritoneum:
(HD), although it is widely accepted that PD
could more effectively preserve the residual renal 1 . The interstitial space
2. The unstirred fluid layers in the peritoneal
cavity
J. Di (*) 3. The capillary wall (endothelium and base-

Division of Nephrology, Third Affiliated Hospital,
Soochow University, Changzhou, Jiangsu, China ment membrane)

234 J. Di
Diffusion Ultrafiltration
uremic toxins uremic toxins
solutes
water
blood peritoneum dialysis fluid

blood peritoneum dialysis fluid
Fig. 18.1 Diffusion is driven by the concentration gradi-
Fig. 18.2 Ultrafiltration driven by the osmotic agent over
ent over the membrane
the membrane
Table 18.1 Compositions of commonly used glucose lactate dialysate

Glucose Osmotic pressure Ion concentration
(C6H12O6·H2O) (g) (mOsmol/L) pH Na Ca Mg Chloride Lactate
1.5% glucose 1.5 346 5.2 132 1.75/1.25 0.25 95–106 35–40
lactate dialysate (4.5–6.5)
2.5% glucose 2.5 396
lactate dialysate
4.25% glucose 4.25 485
lactate dialysate
4 . The unstirred fluid layer in the capillaries Furthermore, accompanied by convective fluid
5.
The mesothelium and its basement absorption, the solute is transported into the sur-
membrane rounding tissues from the peritoneal cavity and
to the blood via the lymphatic vessels.
The major transport barrier for transperitoneal Lactate dialysates with different concentra-
exchange is recognized as the capillary wall. The tions of glucose, thereby with different osmotic
interstitium of the capillary wall is particularly pressure, are used in clinical practice.
important in long-term PD patients whose Composition of commonly used glucose lactate
submesothelial tissues are markedly of increased dialysates is shown in Table 18.1.
thickness. On the contrary, the mesothelium is
not an important transport barrier because of its
highly permeable character [5]. 18.3 Catheter Design
In the process of PD, diffusion is the main way and Insertion Techniques
for solutes to be bidirectionally transported
through the peritoneal barrier. The concentration Several different types of catheters and catheter
gradient over the membrane can drive diffusive insertion techniques are used in PD. The advan-
transport through membrane (Fig. 18.1). To a tages and disadvantages of different techniques
lesser extent, solutes are transported into the peri- for catheter insertion are summarized in Table 18.2.
toneal cavity by convection because of osmotic Flexible catheters—As the gold standard for
disequilibrium resulted from osmotic agent and PD access, Tenckhoff catheter is the most widely
hydrostatic pressure differences (Fig. 18.2). used in patients with chronic dialysis.
18 Peritoneal Dialysis 235
Table 18.2 Advantages and disadvantages of different catheter insertion techniques

Advantages Disadvantages
Percutaneous • Can be performed at bedside, allowing rapid • Risk of bowel or bladder injury
(bedside) initiation of dialysis
• Physician or nurse can be trained to perform • Not suitable for patients with previous
the procedure midline surgical scars or risk of adhesions
Open • Available in most centers • Requires surgical scheduling, with available
surgical operating theater time at a premium
• Lower cost of consumables than that with
laparoscopy
Laparoscopic • Lower incidence of leakage • Requires skilled personnel
• Ability to perform adjunctive procedures • High cost of consumables
• Ability to place the catheter in the pelvis
under vision
Rigid catheters—By using a trocar device, the Table 18.3 Contraindications for peritoneal dialysis
catheter can be inserted directly to the iliac fos- Absolute Relative
sae. Dialysis using these catheters is less efficient • Loss of peritoneal • Recent abdominal
although they are easy to be inserted. Also, this function aortic graft
catheter design tends to generate some complica- • Producing inadequate • Ventriculoperitoneal
clearance shunt
tions, such as bladder or bowel perforation,
• Adhesions blocking the • Intolerance to
bleeding, leakage of dialysate, and obstruction dialysate flow intra-abdominal
owing to the small side holes and lumen [4]. fluid loading
• Surgically uncorrectable • Large muscle mass
abdominal hernia
18.4 Indications • Abdominal wall stoma • Morbid obesity
• Diaphragmatic fluid • Severe malnutrition
and Contraindications for PD leakage
• Inability to perform • Skin infection
18.4.1 Indications exchanges in the absence • Bowel disease
of suitable assistant
PD is recommended as the first-line treatment
modality of renal replacement theraphy for the
following patients with CKD stage 5: (1) chil- 1. Continuous ambulatory peritoneal dialysis

dren aged ≥2 years, (2) individuals with residual (CAPD)—Patients undergo PD throughout
renal function, and (3) adults with no signifi- the day.
cant related comorbidities. 2.
Continuous cycling peritoneal dialysis
(CCPD)—Patients undergo PD throughout
the day, which is assisted by automated
18.4.2 Contraindications machines overnight.
3.
Intermittent peritoneal dialysis (IPD)—
Contraindications for PD are summarized in Patients undergo intermittent PD.
Table 18.3. 4.
Automated peritoneal dialysis (APD)—
Patients undergo PD assisted by automated
machines.
18.5 PD Modalities
Since the invention of Tenckhoff catheter in
Several major PD modalities exist, which include 1968 and appearance of wearable/portable equi-
the following: librium dialysis technique in 1976, CAPD has
236 J. Di
been used as a feasible modality of renal replace- 18.6 Assessment

ment therapy in the long-term treatment of
patients with end-stage renal disease (ESRD). 18.6.1 Peritoneal Equilibration Test
Twin bags are used in CAPD patients to reduce (PET)
the number of connections and disconnections
required to be established everyday [5]. The most commonly used method for evaluating
CCPD is suitable for patients requiring help the transport characteristic of peritoneal mem-
(such as children, blind individuals, and the brane is PET. As a simple clinical method, PET is
elderly) or daytime workers. Patients can carry widely used to assess the rapidity of urea, creati-
out their own activities and work with the perito- nine, and other solutes diffusion across the perito-
neal dialysate in the abdominal cavity throughout neal membrane. It has become a routine method
the day and have good sleep assisted by auto- for the evaluation of clinically important altera-
mated machines overnight. tions in peritoneal transport characteristics. In this
IPD is applied to acute or chronic renal failure test, the dialysate to plasma solute concentration
for the initial 3–10 days of CAPD. IPD removes (D/P) ratio for particular solutes is measured dur-
more water, is associated with fewer complica- ing an exchange with conventional PD fluid [5].
tions of peritonitis, and can discharge more The standard procedure for PET is listed
nitrogen. below [8]:
The advantage of APD is that it needs less
intensive nursing care, but the disadvantage is that 1. After total drainage of the prior dwell (if

it increases the financial burden. During APD, a CAPD, typically 8 h), perform this test in the
variety of highly efficient treatment arrangements morning.
can be provided by the use of high flows of 2. Use dextrose dialysate (2.5%) to instill the
dialysate, individualized intraperitoneal fluid vol- usual fill volume.
umes, and short residence times. 3. After infusion, immediately (0 h) and at 2 and
Overall, there exists no evidence on signifi- 4 h, collect dialysate sample to determine the
cant differences in critical outcomes among concentrations of glucose, creatinine, and
modalities, such as quality of life, mortality, urea.
adverse events, nutritional status, and technique 4. After dialysate infusion, collect blood sample
survival for patients treated with CAPD and at 2 h to determine the concentrations of glu-
APD. Therefore, adults and children can opt for cose, creatinine, and urea.
CAPD, CCPD, or APD. However, APD has been 5. Record the drainage volume when the dialy-
recommended as the preferred option for infants sate is drained at 4 h. Calculate the D/P ratios
and children on a liquid diet based on clinical for urea and creatinine at 2 and 4 h.
experience. The National Kidney Foundation– 6. Calculate and compare the dialysate glucose
Dialysis Outcomes Quality Initiative (NKF– concentrations at 2 and 4 h to the beginning
DOQI) guidelines recommended Kt/V target of concentration (D/D0).
2.0 for CAPD and 2.1 for CCPD every week in 7. Draw these on standard PET graphs to deter-
1997. Because higher daily dialysis solution vol- mine the peritoneal membrane type.
umes can be easier and more convenient deliv-
ered by using automated machines, cycler This protocol is usually simplified in clinical
utilization is increased in order to achieve these practice. Dialysate samples are collected immedi-
high targets. Nevertheless, in recent NKF–DOQI ately after infusion, and then collected 2 and 4 h
guidelines, the Kt/V targets for CAPD have been later. The dialysate is drained and the volume is
mildly reduced to 1.7. The use of APD has sig- recorded after 4 h. At 2 h dwell time a blood sample
nificantly increased since its reintroduction, is drawn. The drainage volume of dialysate which is
probably because its use promotes positive used as a measure for evaluating ultrafiltration
changes in the lifestyle of dialysis patients [2]. capacity, the D/D0 ratio for glucose and the D/P ratio
for creatinine, are usually compared to standard val- The NKF–DOQI guidelines recommended a
ues. The D/D0 for glucose and D/P for creatinine weekly Kt/V target above at least 1.7. Increasing
from the PET will be closely correlated with the dif- the dialysis dose by increasing the number of
fusive mass transport coefficient for these solutes. exchanges is a common technique to increase
This test can categorize patients into four dif- Kt/V.
ferent transport groups according to Twardowski’s
initial classification: high transporters, high aver-
age transporters, low average transporters, and 18.6.3 Residual Renal Function
low transporters. Because of faster glucose
absorption, high transporters and high average Residual renal function refers to the clearance
transporters have poorer net ultrafiltration, but and endocrine function of renal tissues after
they have more rapid creatinine equilibration. On injury and is an important parameter that most
the other hand, low transporters and low average likely changes with time in PD patients. As resid-
transporters have lower solute transport, leading ual creatinine clearance could be overestimated
to slower glucose absorption and higher net ultra- by the secretion of creatinine when the renal
filtration but lower peritoneal clearances for function is low, it is recommended to express this
larger solutes and creatinine. as the mean of urea and creatinine clearances.
This test provides evidence for further refining The residual creatinine clearance rate is signifi-
the dialysis prescription. Low transporters can cantly higher in PD patients with residual renal
maintain volume control on a standard CAPD function than in those without. The residual renal
prescription even when the residual renal func- function is directly related to the survival rate and
tion has lost. High transporters require short, fre- prognosis of PD patients. Preserving the residual
quent exchanges to acquire adequate renal function can effectively improve the quality
ultrafiltration. Clinical management and out- of life of dialysis patients. However, as the dura-
comes of PD patients are significantly affected by tion of PD increases, the residual renal function
their peritoneal transport characteristics. gradually decreases.
Similarly, optimal dialysis prescriptions in regard
to ultrafiltration and small solute clearances are
greatly affected by the peritoneal small solute 18.7 P
D for Acute Kidney Injury
transport characteristics of patients. In addition, (AKI)
an important risk factor for both PD technique
failure and mortality is thought to be a high peri- In the 1920s, PD was first used in the treatment of
toneal transport rate. AKI patients. At present, PD is still a treatment
modality often used for AKI in developing world.
There are many superiorities for PD to treat patients
18.6.2 Kt/Vurea Measurement with AKI. Several studies have suggested that out-
comes with PD can be comparable to that with
Kt/Vurea measurement (urea clearance over time) extracorporeal renal replacement therapy [2].
is often used to assess the dose and/or efficacy of
PD, where, K = volume of dialysate drained mul-
tiplied by dialysate/plasma urea concentration, 18.7.1 Advantages
t = dialysis duration, V = urea distribution volume
(total body water calculated as 0.5 [for females] PD has minimal equipment requirements and is of
or 0.6 [for males] multiplied by body weight), lower cost and technically simple. PD is a better
and Kt/Vurea is the main indicator used to evaluate modality especially for patients at risk of bleed-
the adequacy of PD and nutritional status of PD ing, with difficult vascular access or increased
patients. Kt/Vurea and total creatinine clearance intracranial pressure. PD has been thought to be
must be determined in clinically stable patients. less inflammatory and more physiological than
238 J. Di
extracorporeal therapies. There is a considerable mal treatment doses for adults should be a com-
interest that toxic cytokines in sepsis can be bined urinary and peritoneal Kt/Vurea of 1.7/week
removed by using high cut-off membranes for or a creatinine clearance of 50 L/week/1.73 m2. If
hemofiltration. PD may provide a great advantage patients are experiencing uremic symptom, the
over conventional HD and filtration because of dialysis dose should be increased. A continuous
the large pores in the peritoneal membrane allow- 24-h PD regimen is preferred over an intermittent
ing the clearance of these molecules [2]. regimen for patients with anuria [3].
The success of a PD program depends on spe-
cialized nurses. They have appropriate skills in
18.7.2 Disadvantages assessing and training patients for PD and in
monitoring treatment. They also have sufficient
Nevertheless, there are still critical concerns resources to provide continued care in the com-
about PD for AKI, including primarily risk of munity. In 2012 the National Renal Workforce
peritonitis, possible inadequate solute clearances, Planning Group suggested a caseload of up to 20
and potentially unpredictable fluid removal rates. PD patients for every nurse. The requirement for
Furthermore, hyperglycemia from glucose- specialized nurses with skills to deal with com-
containing dialysate, glucose absorption, and plex patient educational issues has been high-
excessive protein loss through the peritoneal lighted in the 2016 International Society for
membrane are other potential PD-specific Peritoneal Dialysis (ISPD) guidelines on teach-
problems. Additionally, reduced functional residual ing PD to patients and caregivers. In order to pro-
capacity coming from impaired diaphragmatic mote PD as a therapeutic option and develop
movement is also a problem, particularly among clinical management policies, a designated lead
mechanically ventilated patients [2]. clinician for PD in each unit is needed[1].
18.8 PD for ESRD 18.9 Complications of PD
PD has long been established as an alternative A number of potential complications are associ-
method for renal replacement therapy in ated with the use of PD. The following are briefly
patients with ESRD. The percentage of PD discussed:
ranges from 0 to 30% in adults with changes
in local practice and resources and reaches >50% • PD-related infections
in children. PD is the preferred initial modality of • Encapsulating peritoneal sclerosis (EPS)
renal replacement therapy for patients with • Mechanical or catheter-related problems
ESRD and is particularly the best option for
infants and small children with ESRD. The 2011
National Institute for Health and Care Excellence 18.9.1 PD-Related Infections
(NICE) clinical guideline suggested PD to be the
primal choice for dialysis treatment of CKD 18.9.1.1 Category
stage 5 in children ≥2 years, adults without sig- PD-related infections include PD-related perito-
nificant associated comorbidities, and individuals nitis and PD catheter infection.
with residual renal function [3].
Peritoneal membrane function should be regu- • PD-related peritonitis
larly monitored at least every 6 months using • PD-related peritonitis is diagnosed by
PET or its equivalent. If clinically or biochemi- the presence of fever, abdominal pain,
cally indicated or to achieve clearance targets, it cloudy dialysate, and a leukocyte count
could be more frequently measured in adults and >100 cells/μL (or polymorphonuclear
children. The NICE recommends that the mini- cells >50%) after a 2-h dwell time. The
eritoneal fluid culture suggests the

p should cover Gram-negative and Gram-positive
species of organisms [3]. bacteria, including Pseudomonas species until
• PD catheter infection getting the results of culture and antibiotic sen-
• PD catheter infection includes exit-site and tun- sitivities are obtained. Although methicillin-
nel infections. Exit-site infection is defined as resistant Staphylococcus aureus require
the presence of pain, swelling, erythema, and systemic treatment, oral antibiotics are as effec-
serous discharge at the exit site. Tunnel infective as intraperitoneal injection [7].
tion is defined as the presence of pain, tender- • PD-related peritonitis
ness, erythema, induration, or any combination • The ISPD guidelines recommend the use of
of these signs and symptoms present over the first- and third-generation cephalosporins for
subcutaneous tunnel of the catheter [3]. empiric therapy. If patients have prior infec-
tions resistant to first-generation cephalospo-
18.9.1.2 Causes rins, vancomycin can be used with a
Touch contamination, catheter-related problems, third-generation cephalosporin. Intraperitoneal
bowel pathology, gynecological disease, or sys- administration is recommended, and intrave-
temic bacteremia. nous administration should be considered for
hospitalized and acutely ill patients. The treat-
18.9.1.3 Results ment course should be lasted for 2 weeks.
Complications resulting from PD-related perito- However, peritonitis caused by S. aureus,
nitis and catheter infections include hospitaliza- Enterococcus sp., Pseudomonas/Stenotrophom
tion, switching to HD (either permanently or onas sp., or multiple organisms needs 3 weeks
temporarily), catheter loss, and death. Peritonitis of treatment. If no organisms are detected,
is probably the most important cause of tech- Gram-negative coverage can be stopped at 96 h
nique failure in PD patients. if the patient is clinically better, and Gram-
positive coverage can be lasted for 2 weeks. In
18.9.1.4 Prevention Strategies the case of relapsing peritonitis (recurrence of
Preventing exit-site infections is appropriate to peritonitis because of the same organism within
reduce the rate of peritonitis. The NICE recom- 4 weeks of therapy completion), it is recom-
mended in 2017 that patients undergo regular mended to remove catheter [7].
revision of their technique. Antibiotic prophy-
laxis should be administered during initial cathe- Fungal peritonitis occurs in patients undergo-
ter insertion, and mupirocin and gentamicin ing PD at a rate of 0.01–0.19 episodes for each
should be used to reduce the frequency of exit- dialysis-year. Frequent episodes of bacterial peri-
site infection and peritonitis [3]. tonitis, recent antibiotic therapy, and immuno-
suppression are main risk factors for fungal
18.9.1.5 Treatment peritonitis. Patients are usually seriously ill with
• PD catheter infection significant abdominal tenderness. Once fungi are
• Exit and tunnel infections can lead to peritonitis identified, it is recommended to remove catheter
and must therefore be treated aggressively. The immediately.
treatment course is at least 2 weeks or until the
exit site appears normal. The ISPD guidelines
emphasize that in case of refractory PD-related 18.9.2 EPS
peritonitis, PD catheter should be timely
removed. Furthermore, when a Pseudomonas 18.9.2.1 Diagnosis
infection or associated tunnel infection is pres- EPS is defined as a potential and rare complica-
ent, PD catheter removal or swap is required in tion of long-term PD, always occurring in patients
refractory exit-site infections and may be on PD for more than 5 years. It is diagnosed by a
required earlier. Initial treatment regimens combination of bowel obstruction and features of
240 J. Di
encapsulation due to peritoneal fibrosis. The

common symptoms of EPS are anorexia, nausea, Key Messages
vomiting, and weight loss. Additionally, it is • PD is a major dialysis modality recom-
important to recognize the stepwise process of mended as the initial renal replacement
symptom progression. therapy for CKD stage 5 in individuals
with residual renal function, children
18.9.2.2 Management aged ≥2 years, and adults without sig-
Some strategies to reduce the risk of EPS include nificant associated comorbidities.
the following [6]: • Tenckhoff catheter is the gold standard
for PD access, and open surgical cathe-
1. Minimizing dialysate glucose exposure but
ter insertion is most widely used in PD
ensuring that the fluid volume status is not centers.
consequently compromised. • PD is a safe and effective method for
2. Using interventions recommended by the
blood purification and fluid removal in
ISPD guidelines for peritonitis to preventing AKI.
acute PD-related peritonitis. • Overall, there are no significant differ-
3. Using neutral-pH, low-glucose degradation
ences in critical outcomes between
product PD solutions (low-grade evidence only). CAPD and APD.
• The NICE recommends that the mini-
Early monitoring of nutritional status and dietetic mal treatment doses for adults should be
referral are essential for patients with EPS. Such a combined urinary and peritoneal
nutritional support is often provided by oral, Kt/Vurea of 1.7/week.
enteral, or parenteral supplementation. Using any • PD-related infections, EPS, and
medical therapy to treat EPS has not been recom- mechanical or catheter-related problems
mended in any clear evidence. Immunosuppressants, are major complications associated with
corticosteroids, and tamoxifen have been used to PD.
treat EPS at the physician’s discretion. Decisions
about the duration of therapy should be tailored to
the individual patient. Clinical and social factors
as well as the patient’s wishes and the principles References
outlined in the ISPD guidelines should be fol-
lowed [6]. 1. Clinical Practice Guideline Peritoneal Dialysis in
Adults and Children. Renal association clinical prac-
tice guideline. BMC Nephrol. 2017;18(333):1–23.
2. Peritoneal dialysis for acute kidney injury. ISPD
18.9.3 Mechanical or Catheter- guidelines/recommendations. Perit Dial Int. 2014;
Related Problems 34(5):494–517.
3. ISPD position statement on reducing the risks of
peritoneal dialysis–related infections. Perit Dial Int.
Catheter obstruction may come from displace- 2011;31(6):614–30.
ment and omental wrapping of the catheter or 4. Kidney disease: peritoneal dialysis in the treatment of
fibrin blockage of the catheter. In the latter situa- stage 5 chronic kidney disease. NICE clinical guide-
tion, flushing the catheter with sterile saline may line 125. 2011. http://www.nice.org.uk/guidance/
CG125.
dislodge the blockage. Once the flow is reestab- 5. Chronic kidney disease, dialysis, and transplantation;
lished, 500–1000 units of heparin need to be 2011, ISBN: 978-1-4377-0987-2.
added to each liter of PD fluid. 6. Length of time on peritoneal dialysis and encapsulat-
Methods for manipulating displaced PD cath- ing peritoneal sclerosis—position paper for ISPD:
2017 update. Perit Dial Int. 2017;37(4):362–74.
eters could include guidewire (blind or fluoro- 7. Hansson JH, Watnick S. Update on peritoneal
scopic) manipulation and laxative use. The dialysis: core curriculum 2016. Am J Kidney Dis.
catheter should be replaced if these methods fail. 2016;67(1):151–64.
Transplantation
19
Hao Ding and Junwei Yang
Abstract patients have improved over the years, this

Renal transplantation is the best modality of population continues to show significant mor-
renal replacement therapy available for most bidity and mortality due to infection.
patients with end-stage renal disease and is Transplantation team should attempt to
one of the breakthroughs in medical science in achieve a balance between preventing allograft
recent decades. Our knowledge of HLA typ- rejection and maintaining immune system
ing, cross-match testing, recipient prepara- integrity.
tion, donor management, and postoperative
care have advanced and brought widespread
benefits, and these are crucial for clinicians to
formulate an appropriate treatment regimen. 19.1 Introduction
Great effects should be paid to selection and
preparation of kidney transplant recipients End-stage renal disease (ESRD) represents a
because of the risks from immunosuppressive growing global public health epidemic, and the
therapy. Reducing acute rejection episodes prevalence of ESRD may rise sharply over the
and minimizing ischemic damage is the main next few decades. Renal replacement therapy is
goal of immunosuppressive therapy. The gen- available as three different modalities, i.e., hemo-
eral concepts that most clinicians agree useful dialysis, peritoneal dialysis, and a kidney trans-
include induction therapy and maintenance plant. Renal transplantation is one of the
treatment. Delayed graft function after kidney pioneering advances in medicine. It not only
transplantation is usually defined as the need improves quality of life of patients with ESRD
for dialysis during the first postoperative but also has been proven to prolong life [1]. Renal
week, anuria, or failure of prompt azotemia transplantation is a relatively young field of med-
resolution, and most studies suggest that icine, with the successful induction of immuno-
patients with DGF have worse long-term out- logical tolerance in rats by Peter Medawar and
comes than patients with immediate function. his colleagues at University College London in
Although the outcomes of renal transplant 1953 and the first successful kidney transplanta-
tion by Joseph Murray and his colleagues at
Harvard in 1954.
H. Ding (*) · J. Yang (*) Our knowledge of HLA typing and cross-
Centre for Kidney Disease, Second Affiliated match testing, immunosuppression, recipient
Hospital, Nanjing Medical University, preparation, donor management, and postopera-
e-mail: dinghao@njmu.edu.cn; jwyang@njmu.edu.cn tive care has advanced and brought widespread

242 H. Ding and J. Yang
benefits. The acute immune response to the patibility methods and their interpretation param-
transplanted tissue can now be controlled such eters is crucial for clinicians to formulate
that short-term graft survival has improved appropriate treatment interventions.
impressively. Nonetheless, this progress has not
been accompanied with the improvement of
long-term graft survival, and antibody-mediated 19.2.1 ABO Incompatibility
rejection (AMR) has adverse long-term effects
on the graft. Managing transplant recipients is The ABO blood group antigen system is the most
challenging even for the most experienced trans- important immune barrier for successful trans-
plant physicians, who need to understand not plantation. At the time of transplantation, ABO-
only the relevant basic research but also clinical incompatible kidneys can be rejected
transplant medicine. immediately. Nevertheless, in some cases, a
With the invention of novel immunosuppres- transplant with a different ABO blood type is
sive drugs, kidney transplantation has made great possible. Several research groups have already
progress in recent years. Unfortunately, the short- developed protocols for transplanting kidneys
age of donated organs remains a major limiting across major ABO barriers. These programs are
factor, and the issues associated with organ dona- based on various techniques and drugs to reduce
tion, retrieval, and preservation are still challeng- the amounts of anti-A or anti-B antibodies. These
ing. Furthermore, the immune system poses antibody reduction methods help to expand the
many problems that have yet to be resolved, and number of patients who may receive a kidney
donor-specific tolerance, which is the ultimate from a living donor [2].
goal of transplantation, has still a long way to go.
Clinical xenotransplantation—a procedure hold-
ing promise to solve the shortage of human donor 19.2.2 HLA Typing
organs—and engineered allografts are unlikely to
be realized in the near future. HLA typing quantifies the number of HLA anti-
gen mismatches between donor and recipient,
and it is one of the most important risk assess-
19.2 Histocompatibility Testing ment tools for predicting non-self-HLA recogni-
tion. Serological tests have been performed in
The recipient’s lymphocytes recognize the cell small plastic trays with a grid of small flat-
surface proteins of the transplanted tissue that are bottomed wells containing antibodies. If lympho-
different from those of the recipient and trigger cytes from an individual have antigens on their
inflammatory events that cause allograft injury. surface that the antibodies can bind, then comple-
Once the patient is determined to be a suitable ment is activated and vital dyes are absorbed into
transplant candidate, HLA typing and antibody those cells on which the membrane attack com-
screening tests are performed by the methods plex forms. Serological typing can yield rapid
described in the following sections. results, which are important for deceased donor
The histocompatibility test should be consid- typing. Nonetheless, small amino acid differ-
ered a risk assessment before transplantation. ences in HLA proteins may have strong immuno-
Therefore, a complete risk assessment of any logical consequences and are not easily detectable
donor–recipient pair must take into account HLA by serological methods. In addition, the number
typing and possibly involve multiantibody detec- of HLA alleles increases annually, and it is diffi-
tion methods. In addition, antibody analysis is cult to find high-quality serum samples with suf-
increasingly being carried out posttransplant as a ficient antibody to identify.
noninvasive predictor of acute and chronic allo- It is now more common to type individuals by
immune complications. Understanding the DNA-based rather than serological methods.
complexity and interactivity of these histocom- Advantages of molecular typing include greater
19 Transplantation 243
accuracy and reproducibility of the reagents. patient’s serum, complement will be activated if
Aside from lymphocytes, typing can be per- the serum contains antibodies that bind to the cell
formed on tissues containing other nucleated surface at sufficient density, and the absorption of
cells. Today’s next-generation sequencing (NGS) vital dyes allows for easy identification of dead
has become an everyday research tool to address cells. For example, in a 50-cell group, the positive
HLA-typing tasks. NGS offers more powerful reaction to 30 cells represents 60% of PRA. The
higher-throughput sequencing, and the protocol CDC PRA assay has serious limitations. For
is getting simpler for clinical laboratories. The example, the percentage of PRA may vary accord-
ultimate goal of accurate high-resolution typing ing to the cell group employed in the screening. In
is to improve transplant outcomes. addition, substantial false-positive results and
false-negative results may be obtained. Finally, it
• Past: RFLP (restriction fragment length is almost impossible to compile an accurate and
polymorphism) complete antibody-specific list in this way.
• Present: SSOP (sequence-specific oligonucle- Due to the limitations of the CDC assay, there
otide probes), reverse SSOP, real-time PCR, is an urgent need for more sensitive analytical
NGS methods. Solid-phase analysis by means of
• Future: NGS affinity-purified HLA antigens is now available
for a variety of platforms. These methods involve
only soluble or recombinant HLA molecules that
19.2.3 HLA Antibody Screening are applied to solid-phase media platforms
(ELISA) or beads; therefore, the solid phase will
Sensitization to HLA antigens occurs during bind HLA antibodies only when recipient serum
pregnancy or in patients who had received blood is added. Neither viable lymphocytes nor com-
transfusion or a previous transplant. Patients with plement fixation is required, and target HLA
circulating anti-HLA antibodies are at a high risk specificity can be determined next by using a
of rejection. Therefore, sensitive and specific panel of HLA antigens from individual donors or
detection of anti-HLA antibodies is necessary for by means of a single HLA antigen. The outputs
the identification of the sensitized recipients. By of the solid-phase analysis can show substantial
considering all relevant antibodies and avoiding interlaboratory differences because there is con-
false-positive cross-matching of antibodies that siderable controversy as to what thresholds
are not clinically relevant, the anti-HLA antibody should be considered a cutoff for positive results.
screening process must ensure a true negative To determine whether the recipient has a donor
cross-match with the intended donor. Over the antibody, the solid-phase antibody screening data
past 40 years, various methods for detecting and should be analyzed in conjunction with cross-
characterizing anti-HLA antibodies have been matching results [3].
developed:
• NIH-CDC 19.2.4 Cross-Matching

• AMOS modified
• Antiglobulin-augmented AHG-CC The cross-match test is the final pretransplanta-
• ELISA tion immunological screening step. Cross-
• Flow cytometry matching determines whether the recipient has
• Luminex antibodies against donor. Just as cytotoxic PRA,
cytotoxic cross-matching may miss low-titer anti-
The complement-dependent lymphocyte tox- bodies, resulting in false negatives or detection of
icity (CDC) assay is the most popular method for false-positive antibodies. To address this issue,
anti-HLA antibody screening. B cells and T cells serum samples from patients with IgM autoanti-
which have variable HLA types incubated with bodies should be heated or treated with dithioth-
reitol to eliminate IgM prior to final cross-pairing. tors associated with good graft survival. The use
Flow-cytometric cross-match (FCXM) assays are of live kidney donors varies widely, and agree-
more sensitive to complement-binding antibodies ments to evaluate potential donors may vary
than standard complement-dependent cytotoxic- widely among medical centers. On the other hand,
ity assays. Nonetheless, the thresholds of positiv- many published expert recommendations can
ity may differ between laboratories. Therefore, serve as the basis for most living donor experi-
there is considerable interlaboratory variability in ments, including the United States guidelines and
the routine methods of FCXM. The status of the Amsterdam living kidney donor guidelines.
FCXM remains controversial, and its role in the
assessment of patients’ immune risk has not been
confirmed. Furthermore, these tests may not be 19.3.1 Informed Consent
available in all laboratories.
An important part of living kidney donation
involves informed consent. According to the con-
19.2.5 Non-HLA Antibodies sensus conference, living donors should be will-
ing to donate, be under no coercion, be suitable
In some cases, antibody-mediated results are his- according to medical and social psychology, and
topathologically or clinically suspicious while must fully understand the risks, benefits, and
circulating anti-HLA antibodies have not been alternative treatments available to the recipient.
detected. Those immunity-associated, non-HLA Donor advocates should ensure that potential
antibodies may contribute to these cases, and donors fully and undeniably understand the
detection of these non-HLA antibodies is still immediate and long-term team risks and benefits
being studied. of organ donation, so that donors can indepen-
dently decide whether to perform a donation
assessment.
19.3 Selection and Preparation
of the Living Kidney Donor
19.3.2 Risks to Donors
Renal transplant is the best treatment for patients
with ESRD; however, it cannot be performed Laparoscopic technique is associated with
without kidney donors. Both living and deceased decreased discomfort and postsurgical pain and
donors contribute critically to the success of the most transplant centers perform this technique.
transplantation endeavor on the individual, Two studies in the United States have estimated
national, and international levels. Nevertheless, perioperative mortality at ~0.02–0.03%. The most
the shortage of cadaveric kidney transplants has common causes of death are a pulmonary embolus
caused patients to wait for longer periods to reap and cardiac events. In addition, there has been
the benefits of transplantation. In comparison concern about the possibility that patients with a
with deceased donor transplantation, live donor single kidney may develop glomerular hyperfil-
transplantation has the following advantages: tration, hypertension, proteinuria, and renal insuf-
ficiency long-term. Living kidney donors are at a
• Better long-term outcomes small but significantly increased risk of ESRD as
• The procedure can be performed preemp- compared with nondonors [4].
tively, thereby helping to avoid dialysis
• This procedure is elective and allows for opti-
mization of the recipient 19.3.3 Evaluation of Living Kidney
• Low rates of delayed graft function (DGF) Donor
Even when corrected for ischemic times and Living-donor evaluation includes a complete
DGF, live donor source is one of the strongest fac- medical history taking, past medical history tak-
ing, physical examination, laboratory tests, sero- recipient outcomes after transplantation in con-
logical screening for infectious diseases, renal temporary cohorts [5].
scintigraphy, radiological imaging, and appropri-
ate cancer screening. Furthermore, people being
considered for the donation should be healthy or 19.4 Selection and Preparation
have only mild diseases that do not cause func- of the Recipient
tional limitations.
Kidney transplantation is the treatment of choice
for patients with ESRD, and there are few condi-
19.3.4 Renal Function Evaluation tions that are absolute contraindications for kid-
ney transplantation. Proper selection and
Serum creatinine and creatinine clearance testing preparation of kidney transplant recipients are
is employed to estimate glomerular filtration rate important goals of the transplant team due to the
(GFR) in most centers, whereas practice varies risks associated with immunosuppressive ther-
widely around the world. In the UK, GFR should apy. The goal of pretransplantation assessment is
be measured by an isotopic method, most often to obtain maximal benefits from transplantation
involving 51Cr-EDTA, and normalized to body which in turn leads to an increase in quality of
surface area (mL/min/1.73 m2). In the USA and life and life expectancy of the patients.
many European countries, GFR is often esti-
mated from creatinine clearance calculated via
24-h urine collection. Renal echography and 19.4.1 Timing of Referral
sequential scintigraphy are helpful for assessing and Contraindications
morphological and function characteristics of the of Transplantation
two kidneys. Imaging of arterial and venous anat-
omy includes In ideal circumstances, preparation for transplanta-
tion begins as soon as progressive CKD is recog-
• Intra-arterial angiography nized. Increased cardiovascular risk, which is a
• Spiral computed tomography (CT) major determinant of posttransplantation morbid-
angiography ity and mortality, can be recognized as soon as the
• Magnetic resonance (MR) angiography (less serum creatinine level is elevated. It is well known
accurate than CT) that preemptive renal transplantation leads to
improved patients’ and allograft outcomes.
Spiral CT angiography has largely replaced Compared with patients who have been on dialysis
intra-arterial angiography because this technique for more than 2 years, patients who have not under-
helps to avoid the complications of arterial punc- gone dialysis (or have been on dialysis for less than
ture and provides accurate arterial and venous 6 months) have longer graft survival time.
phase images. Furthermore, 3D reconstruction of Contraindications to transplantation are listed
spiral CT is helpful for planning laparoscopic below:
nephrectomy.
• Active or metastatic cancer
• Untreated current infection
19.3.5 Summary • Severe irreversible extrarenal disease
• Uncontrolled psychiatric illness impairing
Comprehensive assessment and education of liv- compliance or consent
ing kidney donors is a complex and time- • Active substance or alcohol abuse
consuming process requiring a thoughtful • Recalcitrant treatment noncompliance
approach and extensive detailed communication • Aggressive recurrent native kidney disease
among all members of the transplant team. There • Limited, irreversible rehabilitative potential
is an urgent need for new studies on donor and • Primary oxalosis
19.4.2 Complete Medical History eliminate any infections that may reactivate dur-
and Physical Exam ing the posttransplant period.
A complete medical history of the transplant can-

didate is crucial. The history may be useful to 19.4.6 Screening for Cancers
ascertain whether the renal disease has a heredi-
tary or familial origin, and a general screening Nine to 12% of deaths among kidney transplant
examination should be conducted when a full recipients are caused by cancer. At baseline,
medical history is obtained. patients with ESRD are at a higher risk of cancer
than is the age-matched control population.
Therefore, detecting cancer and reducing risk
19.4.3 Evaluation of Renal Disease factors of cancer are important components of
pretransplant evaluation. In addition, immuno-
The history of kidney disease should be reviewed suppressive drug application increases the risk of
with a focus on the nature and duration of pri- cancer, and existing cancer may turn more
mary kidney disease. All forms of glomerulone- aggressive.
phritis may recur after transplantation and may
lead to graft failure, but the risks of disease recur-
rence and its consequences differ among the vari- 19.5 Immunosuppressive
ous subtypes of glomerulonephritis. Medication and Protocols
for Kidney Transplantation
19.4.4 Screening for Cardiovascular Management of renal transplant recipients to

Disease achieve long-term survival is the main goal of
transplant physicians. An immunosuppressant
Cardiovascular disease occurs early after trans- treatment that reduces acute rejection reactions
plantation, and these events are the most common and minimizes ischemic damage is the corner-
cause of death after renal transplantation. Almost stone of successful management of these delicate
half of the deaths of patients who have functional organs. Prevention of rejection while favoring the
grafts within 30 days after transplantation are due development of an immunological adaptation is
to a cardiovascular event, mainly acute myocar- the main goal of immunosuppressive therapy.
dial infarction. Careful study of the cardiovascu- More potent and specific immunosuppressive
lar system and proper treatment of aberrations agents have enabled a significant reduction in the
before placement of candidates on an active wait- incidence and severity of rejection.
ing list are necessary because cardiovascular dis-
ease is the main cause of late graft loss and
long-term mortality. 19.5.1 History
of Immunosuppression
and Transplant
19.4.5 Screening for Infectious
Diseases The ability of the immune system, particularly T
lymphocytes, to mediate acute rejection of organs
Infection may worsen with immunosuppressive transplanted between genetically nonidentical
drug application which is the second most com- individuals was well known before the first suc-
mon cause of death among patients with cessful renal transplant, in 1954. In the absence
ESRD. Kidney transplant candidates must be of any means of suppressing the immune system,
screened to determine the presence of infection, this first transplant was performed between iden-
and pretransplantation screenings are designed to tical twins.
Whole-body irradiation was used for the first Table 19.1 Potential advantages and disadvantages of
depleting-antibody induction
attempt at immunosuppression; azathioprine was
introduced in the early 1960s and was soon fol- Potential advantages
lowed by prednisone. Polyclonal antilymphocyte • Improved graft survival for high-risk patients
• Onset of first rejection is delayed
globulin and antithymocyte globulin came onto • Period of delayed graft function may be
the scene in the 1970s. The introduction of cyclo- foreshortened
sporine in the 1980s was a seminal milestone, • May allow for less aggressive maintenance
which reduced the acute rejection rate signifi- regimen
Potential disadvantages
cantly and transformed the kidney transplanta-
• Risk of first-dose reactions
tion scenario, with improvement in 1-year graft • May prolong hospital stay and increase cost
survival to more than 80%. In 1985, the first • Higher incidence of cytomegalovirus infection
monoclonal antibody OKT3 was introduced into • May increase mortality
clinical practice because of the ability to treat the
first acute rejection. Tacrolimus and mycopheno-
late mofetil (MMF), which are two other major teins. The use of specialized induction agents has
developments, then followed. In 1999, sirolimus increased over time, with 87% of patients under-
was introduced, and later, everolimus was going kidney transplantation in the Unites States
approved in 2007. Due to the constant research in 2012 receiving such medication according to
into the immune system, tremendous progress Organ Procurement and Transplantation Network
has been made in kidney transplantation. The data. Two T-cell-depleting agents—rabbit anti-
short-term survival and mid-term survival of kid- thymocyte (rabbit ATG, thymoglobulin) and
ney transplants are now satisfactory. alemtuzumab (Campath)—and one nondepleting
agent, basiliximab (Simulect), are used for induc-
tion therapy in most cases. The advantages and
19.5.2 Induction disadvantages of depleting-antibody induction
Immunosuppression are outlined in Table 19.1.
Induction therapy is a boost of immunosuppres-

sion for approximately several days immediately 19.5.3 Maintenance
after the surgical operation (although it usually Immunosuppression
starts immediately before the operation) in order
to “shut down” the immune system after trans- Maintaining immunosuppression is intended to
plantation to reduce the possibility of accelerated prevent acute and chronic immune system-
rejection and acute rejection. There are several mediated graft injury. Continuous development
important reasons for the use of induction ther- of immunosuppressive drugs has led to several
apy. First, induction agents can significantly new options that can further prevent rejection and
reduce the rate of acute rejection and improve improve outcomes in the long run.
1-year graft survival. Second, induction therapy Immunosuppressive drug application requires
is important for preventing early calcineurin careful selection and dose titration to balance the
inhibitor (CNI)-induced nephrotoxicity. In addi- risks of rejection and toxicity. Table 19.2 lists
tion, these drugs are also considered for high-risk maintenance agents used in clinical practice.
patients such as those with multiple HLA mis- The immunosuppressive treatment regimens
matches, with organ transplant history, or with for transplant centers vary, and the 2009 KDIGO
preformed antibodies. guidelines on maintenance immunosuppression
Induction therapeutic agents are pharmaco- suggest the use of a CNI, antimetabolite, and cor-
logically classified as monoclonal or polyclonal ticosteroid in combination. This drug selection
antibodies. Nevertheless, it is more accurate to method also helps to minimize drug-related
classify them as depleting or nondepleting pro- adverse events [6]. Selecting a suitable immuno-
Table 19.2 Maintenance agents in renal transplantation [7] nance immunosuppression, and additional patient
Calcineurin inhibitors factors including age and comorbidities such as
• Cyclosporine cardiovascular disease, pulmonary disease, and
• Tacrolimus prior cancer. T-cell-depleting agents such as rabbit
Antimetabolites
ATG or alemtuzumab are associated with lower
• Mycophenolate mofetil
• Azathioprine acute rejection rates but higher rates of leukopenia
mTOR inhibitors and infection as compared to basiliximab. An indi-
• Sirolimus vidual patient’s risk of rejection should be carefully
• Everolimus weighed against potential complications due to
Corticosteroids overimmunosuppression and/or drug-related tox-
Reproduced with permission from Kennedy et al. [7] icities. Maintenance immunosuppressive therapy
has greatly evolved too. Although CNI-based ther-
suppressive agent should be patient specific. The apy with tacrolimus, mycophenolate, with or with-
most important adverse effects of generalized out corticosteroids continues to be the standard
immunosuppression are cancer and infection, (most commonly utilized) regimen ensuring low
including opportunistic infections. Individual rates of acute rejection, the associated medication-
drugs have a specific profile of adverse effects. related toxicities continue to contribute to morbid-
ity and mortality.
19.5.4 Monitoring the Levels

of Immunosuppressive Drugs 19.6 Allograft Dysfunction
The avoidance of over-immunosuppression and With a living donor kidney transplant, the graft
under-immunosuppression is a major challenge usually begins to function soon after the vascular
in clinical practice. Patients are routinely moni- anastomosis is complete. Although immunosup-
tored for signs of drug toxicity by means of serum pressive agents, surgical techniques, and histo-
drug levels including CNI concentrations, mam- compatibility tests have improved, allograft
malian target of rapamycin inhibitor (mTORi) dysfunction remains the most common complica-
levels, and at certain centers, MMF/MPA con- tion of renal transplantation [8].
centrations. Nevertheless, extreme drug levels
are helpful but not definitive in the diagnostic
process. Moreover, dosing of immunosuppres- 19.6.1 Immediate Posttransplant
sive drugs remains rather empirical, and there is Period
no test for biological activity of the drugs used in
transplantation. With a living donor kidney transplant, the graft
usually begins to function soon after the vascular
anastomosis is complete. Impairment of graft
19.5.5 Conclusion function is suggested by a decrease in urine out-
put and/or a rise in creatinine levels. The defini-
Kidney transplantation has greatly evolved and has tion of DGF varies among transplantation centers,
seen many advances in immunosuppressive ther- and the most common definition is dialysis that is
apy, with an increasing number of immunosuppres- required within 7 days. On the other hand, the
sive agents available for use in various combinations current definition of DGF does not enable clini-
allowing for more options and personalization of cians to distinguish the causes of DGF from other
immunosuppressive therapy. When selecting an types of graft dysfunction and can lead to mis-
induction immunosuppressive agent, a clinician classification of patients. Furthermore, there are
must carefully consider several factors including different criteria for dialysis prescription among
immunological risk of the patient, the cumulative nephrologists. The main causes of DGF are listed
immunosuppression burden, concomitant mainte- in Table 19.3.
Table 19.3 Main causes of DGF Table 19.4 Main measures for preventing DGF
Prerenal Donor
• Hypotension, hypovolemia • Normovolemia
• Arterial thrombosis, venous thrombosis • Maintain blood pressure
Parenchymal • Optimize cardiac output
• Acute tubular necrosis (Ischemia, drug) • Adequate kidney perfusion
• Rejection (hyperacute, acute) Kidney perfusion
• Thrombotic microangiopathy (CNIs, mTOR • Selection of renal preservation solutiona
inhibitors) • The use of pulsatile machine perfusion
• Recurrence of original disease (FSGS, HUS, Cold ischemia time
primary hyperoxaluria) • Maintain <12–24 h when possible
Postrenal Ischemia-reperfusion injury
• Ureteral obstruction (ureteral kinking, ureteral • Multiple anti-inflammatory and antioxidant
stenosis, blood clots, lymphocele) therapiesa
• Urine leakage Recipient
• Urine fistula
• Check blood volume
DGF delayed graft function, CNI calcineurin inhibitor, • Low-dose dopamine
mTOR mammalian target of rapamycin, FSGS focal segmen- • Loop diuretics
tal glomerulosclerosis, HUS hemolytic uremic syndrome
DGF delayed graft function
Requires more research
a
19.6.2 Management of DGF Table 19.5 Causes of allograft dysfunction in the early
postoperative period
Patients with DGF show longer hospitalization Prerenal

• Transplant artery stenosis
and are at a higher risk of occult rejection or other
• Hypovolemia/hypotension
undiagnosed insults to the graft. Most studies • Renal vessel thrombosis
suggest that patients with DGF have worse long- • CNIs
term outcomes than patients with immediate Parenchymal
function. Great efforts should be made to reduce • Acute thrombotic microangiopathy
• Acute allergic interstitial nephritis
the damage during the transplantation process;
• Recurrence of primary disease
these measures include optimal management of • Acute rejection
donors, a precise surgical technique, optimizing • Acute CNI nephrotoxicity
allograft perfusion, minimizing cold ischemia • Toxic/ischemic acute renal tubular necrosis
• Acute pyelonephritis
time, and ensuring adequate preparation of the
Postrenal
recipient (Table 19.4).
• Urine leaks
• Urinary tract obstruction
CNI calcineurin inhibitor
19.6.3 Early Posttransplant Period
Early posttransplant allograft dysfunction is and those of early acute dysfunction [9]. The rea-
often defined as a sustained increase in plasma sons of late chronic allograft dysfunction are
creatinine concentration, and the reasons are listed in Table 19.6.
listed in Table 19.5 [9].
19.6.5 Management of Late Allograft

19.6.4 Late Posttransplant Period Dysfunction
There is an apparent overlap between the causes The main focus of the current research in this
and assessment of acute allograft dysfunction in field is the prevention of chronic allograft dys-
the late period (3–6 months after transplantation) function. The medical history should be carefully
Table 19.6 Reasons of late chronic allograft dys- monly used in renal transplantation although
function [10]
there are no randomized controlled trials. When
Prerenal GFR deteriorates, patients should be ready to
• Heart failure resume dialysis. Erythropoietin, vitamin D ther-
• Transplant renal artery stenosis
Parenchymal
apy, and other ancillary measures should be
• Chronic active antibody-mediated rejection applied. The “CKD management” of patients
(ABMR) who fail in transplantation may be difficult due
• Chronic active T-cell-mediated rejection (TCMR) to the adverse effects of immunosuppressive
• Drug and radiocontrast nephrotoxicity agents [10].
• Hypertension
• Interstitial fibrosis and tubular atrophy, no specific
etiology
• Chronic BK virus nephritis 19.7 U
pdated Banff Classification
• Donor-related disease and/or perioperative injury Categories
• Chronic CNI toxicity
• Chronic BK virus nephritis
• Late recurrence of primary disease Among living and deceased donor transplant
• Diabetic nephropathy recipients, the incidence of acute rejection within
• New disease the first year posttransplant decreased to 7.9% for
Postrenal
both categories during 2013 and 2014. The devel-
• Urinary tract obstruction
opment of donor-specific antibody (DSA) and
CNI calcineurin inhibitor (Reproduced with permission
from Magee et al. [10])
AMR negatively affects graft survival, and the
present-day diagnosis of AMR in the absence of
peritubular capillary C4d staining has been incor-
examined, especially with respect to primary kid- porated into the Banff classification system [11].
ney disease, early posttransplantation course, Updated Banff classification categories are listed
acute rejection episodes, degree of hypertension, in Table 19.7.
CNI levels, and compliance. Urinalysis and renal
ultrasonography should be performed to rule out
primary kidney disease and obstructive cause. 19.8 I nfection After Kidney
Allograft biopsy is often performed because Transplantation
endogenous nephropathy is the leading cause of
dysfunction [10]. Although the outcomes of renal transplant
If there is a histological evidence of acute patients have improved over the years, this popu-
TCMR components, pulsed steroids are usually lation continues to show significant morbidity
prescribed, and baseline immunosuppression is and mortality due to infection. Infection accounts
increased. How to manage chronic TCMR is not for 15–20% of deaths after transplantation, and it
clear. If there is evidence of an acute AMR com- is the second most common cause of hospital
ponent, plasmapheresis and/or IVIg protocol admission among kidney transplant patients in
may be performed. How to manage chronic the first year posttransplant [12]. Therefore, a
AMR is not clear either. In most cases, when transplantation team attempts to achieve a bal-
allograft injury due to CNI toxicity, and with no ance between preventing allograft rejection and
evidence of active rejection, reducing the CNI maintaining immune system integrity for defense
dose is a reasonable action. Alternative medica- against pathogens. In addition to immunosup-
tion such as MMF or sirolimus may be initiated pressive agents, several factors contribute to a
as a replacement, but it is important to pay close decrease in immune status, including uremia,
attention to late acute rejection of patients. nutrition, diabetes, dialysis, age, and ESRD-
ACE-I/angiotensin receptor blockers are com- related malnutrition.
Table 19.7 Updated Banff classification categories 19.8.1 Pretransplant Recipient

Category 1: Normal biopsy or nonspecific changes and Donor Evaluation
Category 2: Antibody-mediated changes
Acute/active ABMR: three features are required Before transplantation, appropriate evaluation
Histological evidence of acute tissue injury and treatment of patients are required, starting
(inflammation, TMA, ATN)
with a detailed medical history taking and physi-
Linear C4d staining
Serological evidence of DSA cal examination. The goal is to assess the condi-
Chronic active ABMR: three features are required tion or exposure that causes the candidate to be
Histological evidence of chronic tissue injury susceptible to future complications, especially
Linear C4d staining those requiring treatment or prevention.
Serological evidence of DSA Predonation kidney transplant donors have also
C4d staining without evidence of rejection been tested several times. Donors can harbor
Category 3: Borderline changes infectious diseases that can be transmitted to
Category 4: TCMR recipients via donor organs.
Acute TCMR
Grades
IA Significant interstitial inflammation (>25%
of nonsclerotic cortical parenchyma) and 19.8.2 Timing of Posttransplant
foci of moderate tubulitis Infections
IB Significant interstitial inflammation
(>25% of nonsclerotic cortical Infection after kidney transplantation is divided
parenchyma) and foci of severe tubulitis
IIA Mild to moderate intimal arteritis
into three stages: 0–1 month, 1–6 months, and
IIB Severe intimal arteritis comprising >25% after 6 months. The recipients are susceptible to
of the luminal area certain infections due to the different levels of
III Transmural arteritis and/or arterial immunosuppression and environmental factors in
fibrinoid change and necrosis of medial each period. Table 19.8 lists the timeline and rel-
smooth muscle cells with accompanying
evant infectious microorganisms after a kidney
lymphocytic inflammation
Chronic active TCMR transplant.
Chronic allograft arteriopathy
Category 5: Interstitial fibrosis and tubular atrophy
Grades 19.8.3 Evaluation of Fevers
I Mild interstitial fibrosis and tubular atrophy
(≤25% of cortical area) Although a fever is not always present in an
II Moderate interstitial fibrosis and tubular
infected immunosuppressed patient, it remains
atrophy (26–50% of cortical area)
III Severe interstitial fibrosis and tubular
the most common manifestation of an infection
atrophy (>50% of cortical area) in a transplant patient. A number of clinical, labo-
Category 6: Other changes not considered to be ratory, and radiological tests on a febrile trans-
rejection plant patient are recommended. Both infection
BK virus nephropathy and rejection can lead to fever in the transplant
Posttransplant lymphoproliferative disorders recipients, and the first differential diagnosis
CNI nephrotoxicity
should be between infection and rejection.
Acute tubular injury
Medical tests for a renal transplant recipient with
Recurrent disease
De novo glomerulopathy a fever are listed in Table 19.9, and Table 19.10
Pyelonephritis lists bacterial, viral, and fungal infections com-
Drug-induced interstitial nephritis mon among renal-transplant recipients.
ABMR antibody-mediated rejection, TMA thrombotic
microangiopathy, ATN acute tubular necrosis, DSA donor-
specific antibody, TCMR T-cell-mediated rejection, CNI
calcineurin inhibitor
Table 19.8 Timeline and infectious organisms after a Table 19.9 Medical tests for a renal transplant recipient
kidney transplant [13] with fever
0–1 month 1–6 months After 6 months Rejection Infection
Nosocomial Cytomegalovirus Community • Creatinine • Blood cell analysis
infection Polyomavirus infections • Urinalysis • Cultures (blood, urine,
Pneumonia Pneumocystis Cytomegalo • Graft secretions)
Urinary tract Cryptococcus virus retinitis ultrasonography • Chest X-ray imaging
infection Nocardia Cryptococcus • Renal biopsy • Echocardiogram
Bloodstream Toxoplasma gondii Herpes virus • Urinary ultrasonography
infections Listeria Polyomavirus (Graft, native kidney)
Wound monocytogenes Mycobacteria • Neurological evaluation
Herpes Candida species • Cerebrospinal fluid
viruses Aspergillus species • Cerebral CT
Oral Histoplasmosis • Intestinal–hepatic tests
candidiasis Coccidioidomycosis • CMV antigenemia
Mycobacteria • Anti-legionella, -candida, or
Other herpes viruses -mycoplasma antibodies
Hepatitides B and C
Reproduced with permission from Santos et al. [13]
Table 19.10 Bacterial, viral, and fungal infections

Bacterial infections Viral infections Fungal infections
• Urinary tract infections • Herpes virus infections • Candidiasis
• Sepsis • Hepatitis viruses • Cryptococcus
• Wound infections • Influenza • Aspergillosis
• Nocardiosis • HIV • Mucormycosis
• Listeriosis • Polyomaviruses • Histoplasmosis
• Coccidioidomycosis
Key Messages team which is a complex and time-con-

• Chronic rejection and overimmunosup- suming process.
pression remain significant clinical prob- • Great effects should be paid to selection
lems. The development of more specific and preparation of kidney transplant recip-
treatments accompanied by reduction in ients because of the risks of immunosup-
toxicity requires further work. pressive therapy.
• Antibody analysis is increasingly carried • Kidney transplantation has greatly evolved
out posttransplant as a noninvasive predic- and has seen many advances in immuno-
tor of acute and chronic alloimmune com- suppressive therapy, with an increasing
plications. Understanding the complexity number of immunosuppressive agents
and interactivity of these histocompatibil- available for use in various combinations
ity methods and their interpretation param- allowing for more options and personaliza-
eters is crucial for clinicians to formulate tion of immunosuppressive therapy.
an appropriate treatment regimen. • DGF after kidney transplantation is usually
• Comprehensive assessment and education defined as the need for dialysis during the
of living kidney donors require communi- first postoperative week, anuria, or failure of
cation among all members of the transplant prompt azotemia resolution. DGF increases
the risk of allograft rejection by 50% as • Although the outcomes of renal transplant
compared with prompt graft function. patients have been great improved in recent
• The development of DSA and AMR years, infectious complications after a
adversely affects graft survival. The modern transplant may induce allograft injury or
diagnosis of AMR in the absence of peritu- graft loss and are a major cause of morbid-
bular capillary C4d staining has been incor- ity and mortality.
porated into the Banff classification system.
and kidney transplantation. New York: Springer; 2013.

References p. 395–409.
8. Massie AB, et al. Early changes in kidney distribution
1. Hart A, et al. OPTN/SRTR 2015 annual data under the new allocation system. J Am Soc Nephrol.
report: kidney. Am J Transplant. 2017;17(Suppl 2016;27(8):2495–501.
1):21–116. 9. Wu WK, et al. Delayed graft function and the risk of
2. Lo P, et al. Preconditioning therapy in ABO- acute rejection in the modern era of kidney transplan-
incompatible living kidney transplantation: a sys- tation. Kidney Int. 2015;88(4):851–8.
tematic review and meta-analysis. Transplantation. 10. Magee CC. Allograft dysfunction: diagnosis and
2016;100(4):933–42. management. In: Core concepts in renal transplanta-
3. Tinckam KJ. Basic histocompatibility testing meth- tion; 2012.
ods. In: Core concepts in renal transplantation; 11. Loupy A, et al. The Banff 2015 kidney meeting
2012. report: current challenges in rejection classification
4. Anjum S, et al. Patterns of end-stage renal disease and prospects for adopting molecular pathology. Am J
caused by diabetes, hypertension, and glomerulo- Transplant. 2017;17(1):28–41.
nephritis in live kidney donors. Am J Transplant. 12. Martin-Gandul C, et al. The impact of infection on
2016;16(12):3540–7. chronic allograft dysfunction and allograft survival
5. Lin J. Medical evaluation of the living kidney donor. after solid organ transplantation. Am J Transplant.
In: Core concepts in renal transplantation; 2012. 2015;15(12):3024–40.
6. Hart A, et al. Kidney. Am J Transplant. 2016;16(Suppl 13. Santos RD, Brennan DC. Prevention and manage-
2):11–46. ment of infectious complications in kidney transplant
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Chronic Kidney

Chronic Kidney Disease

ISBN 978-981-32-9130-0 ISBN 978-981-32-9131-7 (eBook)

© Springer Nature Singapore Pte Ltd. 2020

Chronic kidney disease (CKD) is a global health problem with an increasing

Nanjing, China Junwei Yang

Part I Chronic Kidney Disease

1 Chronic Kidney Disease: Overview������������������������������������������������ 3

Part II Complications of Chronic Kidney Disease

9 Cardiovascular Disease in Chronic Kidney Disease �������������������� 111

12 Immune Deficiency and Infection in Chronic Kidney

Part III Management of Chronic Kidney Disease

14 Nutritional Management of Chronic Kidney Disease������������������ 173

Ting Cai, PhD Candidate Nanjing Medical University, Nanjing, Jiangsu,

Jining Wu, MD, PhD Centre for Kidney Disease, Second Affiliated

Abstract overview definition, epidemiology, cost, and

© Springer Nature Singapore Pte Ltd. 2020 3

CKD is defined as abnormalities of kidney struc- 1.4 Causes and Risk Factors

Table 1.3 Albuminuria categories in CKD

concentration. Stop RAS antagonist therapy if Patients with features summarized in

© Springer Nature Singapore Pte Ltd. 2020 13

Renal parenchymal cells Chemokines Infiltrating immune cells

Ang-II, TGF-β, CTGF, FGF, ROS. . .

Podocytes injury Mesangial expansion

Glomerosclerosis Interstitial fibrosis

Chronic kidney disease

interstitial fibrosis. Thorough knowledge of the Glomerulosclerosis is characterized by an

2.4.3 Wnt Signaling Pathway signaling events, active β-catenin is translocated

increased pS6 expression, glomerular hypertro- 2.4.5 MicroRNAs (miRNAs)

that a switch of metabolism from OXPHOS to 2.5 Conclusion

Ang II TGF-β1 Wnt

AT1R TGFβRI TGFβRII Glucose

Biological actions (dedifferentiation, transdifferentiation, hypertrophy, apoptosis, proliferation)

8. Liu XL, et al. Characterization of the interac-

63. Chau BN, et al. MicroRNA-21 promotes fibrosis

Abstract renin–angiotensin–aldosterone system block-

© Springer Nature Singapore Pte Ltd. 2020 33

Fig. 3.2 Histopathological manifestations in diabetic Fig. 3.3 Histopathological manifestations in diabetic

more advanced tubulointerstitial and vascular • Macroalbuminuria

Screening for DKD should begin at 5 years

• Screen for ACR every 12 months

ACR ≥ 30 mg/g on two separate tests ACR < 30 mg/g

• Presence of DR Typical clinical features of DKD Screen by

NO OR • Slow progression of ACR NO • Urine microscopy

DKD Renal biopsy if necessary

1. eGFR rapidly declines, or renal dysfunction

lone methyl group. The Bardoxolone Methyl References

Abstract 4.1 Introduction

© Springer Nature Singapore Pte Ltd. 2020 45

4.2 Benign Nephrosclerosis

4.2.5 Pathological Manifestations epithelial–mesenchymal transition and tubuloint-

Table 4.5 Diagnostic threshold values for ABPM (in

Table 4.4 Reference values for normal ambulatory • Renal atherosclerotic disease

or diastolic BP is >100 mmHg or if systolic BP is creatinine and potassium concentration. However,

BP exceeds individualized target

hypertension. New diastolic murmurs could be • Cerebrovascular event

in September 1997, fenoldopam has been shown

References 10. Shlipak MG, Matsushita K, Ärnlöv J, et al. Cystatin C

Abstract 5.1 Introduction

Nanjing, China Junwei Yang

Part I Chronic Kidney Disease

1 Chronic Kidney Disease: Overview�� 3

Part II Complications of Chronic Kidney Disease

9 Cardiovascular Disease in Chronic Kidney Disease �� 111

12 Immune Deficiency and Infection in Chronic Kidney

Part III Management of Chronic Kidney Disease

14 Nutritional Management of Chronic Kidney Disease�� 173

CKD is defined as abnormalities of kidney struc- 1.4 Causes and Risk Factors

2.4.3 Wnt Signaling Pathway signaling events, active β-catenin is translocated

increased pS6 expression, glomerular hypertro- 2.4.5 MicroRNAs (miRNAs)

that a switch of metabolism from OXPHOS to 2.5 Conclusion

Abstract 4.1 Introduction

4.2 Benign Nephrosclerosis

4.2.5 Pathological Manifestations epithelial–mesenchymal transition and tubuloint-

Abstract 5.1 Introduction

If a patient with CKD mentioned above 5.3 Pregnancy Management

6.3 Diagnosis elderly, which leads to unnecessary medical

The KDIGO criteria allow for correction of 7.2.2 Epidemiology

7.2.3.3 Causes of Renal AKI cidofovir, tenofovir, intravenous immunoglobu-

• CKD is one of possible factors leading to 7.4 KI on CKD (Also Applicable

1. Urinalysis. 7.4.2 Biomarkers of Kidney Injury

7.4.4.2 Hemodynamic Optimization • Optimization—When the patient’s hemo-

Abstract 8.1 Introduction

sampling bias. Nuclear medicine-based tech- 8.2.2 Color-Doppler Ultrasound

8.4.6 Magnetic Resonance ous, such as relatively high radiation exposure,

Radionuclide imaging, which is a functional 8.6 Conclusion

Cardiovascular diseases (CVD) including coro- 9.2 Epidemiology

9.4 Clinical Manifestations

9.4.1 Cardiomyopathy Untreated uremic pericarditis is rare, although

9.4.4 Arrhythmia and Sudden

9.6.1.2 Intervention for PTH levels is 150–300 pg/mL. Severe

9.6.2 Treatment of CKD 1. Predialysis BP goal of >140/90 mmHg while

used cautiously, with particular attention to 9.6.2.7 Atrial Fibrillation

Abstract 10.1 Introduction

Y. Fang () · W. He () Anemia is a state of reduction in blood hemoglo-

umes, such as residual blood in the dialyzer 10.4.3 Inhibitors of Erythropoiesis

Hypophosphatemia, which may be induced 10.5 Clinical Symptoms

11.3.1 Calcium unbound Pi is filtrated by the glomerulus freely,

during embryogenesis. Paradoxically, in both 11.4.1 Treatment Targeted at

11.4.3 Parathyroidectomy in conjunction with clinical judgments, and

Table 12.1 Functional disturbances of immune cells 12.2.2 CKD-Associated Innate

12.2.3 CKD-Associated Adaptive adaptive immune system. The deficiency of the

12.3.2 Immunosuppressive Agents- • Detection of galactomannan (GM) in bron-

13.2 Neurocognitive Dysfunction aged 20–59 years, moderate CKD (eGFR

during the same 2-week period that represent a 13.3.5 Management