Seminar: Kamyar Kalantar-Zadeh, Tazeen H Jafar, Dorothea Nitsch, Brendon L Neuen, Vlado Perkovic

Seminar
Chronic kidney disease

Kamyar Kalantar-Zadeh, Tazeen H Jafar, Dorothea Nitsch, Brendon L Neuen, Vlado Perkovic
Lancet 2021; 398: 786–802 Chronic kidney disease is a progressive disease with no cure and high morbidity and mortality that occurs commonly
Published Online in the general adult population, especially in people with diabetes and hypertension. Preservation of kidney function
June 24, 2021 can improve outcomes and can be achieved through non-pharmacological strategies (eg, dietary and lifestyle
https://doi.org/10.1016/
adjustments) and chronic kidney disease-targeted and kidney disease-specific pharmacological interventions. A plant-
S0140-6736(21)00519-5
dominant, low-protein, and low-salt diet might help to mitigate glomerular hyperfiltration and preserve renal function
Division of Nephrology,
Hypertension and for longer, possibly while also leading to favourable alterations in acid-base homoeostasis and in the gut microbiome.
Kidney Transplantation, Pharmacotherapies that alter intrarenal haemodynamics (eg, renin–angiotensin–aldosterone pathway modulators
University of California Irvine, and SGLT2 [SLC5A2] inhibitors) can preserve kidney function by reducing intraglomerular pressure independently of
Orange, CA, USA
blood pressure and glucose control, whereas other novel agents (eg, non-steroidal mineralocorticoid receptor
(Prof K Kalantar-Zadeh MD);
Tibor Rubin Veterans Affairs antagonists) might protect the kidney through anti-inflammatory or antifibrotic mechanisms. Some glomerular and
Medical Center, Long Beach, cystic kidney diseases might benefit from disease-specific therapies. Managing chronic kidney disease-associated
CA, USA (Prof K Kalantar-Zadeh); cardiovascular risk, minimising the risk of infection, and preventing acute kidney injury are crucial interventions for
Duke-NUS Graduate Medical
these patients, given the high burden of complications, associated morbidity and mortality, and the role of
School, Singapore
(Prof T H Jafar MD); Department non-conventional risk factors in chronic kidney disease. When renal replacement therapy becomes inevitable, an
of Renal Medicine, Singapore incremental transition to dialysis can be considered and has been proposed to possibly preserve residual kidney
General Hospital, Singapore function longer. There are similarities and distinctions between kidney-preserving care and supportive care.
(Prof T H Jafar); Duke Global
Health Institute, Durham, NC,
Additional studies of dietary and pharmacological interventions and development of innovative strategies are
USA (Prof T H Jafar); Faculty of necessary to ensure optimal kidney-preserving care and to achieve greater longevity and better health-related quality
Epidemiology and Population of life for these patients.
Health, London School of
Hygiene & Tropical Medicine,
London, UK (Prof D Nitsch MD);
Introduction leading cause of death globally—one of the largest
United Kingdom Renal Chronic kidney disease is a progressive condition projected increases of any major cause of death.4
Registry, Bristol, UK characterised by structural and functional changes to The prevalence of different aetiologies of chronic
(Prof D Nitsch); Department of the kidney due to various causes. Chronic kidney kidney disease varies considerably by region. There are
Nephrology, Royal Free London
NHS Foundation Trust,
disease is typically defined as a reduction in kidney many causes of chronic kidney disease, including those
London, UK (Prof D Nitsch); function, an estimated glomerular filtration rate that are common and well researched, such as diabetes,
The George Institute for Global (eGFR) of less than 60 mL/min per 1·73 m², or markers glomeru lonephritis, and cystic kidney diseases, but
Health (B L Neuen MD), and of kidney damage, such as albuminuria, haematuria, causation in chronic kidney disease is not yet fully
Faculty of Medicine
(Prof V Perkovic MD), University
or abnormalities detected through laboratory testing or understood. For instance, despite a close association
of New South Wales Sydney, imaging and that are present for at least 3 months between chronic kidney disease and hypertension,
Sydney, NSW, Australia (appendix p 5).1 The global burden of chronic kidney whether hypertension is a cause or a consequence of
Correspondence to: disease is substantial and growing: approximately 10% of chronic kidney disease is controversial.5 As another
Prof Kamyar Kalantar-Zadeh, adults worldwide are affected by some form of chronic example, chronic kidney disease of unknown aetiology
Division of Nephrology,
Hypertension and Kidney
kidney disease, which results in 1·2 million deaths and and for which there is no known treatment is found in
Transplantation, University of 28·0 million years of life lost each year.2,3 By 2040, some agricultural communities in south Asia and
California Irvine, chronic kidney disease is estimated to become the fifth central America; recurrent volume depletion has been
Orange 92868-3217, CA, USA speculated to be a cause, especially with the increasing
kkz@uci.edu
frequency of climate change-related heat waves.6 This
See Online for appendix Search strategy and selection criteria possible cause of chronic kidney disease of unknown
We reviewed biomedical literature to identify all studies in aetiology highlights the potential role of adequate
which the effects of diet and lifestyle modifications and hydration as a kidney-preserving strategy. The global
pharmacotherapeutic interventions were examined for burden of chronic kidney disease has also been
conservative or preservative management of chronic kidney attributed to air pollution, and is disproportionally
disease. Both the PubMed and Google Scholar databases were borne by some world regions.7 Chronic kidney disease
searched for studies published in English or with an English severity also varies from kidney damage with normal
abstract between Jan 1, 1970, and Feb 1, 2021, using the function to kidney failure (or end-stage renal disease),
terms “chronic kidney disease”, “kidney-preserving therapy”, which typically occurs when eGFR decreases to less
“conservative management”, “diet”, “lifestyle modifications”, than 15 mL/min per 1·73 m². In general, the prevalence
“pharmacological strategies”, and “renal hyperfiltration”. of chronic kidney disease increases with age and, in
Full-text articles deemed pertinent were selected and the high-income countries, is more common in people with
reference lists of the identified reports and articles were obesity, diabetes, and hypertension.8,9
searched for further material. Chronic kidney disease is usually insidious, and
most affected individuals are asymptomatic until the
786 www.thelancet.com Vol 398 August 28, 2021

Supportive care
Seminar
Symptom management
Palliative care
Stop, reduce
frequency, or do
not start dialysis
Kidney-preserving care
Slow progression, prevent or delay dialysis, improve cardiovascular risk
Pharmacotherapy
Diet and lifestyle
• Plant-dominant, low- For disease progression For cardiovascular risk For other comorbidities
protein diet • RAAS blockers management • Acidosis management Preservation of
• Low salt intake • SGLT2 inhibitors • BP-lowering drugs • Potassium binders residual renal
Conventional care
• Physical activity • MR antagonists • Glucose-lowering drugs • Anaemia management function

• Weight loss • Disease-specific • Lipid-lowering drugs • Bone health
• Smoking cessation drugs • Diuretics maintenance
Infection control and acute kidney injury prevention
Incremental Renal replacement therapy:

transition to dialysis dialysis or transplantation
Estimated GFR 90 60 45 30 25 15 10 5 mL/min per 1·73 m2

Hyperfiltration Albuminuria Declining GFR ↑Uraemia Loss of residual kidney function
Figure 1: Conservative and preservative management of chronic kidney disease without dialysis or renal transplantation
This chart highlights the role of preservative management and its goals (green domain) within the overall conservative management of chronic kidney disease without
dialysis (blue zone), juxtaposing renal replacement therapy including dialysis and kidney transplantation (yellow zone). The X axis (showing chronic kidney disease
progression) should be read exclusively from left to right. The bottom half of the chart represents conventional (life-prolonging and kidney-prolonging) strategies,
whereas the top half represents supportive care, including palliative and hospice care, in which dialysis is often avoided or withdrawn (violet domain).17 The oblique dotted
line between the two main zones (conservative management vs renal replacement therapy) suggests that there is variability in transitioning to dialysis therapy (moving
from bottom left to top right), including timing (early vs late vs never), level of care (life-prolonging vs supportive care), and type of dialysis (conventional vs incremental).
The symptom management (purple) domain provides wide ranges of interventions to encompass the goals of care under both kidney preserving care and palliative and
hospice care. Preservative management can preserve residual kidney function for longer, especially after incremental transition to dialysis. See appendix p 6 for an
overview of these strategies over the course of chronic kidney disease progression. BP=blood pressure. GFR=glomerular filtration rate. MR=mineralocorticoid receptor.
RAAS=renin–angiotensin–aldosterone system.
disease becomes advanced (ie, eGFR of less than Approaches to preserving kidney function
30 mL/min per 1·73 m²). The rate of loss of kidney There has been growing recognition that conservative
function varies by aetiology, exposures, and inter management without dialysis is a viable, patient-centred
ventions but, in most cases, progression to kidney treatment option for a substantial proportion of patients
failure typically takes between months and decades to with chronic kidney disease.16 Within conservative
develop. Signs and symptoms of kidney failure result management strategies, there are several overlapping
from progressive uraemia, anaemia, volume overload, intervention domains, with similarities and differences,
electrolyte abnormalities, mineral and bone disorders, that can be offered to patients with chronic kidney disease
and acidaemia, and inevitably lead to death if left (figure 1).17 Kidney-preserving care is a life-sustaining
untreated.10 conservative management therapy with the primary goal
Renal replacement therapy, either in the form of of slowing chronic kidney disease progression and
chronic dialysis or kidney transplantation, is a life- preserving kidney function to avoid dialysis for as long as
sustaining treatment for people with kidney failure. possible or, ideally, altogether. This approach strives to
Because of the shortage of kidney donors and of the achieve the greatest possible survival, improved cardio
comorbidities that develop with age and often preclude vascular health, and superior health-related quality of
kidney transplantation,11,12 dialysis remains the prevailing life through effective treatment of renal and non-renal
treatment option for most people with kidney failure.13 comorbidities and their associated symptoms.18,19
Kidney failure requiring dialysis is often associated with Given that conservative management is defined as
substantially reduced quality of life and high mortality chronic kidney disease care without dialysis or kidney
rates,14 especially in the first year after transition to transplantion,20 misconceptions of dialysis-free manage
dialysis,15 underscoring the importance of preserving ment as so-called no care, or misguided conflation with
kidney function in people with, or at high risk of, chronic hospice care might have contributed to an underuse of
kidney disease. the full spectrum of kidney-preserving management.12,18
www.thelancet.com Vol 398 August 28, 2021 787

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Advantages and rationale Disadvantages Additional comments

Diet and lifestyle
Plant-dominant, low-protein diets* Patient-centred, inexpensive, improves Risk of muscle loss and frailty; risk of diet- Effects on patient-level kidney outcomes not
metabolic markers, and mitigates acidosis; induced hyperkalaemia yet confirmed in randomised controlled trials
might slow disease progression and attenuate
uraemia
Nutrient-focused dietary interventions (low Experience in clinical practice Uncertain effectiveness of single-nutrient Potassium-restricted diets might cause more
sodium, low phosphate, and low potassium)*† approaches (eg, strict phosphate control) on harm than no intervention by limiting intake of
patient-level outcomes potassium-rich, healthy fruits and vegetables
Increasing physical activity, weight reduction, Numerous clear health benefits Sustained goals can be challenging to achieve See table 2 for more details
and smoking cessation*†
Pharmacological agents to slow chronic kidney disease progression
Renin–angiotensin–aldosterone system Proven benefit in preventing kidney failure in Risk of AKI and of hyperkalaemia Uncertain benefits for non-diabetic kidney
blockade (ACEi, ARB)‡ randomised trials in people with diabetes disease with proteinuria <0·5 g/day
SGLT2 inhibitors‡ Clear reductions in patient-level adverse Risk of mycotic genital infections, volume Less data for initiation at eGFR <30mL/min
cardiovascular and renal outcomes in people depletion, and euglycaemic ketoacidosis; per 1·73 m²; emerging evidence of benefit in
with type 2 diabetes reported increased risk of limb amputation not people with non-diabetic kidney disease
substantiated
Non-steroidal mineralocorticoid receptor Reduction in adverse cardiovascular and renal Risk of hyperkalaemia Uncertain effects of steroidal mineralocorticoid
antagonists†‡ outcomes in people with type 2 diabetes; receptor antagonists (eg, spironolactone) on
potential anti-inflammatory and antifibrotic patient-level kidney outcomes; non-steroidal
effects mineralocorticoid receptor antagonists have
not yet been evaluated in non-diabetic kidney
disease
Tolvaptan for polycystic kidney disease*† Slowed decline in glomerular filtration rate Risk of polydipsia or polyuria and deranged Tolvaptan might delay the predicted onset of
liver function kidney failure
Rituximab for primary membranous Increased likelihood of long-term remission Little data from randomised controlled trials Effect of combination therapies to be
nephropathy*† compared with ciclosporin directly comparing with alkylating agents determined
Steroids for IgA nephropathy*† Experience in clinical practice Mixed results in clinical trials; increased risk of Additional trial ongoing (NCT01560052)
adverse events, especially serious infection
Pharmacological strategies to reduce cardiovascular risk
Lipid-lowering treatments‡ Reduction in adverse cardiovascular events in No clear benefit for initiating treatment in Few data on new lipid-lowering therapies in
people with chronic kidney disease; people requiring dialysis chronic kidney disease
well tolerated
Blood pressure-lowering treatments‡ Reduction in adverse cardiovascular and Possibly greater risk of adverse events as Addressing volume overload is a crucial
potentially renal outcomes kidney function declines aspect of blood pressure-lowering in
advanced chronic kidney disease
Glucose-lowering drugs‡ SGLT2 inhibitors and GLP-1 receptor agonists Risk of hypoglycaemia and other treatment- Inconsistent benefits for cardiovascular and
reduce adverse cardiovascular events in people related adverse events with intensive glucose kidney outcomes with intensive glucose
with type 2 diabetes reduction control; cardiovascular and renal benefits
vary with class of glucose-lowering drug
Pharmacological and other strategies to slow progression and manage uraemia and associated symptoms
Sodium bicarbonate and veverimer for acidosis Sodium bicarbonate improves acidosis, might Effect on long-term outcomes uncertain; Veverimer might improve acidosis without
management*† slow progression of chronic kidney disease sodium bicarbonate might worsen sodium causing sodium retention; randomised trial
and fluid retention ongoing (NCT03710291)
Potassium binders (sodium polystyrene, Reduced risk of hyperkalaemia; enables use of No data on patient-level outcomes or Randomised trial ongoing (NCT03888066)
zirconium, and patiromer)*† ACEi and ARB progression of kidney disease
Sodium and volume management (sodium Experience in clinical practice Uncertain effect on chronic kidney disease Few data from randomised controlled trials
restriction, loop diuretics, and thiazide progression
diuretics)*†
Symptom management (eg, for pruritus, pain, Important priority for patients with Unlikely to influence need for renal Few data from randomised controlled trials
fatigue, and sleep disorders)*† unpleasant symptoms replacement therapy or to affect risk of
chronic kidney disease progression
Prevention of AKI* AKI might increase future risk of chronic Effect of sick day advice (ie, temporary Some drug combinations (eg, ACEi and ARB)
kidney disease discontinuation of ACEi or ARBs) on incidence increase risk of AKI
of AKI not yet evaluated in randomised trials
Prevention of infection (eg, hepatitis C and Many infectious events might cause AKI, Direct kidney involvement unknown Effect of infection prevention strategies not
COVID-19)* chronic kidney disease, or both clear
Footnotes indicate the strength of the evidence for intervention efficacy (two footnotes signify that the evidence ranges between the two levels). For the potential roles of these measures in secondary and
tertiary prevention of chronic kidney disease see appendix p 7. ACEi=ACE inhibitors. AKI=acute kidney injury. ARB=angiotensin receptor blockers. eGFR=estimated glomerular filtration rate. *Supported by
biological or observational data but little or no evidence from randomised controlled trials. †Some evidence from small randomised trials or trials evaluating effects on surrogate outcomes. ‡Supported by data
from large randomised trials assessing effects on patient-level outcomes.
Table 1: Intervention strategies to preserve kidney function in people with chronic kidney disease

Seminar
Effect on chronic kidney disease Effect on cardiovascular disease Comments Recommendations

progression and mortality
Physical activity Slower decline in kidney function Lower risk of adverse Evidence on physical activity and progression Target of 150 min/week of moderate
cardiovascular outcomes and of kidney disease and cardiovascular outcomes intensity physical activity for
mortality is largely based on observational studies; patients with chronic kidney disease;
small trials of physical activity show exercise should be individualised for
improvements in kidney function and blood patients according to comorbidities
pressure in people with chronic kidney disease and functional status (mixed data in
not receiving dialysis; small trials in patients dialysis-dependent patients)
receiving dialysis show improvements in
physical function and health-related quality
of life
Smoking cessation or Smoking is associated with a greater Smoking is associated with Smoking cessation should be prioritised in all Smoking cessation for all patients
avoidance risk of incident chronic kidney disease increased risk of all-cause individuals for numerous recognised health with behavioural counselling and
mortality, including vascular benefits pharmacological therapies as
causes and cancer, in people with required, with appropriate dose
chronic kidney disease adjustment for patients with chronic
kidney disease
Dietary sodium restriction Reduced albuminuria and improved Reduces blood pressure and People with chronic kidney disease are more Limit sodium intake to a maximum
fluid status in people with and without improves arterial stiffness in likely to have salt-sensitive hypertension of 2·3 g/day (<100 mmol) according
chronic kidney disease people with and without chronic to the American Heart Association
kidney disease
Higher proportion of Higher proportion of plant-based Higher red meat intake might be Reducing dietary protein intake can increase Higher intake of complex
plant-based protein in diet protein and fibre intake might improve associated with atherosclerosis the risk of muscle mass loss and frailty; protein carbohydrates and fresh fruits and
acidosis, mitigate inflammation, reduce due to higher carnitine intake recommendations vary depending on vegetables as opposed to processed
phosphorus burden, slow progression generation via gut microbiota chronic kidney disease stage, acute kidney carbohydrates
of chronic kidney disease, and create injury, and need for dialysis
less uraemic toxins
Weight reduction Improved cardiometabolic health; Improves blood pressure Little evidence from randomised controlled Multidisciplinary approach to weight
potentially slower decline in kidney trials to guide the dietetic management of loss in overweight and obese
function and improved albuminuria people with overweight and obesity and individuals with chronic kidney
chronic kidney disease disease with involvement of a renal
dietitian; mixed data in dialysis
patients related to the obesity paradox
See also appendix p 6 for schematic depictions of these strategies over the course of chronic kidney disease progression.
Table 2: Lifestyle modification strategies to slow the progression of chronic kidney disease and preventing adverse cardiovascular outcomes
Notwithstanding heterogeneity in definitions, provision controversial, targeted screening of individuals with risk
of (or access to) care, and patient demographics or factors (eg, obesity, hypertension, and diabetes) through
socioeconomic status across different domains of the regular assessments of eGFR and albuminuria is
conservative management of chronic kidney disease, the recommended.36
use of conservative management is rising, with a greater For individuals with established chronic kidney disease,
focus on kidney-preserving strategies.21–33 addressing complications and associated comorbidities
The focus of efforts to slow the loss of kidney function and managing symptoms in addition to protecting kidney
varies depending on the severity of chronic kidney disease function are important steps. Slowing the progression of
and underlying causes, encompassing a range of chronic kidney disease can be achieved through a
pharmacological and non-pharmacological approaches range of lifestyle, dietary, and pharmacological strategies,
(figure 1; appendix pp 6–7), given that these measures are which include weight loss, moderate dietary protein
consistent with the secondary and tertiary prevention of restriction, blood pressure and glucose control, and renin–
chronic kidney disease34 (table 1). In patients with chronic angiotensin–aldosterone system blockade (appendix
kidney disease (as in the general population), lifestyle and pp 6–7). For specific aetiologies, such as primary
dietary modifications (table 2) should be prioritised glomerulonephritis and autosomal dominant polycystic
because these can improve cardiometabolic health and are kidney disease, newer targeted therapies also have an
likely to have favourable long-term effects on the kidney. important role. Because cardiovascular disease is a more
The focus of care in primary prevention is to achieve common cause of death than kidney failure in patients
optimal control of risk factors for chronic kidney disease with chronic kidney disease, reducing cardiovascular risk
by addressing physical inactivity and obesity, smoking, is a fundamental aspect of care for this population.37
high blood pressure, and high blood glucose.35 Addressing Large-scale, collaborative meta-analyses have shown
these risk factors is important across the spectrum that eGFR and albuminuria are strongly and indepen
of kidney function. Although the cost-effectiveness of dently associated with risk of a range of adverse
population-wide screening for chronic kidney disease is outcomes, including progression to kidney failure,

Seminar
cardiovascular events, and death, and both kidney bariatric surgery is associated with a lower risk of patient-
markers should be used to inform prognosis and direct level kidney outcomes.56 Gastric bypass surgery increases
care priorities for people with chronic kidney disease.38–42 remission of albuminuria in people with type 2 diabetes,
The Kidney Disease: Improving Global Outcomes obesity, and microalbuminuria when compared with
(KDIGO) classification of chronic kidney disease incor optimal medical treatment, and might represent an
porates eGFR and the urine albumin-to-creatinine ratio important treatment option for selected individuals.57
into a two-dimensional framework to stratify individuals’ In more advanced chronic kidney disease, prolonged
risk, focus management priorities, and guide referral to survival has been paradoxically reported with larger
specialist care, and is perhaps the most widely used body-mass index, a phenomenon that is known as the
staging system for chronic kidney disease (appendix p 5).43 obesity paradox or reverse epidemiology.58 Conversely,
Other tools, such as the Kidney Failure Risk Equation44 weight loss can contribute to poorer outcomes, whereas
to estimate the risk of kidney failure, and the Dialysis effective nutritional interventions to gain weight
Transition Mortality Prediction Score,45 to estimate including muscle mass might improve longevity.59 Any
mortality in the first year of dialysis, can also be used unintentional weight loss warrants prompt investigation
to inform discussion, facilitate specialist referral, and and dietary interventions, and unnecessary weight loss
contribute to shared decision making. After progression in advanced chronic kidney disease should be avoided,
to advanced chronic kidney disease, when uraemia unless absolutely required (eg, as a strict requirement for
cannot be controlled without renal replacement therapy, imminent kidney transplantation or other life-saving
incremental transi tion to peritoneal or haemodialysis procedures that require a lower weight).60
therapy might be a preferred approach with the goal of
preserving residual kidney function while reducing the Plant-dominant, low-protein diet
frequency of dialysis, although clinical trials are needed In many causes of chronic kidney disease, afferent
to examine this and other alternative dialysis transition arterioles are relatively dilated and efferent arterioles are
strategies.46 relatively contracted as a compensatory mechanism
to maintain glomerular filtration rate in the short
Physical activity, obesity, and weight loss term—a process known as glomerular hyperfiltration or
Obesity is the hallmark of metabolic syndrome and intraglomerular hypertension. This interaction is partly
associated with chronic kidney disease.47 Evidence regulated via tubuloglomerular feedback.49 In the long
suggests that increased adiposity measures (eg, body- term, glomerular hyper filtration can cause further
mass index and waist circumference) are independently damage to the kidney through mechanisms such as
associated with a decline in glomerular filtration rate.48 mechanical stress and activation of inflammatory
This association might result from systemic and mediators that promote interstitial fibrosis.61,62 Dietary
intraglomerular hypertension, the effect of prediabetes protein restriction, by enhancing the afferent arteriole
concentrations of blood glucose on podocyte stress, and tone, might alleviate intraglomerular hypertension,
other unrecognised factors.49,50 Physical activity is the mitigate renal interstitial fibrosis,61,62 and slow the
core component of lifestyle modification strategies to progression of chronic kidney disease (figure 2). This
manage weight for a positive effect on chronic kidney effect acts in parallel and is complementary to the
disease progression. postglomerular effect of renin–angiotensin–aldosterone
The Look AHEAD trial,51 in which 5145 people with pathway modulators, such as angiotensin-converting
obesity and type 2 diabetes were randomly assigned to enzyme (ACE) inhibitors and angiotensin receptor
intensive lifestyle intervention or diabetes support and blockers, which reduce intraglomerular pressure by
education, showed that intensive lifestyle intervention promoting efferent arteriolar vasodilatation.63
reduced weight by an average of 4 kg and resulted in a Evidence from randomised controlled trials supporting
relative risk reduction of onset of very high-risk chronic the beneficial effect of dietary protein restriction comes
kidney disease (according to the KDIGO classification from the Modification of Diet in Renal Disease study,
system) of approximately 30% compared with control which randomly assigned 585 participants with non-
(p=0·0016). diabetic kidney disease to assess the effect of typical
A range of weight loss interventions can be (1·3 g/kg per day) versus low-protein diets (0·58 g/kg
recommended to people with chronic kidney disease. per day) on eGFR decline. Although the primary results of
Caloric restriction, in conjunction with a plant-dominant, this trial were inconclusive, they did not take into account
low-protein diet, can lead to gradual weight loss in most the acute effect of dietary protein restriction, which reduces
people with obesity and chronic kidney disease.52,53 Efforts short-term glomerular filtration rate through afferent
to identify pharmacological agents that can reduce arteriolar constriction, similarly to what is observed
bodyweight and improve clinical outcomes have yielded with initiation of ACE inhibitors or angiotensin receptor
few or modest results.54 The role of bariatric surgery in (AGTR1) blockade therapy. Subsequent analyses of the
mitigating the risk of chronic kidney disease is also Modification of Diet in Renal Disease study data excluding
uncertain.55 Observational studies have suggested that the acute effect of the dietary intervention on glomerular

Seminar
filtration rate suggested that there was a benefit of dietary

protein restriction (appendix p 2).64 Additional analyses Improved tubular structure,
integrity, and function
also showed that dietary protein restriction might reduce (decreased sodium and glucose Low-salt diet, blood
blood pressure and proteinuria.65 The findings from this reabsorption and tubular
Low-protein diet, pressure-lowering
energy expenditure) agents
study are supported by meta-analyses that show a reduced • Dietary sodium restriction
weight loss, SGLT2
inhibitors
risk of progression to kidney failure and improvements in • Glucose-lowering drugs ole
rt eri
• SGLT2 inhibitors Vasoconstriction Reduction in
proteinuria and other favourable biochemical outcomes, ta
e ren intraglomerular
such as higher serum concentrations of bicarbonate, M Aff pressure
lower azotaemia, and lower serum concentrations of (modulation of
M
tubuloglomerular
phosphorus.66–69 The benefits of dietary protein restriction
Distal tubule
↓GFR Tubulo- feedback, afferent and
↓Intraglomerular glomerular
need to be considered in the context of potential risks to ↓Hyper- pressure
efferent arteriole tone,
filtration feedback and distal sodium and
protein-energy wasting and loss of muscle mass and chlorine delivery)
strength, particularly in frailer people or older than M • Plant-dominant low
ximal tube
M Eff protein diet
80 years.70 Therefore, current guidelines recommend a ere
nt • Acidosis mitigation
conserva tively low range of 0·6–0·8 g/kg per day of art
eri therapy
Pro
ole
dietary protein in people with substantial albuminuria Vasodilation
• SGLT2 inhibitors
• RAAS blockade
(more than 300 mg/g) to ensure safety and adequate
RAAS modulators
nutritional intake (appendix p 2).71
Decreased inflammation and
More recent data suggest salutary effects of plant- interstitial fibrosis
dominant, low-protein diets,52 in which more than 50% of (modulation of mesangial cell and signal
transduction)
ingested protein is derived from non-animal sources • Plant-dominant, low protein diet
(ie, fruits, vegetables, nuts, legumes, and seeds). There • Mineralocorticoid receptor antagonists
• Disease-specific therapies
are different types of plant-dominant diets, listed here ↓ Reduction effect
with increasing amounts of foods from plant sources:72
Figure 2: Effects of dietary protein and sodium intake and pharmacological therapies on afferent and efferent
vegan or strict vegetarian diets that not only exclude meat,
arteriolar tone, intraglomerular pressure, and glomerular structures and functions
poultry, and seafood but also eggs and dairy products; Dietary protein restriction results in contraction of the afferent arterioles leading to reduced intraglomerular
lacto-vegetarian, ovo-vegetarian, or lacto-ovo-vegetarian pressure, reducing damage to glomerular structure and function in the long term. The kidney-protective effects
diets that can include dairy products and eggs; and of a plant-dominant, low protein diet act in parallel and might be complementary to the effect of
SGLT2 inhibitors, RAAS blockade, mineralocorticoid receptor antagonism, and other blood pressure-lowering
pescatarian or pesco-vegetarian diets that include a
agents, thereby more effectively reducing intraglomerular pressure and mitigating interstitial fibrosis.
vegetarian diet combined with occasional intake of some GFR=glomerular filtration rate. M=mesangial cells. RAAS=renin–angiotensin–aldosterone system.
or all types of seafoods, mostly fish.72 Although some, but
not all studies have shown that plant-dominant diets are as inflammation, oxidative stress, endothelial dysfunction,
associated with a lower risk of chronic kidney disease muscle wasting, renal interstitial fibrosis, worsening
and glomerular filtration rate decline, less proteinuria, proteinuria, accelerated chronic kidney disease progres
amelioration of acidosis, and better cardiovascular sion, and insulin resistance.80–82 Therefore, a high-fibre,
profile,73 and although experimental data also suggest that plant-dominant, low-protein diet has been proposed, but
such diets can reduce uraemic toxin generation and exert not yet proven in clinical trials, to favourably modulate
favourable effects on cardiovascular health in people with microbiome, reduce uraemic toxin generation, and help
kidney failure,52,53,74,75 these effects have not yet been to control uraemia without dialysis, potentially while
definitively shown in randomised controlled trials.76 enhancing cardiovascular health, which is consistent with
There is growing interest in the role of the gut the goals of the conservative and preservative management
microbiome in chronic kidney disease, although the role of of chronic kidney disease.83
any microbiome-related interventions is not yet proven.76
The gut microbiome in chronic kidney disease might be Intravascular volume and acid-base and
altered by uraemia, natural intake of probiotics,77 and the electrolyte homoeostasis
type of diet (including plant-origin vs animal-origin foods).78 Subclinical volume overload is highly prevalent in people
A plant-dominant, fibre-rich, low-protein diet can lead to with chronic kidney disease and perturbations in systemic
favourable alterations in the gut microbiome, which might haemodynamics are strongly associated with risk of poor
modulate uraemic toxin generation.52 Several gut-derived cardiovascular and kidney outcomes.84–86 Optimisation of
uraemic toxins, including indoxyl sulfate, indole-3 acetic intravascular volume is, therefore, an important focus of
acid, p-cresyl sulfate, trimethylamine N-oxide, and care, particularly as kidney function declines, and can be
phenylacetylglutamine, are associated with cardiovascular achieved through dietary sodium restriction and diuretics.
disease and mortality in chronic kidney disease.79 Many patients with chronic kidney disease exhibit a
Circulating p-cresyl sulfate and indoxyl sulfate (protein- tendency for salt-sensitive hypertension.87 Although loop
bound uraemic retention solutes) and other catabolic diuretics are the mainstay pharmacological therapy for
by-products of protein metabolism can exert harmful the management of excess fluid, emerging data from
effects on several organs and homoeostatic pathways, such randomised controlled trials suggest that distal thiazide

Seminar
diuretics can reduce blood pressure and extracellular stroke, heart failure, or cardiovascular death).102 Several
volume even at lower eGFRs,88 with additional trials studies have suggested that the older steroidal
ongoing.89 mineralocorticoid receptor antagonist spironolactone
The prevalence of hyperkalaemia increases as kidney reduces proteinuria in diabetic kidney disease,103 but
function declines, and epidemiological data show a clear data regarding its effects on hard outcomes such as
U-shaped association between serum potassium and kidney disease progression or need to start dialysis are
adverse outcomes.90 Commonly used treatments such not currently available. Renin–angiotensin–aldosterone
as ACE inhibitors, angiotensin receptor blockers, and pathway modula tion with angiotensin-converting
mineralocorticoid receptor antagonists increase the risk enzyme inhibitors or angiotensin receptor blockade
of hyperkalaemia. Although dietary potassium restriction therapy is also generally recommended for people with
is traditionally recommended for people with advanced type 1 diabetes and kidney disease98 and for those without
chronic kidney disease, there are concerns that such diabetes but with significant proteinuria;104 the effects in
diets might limit the consumption of healthy plant people with little or no proteinuria are uncertain.
proteins, fruit, and vegetables.91 Traditional and newer Although blood pressure reduction per se probably
potassium binders might allow more effective control of reduces the risk of kidney failure,105,106 the haemodynamic
hyperkalaemia, and trials are underway to test the effect effect of intensive blood pressure lowering might
of newer potassium binders on clinical outcomes.92,93 paradoxically induce a more rapid decline in kidney
Metabolic acidosis in chronic kidney disease results function.107–110 Notwithstanding such mixed data, the
from the inability of the kidney to excrete endogenous KDIGO guidelines recommend a systolic blood pressure
acid, and has been shown to be associated with loss of target of less than 120 mm Hg in people with chronic
kidney function and unfavourable effects on muscle kidney disease not on dialysis to reduce the risk of
mass and bone health.94 Small trials have collectively cardiovascular events and mortality. However, indivi
suggested that correction of metabolic acidosis with dualisation of blood pressure targets is crucial
bicarbonate might slow progression of chronic kidney and should take into account comorbidities, frailty, and
disease.95 In 2019, veverimer (a novel binder of patient preferences, given the ongoing uncertainty about
hydrochloric acid in the gastrointestinal tract) was shown the risk–benefit profile of intensive blood pressure targets
to increase serum bicarbonate concentrations in people in patients with moderate-to-advanced chronic kidney
with chronic kidney disease, with an ongoing trial to test disease.107
the effect of this agent on clinical outcomes, including
progression of kidney disease or kidney failure requiring Glucose-lowering therapies
dialysis.96 Glucose-lowering therapies could potentially reverse
the fundamental metabolic abnormality pathognomonic
Traditional and emerging pharmacotherapies of diabetes.111 Although post-hoc analyses of the
Renin–angiotensin–aldosterone system inhibition, ADVANCE trial112 suggested that the risk of kidney
mineralocorticoid receptor antagonism, and other failure might be smaller in people treated to lower targets
blood pressure-lowering therapies of haemoglobin A1c; meta-analyses of more intensive
Renin–angiotensin–aldosterone pathway modulators, versus less intensive glucose reduction did not show
specifically ACE inhibitors or angiotensin receptor clear effects on the risk of kidney failure.113 Subsequent
blockers, have been the cornerstone of kidney-preserving studies have further shown clear differences between
pharmacological therapies for several decades. The different classes of glucose-lowering therapies.
evidence is strongest in people with type 2 diabetes and
albuminuric chronic kidney disease, for whom the SGLT2 inhibitors
angiotensin receptor blockers losartan (RENAAL trial) and SGLT2 (SLC5A2) inhibitors were developed to reduce
irbesartan (IDNT trial) have been shown to reduce the blood glucose in people with diabetes by blocking
risk of kidney failure, doubling of creatinine, or death proximal tubular glucose reabsorption, thus inducing
(appendix p 8).97,98 Importantly, several studies99–101 have glycosuria (figure 2). Early studies in type 2 diabetes
shown an increased risk of adverse outcomes and no clear identified that these drugs significantly reduce
benefits with multi-agent renin–angiotensin–aldosterone proteinuria and have a clear beneficial effect on kidney
system blockade, for which reason angiotensin-converting haemodynamics. This is manifest clinically as an acute
enzyme inhibitors and angiotensin receptor blockade reduction in eGFR (approximately 3–5 mL/min per
combination therapy is strongly discouraged. 1·73 m²) followed by stabilisation of kidney function
The FIDELIO-DKD trial of the non-steroidal mineral compared with either placebo or sulfonylurea therapy,
ocorticoid receptor antagonist finerenone in diabetic benefits that are observed on top of renin–angiotensin–
kidney disease showed a significant reduction in aldosterone system blockade. (appendix p 8).114 Several
the risk of the primary kidney outcome (sustained cardiovascular safety studies mandated by regulatory
40% reduction in eGFR, kidney failure, or kidney death) authorities have successively shown reductions in com
and cardiovascular outcome (myocardial infarction, posite outcomes based on reductions in eGFR or

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doubling of creatinine, kidney failure, and death due to randomly assigned to linagliptin or placebo. The trial
kidney disease.115–117 However, these trials were done in showed that linagliptin did not increase the risk of
people at high risk of cardiovascular disease, less than cardiovascular events, but also did not reduce the risk of a
25% of whom had kidney disease. composite renal outcome of 40% eGFR decline, kidney
The first primary kidney trial of SGLT2 inhibitors failure, or renal death, despite over 600 kidney-related
assessing efficacy on major clinical outcomes was the endpoints being observed in the trial. Therefore, the
CREDENCE study.118 A total of 4401 participants with available data suggest that DPP4 inhibitors do not
albuminuric diabetic kidney disease (albuminuria meaningfully reduce the risk of kidney disease progression
300–5000 mg/g, eGFR 30–90 mL/min per 1·73 m²) were in patients with type 2 diabetes.
randomly assigned to receive canagliflozin or placebo
(appendix p 8). The trial was stopped early for efficacy GLP-1 receptor agonists
after the primary outcome (doubling of serum creatinine, There have not yet been any outcome studies sufficiently
kidney failure, or death due to cardiovascular or kidney powered to detect effects on clinically important kidney
disease) was reduced by 30%, with similar reductions in a outcomes with the use of GLP-1 receptor agonists, another
range of renal outcomes, including kidney failure and class of drugs developed in the past 10 years to improve
the need for dialysis or kidney transplantation.118 Major glucose control in type 2 diabetes. GLP-1 receptor agonists
cardiovascular events (myocardial infarction, stroke, or have been shown to reduce the risk of cardiovascular
cardiovascular death) and hospitalisations for heart events in meta-analyses of completed cardiovascular
failure were also significantly reduced. On the basis of outcome trials.124 Similar meta-analyses of these trials
these findings, major treatment guidelines worldwide suggest that the risk of a composite kidney outcome
have now been updated to recommend SGLT2 inhibitors (including progression of albuminuria, substantial losses
for people with diabetic kidney disease. of renal function [40% or 57% reductions in eGFR], renal
The kidney-protective effects of SGLT2 inhibition have failure, or kidney-related death) is significantly reduced by
also been observed in people with non-diabetic kidney GLP-1 receptor agonists. However, this reduction appears
disease. The DAPA-CKD trial119 showed that dapagliflozin to be primarily driven by effects on albuminuria; no other
reduces the risk of sustained 50% decline in eGFR, clear benefit was observed on kidney outcomes.124 A
kidney failure, or death due to cardiovascular or kidney dedicated kidney outcome study (FLOW, NCT03819153) is
disease by 44% in people with chronic kidney disease currently underway, specifically recruiting people with
(eGFR 25–75 mL/min per 1·73 m², urine albumin- chronic kidney disease and com paring the effects of
to-creatinine ratio 200–5000 mg/g), with clear and semaglutide versus placebo on the risk of major kidney
independent benefits irrespective of diabetes status or and cardiovascular outcomes.
aetiology of chronic kidney disease.120 The trial also
showed that dapagliflozin substantially reduced the risk Examples of treatment of primary
of hospitalisation for heart failure or cardiovascular glomerulonephritides and cystic disorders
death and all-cause mortality, irrespective of diabetes IgA nephropathy, the most common idiopathic glomeru
status. On the basis of these findings, SGLT2 inhibitors lonephritis worldwide, is currently treated by optimising
are anticipated to be routinely offered to people with blood pressure control with ACE inhibitors or angiotensin
albuminuric chronic kidney disease, regardless of receptor blockers, along with lifestyle modifications,
the presence of diabetes. A trial of empagliflozin in such as salt and protein restriction and weight loss.125 The
non-diabetic kidney disease that includes people with low role of corticosteroids in managing IgA nephropathy is
or normal albuminuria is ongoing.121 The mechanisms controversial because of the conflicting evidence from
underpinning the cardiovascular and kidney benefits randomised trials that yielded both negative and positive
of SGLT2 inhibition are an area of active investigation, data.126,127 New therapeutic strategies for IgA nephropathy
but are probably multifactorial, including reductions in are an area of active investigation, and several agents are
intraglomerular pressure, favourable effects on the currently being tested, including combined angiotensin
extracellular fluid compartment, and multiple direct and endothelin receptor blockade and drugs targeting
effects on cellular and metabolic functions.122 complement pathways.128,129
Primary membranous nephropathy is another globally
DPP4 inhibitors prevalent glomerulonephritis. Although the discovery
DPP4 inhibitors are widely used to improve glycaemic that it is an autoimmune condition has led to substantial
control in people with type 2 diabetes. The effects on hard changes in the diagnosis, treatment, and monitoring
kidney outcomes, such as progression of kidney disease of this disease,130–132 many of these patients will develop
and end-stage renal disease, were formally assessed in the spontaneous remission; as with other causes of
CARMELINA trial,123 in which almost 7000 participants proteinuric chronic kidney disease, optimal supportive
with type 2 diabetes enriched for either or both cardio care should include the maximum tolerated ACE inhibitor
vascular disease and kidney disease (reduced glomerular or angiotensin receptor blockade therapy.133 For patients
filtration rate, increased albuminuria, or both) were with more severe proteinuria, at high risk of disease

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4·0 eGFRcystatin C
The management of cardiovascular disease in chronic
eGFRcreatinine
kidney disease is challenging (appendix p 9).152 These
Hazard ratio of cardiovascular events
3·0 challenges include interpretation of cardiac biomarkers

that are used to diagnose myocardial infarction, the
exclusion of individuals with more advanced chronic
2·0
kidney disease from cardiovascular outcome trials, and
1·5 the absence of a clear benefit of revascularisation for
individuals with chronic kidney disease and stable
coronary artery disease.153–156 The mainstays of cardio
1·0
vascular risk reduction in chronic kidney disease include
0·8 lifestyle modification (table 2), blood pressure reduction
15 30 45 60 75 90 105 120 5 10 30 300 1000
with renin–angiotensin–aldosterone pathway modulators,
eGFR (mL/min per 1·73 m²) Urinary albumin-to-creatinine ratio (mg/g)
lipid reduction with statins, and specific glucose-lowering
Figure 3: Association of eGFR and albuminuria with hazard ratio of cardiovascular events drugs that have been shown to reduce cardiovascular
Association of eGFR (creatinine-based eGFR presented with cystatin C-based eGFR for comparison) and outcomes in people with type 2 diabetes (appendix
albuminuria with hazard ratio of cardiovascular events after adjustment for traditional cardiovascular risk factors.
Data from the Chronic Kidney Disease Prognosis Consortium of 637 315 individuals from 24 cohorts (ie, general pp 3–4).124,157 Evidence suggests that in people with
population, high risk of chronic kidney disease, and established chronic kidney disease), followed up for a mean of non-dialysis-dependent chronic kidney disease, higher
8·9 years, during which time 10 605 cardiovascular deaths, 6283 coronary heart disease events, 180 stroke physical activity is associated with slower disease
events, and 2066 heart failure events occurred. Cystatin C-based eGFR data from a meta-analysis of ten general progression,158 lower risk of cardiovascular events and
population cohorts with 64 010 participants, of whom 3193 died from cardiovascular causes during follow-up.
eGFR=estimated glomerular filtration rate. The blue shaded area around the line represents the 95% CI. Adapted mortality,159,160 and some improvements in kidney function
from Matsushita and colleagues42 by permission of Elsevier and from Shlipak and colleagues.143 and blood pressure;161 in patients receiving dialysis,
improvements in physical function and health-related
progression, or both, other treatments are recommended, quality of life are also observed.162 Smoking is associated a
including alkylating agents such as cyclophosphamide,134 greater risk of incident chronic kidney disease163 and
calcineurin inhibitors,135,136 rituximab,137 or a combination increased risk of all-cause mortality in people with
of these agents.138 For other primary glomerular diseases, chronic kidney disease.164 Dietary sodium restriction
there is a paucity of evidence from randomised controlled improves albuminuria, hypertension, fluid status, and
trials.139 Autosomal dominant polycystic kidney disease is arterial stiffness in people with and without chronic
another non-glomerular disease common worldwide and kidney disease,165–167 which is also more likely to harbour
for which tolvaptan, a vasopressin receptor antagonist, salt-sensitive hypertension.168 Higher plant-based sources
has shown an effect in slowing the rate of kidney growth of protein and dietary fibres may have salutary effects,52
and glomerular filtration rate decline140 in early and late whereas higher red meat intake may be deleterious to
stages.141 patients with chronic kidney disease.169 Protein intake
These traditional and emerging pharmacotherapies recommendations vary depending on the stage of the
strategies are summarised in table 1 and in figure 1 (see disease, acute kidney injury events, and need for dialysis.70
also appendix pp 3–4). Weight reduction improves blood pressure in chronic
kidney disease,170,171 notwithstanding the obesity paradox
Addressing cardiovascular risk during chronic in patients requiring dialysis.59
kidney disease progression However, there is insufficient evidence to support com
Cardiovascular disease is a leading cause of death in mencing lipid-lowering therapy for primary prevention
patients with chronic kidney disease, and is therefore a of cardiovascular disease in most people with advanced
major focus of preservative care in this population.142 chronic kidney disease requiring dialysis, especially in
Lower eGFR and higher albuminuria are independently the absence of high concentrations of serum LDLs.172
associated with a higher risk of cardiovascular events (in In people with type 2 diabetes, guidelines recommend
addition to the risk conferred by traditional risk factors that SGLT2 inhibitors and GLP-1 receptor agonists be
such as blood pressure, high cholesterol, and lifestyle) prioritised in people with chronic kidney disease.173,174
(figure 3).42,143 Although antiplatelets are often offered for secondary
Whereas the traditional shared risk factors such as cardiovascular prevention, the relative benefits and
overweight, hypertension, diabetes, dyslipidaemia, and harms for primary prevention are unknown,175 as is the
smoking are associated with cardiovascular disease in role of anticoagulation with warfarin versus direct acting
patients with earlier chronic kidney disease stages, a oral anticoagulants in advanced chronic kidney disease.176
host of non-traditional risk factors magnify the risk In a randomised controlled trial of patients with a history
of cardiovascular disease, especially in patients with of acute coronary syndrome in the previous 3 months,
advanced chronic kidney disease. Some of these so-called type 2 diabetes, and low concentrations of HDLs,
kidney-specific factors include inflammation with or apabetalone (a novel epigenetic modulator) added to
without protein-energy wasting, mineral and bone standard therapy resulted in a 52% reduction in the risk
disorders, and endothelial dysfunction.144–151 of major adverse cardiovascular events among subgroups

Seminar
Kidney-preserving care Supportive care level of Comments

level of relevance relevance
Slowing chronic kidney disease Strongly relevant Possibly relevant to Important goal across both domains of care, but not the primary goal of supportive care
progression moderately relevant
Preventing or delaying dialysis Strongly relevant Strongly relevant Both domains aim to prevent or delay initiation of dialysis
Symptom management Possibly relevant to Strongly relevant Addressing symptoms is one of the key priorities of supportive care, but should also have an
moderately relevant important role in preservative management
Health-related quality of life and Moderately relevant to Strongly relevant Each domain aims to improve quality of life through different approaches: kidney-preserving care
patient-reported outcomes strongly relevant prioritises aggressive treatments to restore and protect health and quality of life, whereas supportive
care places a greater focus on maintaining quality of life by minimising invasive interventions
Prioritising overall survival with Strongly relevant Not relevant to possibly Preventing complications, addressing comorbidities, and prolonging survival are among the
life-prolonging and kidney- relevant highest priorities of kidney-preserving care, whereas alleviating symptoms is prioritised over
prolonging care prolonging survival with supportive care
Cardiovascular health Strongly relevant Not relevant to possibly Reducing cardiovascular risk is a fundamental aspect of kidney-preserving care, and less of a
relevant priority with supportive care
Minimising risk of acute kidney Strongly relevant Possibly relevant to Important aspect of both domains
injury and infection moderately relevant
Diet and lifestyle modifications Strongly relevant Possibly relevant Dietary strategies (eg, plant-dominant, low-protein diet) are an important component of kidney-
preserving care, whereas dietary approaches can be more flexible with supportive care, focusing on
quality of life and comfort care
Chronic kidney disease Strongly relevant Possibly relevant Targeted and non-targeted pharmacotherapies aimed at preserving kidney function are less of a
pharmacotherapy priority with supportive care, in which pharmacotherapy is mostly for symptom management
Treating uraemia and complications Strongly relevant Possibly relevant to Priorities in the management of chronic kidney disease-related complications are primarily to
of chronic kidney disease moderately relevant avoid unpleasant symptoms with supportive care
Preserving residual kidney function Strongly relevant Possibly relevant Kidney-preserving care places a greater emphasis on protecting residual kidney function
after transition to dialysis and less (eg, incremental transition to dialysis), whereas palliative dialysis can be infrequent as well as
frequent dialysis include decremental dialysis regimens
Shared decision making and Moderately relevant Strongly relevant Fundamental concept in the care of all people with kidney disease and that is often more clearly
advance care planning highlighted under supportive care, including palliative care and hospice medicine
See also figure 1 for schematic representations of the domains within the chronic kidney disease management chart.
Table 3: Similarities and distinctions between kidney-preserving management and supportive and palliative care
of participants with pre-existing, stage 3 chronic kidney decompensated heart failure leading to venous
disease.177,178 Patient-reported outcomes, including health- congestion and impaired kidney blood flow, or coronary
related quality of life, should be considered a key outcome artery bypass and other major surgeries with possible
for a holistic assessment of interventions in all intraoperative hypotensive episodes.184,185
cardiovascular outcome trials involving patients with
chronic kidney disease.19,179 Role of supportive care and of palliative and
hospice medicine
Acute kidney injury People with advanced chronic kidney disease, particularly
Patients with chronic kidney disease, especially in those with kidney failure, often have a high symptom
more advanced stages (eGFR of less than 30 mL/min burden that substantially affects their health-related
per 1·73 m²) often do not exhibit linear progression of quality of life.186 Although there is little evidence from
disease, which might be related to superimposed randomised controlled trials, observational studies sug
episodes of acute kidney injury or other factors.180 Some gest that chronic dialysis might not be associated with
(but not all) studies suggest that each acute kidney improved survival in some patients older than 80 years
injury event might accelerate progression of chronic with a high burden of comorbidities, and that at least
kidney disease.181,182 Therefore, preventing acute kidney some of these patients might regret their decision to
injury is an important component of the management commence dialysis in view of treatment-related complica
of chronic kidney disease. This prevention involves tions, high symptom burden, and poor quality of life.187,188
avoiding acute kidney injury-associated drug com These factors have led to an increased recognition of the
binations (eg, ACE inhibitors or angiotensin receptor importance of supportive care of kidney failure (figure 1).
blockers in conjunction with loop diuretics and non- There are similarities and distinctions between
steroidal anti-inflammatory drugs)183 and preventing kidney-preserving management and supportive care,
infections that can precipitate hypotension or septic including palliative care and hospice medicine (table 3).
shock necessitating the use of potentially nephrotoxic Both strategies are expected to minimise the risk of
antimicrobials. Other contribu tors to acute kidney adverse events or complications, such as acute kidney
injury include cardiovascular events, particularly injury, as chronic kidney disease progresses, although

Seminar
kidney-preserving management is more strongly progression, although this approach has not been
focused on kidney function longevity. Whereas palliative assessed in clinical trials.198
care strat egies are often considered for those with During the COVID-19 pandemic, data suggest a
advanced age (ie, older than 80 years) or more severe two times increase in mortality from COVID-19 in the
comorbidities, such as terminal cancer,21–24,26–33 kidney- presence of chronic kidney disease.199 Despite screening
preserving management is a kidney-sustaining and life- and isolation of affected patients, outbreaks cannot
sustaining strategy for all individuals and at any stage of always be prevented because some infected individuals
chronic kidney disease. can have long incubation periods or be asymptomatic
The goal of supportive care is to improve symptoms carriers.199 To maintain adequate staffing and to protect
and quality of life through a multidisciplinary approach patients, outpatient chronic kidney disease care has
that incorporates shared decision making, detailed undergone a radical transformation with the use of
communication with patients and their care partners, telemedicine and remote care to guide dietary and
advanced care planning, and psychological and social therapeutic decisions.200 Advance care planning and
support.189,190 Standardised tools to identify those who ensuring completion of renal replacement therapy
might benefit the most from supportive care are not plans are of even higher importance because COVID-19
widely validated, and thus treatment decisions, such as can cause acute kidney injury through septic shock,
fluid management, must be individualised—including cytokine release, or direct renal tropism of the virus.201,202
for those who decide to reduce dialysis dose and Ongoing and future trials are expected to examine
frequency to a minimum (the so-called decremental or whether ACE receptor modulators or other modulators
palliative dialysis), or to withdraw completely from renal of kidney function can avert COVID-19 involvement
replacement therapy (figure 1).191 Novel prediction tools in acute kidney injury and chronic kidney disease
have been developed to identify individuals who would progression.201–203
have the highest mortality in the first year after
transitioning to dialysis and who might therefore benefit Global and regional disparities in preserving
from palliative care,45 but these tools need to be more kidney care
widely validated. The decision must be according to the Preserving kidney function in people with chronic kidney
free choice of the patient, without pressure by family disease is confounded by regional and global health
members and care partners or health-care professionals, inequalities, disparities in health-care models, phar
and it should not be influenced by rationing dialysis maceutical industry policies, and geopolitical and fiscal
care such as during COVID-19 pandemic surges or complexities.204 Income disparities, poverty, and social
other resource constraints.17 Importantly, preservation of disadvantages have a dominant effect on the risk of
kidney function and supportive care are entirely com incident chronic kidney disease and its progression.205,206
plementary and should be considered as parts of the full Many people at risk of chronic kidney disease in
spectrum of conservative management of chronic kidney low-income and middle-income countries are not
disease, depending on the severity of the disease and on provided with appropriate infrastructure for screening
the goals of the individual (figure 1; table 3). and identification of chronic kidney disease. The
awareness of chronic kidney disease is relatively poor,
Infection control and management of chronic and opportunities for updating knowledge and education
kidney disease in the COVID-19 pandemic on preserving kidney health are scarce.207
Evidence suggests that uraemia is associated with worse In low-income and middle-income countries, diet and
immune response, as exemplified by the diminished lifestyle modification might offer an inexpensive approach
antibody response to hepatitis B vaccination or by the for primary, secondary, and tertiary prevention of chronic
higher risk of infections as kidney function worsens, not kidney disease, notwithstanding the little scientific
otherwise explained by concurrent comorbidities, and by evidence to justify population-based programmes for
the historical observation that autoimmune diseases such lower sodium intake, promotion of plant-based diets,
as systemic lupus erythematosus are less aggressive once and adequate hydration. Whereas pharmacotherapy and
patients have uraemia.192 Similarly, some infections, dialysis treatment are almost universally accessible in
such as hepatitis C, might cause chronic kidney disease if high-income countries, many people in low-income and
untreated,193,194 or can lead to faster disease progression middle-income countries are unable to access these
and greater mortality in the case of pre-existing chronic options.208 The out-of-pocket expenditure for chronic
kidney disease.195 Conversely, treatment of hepatitis C kidney disease preserving pharmacotherapy is high
might possibly have a salutary effect in preserving kidney relative to income; for instance, in India, the high costs
function.196 Patients with chronic kidney disease have of SGLT2 inhibitors or renal replacement therapy are
a two times higher risk of death after respiratory more likely to push people into the poverty range than
infections;197 therefore, influenza and pneumococcal communicable diseases.209
vaccinations might be an indirect way to prevent acute In some high-income nations, such as the USA, there
kidney injury and avoid chronic kidney disease are racial disparities in chronic kidney disease care.210

Seminar
Black Americans are far more likely to develop chronic Contributors

kidney disease and exhibit faster disease progression All authors contributed equally to the conception, interpretation of the
relevant literature, writing, and critical revision of this Seminar.
than White Americans.211 This disparity might be related
to socioeconomic factors such as access to care, exposing Declaration of interests
KK-Z reports commercial honoraria and support from Abbott, AbbVie,
many Black Americans to higher chronic kidney disease Alexion, Amgen, AstraZeneca, Aveo, Chugai, DaVita, Fresenius,
risks; furthermore the higher prevalence of a pathogenic Genentech, Haymarket Media, Hospira, Kabi, Keryx, Novartis, Pfizer,
APOL1 allele in Black Americans might partly explain Relypsa, Resverlogix, Sandoz, Sanofi, Shire, Vifor, UpToDate, and
the high burden of chronic kidney disease in this ZS Pharma. DN is part of the steering group of GlaxoSmithKline-funded
studies investigating aspects of kidney disease in sub-Saharan Africa.
population.212 The current creatinine-based eGFR BLN reports travel support from Janssen and consultancy fees (trial
equations have a race index for Black Americans, which steering committee member) from Bayer paid to institution. VP has
inflates the eGFR value by as high as 16% compared served on steering committees, advisory boards, or given scientific
with non-Black Americans with the same serum presentations supported by AbbVie, Amgen, Astellas, AstraZeneca, Bayer,
Baxter, Bristol Myers Squibb, Boehringer Ingelheim, Chinook, Dimerix,
creatinine concentration.213 In an effort to reduce racial Durect, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Janssen,
disparities in chronic kidney disease care, race indices Merck Sharp & Dohme, Metavant, Mitsubishi Tanabe, Mundipharma,
have been suggested to be removed from eGFR equations Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Sanofi,
Servier, Vifor, Vitae, UpToDate, and Tricida. THJ declares no competing
to enable a more commensurate approach to the burden
interests.
of chronic kidney disease.214 Race-free measurements,
Acknowledgments
such as serum cystatin C-derived eGFR equations, could
THJ is supported by the Singapore National Medical Research Council.
be used instead, especially given their more linear This work was supported by research grant K24-DK091419 from the
associations with clinical outcomes (figure 3).143,214 National Institutes of Health and by philanthropic grants from
Harold Simmons and Joseph Lee.
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Chronic kidney disease

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• Physical activity • MR antagonists • Glucose-lowering drugs • Anaemia management function

Infection control and acute kidney injury prevention

Incremental Renal replacement therapy:

Estimated GFR 90 60 45 30 25 15 10 5 mL/min per 1·73 m2

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Advantages and rationale Disadvantages Additional comments

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Effect on chronic kidney disease Effect on cardiovascular disease Comments Recommendations

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filtration rate suggested that there was a benefit of dietary

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3·0 challenges include interpretation of cardiac biomarkers

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Kidney-preserving care Supportive care level of Comments

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Black Americans are far more likely to develop chronic Contributors

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