Clinical Kidney Journal, 2023, vol. 16, no.

11, 1737–1750

https:/doi.org/10.1093/ckj/sfad101
Advance Access Publication Date: 26 April 2023
CKJ Review

CKJ REVIEW

Management of traditional risk factors for the

development and progression of chronic kidney

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disease
Robin Lo1 , Yoko Narasaki1,2 , Sean Lei1 and Connie M. Rhee1,2
1
Harold Simmons Center for Chronic Disease Research and Epidemiology, Division of Nephrology and
Hypertension, University of California Irvine, Orange, CA, USA and 2 Tibor Rubin Veterans Affairs Medical
Center, Long Beach, CA, USA
Correspondence to: Connie M. Rhee; E-mail: crhee1@uci.edu

ABSTRACT
Chronic kidney disease (CKD) and its downstream complications (i.e. cardiovascular) are a major source of morbidity
worldwide. Additionally, deaths due to CKD or CKD-attributable cardiovascular disease account for a sizeable proportion
of global mortality. However, the advent of new pharmacotherapies, diagnostic tools, and global initiatives are directing
greater attention to kidney health in the public health agenda, including the implementation of effective strategies that
(i) prevent kidney disease, (ii) provide early CKD detection, and (iii) ameliorate CKD progression and its related
complications. In this Review, we discuss major risk factors for incident CKD and CKD progression categorized across
cardiovascular (i.e. hypertension, dyslipidemia, cardiorenal syndrome), endocrine (i.e. diabetes mellitus, hypothyroidism,
testosterone), lifestyle (i.e. obesity, dietary factors, smoking), and genetic/environmental (i.e. CKDu/Mesoamerican
nephropathy, APOL1, herbal nephropathy) domains, as well as scope, mechanistic underpinnings, and management.

LAY SUMMARY
In this Review, we discuss major risk factors for incident chronic kidney disease (CKD) and CKD progression
categorized across cardiovascular (i.e. hypertension, dyslipidaemia, cardiorenal syndrome), endocrine (i.e. diabetes
mellitus, hypothyroidism, testosterone), lifestyle (i.e. obesity, dietary factors, smoking), and genetic/environmental
(i.e. CKDu/Mesoamerican nephropathy, APOL1, herbal nephropathy) domains, as well as scope, mechanistic
underpinnings, and management.

Keywords: chronic kidney disease, risk factors, traditional

INTRODUCTION mortality, deaths due to CKD or due to CKD-attributable cardio-

vascular disease are estimated at 1.2 million and 1.4 million,
The global prevalence of chronic kidney disease (CKD) is ap-
respectively [1, 3]. International data show that, while the age-
proximately 9.1%–13.4% [1, 2], and is a major source of mor-
standardized mortality for other chronic diseases (i.e. cardiovas-
bidity and mortality. As the twelfth leading cause of worldwide
cular disease, cancer, chronic obstructive pulmonary disease)

Received: 6.6.2022; Editorial decision: 3.4.2023

© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA. This is an Open Access article distributed under the terms of the Creative
Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution,
and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

1737
 1738 R. Lo et al.

has declined over the past two decades, a similar reduction in American Heart Association Hypertension (ACC/AHA) guide-
age-standardized deaths has not been observed for CKD [1]. lines target a goal of blood pressure ≤130/80 mmHg in CKD pa-
Given the ill effects of CKD on health and survival [4], there is tients, while the European Society of Hypertension-European
compelling need to (i) identify populations at risk of and in early Society of Cardiology committee recommends a goal blood pres-
stages of kidney disease, and (ii) improve access to evidence- sure of less than 140/90.
based treatments that retard or halt kidney disease progression. The rationale behind the targets recommended by these var-
Globally, executive orders such as the US Advancing American ious organizations largely rests on five randomized clinical tri-
Kidney Health Initiative have sought to stimulate greater at- als comparing intensive vs. standard blood pressure control reg-
tention to kidney health in the public health agenda [5]. Addi- imens [11, 18–21], summarized in Table 2. Briefly, earlier trials
tionally, the advent of new pharmacotherapies and diagnostic that examined blood pressure targets in CKD patients alone
tools have catalysed a renewed focus on targeting key contrib- found that intensive control only provided benefit at reducing
utors to CKD. In this Review, we summarize the major risk fac- the rate of eGFR decline in patients with baseline proteinuria
tors for the development of incident CKD and CKD progression, >1 g/day. These trials did not detect differences in mortality nor
categorized across cardiovascular, endocrine, lifestyle, and ge- cardiovascular protection but were underpowered to detect
netic/environmental domains. Focusing on their most common these outcomes [18–20]. The Action to Control Cardiovascular

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traditional CKD risk factors, we discuss their prevalence, mech- Risk in Diabetes (ACCORD-BP) trial was a subsequent larger
anistic underpinnings, and management (Table 1). trial examining primarily cardiovascular outcomes based on
differing blood pressure targets in diabetic patients but had
strict exclusion criteria to remove CKD patients from their
RISK FACTORS FOR CHRONIC KIDNEY DISEASE
study population [21]. It was not until the 2015 Systolic Blood
Cardiovascular Pressure Intervention Trial (SPRINT), a large randomized clin-
ical trial of 9361 patients, where the cardiovascular bene-
Hypertension
fits of intensive blood pressure reduction were more clearly
Hypertension is estimated to affect approximately 1.39 billion shown [11]. Despite not analysing renal outcomes as their pri-
people (31.1%) worldwide, and it is closely linked to CKD [6]. In mary outcome, a post hoc analysis examining the substan-
the USA, CKD was found to be present in about 15% of all hy- tial CKD subcohort of 2646 patients in the SPRINT trial still
pertensive patients, while hypertension was comorbid in about showed significant reductions in cardiovascular outcomes and
90% of the Medicare CKD population [7, 8]. In terms of underlying overall mortality with the lower blood pressure goal of SBP
pathophysiology, chronically elevated systemic blood pressure <120 mmHg but did not find differences in renal outcomes
results in remodelling of the afferent arteriole, hampering its [22]. These findings of cardiovascular and mortality benefit
ability to autoregulate intraglomerular pressure. Subsequently, with stricter blood pressure control in the CKD population
elevated systemic pressures are directly transmitted to the vas- continue to be supported by meta-analyses of these clinical
cular beds resulting in glomerular hypertension and progressive trials [23, 24].
nephrosclerosis [9]. Non-pharmacologic interventions to reduce blood pressure
Accurate blood pressure readings are critical to hypertension in CKD patients should be attempted first or used in conjunc-
diagnosis and management. Major clinical trials rely on at least tion with pharmacologic therapies. Current guidelines still rec-
two serial in-office blood pressure measurements: avoidance of ommend a low salt diet, targeting <2 g per day [17]. Studies have
caffeine and exercise 30 minutes before, quiet rest 5 minutes correlated higher urinary sodium excretion to both worse re-
before, sitting down with feet flat to the ground and back sup- nal and cardiovascular outcomes [25, 26], and reduced dietary
port, and placing the cuff arm at the level of the atrium [9–11]. sodium intake can cause reductions in proteinuria by 22% [27].
However, the CKD population has shown a tendency towards Of note, a recent clinical trial comparing the use of salt substi-
blood pressure variability outside the detection of in-office mea- tutes (25% potassium chloride) compared to regular salt (100%
surements, such as masked hypertension or nocturnal hypoten- sodium chloride) found decreased rates of stroke, major adverse
sion [12]. These entities are often underdiagnosed and under- cardiovascular events, and death [28]. Whereas this study found
appreciated in specific subpopulations, with the Jackson Heart no impact on safety events related to hyperkalaemia in the gen-
Study showing a prevalence of masked hypertension in more eral population, a modelling study did report an increase in mor-
than half of its black participants (52.2%) and another study in tality attributable to hyperkalaemia from salt substitutes in the
CKD patients showing a prevalence of 27.8% [13, 14]. Multiple CKD population albeit with an overall net reduction in mortality
studies have shown that cardiovascular risk is more accurately when compared to its cardiovascular benefits [29].
predicted by home blood pressure monitoring and 24-hour am- Other lifestyle interventions impacting hypertension in CKD
bulatory blood pressure monitoring compared to in-office mea- patients include moderate-intensity exercise for at least 150
surements [15, 16]. However, it is notable that no large clini- minutes per week, treatment of sleep apnoea, weight loss,
cal trial completed thus far has used 24-hour ambulatory blood and avoiding nonsteroidal anti-inflammatory pain medications.
pressure monitoring to guide therapy for hypertension, and thus More recently, trials have demonstrated the potential utility of
targets based on ambulatory blood pressure are not strictly evi- renal denervation, or radiofrequency ablation of nerves around
dence based. the renal artery, to treat refractory or resistant hypertension [30].
Blood pressure target recommendations currently differ A small study explored renal denervation in stages 3–4 CKD pa-
across various organizational guidelines. Recently, the Kidney tients with about 30 mmHg reduction in SBPs and significant
Disease Improving Global Outcomes (KDIGO) 2021 guidelines decreases in nocturnal ambulatory blood pressures as well [31].
recommended targeting a systolic blood pressure (SBP) goal of Larger trials will be needed before this procedure can be recom-
less than 120 mmHg in CKD patients, although placing a heavy mended in CKD hypertension guidelines.
emphasis on individualizing goals based on patient characteris- In terms of pharmacologic therapies, the renin-angiotensin-
tics and tolerance of intensive blood pressure therapy [17]. On aldosterone system (RAAS) inhibitors such as angiotensin-
the other hand, the 2017 American College of Cardiology and converting enzyme inhibitors (ACEi) or angiotensin II receptor
 Traditional Risk Factors in CKD 1739

Table 1: Prevalence, mechanisms, and management of risk factors for the development and progression of CKD.

Risk factor Prevalence Mechanisms Management

Endocrine
Diabetes Mellitus 25%–40%a Glomerular hyperfiltration Individualized HgbA1c targets <6.5%–8.0%
[143] Overactivation of RAAS RAAS blockade
Oxidative stress GLP-1 receptor analogues
Immune dysfunction SGLT-2 inhibitors
Hypothyroidism 55.5%b Decreased cardiac output Levothyroxine replacement
Decreased RAAS activity
Altered renal haemodynamics
Increased tubuloglomerular feedback
Testosterone Further research Oxidative stress Further research needed
needed Fas-FasL mediated apoptosis
Excessive extracellular matrix deposition

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Hypertension
Cardiovascular
Hypertension 15%–30%a Remodelling of afferent arteriole → direct Lifestyle modifications
[7, 143] transmission of blood pressure → progressive - Low salt diet
nephrosclerosis - Exercise
- Weight loss
ACEi/ARB
- First line in proteinuric CKD
Diuretics
CCBs
MRAs
SGLT-2 inhibitors
Dyslipidaemia 53.9%b Lipid accumulation → oxidative stress, lipid Lifestyle modifications
peroxidation and mitochondrial damage Statin therapy for eGFR <60 ml/min/1.73 m2
indicated if:
- Age ≥50 years old, or
- Age 18–49 and one of the following:
◦ Coronary artery disease
◦ Diabetes mellitus
◦ Prior ischaemic stroke
◦ 10-year risk of coronary death or
myocardial infarction >10%
Cardiorenal 49%–91%a Reduced cardiac output → reduced renal Symptomatic Management
[60, 61] perfusion → renal ischaemia - Loop diuretics ± Metolazone
Increased central venous and intra- Survival Management
abdominal pressures → renal venous - β-blockers
congestion - ACEi/ARBs
Oxidative stress - MRAs
Inflammatory mediators - Ivabradine
- Angiotensin receptor neprilysin inhibitors
- SGLT-2 inhibitors
- Device therapies
Lifestyle
Obesity 17%a [143] Altered renal haemodynamics Weight loss, esp. bariatric surgery
Inflammation GLP-1 receptor agonists
Oxidative stress RAAS blockade
Dietary Factors Further research Dietary acid load Plant-based low protein (PLADO) diet intake
needed Uremic toxins by gut microbiota ↓ saturated fat intake, ↑ mono and unsaturated
Cardiovascular comorbidities fat intake
↓ sodium intake
Smoking 50%b Oxidative stress Smoking cessation
Environmental
CKDu 9%–18%b Intense heat & strenuous working Hydration
conditions → dehydration → pre-renal injury
APOL1 20%b Podocyte cytotoxic injury Avoid preventable infections
Herbal Nephropathy 50%b Interstitial fibrosis Avoid offending agents

a
Prevalence of CKD in risk factor population.
b
Prevalence of risk factor in CKD population.
Abbreviations: RAAS, renin-angiotensin-aldosterone system; GLP-1, glucagon-like peptide-1; SGLT-2, sodium-glucose cotransporter-2; CKD, chronic kidney disease; ACEi,
angiotensin-converting enzyme inhibitor; ARB, aldosterone receptor blocker.
 1740
R. Lo et al.

Table 2: Randomized clinical trials comparing intensive vs. standard blood pressure control regimens in CKD patients.

BP goal CKD population Results

Trial Year Primary outcome Standard Intensive Key characteristics Size Mortality CV protection Renal protection

MDRD 1995 Rate of eGFR MAP ≤ 107 mmHg MAP ≤ 92 mmHg eGFR 15–55 ml/min/ 840 n/a n/a Decreased eGFR
change; change 1.73 m2 decline in intensive
in proteinuria BP control group if
baseline proteinuria
>1 g/day
AASK 2002 Rate of eGFR MAP 102–107 mmHg MAP ≤ 97 mmHg eGFR 20–65 ml/min/ 1094 No difference No difference Decreased eGFR
change; 1.73 m2 (not powered) (not powered) decline in intensive
composite 50% African-American BP control group if
reduced GFR, Non-diabetic baseline proteinuria
ESRD, or death >1 g/day
REIN-2 2005 Time to ESRD DBP < 90 mmHg BP < 130/80 mmHg eGFR <70 ml/min/ 335 No difference No difference No difference in
1.73 m2 (not powered) (not powered) time to ESRD
Proteinuria > 1 g/day
Non-diabetic
On ACEi
ACCORD 2010 Composite of MI, SBP < 140 mmHg SBP < 120 mmHg Type 2 diabetics n/a No difference Decreased stroke n/a
stroke, or CV Creatinine ≤ 1.5 mg/dl risk in intensive
death Proteinuria < 1 g/day BP control group
SPRINT 2015 Composite of MI, SBP < 140 mmHg SBP < 120 mmHg eGFR >20 ml/min/ 2646 Decreased in Decreased No difference in
other ACS, 1.73 m2 CKD cohort in primary outcome renal outcomes
stroke, HF, or CV Non-diabetic intensive BP in CKD cohort in
death control group intensive BP
control group

Abbreviations: MDRD, Modification of Diet in Renal Disease; AASK, African-American Study of Kidney Disease and Hypertension; REIN-2, blood pressure control for renoprotection in patient with non-diabetic chronic renal disease;
MAP, mean arterial pressure; DBP, diastolic blood pressure, BP, blood pressure; CV, cardiovascular.

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 Traditional Risk Factors in CKD 1741

blockers (ARB) are considered first line for patients with hyper- 1.4-, 3.1-, and 3.8-fold, respectively [47]. While another Japanese
tension and proteinuric CKD [17, 32]. Studies have demonstrated study showed that hypercholesterolaemia, hypertriglyceri-
their ability to reduce the risk for developing CKD progression daemia, and low high-density lipoprotein (HDL) levels were all
and cardiovascular morbidities by about 50% [33]. Even in pa- independently associated with worsening proteinuria in a 10-
tients reaching stages 4-5 CKD, a recent trial found that contin- year follow-up study, the overall literature suggests the associ-
uing ACEi/ARB therapy was associated with decreased mortality ation with progression of CKD is still controversial [48, 49]. An-
and major cardiovascular events, albeit with an increased risk other important regulator of lipid homeostasis, proprotein con-
of initiated kidney replacement therapy [34]. In non-proteinuric vertase subtilisin/kexin type 9 (PCSK9), was recently shown to
CKD, the evidence is less clear regarding the superiority of RAAS be associated with increased risk of cardiovascular disease in a
inhibitors compared to other anti-hypertensives. Combinations CKD population, but had no relation with eGFR or albuminuria
of ACEi with an ARB or direct renin inhibitor are not recom- [50]. In terms of pathophysiology, the dyslipidaemia associated
mended. Serum creatinine may be expected to rise to 30% within with CKD seems to primarily be comprised of high triglyceride
the first 4 weeks of starting RAAS blockade, but should be discon- levels, low HDL levels, and variable LDL levels [51, 52]. Excess
tinued for increases of >30% [17]. lipid accumulation causes damage to podocytes, tubular cells,
Mineralocorticoid receptor antagonists (MRAs) such as and tubulointerstitial tissue by various mechanisms including

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spironolactone and eplerenone have been shown to reduce pro- production of reactive oxygen species, lipid peroxidation, and
teinuria as well [35] but should be closely monitored for hyper- mitochondrial damage leading to glomerular and tubular lesions
kalaemia in CKD patients with eGFR <45 ml/min/1.73 m2 [17]. [51].
Finerenone, in particular, a nonsteroidal and selective MRA, has Guidelines for initiating and monitoring statin therapy by the
recently been shown to reduce CKD progression and cardiovas- United States Preventive Services Task Force and the ACC/AHA
cular events in patients with comorbid CKD and type 2 diabetes currently do not comment specifically on individuals with CKD.
[36, 37]. Cardiovascular outcomes were shown to be improved The atherosclerotic cardiovascular (ASCVD) risk calculator also
even in stages 1-2 CKD patients with severely elevated albumin- does not include CKD status [32, 53]. KDIGO guidelines recom-
uria [38]. mend measuring a lipid profile for newly diagnosed CKD and
Diuretics are another important tool to help reduce the vol- starting statin or statin-ezetimibe combination therapy in adults
ume overload seen in CKD patients. Thiazides such as chlorthali- aged ≥50 years old with eGFR <60 ml/min/1.73 m2 . For adults
done are initially preferred due to their long half-life [32], with aged 18–49 with CKD, the guidelines recommend statin therapy
recent clinical trial data showing improvement in blood pres- if there is also one of the following comorbidities: known coro-
sure at advanced stages of CKD (i.e. stage 4 CKD) [39]. While nary disease, diabetes mellitus, previous ischaemic stroke, or
loop diuretics such as furosemide remain effective for diuresis 10-year risk of coronary death or non-fatal myocardial infarc-
at lower GFRs relative to thiazides, benefit on clinical outcomes tion >10% [54]. Studies have demonstrated cardiovascular ben-
have not yet been demonstrated [17]. Sodium-glucose cotrans- efits for starting statin therapy in the CKD population, with re-
porter 2 (SGLT-2) inhibitors, which also have both diuretic and duction of major cardiovascular events by 23%–28% [55]. How-
antihypertensive effects, can decrease blood pressure by about ever, this reduction becomes relatively smaller as eGFR declines
7–9 mmHg, although not all the renal and cardiovascular bene- [56] and no major trials thus far have demonstrated any bene-
fits can be explained by blood pressure reduction alone [40– 43]. fit of statin therapy for preventing or ameliorating adverse renal
Both non-dihydropyridine (i.e. verapamil, diltiazem) and outcomes [57–59]. Other pharmaceuticals besides statin therapy
dihydropyridine (i.e. amlodipine, felodipine) calcium channel including niacin, fibrates, fish oil, bile acid resins, and (PCSK9
blockers (CCBs) have been shown to be efficacious in reduc- inhibitors have not been well studied in the CKD population, al-
ing proteinuria in CKD patients when used in conjunction with though there is emerging interest in niacin for its phosphorus-
RAAS blockade [44, 45]. The combination of benazepril with am- lowering effects [52].
lodipine in particular was shown to be more effective than the
combination with hydrochlorothiazide in the Avoiding Cardio-
Cardiorenal syndrome
vascular events through Combination therapy in Patients Living
with Systolic Hypertension (ACCOMPLISH) trial at preventing the The cardiorenal syndrome, a term used to describe the syn-
doubling of serum creatinine and end-stage renal disease (ESRD) chronous dysfunction of the heart and kidneys by complex feed-
[45]. back mechanisms, also contributes significantly to the CKD pop-
Other agents such as β-blockers, α-blockers, and direct va- ulation. One meta-analysis estimates CKD (eGFR <60 ml/min/
sodilators like minoxidil and hydralazine have not been shown 1.73 m2 ) to be prevalent in about half (49%) of the total heart fail-
to have significant renoprotective effects and should not be used ure population, with higher prevalence in the acute heart failure
before the aforementioned agents have been exhausted [46]. (53%) compared to chronic heart failure (42%) [60]. In another
However, in clinical practice, it is common to encounter the database, the Acute Decompensated Heart Failure National Reg-
use of later line agents in advanced CKD patients due to the istry (ADHERE), 91% of the more than 105 000 participants had
side-effect profile of the aforementioned agents such as hypona- some degree of renal dysfunction (eGFR <90 ml/min/1.73 m2 )
traemia (i.e. thiazides), hyperkalaemia (i.e. ACEi/ARB, MRAs), and [61]. Heart failure patients with CKD also portend a greater than
oedema (i.e. CCBs). 2-fold higher mortality risk compared to their non-CKD counter-
parts [60].
Management of heart failure patients focus on both
Dyslipidaemia
symptoms and overall survival. Diuretic therapies with loop
Patients with dyslipidaemia show heightened risk of develop- diuretics are often required at higher doses and/or used in
ing CKD. One recent study of 5183 patients in China during combination with metolazone in patient with lower GFRs to
a 6-year follow-up period showed that in the highest quar- help improve shortness of breath and peripheral oedema. While
tiles of low-density lipoprotein (LDL), triglycerides, and total thiazide diuretics were previously thought to be ineffective in
cholesterol, the risk of developing incident CKD increased by stages 4–5 CKD [62], a recent clinical trial has shown efficacy
 1742 R. Lo et al.

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Figure 1: Conceptual figure of endocrine risk factors of CKD.

of chlorthalidone in improving blood pressure among advanced tion to CKD DALY burden of any cause and the only cause to
CKD patients with poorly controlled hypertension [39]. Notably, show a significant increase in DALY rate from 1990 to 2017 [1].
most heart failure clinical trials have excluded patients with The pathophysiological mechanisms of diabetic kidney disease
eGFR <30 ml/min/1.73 m2 . However, trials have demonstrated include glomerular hyperfiltration from overactivation of the
survival benefit in patients with both heart failure with re- RAAS system, oxidative stress, and immune dysfunction leading
duced ejection fraction and stages 1–3 CKD for β-blockers [63], to mesangial expansion and glomerular filtration barrier dam-
ACEi/ARBs [64], and MRAs [65]. Other newer medications have age [74].
also demonstrated benefit. Ivabradine and angiotensin receptor Cornerstones of CKD management in diabetic patients in-
neprilysin inhibitors both demonstrated improved cardiac death clude strict glycaemic control to prevent CKD onset and early
and heart failure hospitalization outcomes in trials with CKD pa- progression, and RAAS blockade, glucagon-like peptide-1 (GLP-
tients [66, 67]. SGLT-2 inhibitors in particular have shown signif- 1) receptor analogues, SGLT-2 inhibitors to prevent progression
icant promise with trials demonstrating not only reductions in of overt CKD. Multiple trials have demonstrated decreased rates
cardiovascular death and heart failure hospitalizations by 25%, of CKD with lower HgbA1c targets, including a 22-year follow-
but also 50% reduction in the incidence of kidney replacement up of the Diabetes Control and Complications (DCCT) trial that
therapy or sustained loss of eGFR [68]. Device therapies for heart showed 50% reduction of CKD incidence in the intensive glu-
failure with reduced ejection fraction, such as cardiac resyn- cose control group [75, 76]. However, other trials involving type 2
chronization therapy and internal cardioverter and defibrilla- diabetes failed to demonstrate improved kidney outcomes with
tors, have demonstrated similar benefit in stage 3 CKD patients stricter control of HgbA1c and instead showed increased mortal-
compared to those with eGFR >60 ml/min/1.73 m2 [69, 70]. Given ity and risk of hypoglycaemia [10, 77]. Thus, current guidelines
the high cardiovascular mortality of CKD patients, further in- recommend selecting an individualized goal from a broader
vestigation of the risks and benefits of permissive hypercrea- range of HgbA1c values, <6.5%–8.0%, balancing the benefits of
tininaemia in the context of interventions that optimize heart renal and cardiovascular protection with the risks of hypogly-
failure status are needed. caemia [78].
Trials examining the effect of ACEis and ARBs on type 2 dia-
betics have shown a reduction in composite endpoint of dou-
Endocrine bling of serum creatinine, death, and kidney failure by 16%–
Diabetes mellitus 20% over three years, independent of blood pressure reduction
[79]. As mentioned in the hypertension section, recent trials re-
There are various endocrine risk factors for CKD, including di- garding finerenone in type 2 diabetic patients have also shown
abetes mellitus (Fig. 1) [71]. Of the estimated 374 million indi- a 17.8% decrease in CKD progression events and a 14.8% de-
viduals with diabetes worldwide [72], about one-half of type 2 crease in cardiovascular events [36]. GLP-1 receptor analogue tri-
diabetics and one-third of type 1 diabetics will develop CKD [73]. als have shown more than 25% decreased risk of stage A3 kid-
One study found that CKD due to diabetes resulted in 11 mil- ney disease (>300 mg urine albumin/g urine creatinine) over 3.8
lion disability-adjusted life years (DALYs), the largest contribu- years in type 2 diabetic patients, alongside their cardiovascular
 Traditional Risk Factors in CKD 1743

protective effects [80–82]. Last, SGLT-2 inhibitor trials have increased reactive oxygen species (ROS) mediated renal injury,
shown considerable promise in reducing cardiovascular out- either by directly inhibiting antioxidant enzymes or indirectly
comes as well as diabetic kidney disease progression [83, 84]. Re- magnifying ROS production during acute renal injury. In con-
cent trials powered for renal outcomes such as the Canagliflozin trast, oestrogen inhibits the production of ROS during acute re-
and Renal Outcomes in Type 2 Diabetes and Nephropathy nal injury [97]. Testosterone can also directly induce renal tubule
(CREDENCE) trial showed reduction by 30% of a composite out- cell injury by activating the Fas-FasL mediated apoptosis path-
come of doubling of serum creatinine, renal or cardiovascular way, which is inhibited when oestradiol is present [98]. Finally,
death, and kidney failure in the canagliflozin arm [85]. The Da- testosterone is associated with hypertension through hypothe-
pagliflozin in Patient with Chronic Kidney Disease (DAPA-CKD) sized RAAS stimulation, increased renal sodium reabsorption,
trial interestingly showed a similar reduction not only in type 2 and/or increased vascular resistance from amplified vascular
diabetics but also for non-diabetic kidney disease, further high- smooth muscle cell proliferation. These mechanisms ultimately
lighting the significance of this class of medications in prevent- result in hypertension-mediated renal injury [99].
ing progression of CKD [86].

Lifestyle
Hypothyroidism

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Obesity
Hypothyroidism is highly prevalent in kidney disease, with
various large population-based studies showing approximately Obesity has been described by multiple epidemiological stud-
25% of patients with moderate-to-advanced CKD affected by ies to be independently associated with CKD. In one study, an
this endocrine disorder [87–89]. Studies have also confirmed increase in weight of >10% of the baseline BMI resulted in an
a higher prevalence of hypothyroidism with increasing sever- approximately 30% increase in the risk for developing CKD in
ity of kidney function. Those with eGFR <30 ml/min/1.73 m2 men [100]. Another study examining a hypertensive population
were twice as likely to have hypothyroidism as those with eGFR found the association between obesity and developing CKD to
>60 ml/min/1.73 m2 [87], and each decrement of 10 ml/min/ be significant even after adjusting for differences in blood pres-
1.73 m2 of eGFR was associated with an 18% higher risk of hy- sure and diabetes, among other covariates [101]. Proposed mech-
pothyroidism and 0.11 mIU/l higher serum TSH level [89]. The anisms for the increased risk of CKD in obese patients include al-
precise mechanisms linking thyroid and kidney disease are still terations in renal haemodynamics possibly from increased salt
unknown. However, several potential mechanisms have been intake [102], to inflammation and oxidative stress [51, 103].
identified, including decreased cardiac output, altered intra- Multiple studies have found that weight loss is associated
renal haemodynamics, reduced RAAS production and activity, with reduction of levels of albuminuria [104, 105]. Bariatric
and increased tubulo-glomerular feedback due to changes in surgery in particular has been found to be the most effective
chloride channel and expression [88]. at reducing hyperfiltration compared to non-surgical interven-
Whereas there is overall limited literature regarding the ef- tions such as low-calorie diets or exercise; however, these un-
fects of levothyroxine replacement in hypothyroid CKD patients, controlled surgical trials included a significant number of pa-
studies have noted decreased renal disease progression in CKD tients without significant microalbuminuria at baseline [106].
patients treated for subclinical hypothyroidism [90, 91], as well GLP-1 receptor analogues are a key class of weight loss medica-
as decreased mortality in those with ESRD [92, 93]. A small ran- tions that, as mentioned above, slow progression of albuminuria
domized trial of 136 patients with subclinical hypothyroidism and prevent cardiovascular events in diabetic patients [80–82].
and early type 2 diabetic nephropathy showed decreased uri- RAAS blockade using ACEi or ARB therapy has also been shown
nary albumin excretion and LDL cholesterol when treated with to decrease proteinuria to 30%–80% of baseline in patients with
48 weeks of levothyroxine versus placebo [94]. Although the TSH obesity-related glomerulopathy [107]. Animal studies of antiox-
target recommendations specifically for the CKD population idants such as SS-31, lycopene, and melatonin show promising
have not yet been established, one study demonstrated that in- novel targets for improving obesity-related glomerulopathy but
crementally higher TSH levels (comparing >5.0 mIU/l with >10.0 require further research to evaluate efficacy and safety for hu-
mIU/L) in CKD patients were associated with higher post-ESRD man therapy [107].
mortality [92]. Given levothyroxine’s narrow therapeutic window
and potential to cause complications such as arrhythmia, re- Dietary factors
duced bone mineral density, and increased protein catabolism
Growing evidence have demonstrated the role of adhering to
in the non-CKD population, larger trials are needed to ensure
healthy dietary patterns (i.e. diet rich in vegetables, fruits,
the safety and efficacy of thyroid hormone supplementation in
legumes, nuts, whole grains, fish, and low-fat dairy; and lower in-
CKD patients.
take of red and processed meats, sodium, and sugar-sweetened
beverages) in the prevention of CKD and its progression [108,
Testosterone
109], including plant-dominant low protein (PLADO) diets. Con-
Males have a higher incidence of CKD and faster progression of current lower production of dietary acid load, uremic toxins by
kidney disease when compared to females [95]. Currently, there the gut microbiota, such as trimethylamine n-oxide (TMAO), in-
are a lack of well-established explanations for this sex discrep- doxyl sulphate, and p-cresyl sulphate, and higher intake of im-
ancy. However, sex hormones have been suggested as a possi- portant nutrients may be driving this protective association be-
ble contributing cause. The glomerular extracellular matrix is tween healthy diet with kidney health vis-a-vis improved gly-
controlled by mesangial cells and is stimulated by transforming caemic control, blood pressure control, weight management,
growth factor-β (TGF-β) [96]. In animal studies, TGF-β expression and cardiovascular risk reduction [110].
is increased by testosterone and decreased by oestradiol, and While the underlying mechanisms have not been fully elu-
excessive expression of TGF-β can lead to glomerulosclerosis- cidated, recent studies have shown biologically plausible evi-
mediated kidney disease from excessive extracellular matrix dence of the association between healthy diets and lower risk
deposition [96]. In addition, testosterone is associated with of CKD (Fig. 2). First, plant-derived foods (i.e. vegetables, fruits,
 1744 R. Lo et al.

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Figure 2: Dietary risk factors of CKD. Abbreviations: MUFA; mono-unsaturated fatty acid, PUFA; poly-unsaturated fatty acid, SFA; saturated fatty acid.

legumes, nuts, whole grains) have higher content of dietary stress mediated nephrotoxicity, and indirect kidney injury by
potassium and fibre. Given that potassium plays an important increasing the risk of developing aforementioned risk factors
role in critical cell functions including muscle contraction and such as diabetes and hypertension [118, 119]. In addition, smok-
cardiac conduction, prescribed diets that are rich in potassium, ing synergistically accelerates the development and progres-
such as the ‘Dietary Approaches to Stop Hypertension’ (DASH) sion of CKD in patients with pre-existing CKD risk factors
diet, have been shown to attenuate cardiovascular risk and [120]. Overall, smoking has been associated in a dose-dependent
thus could potentially improve kidney health [111]. Dietary fi- manner with new-onset CKD and progression of kidney dis-
bre is needed to process/absorb nutrients, as well as micronu- ease [121, 122]. Smoking cessation drastically improves health-
trients (antioxidants), and contributes to improved blood pres- related quality of life and well-being [123], and various phar-
sure, glycaemic control, dyslipidaemia, gastrointestinal motil- macotherapeutic interventions for smoking cessation have been
ity/constipation, and gut microbiota composition, which may implemented in the non-CKD population (Table 3). However,
reduce other CKD risk factors such as obesity and diabetes studies have shown that more than 20 years of abstinence in
[112]. Second, nuts and fish, which are key components of the former smokers are required to decrease the risk of new-onset
Mediterranean diet, bear healthier types of dietary fat (i.e. high smoking-associated CKD, emphasizing the lingering adverse ef-
mono- and poly-unsaturated fatty acid and lower saturated fat fects of smoking [121, 124].
content), which could improve kidney health through improv-
ing plasma lipid profiles, insulin resistance, and high blood pres-
sure [113]. Third, despite ongoing controversy with regards to re- Environmental and genetic
verse causality at extremely low levels of dietary sodium intake, CKDu/Mesoamerican nephropathy
greater sodium consumption may be detrimental with respect
to CKD progression due to increased blood pressure and extra- There are specific regions of the world where healthy popula-
cellular volume [114]. Fourth, given that observational studies tions develop CKD without the apparent aforementioned risk
in both the general and CKD populations have shown that the factors. This phenomenon is described as CKD of unknown
higher dietary phosphorus intake and elevated serum phospho- causes (CKDu). CKDu was first documented in El Salvador, and
rus levels are associated with increased risk of cardiovascular later found in rural populations of the Pacific Ocean coastline of
disease, phosphorus from plant-derived foods are less likely to southern Mexico and Central America, often collectively called
contribute to dietary phosphorus burden. For example, dietary Mesoamerican nephropathy [125]. Similar cases of CKDu were
phosphorus from plant-based foods typically occurs in the form also described in other parts of world, such Sri Lanka and India,
of phytates and have much lower bioavailability due to lack of respectively, referred to as Sri Lanka nephropathy and Uddanam
the degrading enzyme phytase in humans [115]. nephropathy [126, 127].
The aetiology of CKDu remains debatable. Currently, there
is no universally agreed aetiology to the disease. However,
based on epidemiologic studies of at-risk populations, com-
Smoking
monly found to be agricultural farmers working under intense
Smoking’s toxic effects are well known, affecting nearly all or- heat and strenuous working conditions, findings suggest re-
gans, including the kidneys [116]. With an estimated 30.8 mil- peated episodes of dehydration and heat stress result in vol-
lion people who are current smokers, a significant portion of ume depletion. Decreased volume status activates the RAAS to
the population is at risk of CKD [117]. Studies have shown increased renal tubular water and salt reabsorption and diver-
that smoking causes direct kidney injury through oxidative sion of renal blood flow via renal vasoconstriction. Permanent
 Traditional Risk Factors in CKD 1745

Table 3: Pharmacological treatment for smoking cessation.

Dosing Renal adjustment Adverse reactions Precaution

Bupropion 150 mg once daily for the first eGFR 15–60: maximum Nausea, constipation Avoid in patients with a history
three days, increase to 150 mg 150 mg daily insomnia, headache, of seizures, anorexia nervosa
twice daily afterward Avoid in eGFR ≤ 15 tachycardia, weight loss or bulimia, psychiatric
(benefit) disorder, suicidal
thoughts/behaviour or
prescribed monoamine
oxidase inhibitors
Varenicline Day 1–3: 0.5 mg once daily eGFR ≤ 30: starting dose Nausea, insomnia, Avoid in psychiatric disorders
Day 4–7: 0.5 mg twice daily 0.5 mg once daily, titrate as abnormal vivid dreams, or suicidal behaviour
Day 8–end: 1.0 mg twice daily needed to maximum dose headache
Minimal duration of treatment of 0.5 mg twice daily
12 weeks

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Nicotine Patch >10 cigarettes/day: No specific adjustment Skin irritation, Avoid in patients with a recent
12 mg/day for 6 weeks, recommendation headache, abnormal heart attack (in 2 weeks),
14 mg/day for 2 weeks, Caution in severe kidney vivid dreams angina
followed by 7 mg/day for disease
2 weeks
≤10 cigarettes/day:
14 mg/day for 6 weeks,
followed by 7 mg/day for 2
weeks

kidney injury arises from renal hypoperfusion caused by recur- with APOL1 associated CKD is HIV infection. As APOL1 is part
rent episodes of volume depletion [128]. With global warming, of the immune system, HIV indirectly increases APOL1 expres-
temperature-driven volume depletion is expected to increase. As sion through direct upregulation of the immune system such
a result, new cases of CKDu will probably be observed in regions as interferon [137]. Other viral infections (i.e. JC virus) or non-
previously not documented [129]. infectious diseases (i.e. systemic lupus) that upregulate the im-
Other suggested CKDu risk factors including toxic elements mune system have also been associated with APOL1 associated
used in agriculture and frequent self-usage of nonsteroidal anti- CKD [137– 139]. While pharmaceuticals to treat genetic condi-
inflammatory drugs have been studied. However, there is no tions such as APOL1 are currently scarce, there is an ongoing
conclusive evidence yet to support a correlation between CKDu clinical trial for VX-147 for adults with APOL1-mediated protein-
and these proposed risk factors [130]. uric kidney disease [140].

Apol1 Herbal nephropathy

CKD is associated with both genomic and environmental risk Herbal medicine, which consists of plant-derived products, is
factors, with heritability estimated to be 30%–75%. Genetic dis- widely used across the globe, estimated to be used in up to 75% of
orders such as COL4A5 Alport syndrome or PKD autosomal dom- the world population [141]. Despite its popularity, usage of herbal
inant polycystic kidney disease have been well studied with medicine can result in kidney injury. Multiple mechanisms have
causal links [131]. However, a well-established correlation for been proposed, including direct nephrotoxicity, nephrolithia-
CKD and African-Americans lacked evidence to support genetic sis, and rhabdomyolysis [142]. A well-documented nephrotoxic
deposition. With the introduction of genome-wide association agent found in herbal medicine is aristolochic acid, found in
studies, Apolipoprotein L1 gene (APOL1) has been strongly asso- the Artistolochiaceae plant and used mainly in Chinese herbal
ciated with CKD in African-Americans [132]. medicine. It leads to interstitial fibrosis with loss of renal tubules
APOL1 is one of six members of APOL gene located on chro- and increased risk of urothelial carcinoma [143]. In addition to
mosome 22 and encodes a protein that functions as part of the the direct nephrotoxic effect of herbal medicine, due to poor
immune system to fight against parasitic infections, such as regulation over herbal medicine, incorrect processing or stor-
African trypanosomes [133]. As African trypanosomes are pri- age can introduce additional nephrotoxic agents [142]. Auramine
marily found in Africa, variants to confer protection were se- O dye, a carcinogenic dye, has been used for colouring herbal
lected and disseminated throughout the African population, re- medicine products, and can cause kidney and liver toxicity when
sulting in the observation of predisposing APOL1 variant alleles consumed [143].
seen only in African ancestry [134].
The pathogenesis of risk alleles to the development of CKD
CONCLUSION
remains under investigation, with proposed molecular mecha-
nisms to be a cytotoxic injury to podocytes from mitochondrial In summary, CKD is a major public health problem engen-
dysfunction or lysosomal rupture, leading to nephropathy [135]. dered by various modifiable and non-modifiable risk fac-
However, the presence of risk alleles does not result in CKD, tors spanning across cardiovascular, endocrine, lifestyle, and
as only 20% of the African-American population with risk alle- genetic/environmental domains. Understanding the major
les develop nephropathy, suggesting contributing environmen- determinants of CKD and the clinical phenotype of high-risk
tal factors [136]. The strongest environmental factor associated populations are essential for prevention, improved detection,
 1746 R. Lo et al.

and earlier implementation of interventions that mitigate pro- 10. Action to Control Cardiovascular Risk in Diabetes Study
gression. With the emergence of new pharmacotherapies, di- G, Gerstein HC, Miller ME et al. Effects of intensive glucose
agnostic tools, and public health initiatives that are directing lowering in type 2 diabetes. N Engl J Med 2008;358:2545–59.
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ther efforts are needed to improve access to these evidence- 11. Group SR, Wright JT Jr, Williamson JD et al. A random-
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populations. trol. N Engl J Med 2015;373:2103–16. https://doi.org/10.1056/
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12. Kanno A, Metoki H, Kikuya M et al. Usefulness of assessing
ACKNOWLEDGEMENTS masked and white-coat hypertension by ambulatory
Results presented in this paper have not been published blood pressure monitoring for determining prevalent
previously in whole or part, except in abstract format. risk of chronic kidney disease: the Ohasama study.
Hypertens Res 2010;33:1192–8. https://doi.org/10.1038/
hr.2010.139
FUNDING 13. Booth JN, 3rd, Diaz KM, Seals SR et al. Masked hy-

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The authors are supported by the research grants from the pertension and cardiovascular disease events in a
NIH/NIDDK including R01-DK122767 (C.M.R.) and R01-DK124138 prospective cohort of Blacks: the Jackson Heart Study.
(C.M.R.), and the Japan Society for Promotion of Science (Y.N.). Hypertension 2016;68:501–10. https://doi.org/10.1161/
HYPERTENSIONAHA.116.07553
14. Drawz PE, Alper AB, Anderson AH et al. Masked hyper-
DATA AVAILABILITY STATEMENT tension and elevated nighttime blood pressure in CKD:
No new data were generated or analysed in support of this prevalence and association with target organ damage. Clin J
research. Am Soc Nephrol 2016;11:642–52. https://doi.org/10.2215/CJN.
08530815
15. Banegas JR, Ruilope LM, de la Sierra A et al. Relation-
CONFLICT OF INTEREST STATEMENT ship between clinic and ambulatory blood-pressure mea-
C.M.R. has received honoraria or grant support from Ardelyx, surements and mortality. N Engl J Med 2018;378:1509–20.
AstraZeneca, Dexcom Inc., Fresenius, Otsuka, Reata, Recor, and https://doi.org/10.1056/NEJMoa1712231
Roche. None of the other authors have disclosures to report. 16. Minutolo R, Gabbai FB, Agarwal R et al. Assessment of
achieved clinic and ambulatory blood pressure recordings
and outcomes during treatment in hypertensive patients
with CKD: a multicenter prospective cohort study. Am J Kid-
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