Kalantar Zadeh Etal 2021 Preserving Kidney Function in People

Seminar Article, THELANCET- D-20-17156-A1
Title:
Preserving Kidney Function in People with Chronic Kidney Disease
(Running Head: Kidney Preserving Care)
Authors:
Kamyar Kalantar-Zadeh, MD, 1,2 Tazeen H Jafar, MD,3, 4, 5 Dorothea Nitsch, MD,6,7,8
Brendon L Neuen, MD,9 and Vlado Perkovic, MD10
Affiliations:
1
Division of Nephrology, Hypertension, and Kidney Transplantation, University of California
Irvine, Orange, California, USA

2
Tibor Rubin Veterans Affairs Medical Center, Long Beach, California, USA
3
Duke NUS Graduate Medical School, Singapore, 4Department of Renal Medicine, Singapore
General Hospital, 5Duke-Global Health Institute, Durham, NC, USA

6
Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical
Medicine, UK
7
United Kingdom Renal Registry, Bristol, UK
8
Department of Nephrology, Royal Free London NHS Foundation Trust, UK
9
The George Institute for Global Health, UNSW Sydney, Australia
10
UNSW Sydney, Faculty of Medicine, Australia
Kalantar, Jafar, Nitsch, Neuen and Perkovic 2 Kidney Preserving Care
Corresponding Author:
Kamyar Kalantar-Zadeh, MD, MPH, PhD
Division of Nephrology, Hypertension and Kidney Transplantation
University of California Irvine Medical Center
101 The City Drive South, Orange, California 92868-3217
Tel: (714) 456-5142, Fax: (714) 456-6034. Email: [email protected]
Vlado Perkovic, MBBS, PhD, FRACP, FASN, FAHMS
Faculty of Medicine, University of New South Wales
Sydney, New South Wales, Australia
Email: [email protected]
Word Count:
Abstract Word Count: 250
Main Text Word Count: 6,371
Figures: 3
Tables: 3
References: 251
Suggested online Appendix: 5 supplemental figures and 2 supplemental tables
Declarations Section
Ethics and consent to participate
Not applicable, this is a Seminar article
Consent to publish
Authors have granted consent to publish this work in Lancet
Availability of data and materials
2
Not applicable, this is a Seminar paper
Competing interests (see attached disclosure forms)
Dr. Kalantar-Zadeh has received commercial honoraria and/or support from Abbott, Abbvie,
Alexion, Amgen, Astra-Zeneca, Aveo, Chugai, DaVita, Fresenius, Genentech, Haymarket
Media, Hospira, Kabi, Keryx, Novartis, Pfizer, Relypsa, Resverlogix, Sandoz, Sanofi, Shire,
Vifor, UpToDate, and ZS-Pharma.
Dr. Dorothea Nitsch is on the steering group of two Glaxo-Smith Kline funded studies,
investigating aspects of kidney disease in Sub-Saharan Africa.
Dr. Brendon L Neuen has received travel support from Janssen and consultancy fees from
Bayer for his role as a trial steering committee member, with all honoraria paid to his
institution.
Dr. Perkovic has served on Steering Committees, Advisory Boards, or given Scientific
Presentations supported by s Abbvie, Amgen, Astellas, Astra Zeneca, Bayer, Baxter, BMS,
Boehringer Ingelheim, Chinook, Dimerix, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck,
Metavant, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, Pharmalink,
Relypsa, Retrophin, Sanofi, Servier, Vifor, Vitae, UptoDate, and Tricida.
Funding from US or other government agencies (such as NIH, MRC) and non-for-profit
foundations or societies (such as ASN, NKF, Wellcome Trust) are not listed.
Funding
This work was supported by research grants from the NIH grant K24-DK091419 and
philanthropic grants from Harold Simmons and Joseph Lee.
THJ is supported by Singapore National Medical Research Council.
Acknowledgements.
None
3
ABSTRACT (250 words)
Chronic kidney disease (CKD) is a progressive disease with no cure and high
morbidity and mortality. It occurs commonly in people with diabetes and hypertension.
Preservation of kidney function can improve outcomes and may be achieved by use of non-
pharmacologic strategies, including dietary adjustments, and CKD-targeted and kidney
disease specific pharmacologic interventions. Plant-dominant low-protein and low-salt diet
may help mitigate glomerular hyperfiltration and preserve kidney function, while also
possibly leading to favorable alterations in acid-base homeostasis and the gut microbiome.
Pharmacotherapies that alter intrarenal hemodynamics including angiotensin pathway
modulators and sodium glucose cotransporter-2 inhibitors can help preserve kidney function
by mechanisms in addition to improving blood pressure and glucose control such as by
reducing intraglomerular pressure, while novel agents such as nonsteroidal mineralocorticoid
receptor antagonists may protect the kidney through anti-inflammatory or anti-fibrotic
mechanisms. Some glomerular and cystic kidney diseases may benefit from disease specific
therapies. Managing CKD associated cardiovascular risk, infection control and prevention of
acute kidney injury are crucial given the high burden of these complications and associated
morbidity and mortality and role of non-conventional risk factors in CKD. When kidney
replacement therapy becomes inevitable, an incremental transition to dialysis may be
considered and has been proposed to possibly preserve residual kidney function longer.
There are similarities and distinctions between kidney preserving and supportive care. To
ensure optimal kidney preserving care and to achieve greater longevity along with superior
health-related quality of life, additional studies on preexisting interventions and development
of innovative strategies are warranted as reviewed here.
4
Keywords:
Kidney preservation, dialysis freedom, plant-dominant low-protein diet, angiotensin pathway
modulators, sodium glucose cotransporter-2 inhibitors, supportive care, palliative and hospice
medicine
5
1. Chronic Kidney Disease
Chronic kidney disease (CKD) is a progressive condition characterized by structural
and functional changes to the kidney, which occur due to a wide variety of etiologies. It is
typically defined as a reduction in kidney function, estimated glomerular filtration rate
[eGFR] <60 ml/min/1.73m2, or markers of kidney damage, such as albuminuria, hematuria or
abnormalities detected on imaging, present for at least 3 months (supplemental Figure S1 in
online appendix).1 The global burden of CKD is substantial and growing; approximately 10%
of adults worldwide are affected by some form of CKD, resulting in 1.2 million deaths and 28
million years-lost-of-life each year.2,3 By 2040, it is estimated that CKD will become the
fifth leading cause of death globally, one of the largest projected increases of any major cause
of death.4
The prevalence of different aetiologies varies considerably by region. There are many
causes of CKD, including those that more common and well-researched such as diabetes,
glomerulonephritis and cystic kidney diseases; however, causation in CKD is not fully
understood. For instance, despite close association of CKD with hypertension, it remains
controversial as to whether hypertension is a cause or consequence of CKD.5 As another
example, in some agricultural societies in South Asia and Central America there exists CKD
of unknown aetiology (CKDu) for which there is no known treatment while recurrent volume
depletion has been speculated as a cause of CKDu especially under the climate change with
more heat waves.6 The global burden of CKD has also been attributable to air pollution and
disproportionally borne by certain regions of the world.7 CKD severity also varies from
kidney damage with normal function, through to kidney failure (or end-stage kidney disease),
which typically occurs when eGFR falls below 15 mL/min/1.73m2. In general, the
prevalence of CKD increases with age, and in high-income countries is more common in
those with obesity, diabetes mellitus and hypertension.8,9
6
Symptoms of CKD are usually insidious and most affected individuals are
asymptomatic until the disease becomes advanced, i.e., eGFR <30 ml/min/1.73m2. The rate
of loss of kidney function varies by etiology, exposures and interventions, but in most cases
progression to kidney failure typically takes months to decades to develop. Signs and
symptoms of kidney failure result from progressive uremia, anemia, volume overload,
electrolyte abnormalities, mineral and bone disorders, and acidemia, and inevitably lead to
death if left untreated.10
Renal (kidney) replacement therapy – either in the form of chronic dialysis or kidney
transplantation – are life-sustaining treatments for people with kidney failure. Because of a
shortage of donor kidneys, as well as comorbidities which develop with increased age and
often preclude kidney transplantation,11,12 dialysis remains the prevailing treatment option
globally for most people with kidney failure.13 Kidney failure requiring dialysis is also
associated with substantially reduced quality of life and high mortality rates14 especially in
the first year upon transition to dialysis,15 underscoring the importance of preserving kidney
function in people with or at high risk of CKD.
2. Approach to preserving kidney function
There has been growing recognition that conservative management without dialysis is
a viable patient-centered treatment option for a substantial proportion persons with CKD.16
As shown in Figure 1, within conservative management strategies there are several mostly
overlapping intervention domains with similarities and distinctions that can be offered to
patients with CKD.17 Kidney preserving care is a life-sustaining type of conservative
management with the primary goal of slowing CKD progression and preserving kidney
function to prolong dialysis-free time for as long as possible, or ideally avoid it altogether.
This approach strives to achieve the greatest survival including improved cardiovascular
7
health and superior health-related quality of life with effective treatment of renal and non-
renal comorbidities and their associated symptoms.18,19
Given that conservative management is defined as CKD care without dialysis or a
kidney transplantion,20 misconceptions of dialysis-free management as “no care” or
conflation with hospice care may have contributed to underutilization of the kidney-
preserving management of CKD across its full spectrum.12,18 Notwithstanding heterogeneity
in definitions, provision of or access to care, and patient demographics or socioeconomic
status across these different domains under the conservative management of CKD, evidence
suggests that there is a rising utilization of conservative management with more focus on
kidney preserving strategies.21-33
The focus of efforts to slow the loss of kidney function vary depending on the severity
of CKD and underlying etiology, encompassing a range of pharmacological and non-
pharmacological approaches as shown in Figure 1 and supplemental Figures S2 and S3
under online appendix, given that these measures are consistent with the secondary and
tertiary prevention of CKD,34 and also summarized in Table 1. In the general population,
lifestyle and dietary modifications should be prioritized as these can improve cardiometabolic
health with likely favorable long-term effects on the kidney. The focus of care in primary
prevention remains achieving optimal control of risk factors for CKD by addressing physical
inactivity and obesity, smoking, as well as elevated blood pressure and blood glucose.35
Addressing these risk factors remains important across the whole spectrum of kidney
function. Whereas the cost-effectiveness of population wide screening for CKD remains
controversial, it is recommended that targeted screening is performed in individuals with risk
factors (e.g. obesity, hypertension and diabetes mellitus) by regular assessment of eGFR and
albuminuria.36
8
For individuals with established CKD, in addition to protecting kidney function,
addressing complications and associated comorbidities, and managing symptoms are also
important. Slowing the progression of CKD can be achieved through a range of lifestyle,
dietary and pharmacological strategies, which include weight loss, moderate dietary protein
restriction, blood pressure and glucose control, as well as renin-angiotensin system blockade
(supplemental Figures S2 and S3). For specific disease etiologies such as primary
glomerulonephritis and autosomal dominant polycystic kidney disease, newer targeted
therapies also have an important role (see below). As many more individuals with CKD die
due to cardiovascular disease than progress to kidney failure, reducing cardiovascular risk is a
fundamental aspect of the care in this population.37
Large-scale collaborative meta-analyses have demonstrated that eGFR and
albuminuria are strongly and independently associated with risk of a range of adverse
outcomes including progression to kidney failure, cardiovascular events, and death, and both
kidney markers should therefore be used to inform prognosis and direct care priorities for
people with CKD.38-42 The Kidney Disease Improving Global Outcomes (KDIGO)
classification of CKD incorporates eGFR and UACR into a two-dimensional framework to
stratify individuals’ risk, focus management priorities and guide referral to specialist care,
and is perhaps the most widely used staging system (supplemental Figure S1).43 Other tools
such as the Kidney Failure Risk Equation,44 or the Dialysis Transition Mortality Prediction
Score45 are also available and can be used to estimate risk of kidney failure and first year
dialysis mortality, respectively, and thus inform discussion, facilitate specialist referral and
contribute to shared decision making. Upon progression to advanced CKD where uremia
cannot be controlled without renal replacement therapy, incremental transition to peritoneal
or hemodialysis therapy may be a preferred approach with the goal to preserve residual
9
kidney function while receiving less than usual dialysis, although clinical trials are needed to
examine this and other alternative dialysis transition strategies.46
3. Physical activity, obesity and weight loss
Obesity is the hallmark of metabolic syndrome and associated with CKD.47 Large-
scale collaborative meta-analyses have demonstrated that increased adiposity measures (e.g.
body mass index and waist circumference) are strongly independently associated with decline
in GFR.48 The precise mechanism by which obesity may contribute to risk of CKD is
uncertain but may include systemic and intraglomerular hypertension, the effect of pre-
diabetes levels of blood glucose on podocyte stress, as well as other unrecognized factors.49,50
Physical activity is the core component of lifestyle modification strategies to manage
weight for impact on CKD progression. The effect of weight reduction on risk of CKD has
been demonstrated in the post-hoc analysis of Look-AHEAD trial, where 5,145 obese
individuals with type 2 diabetes were randomized to intensive lifestyle intervention or
diabetes support and education.51 The trial demonstrated that intensive lifestyle intervention
reduced weight by 4 kg on average and reduced the onset of very high risk CKD according to
the KDIGO classification system by approximately 30%.
A range of interventions may be employed for weight loss in people with CKD.
Caloric restriction such as in a plant-dominant, low-protein diet can lead to gradual weight
loss in most obese persons with CKD.52,53 Efforts to identify pharmacological agents which
can lower body weight and improve clinical outcomes have yielded limited or modest
results.54 The role of bariatric surgery to mitigate the risk of CKD also remains uncertain.55
Observational studies have suggested that bariatric surgery is associated with lower risk of
patient-level kidney outcomes.56 Although these effects have not been clearly demonstrated
in trials, there is randomized evidence that gastric bypass surgery increases remission of
10
albuminuria in people with type 2 diabetes, obesity and microalbuminuria when compared to
optimal medical treatment, and may represent an important treatment option in select
individuals.57
In more advanced CKD, prolonged survival has been paradoxically reported with
larger body mass index, a phenomenon that is known as the obesity paradox or reverse
epidemiology, while lower BMI may reflect poorer nutritional status or weight loss due to
sarcopenia or multimorbidity.58 Alternatively, weight loss may contribute to poorer
outcomes while effective nutritional interventions to gain weight including muscle mass may
improve longevity.59 Any unintentional weight loss warrants timely work-up and dietary
interventions, and unnecessary weight loss in advanced CKD should be avoided, unless
absolutely required, e.g., for a strict requirement of an imminent kidney transplantation that
stipulates lower weight or other life-saving procedures.60
4. Plant-Dominant Low-Protein Diet
For many causes of CKD including diabetic kidney disease, afferent and efferent
arterioles tend to be relatively dilated and contracted, respectively, as a compensatory
mechanism partially regulated via tubuloglomerular feedback to maintain GFR in the short-
term – a process known as glomerular hyperfiltration or intraglomerular hypertension.49 In
the long-term this can cause further damage to the kidney through mechanisms including
mechanical stress and activation of inflammatory mediators which promote interstitial
fibrosis.61,62 Dietary protein restriction, by enhancing afferent arteriole tone, may alleviate
intraglomerular hypertension, mitigate renal interstitial fibrosis61,62 and slow the progression
of CKD (Figure 2). The pre-glomerular effect of dietary protein restriction acts in parallel
and is complementary to the post-glomerular effect of angiotensin pathway modulators
including angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers
11
(ARBs), which lower intraglomerular pressure by promoting efferent arteriolar
vasodilatation.63
Key randomized evidence supporting the beneficial effect of dietary protein
restriction comes from the Modification of Diet in Renal Diseases (MDRD) study, which
randomized 585 participants with non-diabetic kidney disease to assess the effect of usual vs.
low protein diets (1.3g vs 0.58g per kg/day) on eGFR decline. While the primary results of
this trial were inconclusive, these did not take into account the acute effect of dietary protein
restriction, which lowers GFR in the short-term due to afferent arteriolar constriction, similar
to what is observed with initiating ACE inhibitors or ARB therapy. Subsequent analyses of
the MDRD data which excluded the acute effect on GFR suggested benefit with dietary
protein restriction (see supplemental Figure S4 in online appendix).64 Additional analyses
also showed that dietary protein restriction may lower blood pressure and proteinuria.65 The
findings from the MDRD study are supported by meta-analyses that demonstrate reduced risk
of progression to kidney failure and improvements in proteinuria and other favorable
biochemical outcomes such as higher bicarbonate and lower azotemia and phosphorus.66-69
The benefits of dietary protein restriction need to be considered in the context of potential
risks to protein-energy wasting and loss of muscle mass and strength, particularly in the
elderly.70 Hence current guidelines recommend a conservatively low range of 0.6-0.8
g/kg/day of dietary protein in people with significant albuminuria (>300 mg/g) to ensure
safety and adequate nutritional intake (see Table 3).71
More recent data suggest salutary effects of plant-dominant low protein diets,52 in
which >50% of the source of protein is derived from non-animal-based sources that include
not only fruits and vegetables, but also nuts, legumes, and seeds. There are different types of
plant-dominant diets with proportionately higher choice of foods from plant sources:72 (1)
Vegan or strict vegetarian diets that not only exclude meat, poultry, and seafood but also eggs
12
and dairy products; (2) Lacto- and/or ovo-vegetarian diets that may include dairy products
and/or eggs; and (3) pescatarian or pesco-vegetarian diets that include a vegetarian diet
combined with occasional intake of some or all types of seafoods, mostly fish.72 While some
but not all studies have shown that plant-dominant diets are associated with lower risk of
CKD and GFR decline, less proteinuria, amelioration of acidosis, and better cardiovascular
profile, 73 these effects remain to be definitively demonstrated in randomised trials.74
Experimental data also suggests such diets may lower uremic toxin generation and exert
favourable effects on cardiovascular health in people with kidney failure;52,53,75,76 however
randomized trials assessing effects on clinical outcomes are needed to confirm or refute these
observations.
There is growing interest in the role of the gut microbiome in CKD, although the role
of any microbiome related interventions remains to be proven.74 The gut microbiome in CKD
may be altered by uremia, natural intake of probiotics,77 and the type of food including plant
versus animal origin.78 A plant-dominant, fiber-rich, low-protein diet may lead to favorable
alterations in the gut microbiome, which may modulate uremic toxin generation.52 Uremic
plasma impairs barrier function and depletes the tight junction protein constituents of
intestinal epithelium.79 The influx of retained uremic solutes from the bloodstream induces
changes in the microbial population along with gut wall inflammation and breakdown of
epithelial junctions.80-91 Bacterial-derived toxins then translocate back across the leaky gut
barrier into the systemic circulation and promote inflammation and multi-organ
dysfunction.80,92 Several gut-derived uremic toxins are associated with cardiovascular disease
and mortality in CKD including indoxyl sulfate, indole-3 acetic acid, p-cresyl sulfate,
TMAO, and phenylacetylglutamine.92 The circulating p-cresyl-sulfate and indoxyl-sulfate,
which are protein-bound uremic retention solutes, and other catabolic by-products of protein
metabolism can exert harmful effects including inflammation, oxidative stress, endothelial
13
dysfunction, muscle wasting, renal interstitial fibrosis, worsening proteinuria and accelerated
CKD progression, as well as insulin resistance.93-95 Hence, it has been proposed, but not yet
proven in clinical trials, that a high-fiber, plant-dominant, low-protein diet, by modulating
microbiome favorably might lower uremic toxin generation and help control uremia without
dialysis, while cardiovascular health may be enhanced, consistent with the goals of the
conservative management of CKD.96
5. Intravascular volume and electrolyte homeostasis
Subclinical volume overload is highly prevalent in people with CKD and
perturbations in systemic hemodynamics are strongly associated with risk of cardiovascular
and kidney outcomes.97-99 Optimization of intravascular volume is therefore an important
focus of care, particularly as kidney function declines, and can be achieved by dietary sodium
restriction and the use of loop and non-loop diuretics. Dietary salt restriction can be
particularly effective for blood pressure and volume control as many patients with CKD
exhibit a tendency for salt-sensitive hypertension.100 Loop diuretics are the mainstay
pharmacological therapy for controlling intravascular volume, especially as kidney function
declines. However there is emerging randomized evidence to suggest that distal thiazide
diuretics can reduce blood pressure and extracellular volume even at lower eGFR,101 with
additional trials ongoing.102 It has also been widely hypothesized that the beneficial effect of
SGLT2 inhibitors on cardiovascular and kidney outcomes may also be partly explain by
favorable effects on the extracellular fluid compartment without depleting intravascular
volume thus avoiding activation of neurohormonal pathways.103
The prevalence of hyperkalemia increases as kidney function declines and
epidemiological data demonstrates a U-shaped association between serum potassium and
adverse outcomes, such that both high and low potassium levels are associated with poor
14
outcomes.104 Commonly used treatments such as ACE inhibitor, ARBs and mineralocorticoid
receptor antagonists increase the risk of hyperkalemia. While dietary potassium restriction is
generally recommended in people with advanced CKD, concerns have been expressed that
such diets may limit the consumption of healthy plant proteins, fruit and vegetables.105
Traditional and newer potassium binders may allow more effective control of hyperkalemia,
enabling potentially beneficial dietary regimens and more effective use of renin angiotensin
aldosterone system blockade, and trials are underway to test the effect of newer potassium
binders on clinical outcomes.106,107
Metabolic acidosis in CKD results from the inability of the kidney to excrete
endogenous acid and has been shown to be associated with loss of kidney function and
unfavorable effects on muscle mass and bone health.108 Small trials have collectively
suggested that correction of metabolic acidosis with bicarbonate may slow progression of
CKD.109 Most recently veverimer, a novel binder of hydrochloric acid in the gastrointestinal
tract, has been shown to increase serum bicarbonate concentrations in people with CKD, with
an ongoing trial to test the effect of this agent agents on a hard kidney outcome.110
6. Traditional and Emerging Pharmacotherapies
These strategies have been summarized in Table 1 and Figure 1 as well as
supplemental Figure S2 and discussed below.
RAAS inhibition, mineralocorticoid receptor antagonism and other BP lowering therapies
The cornerstone of kidney-preserving pharmacologic therapies over recent decades
has been angiotensin pathway modulators that block the renin-angiotensin-aldosterone
system, specifically ACE inhibitors or ARBs. The evidence is strongest in people with type 2
diabetes and albuminuric CKD, in whom the RENAAL and IDNT trials demonstrated that the
15
respective ARBs losartan and irbesartan reduced the risk of a kidney failure, doubling of
creatinine or death.111,112 In the RENAAL study, the risk of kidney failure was separately
significantly reduced (see Supplemental Figure S4).111 These agents have thus been
considered standard-of-care for people with type 2 diabetes and diabetic kidney disease
(DKD) for the best part of two decades. Importantly, several studies113-115 have demonstrated
an increased risk of adverse outcomes with multi-agent RAAS blockade without clear
benefits, so combination ACEI and ARB therapy is strongly discouraged.
More recently, the FIDELIO trial of the non-steroidal mineralocorticoid receptor
antagonist finerenone in DKD showed a significant reduction in the risk of the primary
kidney (sustained 40% reduction in eGFR, kidney failure or kidney death) and cardiovascular
(myocardial infarction, stroke, heart failure or CV death) outcomes.116 Several studies have
suggested that the older aldosterone antagonist spironolactone reduces proteinuria in DKD,117
but clear data regarding effects on hard outcomes are not currently available.
RAS blockade with ACEI or ARB are also generally recommended for people with
type 1 diabetes and kidney disease.112 They are also widely recommended for other types of
kidney disease largely based on smaller studies and meta-analyses. In non-diabetic kidney
disease, the available data from a meta-analysis suggest that the kidney protective effects are
clearest in people with significant proteinuria,118 with uncertainty about effects in people with
little or no proteinuria.
While BP lowering per se likely reduces the risk of kidney failure overall,119,120this
remains somewhat controversial as intensive BP lowering (systolic target <120mmHg) may
be associated with more rapid decline in kidney function. Available data suggests this may
reflect drug induced hemodynamic effects with no deleterious impact on the long-term risk of
kidney failure.121 Based largely on results from the SPRINT study, in people with CKD who
do not have diabetes, intensive BP lowering reduces the risk of cardiovascular events and
16
death and recently updated KDIGO guidelines therefore recommend a systolic BP target of
less than 120 in people with CKD based on these effects. However, individualization of BP
targets is crucial, taking into account comorbidities, frailty and patient preferences, given
ongoing uncertainty about the risk-benefit profile of intensive BP targets in patients with
moderate-to-advanced CKD.122 For kidney diseases not associated with high blood pressure
or diabetes (as for example CKDu) it is unknown whether ACEI/ARB are beneficial.
Glucose lowering therapies.
Glucose lowering therapies in people with diabetes could potentially reverse the
fundamental metabolic abnormality pathognomonic of the disease.123 While post-hoc
analyses of the ADVANCE trial suggested the risk of kidney failure might be lower in people
treated to lower hemoglobin A1c targets,124 analyses of eGFR loss over time showed no
difference, and meta-analyses of more vs less intensive glucose lowering did not demonstrate
clear effects on the risk of kidney failure.125 Subsequent studies have further demonstrated
clear differences between different classes of glucose lowering therapies.
SGLT2 inhibitors
Sodium glucose cotransporter 2 inhibitors (SGLT2i) were developed to lower blood
glucose in people with diabetes by blocking proximal tubular glucose reabsorption thus
inducing glycosuria. Early studies in type 2 diabetes identified that these agents significantly
lower proteinuria and have a clear effect on kidney hemodynamics. This manifests as an
acute reduction in eGFR of approximately 3-5 ml/min/1.73m2 followed by stabilization of
kidney function compared to either placebo or sulfonylurea therapy, a benefit that was in
addition to that conferred by ACEi/ARB therapy.126
17
A number of cardiovascular safety studies mandated by regulatory authorities
successively demonstrated reductions in composite outcomes based on reductions in eGFR or
doubling of creatinine, kidney failure and death due to kidney disease.127-129 However, these
trials were done in people at high cardiovascular risk, a minority of whom had kidney
disease.
The first primary kidney trial of SGLT2i assessing efficacy on major clinical
outcomes was the CREDENCE trial, where 4401 participants with albuminuric DKD
(albuminuria 300-5000 mg/g, eGFR 30-90 mL/min/1.73m2) were randomized to
canagliflozin or placebo130 (see Supplemental Figure S4). The trial was stopped early for
efficacy, as the primary outcome was reduced by 30%, with similar reductions in a range of
kidney outcomes including kidney failure alone, and the need for dialysis or kidney
transplantation. Major cardiovascular events (myocardial infarction, stroke or cardiovascular
death) and hospitalizations for heart failure were also significantly reduced. Major treatment
guidelines around the world have now been updated to recommend SGLT2i in people with
DKD based on these findings.
The kidney protective effects of SGLT2 inhibition have also been demonstrated in
people with non-diabetic kidney disease. The DAPA-CKD trial131 demonstrated that
dapagliflozin reduces the risk of sustained 50% decline in eGFR, kidney failure or death due
to cardiovascular or kidney disease by 44% in people with CKD (eGFR 25-75
mL/min/1.73m2 and UACR 200 to 5,000 mg/g), with clear, separate benefits irrespective of
diabetes status or etiology of CKD.132 The trial also demonstrated a substantial reduction in
hospitalization for heart failure or cardiovascular death as well as all-cause death. Based on
these findings, it is anticipated that SGLT2 inhibitors are likely be routinely offered to people
with albuminuric CKD regardless of the presence of diabetes. A trial of empagliflozin in non-
18
diabetic kidney disease, which includes people with low or normal albuminuria, is
ongoing.133
DPP4 inhibitors
The Dipeptidyl Peptidase-4 (DPP4) inhibitors are widely used to improve glycemic
control in people with type 2 diabetes. The effects on hard kidney outcomes were formally
assessed in the CARMELINA trial, where almost 7000 participants with type 2 diabetes
enriched for kidney disease (reduced GFR, increased albuminuria, or both) and/or
cardiovascular disease were randomized to linagliptin or placebo.134 The trial demonstrated
that linagliptin did not increase the risk of cardiovascular events, but also did not reduce the
risk of a composite renal outcome of 40% eGFR decline, kidney failure or renal death,
despite over 600 kidney endpoints being observed in the trial. The available data therefore
suggest that this class of agents does not meaningfully reduce the risk of kidney disease
progression in type 2 diabetes.
GLP 1 agonists
There have not yet been any outcome studies powered to detect effects on clinically
important kidney outcomes with the glucagon-like peptide 1 (GLP1) receptor agonists,
another class of agents recently developed to improve glucose control in type 2 diabetes.
These agents have been shown to reduce the risk of cardiovascular events in meta-analyses of
completed cardiovascular outcome trials.135 Similar meta-analyses of these trials suggest that
the risk of a composite kidney outcome (including progression of albuminuria, substantial
losses of kidney function (40% or 57% reductions in eGFR), kidney failure or kidney related
death) is significantly reduced by the GLP1 receptor agonists; however, this appears to be
primarily driven by effects on albuminuria as no clear benefit observed on kidney outcomes
19
excluding progression of albuminuria.135 A dedicated kidney outcome study (FLOW,
NCT03819153) is currently underway, specifically recruiting people with CKD and
comparing the effects of semaglutide vs placebo on the risk of major kidney and
cardiovascular outcomes.
Examples of treatment of primary glomerulonephritides and cystic disorders
IgA nephropathy, the most common idiopathic glomerulonephritis worldwide, is
currently treated by optimizing blood pressure control with ACE inhibitors or ARBs, along
with lifestyle modifications including salt and protein restriction and weight loss,136 while the
role of corticosteroids remains controversial with conflicting evidence from randomized trials
including both negative137,138 and positive data..137,138 New therapeutic strategies for IgA
nephropathy are an area of active investigation, and several agents are currently being tested,
including combined angiotensin and endothelin receptor blockade and drugs targeting
complement pathways.139,140 Primary membranous nephropathy is another globally prevalent
glomerulonephritis. Although the discovery that it is an autoimmune condition has led to
substantial changes in the diagnosis, treatment and monitoring of this disease,141-143 many of
these patients will develop spontaneous remission; as with other etiologies of proteinuric
CKD, optimal supportive care should include maximum tolerated ACE inhibitor or ARB.144
For those with more severe proteinuria and/or at high risk of disease progression other
treatments are recommended including alkylating agents such as cyclophosphamide,145
calcineurin inhibitors,146,147 rituximab,148 or a combination of these agents.149 For other
primary glomerular diseases, there is a paucity of randomized evidence.150 Autosomal
dominant polycystic kidney disease (ADPKD) is a common non-glomerular disease
worldwide. In recent years, disease modifying therapy, specifically the vasopressin-receptor
antagonist tolvaptan has shown slowed rate of kidney growth and GFR decline151 in early and
later stage disease.152
20
7. Addressing cardiovascular risk during CKD progression
Cardiovascular disease (CVD) is a leading cause of death in patients with CKD and is
therefore a major focus of care in this population.153 Lower eGFR and higher albuminuria are
independently and positively associated with cardiovascular outcomes beyond traditional risk
factors in all ages (Figure 3).42,154 Whereas the traditional “shared” risk factors including
overweight hypertension, diabetes, dyslipidemia, and smoking are associated with CVD in
patients with CKD, a host of non-traditional risk factors magnify the risk of CVD especially
in advanced CKD. Some of these “kidney specific” factors include increased activity of
renin-angiotensin system, neurohormonal activation, water and sodium retention, anemia,
inflammation with or without protein-energy wasting, mineral and bone disorders (including
calcium and phosphorus dysregulation, increased parathyroid hormone and FGF-23 and alpha
klotho deficiency), and endothelial dysfunction.155 156-162
Management of cardiovascular disease in CKD remains challenging (Figure S5
under online Appendix).163 These challenges include interpretation of cardiac biomarkers
which are used to diagnose myocardial infarction, the exclusion of individuals with CKD
from cardiovascular outcome trials (particularly those receiving dialysis), and higher
proportion of non-atherosclerotic cardiovascular events as kidney function declines with no
clear benefit for revascularization for individuals with CKD and stable coronary artery
disease.164-167 The mainstays of cardiovascular risk reduction in CKD include blood pressure
lowering with renin-angiotensin aldosterone system blockade, lipid lowering with statins, and
specific glucose lowering agents that have been shown to reduce cardiovascular outcomes in
people with type 2 diabetes.135,168 While lipid lowering with statin therapy improves
cardiovascular outcomes in people with CKD not on dialysis, there is insufficient evidence to
support commencing lipid-lowering therapy for primary prevention of CVD in most people
21
with kidney failure requiring dialysis, especially in the absence of high serum LDL-
cholesterol levels.169 In people with type 2 diabetes, guidelines recommend that SGLT2
inhibitors and GLP-1 receptor agonists be prioritized in people with CKD.170,171 While
antiplatelets should be routinely offered for secondary cardiovascular prevention, relative
benefits and harms for primary prevention remain uncertain due to increased bleeding risk.172
The role of anticoagulation with warfarin versus direct acting oral anticoagulants in advanced
CKD also remains uncertain and is subject to ongoing evaluation in randomized trials.173
A recent randomized control trial showed that among patients with recent acute
coronary syndrome, type 2 diabetes, and low high-density lipoprotein cholesterol levels, the
selective bromodomain and extra-terminal protein inhibitor apabetalone, a novel epigenetic
modulator, added to standard therapy did not significantly reduce the risk of major adverse
cardiovascular events;174 however, in the subgroup analysis, there was 50% reduction in CVD
events among participants with preexisting CKD stage 3.175 Future cardiovascular outcome
trials should focus on enrolling substantial proportions of patients with CKD and ideally
prespecify the assessment of treatment effects according to eGFR and albuminuria.
Additionally, patient-reported outcomes including health related quality of life should be
considered a key outcome for holistic assessment of interventions in all cardiovascular
outcome trials involving patients with CKD. 19 It is equally important to integrate and
measure quality of life and other patient-related outcomes into routine clinical measurement
for continuous quality improvement in health systems and optimization of patient-centered
care.176
8. Acute Kidney Injury
Patients with CKD, especially in more advanced stages (eGFR <30 ml/min/1.73m2)
often do not exhibit linear progression of disease, which may be related to superimposed
episodes of acute kidney injury (AKI), as well as other factors.177 Some but not all studies
22
suggest that each AKI event may accelerate progression of CKD.178,179 Hence, preventing
AKI is an important components of the management of CKD. This involves avoiding AKI-
associated drug combinations e.g., ACE inhibitors or ARBs in conjunction with loop
diuretics and non-steroidal anti-inflammatory drugs,180 as well as preventing infections which
can precipitate hypotension or septic shock necessitating the use of potentially nephrotoxic
antimicrobials. Other contributors to AKI include cardiovascular events, particularly
decompensated heart failure leading to venous congestion and impaired kidney blood flow, or
coronary artery bypass and other major surgery with possible intra-operative hypotensive
episodes.181,182
9. Role of supportive care and palliative and hospice medicine
People with advanced CKD, particularly those with kidney failure, often experience a
high burden of symptoms, which impacts substantially on health-related quality of life.183
While randomized evidence is limited, observational studies suggest that chronic dialysis
may not be associated with improved survival in some older patients with a high burden of
comorbidities, and that at least some of these elderly people might regret their decision to
commence dialysis in view of treatment related complications, high symptom burden and
poor quality of life.184,185 These factors have led to increased recognition of the importance of
supportive care of kidney failure with focus on palliative care and hospice medicine (Figure
1).
There are similarities and distinctions between the kidney preserving management and
supportive care, which includes palliative care and hospice medicine, as shown in Table 3.
Both strategies are expected to minimize risk of adverse events or complications including
AKI as CKD progresses, although the kidney-preserving management is more strongly
focused on kidney function longevity. Whereas palliative care strategies are often considered
23
for those with advanced age or more severe comorbidities such as terminal cancer,21-24,26-33
kidney-preserving management is a kidney and life sustaining strategy for all individuals and
at any stage of CKD.
The goal of supportive care including palliative and hospice medicine is to help
individuals maximize the benefits of treatment and to improve symptoms and quality of life
by delivering effective symptom-focused treatment through a multidisciplinary approach that
incorporates shared decision making, detailed communication with patients and their
caregivers, advanced care planning, and psychological and social support.186,187 Standardized
tools to identify those who may benefit most from supportive care are not widely validated,
and thus treatment decisions must be individualized. People who may benefit from supportive
care with more focus on palliative and hospice medicine engagement include those with
advanced kidney disease who have exhausted preservative management of their kidney
disease and who do not wish to commence chronic dialysis due to very advanced age,
complex comorbidities with a short life expectancy or other life limiting illnesses and those
who decide to reduce dialysis dose and frequency to minimum such as fluid management, the
so-called decremental dialysis, or to withdraw completely from renal replacement therapy.188
Novel prediction tools have been developed to identify those individuals who would have the
highest mortality in the first year upon transitioning to dialysis and who may therefore benefit
from palliative care;45 however, these tools need to be more widely validated in different
populations and thus individualized approach based on the preference of the patient and
his/her care-partner remains key. The decision must be according to free choice of the patient
without pressure by family members and care-partners or health care professionals, nor
should it be influenced by rationing dialysis care such as during COVID-19 pandemic surges
or other resource constrains.17 Importantly, preservation of kidney function and supportive
care are entirely complementary and should be considered as parts of the full spectrum of
24
conservative management of kidney disease depending on the severity of CKD and goals of
the individual, rather than mutually exclusive choices (see Figure 1 and Table 3).
10. Infection Control and Management of CKD in the COVID-19 Pandemic
Evidence suggests that uremia is associated with worse immunologic response, as
exemplified by diminished antibody response to hepatitis B vaccination or higher risk of
infections as kidney function worsens not explained otherwise by concurrent comorbidities,
as well as the historical observation that autoimmune diseases such as systemic lupus
erythematosus are less aggressive once patients are uremic.189 Similarly, some infection such
as hepatitis C virus may cause CKD if remain untreated, or may lead to CKD,190,191 or with
pre-existing CKD may lead to faster disease progression and greater mortality.192 Conversely,
it is possible that treatment of hepatitis C can have a salutary effect in preserving kidney
function.193 Patients with CKD have a two-fold higher risk of death after respiratory
infections,194 hence, influenza and pneumococcal vaccination may be an indirect way to
prevent AKI and avoid CKD progression although this has not been assessed in clinical
trials.195
During the COVID-19 pandemic, data suggest a two-fold increase of mortality from
COVID in the presence of CKD.196 Despite screening and isolation of affected patients,
outbreaks cannot always be prevented, given cases with long incubation period or
asymptomatic carrier status.196 In order to maintain staffing levels and to protect patients,
outpatient CKD care has undergone a radical transformation by using telemedicine, remote
care and minimising blood testing to those tests that guide dietary and therapeutic
decisions.197 Advance care planning and ensuring completion of renal replacement therapy
modality plans are of even higher importance, as COVID-19 can cause AKI, which could be
due to septic shock and cytokine release or from direct renal tropism of the virus.198,199 The
25
disproportionately high incidence of AKI requiring frequent or continuous renal replacement
therapy in critically sick patients with COVID-19 may have implications for long-term
kidney longevity in COVID-19 survivors, Ongoing and future trials are expected to address
these questions including as to whether ACE-receptor modulators or other modulators of
kidney function can avert COVID involvement in AKI and CKD progression.200
11. Global and Regional Disparities in Preserving Kidney Care
Preserving kidney function in people with CKD is confounded by regional and global
health inequalities, disparities in healthcare models, pharmaceutical industry policies, and
geopolitical and fiscal consrellations.201 Income disparities including poverty and social
disadvantage have a dominant impact on risk on incident CKD and its progression.202,203
Many people at risk of CKD in low- and middle-income countries (LMIC) are not provided
with appropriate infrastructure for screening and identification of CKD. The awareness of
CKD is relatively poor, and opportunities for updating knowledge and education on
preserving kidney health are limited.204
In LIMCs, diet and lifestyle modification may offer an inexpensive approach for
secondary and tertiary prevention of CKD notwithstanding limited scientific evidence to
justify population-based programs with lower sodium and higher plant-based diet intake.
Whereas pharmacotherapy and dialysis treatment are almost universally accessible in high-
income countries, many people in LMICs are unable to access these options.205 The out-of-
pocket expenditure for CKD preserving pharmacotherapy is high relative to income; for
instance, in India, the high costs for SGLT2 inhibitors or renal replacement therapy are more
likely than communicable diseases to push people into poverty range.206
In some affluent nations including the USA there are racial disparities in CKD care.207
Black Americans are by far more likely to develop CKD and exhibit faster disease
26
progression than Caucasians.208 This disparity may be related to socioeconomic factors
exposing many US Blacks to higher CKD risks notwithstanding high prevalence of APOL1-
gene allele with higher ESKD likelihood, which may confound kidney preserving
therapies.209 The current creatinine based eGFR equations have a race index for Blacks,
which inflates the eGFR value by as high as 16% compared to non-Blacks with the same
serum creatinine level.210 In an effort to reduce racial disparities in CKD care, race indices
has been suggested to be removed from eGFR equations to enable more commensurate
approach to burden of CKD211 and instead, race-free measurements such as serum Cystatin C
derived eGFR equations could be used, also given their more linear associations with clinical
outcomes as shown in Figure 3.154,211
12. Conclusion remarks and future steps
The primary goal of kidney preserving care is to slow CKD progression and preserve
kidney function to prolong dialysis-free time while striving to achieve the greatest quality of
life and survival. These strategies also include effective treatment of renal and non-renal
comorbidities and their associated symptoms.18 There are similarities and distinctions
between kidney preserving management and supportive care in CKD. Dietary interventions
using plant-dominant low-protein diet and pharmacotherapies including angiotensin pathway
modulators and SGLT2 inhibitors as well as newer non-steroidal mineralocorticoid receptor
antagonists should be leveraged. In kidney preserving care, the choice of blood pressure
lowering medication is guided by factors beyond hypertension therapy, and similarly, the
choice of glucose lowering agents should be driven by their kidney protective efficacy
beyond glycemic control. When dialysis therapy is necessary and kidney transplantation
cannot be offered, transition to dialysis treatment may be able to be commenced gradually
and incrementally with the goal to preserve residual kidney function longer. Some patients
may benefit from sporadic dialysis such as peritoneal or hemodialysis for ultrafiltration as a
27
prelude to incremental transition to dialysis.212 Other strategies for future studies in lieu of (or
to compliment) dialysis may include – but not limited to –intestinal dialysis models 213,214 and
diaphoresis therapy for control of uremia and management of fluid and electrolytes,215,216
given relevant animal models.217 Because transition to dialysis may be associated with
adverse consequences and burdens of therapy while survival may not be much improved in
certain persons irrespective of age, future studies are needed to refine current interventions
and to examine novel models and strategies to prolong kidney and patient survival without
dialysis if possible and to live long and well with kidney disease.19
28
AUTHORS’ CONTRIBUTIONS:
Drs. KKZ, THJ, DN, BN, and VP have equally substantially contributed to the conception
and design of the article and interpreting the relevant literature, drafted the article and revised
it critically for important intellectual content.
AUTHORS’ DISCLOSURES:
See posted authors disclosures.
29
TABLES
Table 3. Similarities and distinctions between the kidney preserving management and
supportive and palliative care.
Table 1. Strategies to preserve kidney function in people with CKD.
Table 3. Lifestyle Strategies for Prevention of Progressive CKD and Cardiovascular
Disease in Patients with CKD.
Additional tables under Online Appendix
Supplemental Table S1. Recommendations for dietary protein intake to preserve kidney
function in people with CKD.
Supplemental Table S2. Pharmacologic Strategies for Prevention of Progressive CKD
and Cardiovascular Disease in Patients with CKD
30
Table 1. Strategies to preserve kidney function in people with CKD. Numeric ranks (i, ii,
and iii) in the first column indicate level of strength of the evidence for intervention efficacy:
(i) supported by established randomized controlled trials, (ii) supported by biological basis
but limited or no controlled trial evidence, and (iii) weak to moderate biological basis. See
also Figure S3 under online Appendix for the potential roles of these measures under
secondary and tertiary prevention of CKD.
* See Table 2 for additional lifestyle strategies including reduced salt intake, weight reduction and
smoking cessation.
Interventions Advantages and Disadvantages Additional comments

rationale
Diet and lifestyle*
Plant-dominant low-protein Patient-centered, in- Concerns expressed about Effect of plant-based diets
diets (ii) expensive, improves risk of muscle loss and on patient-level kidney
metabolic parameters, frailty. Concerns about outcomes remains to be
mitigates acidosis. May slow hyperkalemia with more definitively demonstrated
progression and attenuate plant-based diet. in randomized trials
uremia
Nutrient focused dietary Traditional familiarity in Effectiveness of single- Restricted K diet may
interventions (ii to iii) clinical practice nutrient approaches (e.g., cause more harm by
(Low Na, low PO4, low K)* strict phosphate control) on limiting healthy K-rich
patient-level outcomes fruits and vegetables.
remains uncertain
Higher physical activity, Numerous clear health Can be challenging to See Table 2 for more
weight reduction, smoking benefits (see Table 2) achieve sustained goals. details.
cessation (ii to iii)
Pharmacological agents to
slow CKD progression
Renin-angiotensin system Proven benefit for preventing Risk of AKI and Kidney benefits in non-
blokade kidney failure in randomized hyperkalemia diabetic kidney disease
(ACEi/ARBs) (i) trials in people with diabetes with proteinuria
<0.5g/day uncertain
SGLT2 inhibitors (i) Clear reductions in patient- Risk of mycotic genital Less data for initiation at
level cardiovascular and infections, volume eGFR <30ml/min/1.73m2
kidney outcomes in people depletion, diabetic Emerging evidence of
with type 2 diabetes ketoacidosis, and limb benefit in people with
amputation. nondiabetic kidney
disease
Mineralocorticoid receptor May slow CKD progression Risk of hyperkalemia. Studies are needed to
antagonists (MRAs) (I to ii) and reduce albuminuria. compare traditional vs.
Potential anti-inflammatory newer MRAs
and anti-fibrotic effects
Tolvaptan for polycystic Slows decline in GFR Risk of polydipsia/polyuria Data on long-term
kidney disease (i to ii) and deranged liver function outcomes data needed
Rituximab for primary Increases likelihood of long- Little randomized data Effect of combination
membranous nephropathy (i term remission compared to compared with alkylating therapies less clear
to ii) ciclosporin agents
Steroids for IgA Extensive clinical experience Mixed results in clinical Large trial ongoing
nephropathy (ii to iii) trials, increased risk of
adverse events, especially
serious infection
Pharmacologic strategies
to reduce cardiovascular
risk
Lipid lowering (ii to iii) Reduces vascular events in No clear benefit for Data on new lipid
people with CKD, well initiating treatment in lowering therapies in
tolerated people on dialysis CKD limited
Blood pressure lowering (i Reduces cardiovascular and Greater risk of adverse Addressing volume
to ii) may reduce kidney outcomes events as kidney function overload crucial aspect of
declines blood pressure lowering
in advanced CKD
Hypoglycemic agents (ii to SGLT2- and GLP-1 receptor Risk of hypoglycemia and Inconsistent benefits for
iii) agonists reduce adverse other treatment related cardiovascular and kidney
cardiovascular events in type adverse events with outcomes with intensive
2 diabetes intensive glucose lowering glucose control
Pharmacologic and other
strategies to slow
progression and manage
uremia
Acidosis management NaHCO3 improves acidosis, Effect on long-term Veverimer may improve
pharmacological strategies may slow progression of outcomes uncertain. acidosis without causing
(sodium bicarbonate CKD NaHCO3 administration sodium retention.
[NaHCO3] and veverimer) may worsen sodium and Randomized trials
(ii to iii) fluid retention ongoing
Potassium binders Reduces risk of No data on patient-level Randomized trials
(Sodium polystyrene, hyperkalemia, enables use of outcomes or progression of ongoing
zirconium and patiromer) (i ACE inhibitors and ARBs kidney disease
to ii)
Sodium and volume Well established clinical Effect on CKD progression Limited randomized data
management experience uncertain
(Sodium restriction, loop
and thiazide diuretics) (ii to
iii)
Symptom management Important priority for patients Unlikely to affect risk of Limited randomized data
e.g. for pruritus, pain, with more unpleasant CKD progression or less
fatigue, sleep disorders, etc. symtoms likely on need for dialysis
(ii to iii)
AKI prevention of and AKI may increase future risk Impact of sick day advice Some drug combinations,
infections (ii to iii) of CKD uncertain, e.g. ACEi and ARB
increase risk of AKI
Infection prevention e.g. Many infectious events may Direct kidney involvement Impact of infection
hepatitis C and COVID-19 cause AKI and/or CKD not certain such as in prevention strategies not
(ii to iii) COVID-19. clear
Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; DPP-4i: dipeptidyl peptidase-4
inhibitors, eGFR, estimated glomerular filtration rate; GLP-1r: glucagon-like peptide-1 receptor agonists, FSGS:
focal segmental glomerulosclerosis, IgA: immunoglobulin A, K: potassium, MBD: mineral and bone disorder,
Na: Sodium, P: phosphorus, PKD: polycystic kidney disease, SGLT2i: sodium glucose cotransporter 2
inhibitors, UTI: urinary tract infection,
32
Table 2. Lifestyle modification strategies for slowing the progression of kidney disease and preventing cardiovascular outcomes. See
also supplemental Figure S2 for schematic depictions of these strategies over the course of CKD progression.
Strategies Effect on kidney disease Effect on cardiovascular Comments Recommendations
progression disease and mortality
Physical Activity Higher physical activity is Higher physical activity is Evidence on physical activity and For patients with CKD, target 150
associated with slower associated with lower risk of progression of kidney disease and minute/week of moderate-intensity physical
decline in kidney function in cardiovascular and mortality cardiovascular outcomes is largely based on activity.
people with CKD218 outcomes219,220 observational studies. Exercise should be individualized for patients
Small trials of physical activity show according to co-morbidities and functional
improvements in kidney function and blood status.
pressure in people with CKD not on Mixed data in dialysis dependent patients,
dialysis.221 unknown benefit of intra-dialytic exercise.
Small trials in patients receiving dialysis
demonstrate improvements in physical
function and health-related quality of life.222
Smoking Current and former smoking Smoking is associated with Smoking cessation should be prioritized in Smoking cessation for all patients with
cessation associated greater risk of increased risk of all-cause all individuals based on numerous behavioral counselling and pharmacologic
incident CKD223 mortality including from vascular recognized health benefits therapies as required and appropriate dosing
and nonvascular (cancer) adjustment for patients with CKD
etiologies in people with CKD224
Dietary sodium Sodium restriction lowers Sodium restriction lowers blood People with CKD are more likely to have Limit sodium intake to < 2.3g/day (<100
restriction albuminuria and improves pressure and improves arterial ‘salt-sensitive’ hypertension228 mmol) according to American Heart
fluid status in people with stiffness in people with and Association
and without CKD225,226 without CKD225,227
Higher plant- Higher plant-based sources Higher red meat intake may be Lowering dietary protein intake may Higher intake of complex carbohydrates and
based of protein and dietary fibers associated with atherosclerosis by increase risk of muscle mass loss and frailty. fresh-fruits and vegetables is recommended as
proportion of may improve acidosis, higher carnitine generation via Protein intake recommendations vary opposed to processes carbohydrates.
protein intake mitigate inflammation, lower microbiota.229 depending on CKD stage, AKI events and
phosphorus burden, and slow need for dialysis70
progression of CKD and
create less uremic toxins,52
Weight reduction Improves cardiometabolic Improves blood pressure 230 Limited randomized evidence to guide the Multidisciplinary approach to weight loss in
health. May slow decline in dietetic management of overweight and overweight and obese individuals with CKD
kidney function and improve obese individuals with CKD with involvement of a kidney dietitian231
albuminuria Mixed data in dialysis patients related to
obesity paradox.59
Table 3. Similarities and distinctions between kidney preserving care, also known as preservative management of kidney disease, and
supportive care including palliative care and hospice medicine. See also Figure 1 for schematic representations of the domains within the
CKD management chart.
Kidney Supportive Comments

Preserving Care Care*
Slowing CKD progression +++ +/++ Important goal across both domains of care but not the primary goal of
supportive care
Preventing or delaying dialysis +++ +++ Both domains aim to prevent or delay initiation of dialysis
Symptom management +/++ +++ Addressing symptoms is one of the key priorities of supportive care but
should also have an important role under preservative management
Health related quality of life and ++/+++ +++ Each domain aims to improve quality of life through different
patient reported outcomes approaches. Kidney preserving care prioritizes aggressive treatments to
restore/protect health and quality of life, whereas supportive care places
greater focus maintaining quality of life by minimizing invasive
interventions
Prioritizing overall survival with +++ -/+ Preventing complications, addressing comorbidities and prolonging
life- and kidney-prolonging care survival is among the highest priorities with kidney preserving care,
while alleviating symptoms is prioritized over prolonging survival with
supportive care
Cardiovascular health +++ -/+ Reducing cardiovascular risk is a fundamental aspect of kidney
preserving care, and less a priority with supportive care
Minimizing risk of AKI and +++ +/++ Minimizing risk of AKI is an important aspect of both domains
infection
Diet and lifestyle modifications +++ + Dietary strategies such as 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
CKD pharmacotherapy +++ + Targeted and non-targeted pharmacotherapies aimed and preserving
kidney function are less a priority with supportive care, where
pharmacotherapy is mostly for symptom management
Treating uremia and +++ +/++ Priorities in the management of CKD related complications are
complications of CKD primarily to avoid unpleasant symptoms with supportive care
34
Preserving residual kidney +++ + Kidney preserving care places greater emphasis on protecting residual
function after transition to kidney function such as incremental transition to dialysis, while
dialysis and less frequent dialysis palliative dialysis can be infrequent as well including decremental
dialysis regimens
Shared decision making and +/++ +++ This is a fundamental concept in the care of all people with kidney
advance care planning disease which is often more clearly highlighted under supportive care
including palliative care and hospice medicine
35
Supplemental Table S1. Target ranges of dietary protein intake for the management of
kidney disease
Dietary Protein Intake Daily grams of protein Comment

Range intake per kg body weight
(g/kg/day)*
Lower protein diet 0.55-0.6 Recommended by KDOQI 2020 guidelines* for CKD
patients without diabetes.
Low-protein diet 0.6-0.8 g/kg/day More consistently recommended for moderate to
advanced CKD (eGFR<45 ml/min/1.73m2 or substantial
proteinuria) regardless of etiology. This range is also
recommended by KDOQI 2020 guidelines* for CKD
patients with diabetes, as well as for PLADO meal
plans with >50% plant source of the protein**
Moderately low-protein 0.8-1.0 g/kg/day Recommended for adults without CKD but at high risk
intake of CKD including those with a solitary kidney, diabetes
mellitus, hypertension, and polycystic kidneys.
Moderate protein intake 1-1.2 g/kg/day Recommended for metabolically stable patients on
maintenance dialysis.
Moderately high-protein 1.2-1.5 g/kg/day Represents the average protein intake of non-vegan
diet adults without CKD in many regions of the world.
*Kidney Disease Outcome Quality Initiatives (KDOQI) clinical practice guidelines in nutrition in kidney
disease 2020232
**Protein-dominant low protein (PLADO) diet consists of 0.6-0.8 g/kg/day of protein with at least 50% from
plant-based sources232
Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; KDOQI: Kidney
Disease Outcome Quality Initiative; PLADO: plant-dominant low-protein diet.
Supplemental Table S2. Pharmacologic strategies for slowing the progression of kidney disease and preventing cardiovascular outcomes
Strategies Effect on kidney disease Effect on Prevention of CVD Events Comments Recommendations
Progression and/or Mortality
Blood lowering No clear benefit of BP Intensive BP lowering (<120 mm Hg) Measure BP using standardized For patients with CKD, consider a systolic BP
and BP targets lowering on risk of kidney reduces cardiovascular events and office technique with multiple of <120 mmHg based on standardized office
failure overall,233,234 mortality in people without diabetes, with consecutive readings using BP measurement.
although benefits may be consistent benefits in people with and automated oscillometric BP Individualization of BP target is critically
present in those with without CKD.236 devices238 important and needs holistic consideration of
albuminuria235 Mortality benefits are likely to be similar Ambulatory BP monitoring is functional status, comorbidities, frailty and
in people diabetic and non-diabetic kidney considered the reference standard for patient preferences.
disease.237 out-of-office BP assessment, with
home BP monitoring being an
acceptable alternative.238
Renin- Reduce the risk of Reduces cardiovascular outcomes in Can cause an acute rise in serum Treatment should be prioritized in all patients
angiotensin progression to kidney people with CKD.240 creatinine due to their effect on with diabetes and albuminuria (>30mg/g) and
system blockade failure in people with intraglomerular pressure, however in those with non-diabetic kidney disease and
diabetic and non-diabetic the benefits of treatment are not high levels of albuminuria (>300 mg/g).
kidney disease with clearest modified by acute changes in serum Treatment with combination of ACEI and ARB
benefit in people with creatinine.241 is not recommended due to the high risk of
substantial albuminuria hyperkalemia and acute kidney injury.
(UACR>300mg/g).118,239
Lipid lowering Likely neutral effect on Combination of simvastatin and ezetimibe The benefit of lipid lowering Statins alone or in combination with CKD
kidney disease significantly reduces risk of major vascular attenuates with decline kidney should be initiated in most adult patients with
progression.242 events in people with CKD.243 function.247 CKD not on dialysis.
Icosapent ethyl and PCSK9 inhibitors can The smaller relative benefit of statins Icosapent ethyl or PCSK9 could be considered
reduce the risk of cardiovascular outcomes at lower eGFR maybe due to a lower in very high-risk patients such as those with
in people atherosclerotic cardiovascular proportion of atherosclerotic persistently elevated LDL or triglyceride levels.
disease, although these trials enrolled compared to non-atherosclerotic
relatively few people with CKD.244-246 cardiovascular events.
Glucose lowering Intensive glucose control Uncertainty with regards to effects on Clear differences between different Individualization of glycemic targets based on
reduces progression of macrovascular outcomes with no clear glucose lowering agents and their goals of care, comorbidities and patient
kidney disease248 effect on mortality249 effect on clinical outcomes preferences is key, with more frail patients
having more lenient targets to avoid
hypoglycemia.
SGLT2 inhibitors Reduces the risk of kidney Reduces the risk of a range of Emerging evidence of heart and Recommended in people with severely
failure in people with type 2 cardiovascular outcomes, particularly heart kidney failure benefits irrespective of increased albuminuria (UACR >300mg/g)
diabetes.250 failure and cardiovascular death as well as the presence of diabetes. irrespective of the presence of diabetes to
all-cause mortality Limited evidence for initiation at reduce the risk of kidney failure, cardiovascular
eGFR <30mL/min/1.73m2 events, or both
GLP-1 receptor Reduces the risk of Reduces cardiovascular events with similar Heterogeneity of relative benefit
agonists albuminuria based relative benefit across different levels of observed across different agents
composite kidney outcomes, kidney function within the class
but effects on patient-level
kidney outcomes uncertain
Antiplatelet No effect on kidney disease Antiplatelet therapy (mostly aspirin) can Antiplatelet therapy increases the risk Decision to use antiplatelets for primary
therapy progression reduce myocardial infarction of major bleeding cardiovascular prevention in CKD needs to
take into account the individual’s
cardiovascular risk as well as bleeding risk, and
preferences
38
FIGURES
Figure 1. Chronic kidney disease (CKD) management chart.
Figure 2. Effects of dietary protein intake and pharmacological therapies on afferent

and efferent arteriolar tone, intra-glomerular pressure and glomerular structures and
functions.
Figure 3. Association of estimated glomerular filtration rate (based on creatinine based

eGFR along with a Cystatin-C based eGFR for comparison) and albuminuria with risk
of cardiovascular outcomes, after adjustment for traditional cardiovascular risk factors
Additional Supplemental Figures under Online Appendix
Supplement Figure S1. KDIGO classification of chronic kidney disease (CKD)
Supplement Figure S2: Primary, secondary and tertiary prevention of chronic kidney
disease.
Supplement Figure S4. Comparing acute and chronic GFR effects of dietary protein
restriction versus kidney protective drugs.
Supplement Figure S1. Combined pharmacological and non-pharmacological

approaches to the management of CKD across all levels of kidney function.
Supplement Figure S5. The conceptual framework of the challenges of CVD

management in CKD
Figure 1. Chronic kidney disease (CKD) management chart. This chart highlights the role of “preservative management” and its goals (green domain) within
the overall “conservative management” of CKD without dialysis (grey zone), juxtaposing the “renal (kidney) replacement therapy” including dialysis and kidney
transplantation (yellow zone). On the X axis, the direction is inherently left to right given CKD progression, while on the Y axis, the patient and his/her care-partner(s) as
well as providers can move in different directions as they choose based on the goals of care. The lower area of the chart represents conventional or life-prolonging strategies,
whereas the in the upper area, supportive care prevails including the “palliative and hospice care” where dialysis is often avoided or withdrawn (red domain). The obliquely
run dotted line between the two main zones suggests that there is variability in transitioning to kidney replacement therapy as moving from lower left to upper right including
timing (early vs. late vs. never), level of care (life prolonging vs. supportive care), and modality (conventional vs. incremental). The symptom management (blue domain)
provides wide ranges of interventions to encompass the goals of care under both the preservative management and palliative and hospice care and can continue after the
patient transitions to kidney replacement therapy. The preservative management can continue to preserve the residual kidney function longer especially upon incremental
transition to dialysis. See also Table 3 for additional comparisons between preservative and supportive care and supplemental Figure S2 under online appendix for overview
of these strategies over the course of CKD progression. (asterisk * under uremia management represents pharmacotherapies for the management of acidosis, anemia and bone
disease).
Figure 2. Effects of lower dietary sodium and protein intake with higher proportion of plant-based protein sources and pharmacological
therapies on afferent and efferent arteriolar tone and intra-glomerular pressure as well as tubuloglomerular feedback and interstitial
fibrosis. Dietary protein restriction results in contraction of the afferent arterioles leading to reduced intra-glomerular pressure. This can lead to less damage
to glomerular structure and function in long-term. The kidney protective effects of plant-dominant low protein diet acts in parallel and may be complementary
to the effect of SGLT2 inhibitors, renin-angiotensin system blockade, mineralocorticoid receptor antagonism, and other blood pressure lowering agents,
thereby more effectively reducing intraglomerular pressure and mitigating interstitial fibrosis.
41
Figure 3. Association of estimated glomerular filtration (eGFR) rate and albuminuria with risk of cardiovascular outcomes, after
adjustment for traditional cardiovascular risk factors. Data are from the CKD Prognosis Consortium of 637,315 individuals from 24 cohorts i.e.,
general population, high risk, and established CKD, followed up for a mean of 8,9 years during which time 10,605 cardiovascular deaths, 6,283 coronary
heart disease events, 180 stroke events, and 2,066 heart failure events occurred. Cystatin C eGFR data are from meta-analysis of 10 general-population
cohorts with 64,010 participants, of whom 3193 died from cardiovascular causes during follow-up (recreated with modification based on figures in
Matsushita et al, Lancet Diab Endo 201542 and Shlipak et al, N Engl J Med 2013154)
42
43
Supplemental Figure S1. KDIGO classification of chronic kidney disease (CKD). Adapted from the 2012 KDIGO classification of CKD. The
colors reflect the ranking of absolute risk of kidney failure: low (green), moderate (yellow), high (orange), and very high (red). Numbers in each cell represent
the adjusted relative risk (RR) of kidney failure for the general population assessing albuminuria using either UACR or urine dipstick.(recreated with
modification from Gansevoort et al, Kidney Int 2011.251)
KDIGO: Kidney Disease Improving Global Outcomes; eGFR: estimated glomerular filtration rate; UACR: urinary albumin/creatinine ratio; ESKD: end-stage kidney
disease.
44
Supplement Figure S2. Combined pharmacological and non-pharmacological approaches to the management of CKD across all levels of
kidney function.
45
Supplement Figure S3: Primary, secondary and tertiary prevention of chronic kidney disease. Highlighting similarities and distinctions
pertaining to primary, secondary, and tertiary preventive measures and their intended goals. The “preservative management” of CKD is consistent with the
secondary and tertiary prevention goals and approaches (recreated with modifications from Li et al, Kidney Int 2020).34 See also Tables 2, 3 and 4 for
detailed strategies.
Supplement Figure S4. Acute and chronic GFR effects of dietary protein restriction and kidney protective drugs. Many interventions that
are kidney protective have short-term effects on GFR that differ from their long-term effects. Dietary protein restriction, renin angiotensin
system blockade and SGLT2 inhibition all lower intraglomerular pressure, which is reflected clinically by an acute reduction in GFR followed
by long-term preservation of GFR. This is demonstrated in the panels below: (Upper Panel) Dietary protein restriction in the MDRD trial3 (Right
Lower Panel) SGLT2 inhibition with canagliflozin in the CREDENCE trial and (Left Lower Panel)130 RAS blockade with losartan in the
RENAAL trial.111
47
Supplement Figure 5. The conceptual framework of the challenges of CVD management in CKD
48
References
1. Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. The lancet 2017;
389(10075): 1238-52.
2. Bikbov B, Purcell CA, Levey AS, et al. Global, regional, and national burden of chronic kidney
disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet
2020; 395(10225): 709-33.
3. Xie Y, Bowe B, Mokdad AH, et al. Analysis of the Global Burden of Disease study highlights
the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016.
Kidney international 2018; 94(3): 567-81.
4. Foreman KJ, Marquez N, Dolgert A, et al. Forecasting life expectancy, years of life lost, and
all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios
for 2016–40 for 195 countries and territories. The Lancet 2018; 392(10159): 2052-90.
5. Ku E, Lee BJ, Wei J, Weir MR. Hypertension in CKD: Core Curriculum 2019. Am J Kidney Dis
2019; 74(1): 120-31.
6. Pearce N, Caplin B. Let's take the heat out of the CKDu debate: more evidence is needed.
Occup Environ Med 2019; 76(6): 357-9.
7. Bowe B, Artimovich E, Xie Y, Yan Y, Cai M, Al-Aly Z. The global and national burden of chronic
kidney disease attributable to ambient fine particulate matter air pollution: a modelling study. BMJ
Glob Health 2020; 5(3): e002063.
8. Cockwell P, Fisher LA. The global burden of chronic kidney disease. Lancet 2020; 395(10225):
662-4.
9. Silverwood RJ, Pierce M, Thomas C, et al. Association between younger age when first
overweight and increased risk for CKD. J Am Soc Nephrol 2013; 24(5): 813-21.
10. Webster AC, Nagler EV, Morton RL, Masson P. Chronic Kidney Disease. Lancet 2017;
389(10075): 1238-52.
11. Cano N, Fernandez JP, Lacombe P, et al. Statistical selection of nutritional parameters in
hemodialyzed patients. Kidney Int 1987; 32: S178-S80.
12. Song MK. Quality of Life of Patients with Advanced Chronic Kidney Disease Receiving
Conservative Care without Dialysis. Semin Dial 2016; 29(2): 165-9.
13. Bello AK, Levin A, Lunney M, et al. Status of care for end stage kidney disease in countries
and regions worldwide: international cross sectional survey. bmj 2019; 367: l5873.
14. Kurella Tamura M, Desai M, Kapphahn KI, Thomas IC, Asch SM, Chertow GM. Dialysis versus
Medical Management at Different Ages and Levels of Kidney Function in Veterans with Advanced
CKD. J Am Soc Nephrol 2018.
15. Kalantar-Zadeh K, Kovesdy CP, Streja E, et al. Transition of care from pre-dialysis prelude to
renal replacement therapy: the blueprints of emerging research in advanced chronic kidney disease.
Nephrol Dial Transplant 2017; 32(suppl_2): ii91-ii8.
16. O'Connor NR, Kumar P. Conservative management of end-stage renal disease without
dialysis: a systematic review. J Palliat Med 2012; 15(2): 228-35.
17. Kalantar-Zadeh K, Wightman A, Liao S. Ensuring Choice for People with Kidney Failure -
Dialysis, Supportive Care, and Hope. N Engl J Med 2020; 383(2): 99-101.
18. Rhee CM, Nguyen DV, Nyamathi A, Kalantar-Zadeh K. Conservative vs. preservative
management of chronic kidney disease: similarities and distinctions. Curr Opin Nephrol Hypertens
2020; 29(1): 92-102.
19. Kalantar-Zadeh K, Kam-Tao Li P, Tantisattamo E, et al. Living well with kidney disease by
patient and care-partner empowerment: kidney health for everyone everywhere. Kidney Int 2021;
99(2): 278-84.
20. Teehan BP, Schleifer CR, Brown JM, Sigler MH, Raimondo J. Urea kinetic analysis and clinical
outcome in CAPD: a five-year longitudinal study. Adv Perit Dial 1990; 6: 181-5.
21. Brown MA, Collett GK, Josland EA, Foote C, Li Q, Brennan FP. CKD in elderly patients
managed without dialysis: survival, symptoms, and quality of life. Clin J Am Soc Nephrol 2015; 10(2):
260-8.
22. Carson RC, Juszczak M, Davenport A, Burns A. Is maximum conservative management an
equivalent treatment option to dialysis for elderly patients with significant comorbid disease? Clin J
Am Soc Nephrol 2009; 4(10): 1611-9.
23. Chandna SM, Da Silva-Gane M, Marshall C, Warwicker P, Greenwood RN, Farrington K.
Survival of elderly patients with stage 5 CKD: comparison of conservative management and renal
replacement therapy. Nephrol Dial Transplant 2011; 26(5): 1608-14.
24. Da Silva-Gane M, Wellsted D, Greenshields H, Norton S, Chandna SM, Farrington K. Quality
of life and survival in patients with advanced kidney failure managed conservatively or by dialysis.
Clin J Am Soc Nephrol 2012; 7(12): 2002-9.
25. Hemmelgarn BR, James MT, Manns BJ, et al. Rates of treated and untreated kidney failure in
older vs younger adults. JAMA 2012; 307(23): 2507-15.
26. Joly D, Anglicheau D, Alberti C, et al. Octogenarians reaching end-stage renal disease: cohort
study of decision-making and clinical outcomes. J Am Soc Nephrol 2003; 14(4): 1012-21.
27. Kamar FB, Tam-Tham H, Thomas C. A Description of Advanced Chronic Kidney Disease
Patients in a Major Urban Center Receiving Conservative Care. Can J Kidney Health Dis 2017; 4:
2054358117718538.
28. Murtagh FE, Marsh JE, Donohoe P, Ekbal NJ, Sheerin NS, Harris FE. Dialysis or not? A
comparative survival study of patients over 75 years with chronic kidney disease stage 5. Nephrol
Dial Transplant 2007; 22(7): 1955-62.
29. Reindl-Schwaighofer R, Kainz A, Kammer M, Dumfarth A, Oberbauer R. Survival analysis of
conservative vs. dialysis treatment of elderly patients with CKD stage 5. PLoS One 2017; 12(7):
e0181345.
30. Seow YY, Cheung YB, Qu LM, Yee AC. Trajectory of quality of life for poor prognosis stage 5D
chronic kidney disease with and without dialysis. Am J Nephrol 2013; 37(3): 231-8.
31. Shum CK, Tam KF, Chak WL, Chan TC, Mak YF, Chau KF. Outcomes in older adults with stage
5 chronic kidney disease: comparison of peritoneal dialysis and conservative management. J
Gerontol A Biol Sci Med Sci 2014; 69(3): 308-14.
32. Teruel JL, Burguera Vion V, Gomis Couto A, et al. Choosing conservative therapy in chronic
kidney disease. Nefrologia 2015; 35(3): 273-9.
33. Verberne WR, Geers AB, Jellema WT, Vincent HH, van Delden JJ, Bos WJ. Comparative
Survival among Older Adults with Advanced Kidney Disease Managed Conservatively Versus with
Dialysis. Clin J Am Soc Nephrol 2016; 11(4): 633-40.
34. Li PK, Garcia-Garcia G, Lui SF, et al. Kidney health for everyone everywhere-from prevention
to detection and equitable access to care. Kidney Int 2020; 97(2): 226-32.
35. Stengel B, Tarver–Carr ME, Powe NR, Eberhardt MS, Brancati FL. Lifestyle factors, obesity
and the risk of chronic kidney disease. Epidemiology 2003; 14(4): 479-87.
36. Komenda P, Ferguson TW, Macdonald K, et al. Cost-effectiveness of primary screening for
CKD: a systematic review. American Journal of Kidney Diseases 2014; 63(5): 789-97.
37. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and
cardiovascular risk: epidemiology, mechanisms, and prevention. The Lancet 2013; 382(9889): 339-
52.
38. Astor BC, Matsushita K, Gansevoort RT, et al. Lower estimated glomerular filtration rate and
higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-
analysis of kidney disease population cohorts. Kidney international 2011; 79(12): 1331-40.
39. Chronic Kidney Disease Prognosis C. Association of estimated glomerular filtration rate and
albuminuria with all-cause and cardiovascular mortality in general population cohorts: a
collaborative meta-analysis. The Lancet 2010; 375(9731): 2073-81.
50
40. Gansevoort RT, Matsushita K, Van Der Velde M, et al. Lower estimated GFR and higher
albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general
and high-risk population cohorts. Kidney international 2011; 80(1): 93-104.
41. Van Der Velde M, Matsushita K, Coresh J, et al. Lower estimated glomerular filtration rate
and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative
meta-analysis of high-risk population cohorts. Kidney international 2011; 79(12): 1341-52.
42. Matsushita K, Coresh J, Sang Y, et al. Estimated glomerular filtration rate and albuminuria for
prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data.
The lancet Diabetes & endocrinology 2015; 3(7): 514-25.
43. Levin A, Stevens PE, Bilous RW, et al. Kidney Disease: Improving Global Outcomes (KDIGO)
CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of
chronic kidney disease. Kidney International Supplements 2013; 3(1): 1-150.
44. Tangri N, Stevens LA, Griffith J, et al. A predictive model for progression of chronic kidney
disease to kidney failure. Jama 2011; 305(15): 1553-9.
45. Obi Y, Nguyen DV, Zhou H, et al. Development and Validation of Prediction Scores for Early
Mortality at Transition to Dialysis. Mayo Clin Proc 2018; 93(9): 1224-35.
46. Obi Y, Rhee CM, Mathew AT, et al. Residual Kidney Function Decline and Mortality in
Incident Hemodialysis Patients. J Am Soc Nephrol 2016; 27(12): 3758-68.
47. Kovesdy CP, Furth SL, Zoccali C, World Kidney Day Steering C. Obesity and kidney disease:
hidden consequences of the epidemic. Oxford University Press US; 2017.
48. Chang AR, Grams ME, Ballew SH, et al. Adiposity and risk of decline in glomerular filtration
rate: meta-analysis of individual participant data in a global consortium. bmj 2019; 364.
49. Tonneijck L, Muskiet MHA, Smits MM, et al. Glomerular hyperfiltration in diabetes:
mechanisms, clinical significance, and treatment. Journal of the American Society of Nephrology
2017; 28(4): 1023-39.
50. Herrington WG, Smith M, Bankhead C, et al. Body-mass index and risk of advanced chronic
kidney disease: prospective analyses from a primary care cohort of 1.4 million adults in England. PloS
one 2017; 12(3): e0173515.
51. Look ARG. Effect of a long-term behavioural weight loss intervention on nephropathy in
overweight or obese adults with type 2 diabetes: a secondary analysis of the Look AHEAD
randomised clinical trial. The Lancet Diabetes & Endocrinology 2014; 2(10): 801-9.
52. Kalantar-Zadeh K, Joshi S, Schlueter R, et al. Plant-Dominant Low-Protein Diet for
Conservative Management of Chronic Kidney Disease. Nutrients 2020; 12(7).
53. Joshi S, McMacken M, Kalantar-Zadeh K. Plant-Based Diets for Kidney Disease: A Guide for
Clinicians. Am J Kidney Dis 2021; 77(2): 287-96.
54. Scirica BM, Bohula EA, Dwyer JP, et al. Lorcaserin and Renal Outcomes in Obese and
Overweight Patients in the CAMELLIA-TIMI 61 Trial. Circulation 2018.
55. Chang AR, Grams ME, Navaneethan SD. Bariatric surgery and kidney-related outcomes.
Kidney international reports 2017; 2(2): 261-70.
56. Chang AR, Chen Y, Still C, et al. Bariatric surgery is associated with improvement in kidney
outcomes. Kidney international 2016; 90(1): 164-71.
57. Cohen RV, Pereira TV, Aboud CM, et al. Effect of Gastric Bypass vs Best Medical Treatment
on Early-Stage Chronic Kidney Disease in Patients With Type 2 Diabetes and Obesity: A Randomized
Clinical Trial. JAMA Surgery 2020: e200420-e.
58. Naderi N, Kleine CE, Park C, et al. Obesity Paradox in Advanced Kidney Disease: From
Bedside to the Bench. Prog Cardiovasc Dis 2018; 61(2): 168-81.
59. Kalantar-Zadeh K, Rhee CM, Chou J, et al. The Obesity Paradox in Kidney Disease: How to
Reconcile it with Obesity Management. Kidney Int Rep 2017; 2(2): 271-81.
60. Rhee CM, Ahmadi SF, Kalantar-Zadeh K. The dual roles of obesity in chronic kidney disease: a
review of the current literature. Curr Opin Nephrol Hypertens 2016; 25(3): 208-16.
51
61. Tovar-Palacio C, Tovar AR, Torres N, et al. Proinflammatory gene expression and renal
lipogenesis are modulated by dietary protein content in obese Zucker fa/fa rats. Am J Physiol Renal
Physiol 2011; 300(1): F263-71.
62. Kalantar-Zadeh K, Fouque D. Nutritional Management of Chronic Kidney Disease. N Engl J
Med 2017; 377(18): 1765-76.
63. Kalantar-Zadeh K, Fouque D. Nutritional management of chronic kidney disease. New
England Journal of Medicine 2017; 377(18): 1765-76.
64. Levey AS, Greene T, Beck GJ, et al. Dietary protein restriction and the progression of chronic
renal disease: what have all of the results of the MDRD study shown? Modification of Diet in Renal
Disease Study group. J Am Soc Nephrol 1999; 10(11): 2426-39.
65. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the
progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med 1995;
123(10): 754-62.
66. Rhee CM, Ahmadi SF, Kovesdy CP, Kalantar-Zadeh K. Low-protein diet for conservative
management of chronic kidney disease: a systematic review and meta-analysis of controlled trials. J
Cachexia Sarcopenia Muscle 2018; 9(2): 235-45.
67. Fouque D, Laville M. Low protein diets for chronic kidney disease in non diabetic adults.
Cochrane Database Syst Rev 2009; (3): CD001892.
68. Kasiske BL, Lakatua JD, Ma JZ, Louis TA. A meta-analysis of the effects of dietary protein
restriction on the rate of decline in renal function. Am J Kidney Dis 1998; 31(6): 954-61.
69. Chewcharat A, Takkavatakarn K, Wongrattanagorn S, et al. The Effects of Restricted Protein
Diet Supplemented With Ketoanalogue on Renal Function, Blood Pressure, Nutritional Status, and
Chronic Kidney Disease-Mineral and Bone Disorder in Chronic Kidney Disease Patients: A Systematic
Review and Meta-Analysis. J Ren Nutr 2020; 30(3): 189-99.
70. Kovesdy CP, Kopple JD, Kalantar-Zadeh K. Management of protein-energy wasting in non-
dialysis-dependent chronic kidney disease: reconciling low protein intake with nutritional therapy.
Am J Clin Nutr 2013; 97(6): 1163-77.
71. Moore LW, Byham-Gray LD, Scott Parrott J, et al. The mean dietary protein intake at
different stages of chronic kidney disease is higher than current guidelines. Kidney Int 2013; 83(4):
724-32.
72. Kalantar-Zadeh K, Moore LW. Does Kidney Longevity Mean Healthy Vegan Food and Less
Meat or Is Any Low-Protein Diet Good Enough? J Ren Nutr 2019; 29(2): 79-81.
73. Kim H, Caulfield LE, Garcia-Larsen V, et al. Plant-based diets and incident CKD and kidney
function. Clinical Journal of the American Society of Nephrology 2019; 14(5): 682-91.
74. Mafra D, Borges NA, Lindholm B, Shiels PG, Evenepoel P, Stenvinkel P. Food as medicine:
targeting the uraemic phenotype in chronic kidney disease. Nat Rev Nephrol 2020.
75. Ko GJ, Rhee CM, Kalantar-Zadeh K, Joshi S. The Effects of High-Protein Diets on Kidney
Health and Longevity. J Am Soc Nephrol 2020.
76. Joshi S, Shah S, Kalantar-Zadeh K. Adequacy of Plant-Based Proteins in Chronic Kidney
Disease. J Ren Nutr 2019; 29(2): 112-7.
77. Koppe L, Mafra D, Fouque D. Probiotics and chronic kidney disease. Kidney Int 2015; 88(5):
958-66.
78. Chauveau P, Combe C, Fouque D, Aparicio M. Vegetarianism: advantages and drawbacks in
patients with chronic kidney diseases. J Ren Nutr 2013; 23(6): 399-405.
79. Vaziri ND, Goshtasbi N, Yuan J, et al. Uremic plasma impairs barrier function and depletes
the tight junction protein constituents of intestinal epithelium. Am J Nephrol 2012; 36(5): 438-43.
80. Lau WL, Kalantar-Zadeh K, Vaziri ND. The Gut as a Source of Inflammation in Chronic Kidney
Disease. Nephron 2015; 130(2): 92-8.
81. Vaziri ND, Yuan J, Rahimi A, Ni Z, Said H, Subramanian VS. Disintegration of colonic epithelial
tight junction in uremia: a likely cause of CKD-associated inflammation. Nephrol Dial Transplant
2012; 27(7): 2686-93.
52
82. Vaziri ND, Yuan J, Nazertehrani S, Ni Z, Liu S. Chronic kidney disease causes disruption of
gastric and small intestinal epithelial tight junction. Am J Nephrol 2013; 38(2): 99-103.
83. Magnusson M, Magnusson KE, Sundqvist T, Denneberg T. Increased intestinal permeability
to differently sized polyethylene glycols in uremic rats: effects of low- and high-protein diets.
Nephron 1990; 56(3): 306-11.
84. Magnusson M, Magnusson KE, Sundqvist T, Denneberg T. Impaired intestinal barrier
function measured by differently sized polyethylene glycols in patients with chronic renal failure. Gut
1991; 32(7): 754-9.
85. Lau WL, Liu SM, Pahlevan S, et al. Role of Nrf2 dysfunction in uremia-associated intestinal
inflammation and epithelial barrier disruption. Dig Dis Sci 2015; 60(5): 1215-22.
86. Wang F, Jiang H, Shi K, Ren Y, Zhang P, Cheng S. Gut bacterial translocation is associated with
microinflammation in end-stage renal disease patients. Nephrology (Carlton) 2012; 17(8): 733-8.
87. Shi K, Wang F, Jiang H, et al. Gut bacterial translocation may aggravate microinflammation in
hemodialysis patients. Dig Dis Sci 2014; 59(9): 2109-17.
88. Feroze U, Kalantar-Zadeh K, Sterling KA, et al. Examining associations of circulating
endotoxin with nutritional status, inflammation, and mortality in hemodialysis patients. J Ren Nutr
2012; 22(3): 317-26.
89. Szeto CC, Kwan BC, Chow KM, et al. Endotoxemia is related to systemic inflammation and
atherosclerosis in peritoneal dialysis patients. Clin J Am Soc Nephrol 2008; 3(2): 431-6.
90. Rossi M, Campbell KL, Johnson DW, et al. Protein-bound uremic toxins, inflammation and
oxidative stress: a cross-sectional study in stage 3-4 chronic kidney disease. Arch Med Res 2014;
45(4): 309-17.
91. McIntyre CW, Harrison LE, Eldehni MT, et al. Circulating endotoxemia: a novel factor in
systemic inflammation and cardiovascular disease in chronic kidney disease. Clin J Am Soc Nephrol
2011; 6(1): 133-41.
92. Lau WL, Savoj J, Nakata MB, Vaziri ND. Altered microbiome in chronic kidney disease:
systemic effects of gut-derived uremic toxins. Clin Sci (Lond) 2018; 132(5): 509-22.
93. Wu IW, Hsu KH, Lee CC, et al. p-Cresyl sulphate and indoxyl sulphate predict progression of
chronic kidney disease. Nephrol Dial Transplant 2011; 26(3): 938-47.
94. Koppe L, Pillon NJ, Vella RE, et al. p-Cresyl sulfate promotes insulin resistance associated
with CKD. J Am Soc Nephrol 2013; 24(1): 88-99.
95. Wu IW, Hsu KH, Hsu HJ, et al. Serum free p-cresyl sulfate levels predict cardiovascular and
all-cause mortality in elderly hemodialysis patients--a prospective cohort study. Nephrol Dial
Transplant 2012; 27(3): 1169-75.
96. Carrero JJ, Gonzalez-Ortiz A, Avesani CM, et al. Plant-based diets to manage the risks and
complications of chronic kidney disease. Nat Rev Nephrol 2020; 16(9): 525-42.
97. Hung S-C, Kuo K-L, Peng C-H, et al. Volume overload correlates with cardiovascular risk
factors in patients with chronic kidney disease. Kidney international 2014; 85(3): 703-9.
98. Tsai Y-C, Tsai J-C, Chen S-C, et al. Association of fluid overload with kidney disease
progression in advanced CKD: a prospective cohort study. American Journal of Kidney Diseases 2014;
63(1): 68-75.
99. Hung SC, Kuo KL, Peng CH, Wu CH, Wang YC, Tarng DC. Association of fluid retention with
anemia and clinical outcomes among patients with chronic kidney disease. Journal of the American
Heart Association 2015; 4(1): e001480.
100. Kimura G, Dohi Y, Fukuda M. Salt sensitivity and circadian rhythm of blood pressure: the keys
to connect CKD with cardiovasucular events. Hypertension Research 2010; 33(6): 515-20.
101. Bovée DM, Visser WJ, Middel I, et al. A Randomized Trial of Distal Diuretics versus Dietary
Sodium Restriction for Hypertension in Chronic Kidney Disease. Journal of the American Society of
Nephrology 2020; 31(3): 650-62.
53
102. Agarwal R, Cramer AE, Balmes-Fenwick M, Sinha AD, Ouyang F, Tu W. Design and Baseline
Characteristics of the Chlorthalidone in Chronic Kidney Disease (CLICK) Trial. American journal of
nephrology 2020; 51(7): 542-52.
103. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-
of-the-art review. Diabetologia 2018; 61(10): 2108-17.
104. Kovesdy CP, Matsushita K, Sang Y, et al. Serum potassium and adverse outcomes across the
range of kidney function: a CKD Prognosis Consortium meta-analysis. European heart journal 2018;
39(17): 1535-42.
105. Clegg DJ, Gallant KMH. Plant-based diets in CKD. Clinical Journal of the American Society of
Nephrology 2019; 14(1): 141-3.
106. Sarwar CMS, Bhagat AA, Anker SD, Butler J. Role of hyperkalemia in heart failure and the
therapeutic use of potassium binders. Heart Failure: Springer; 2017: 537-60.
107. Georgianos PI, Agarwal R. Revisiting RAAS blockade in CKD with newer potassium-binding
drugs. Kidney international 2018; 93(2): 325-34.
108. Kraut JA, Kurtz I. Metabolic acidosis of CKD: diagnosis, clinical characteristics, and treatment.
American journal of kidney diseases 2005; 45(6): 978-93.
109. Navaneethan SD, Shao J, Buysse J, Bushinsky DA. Effects of treatment of metabolic acidosis
in CKD: a systematic review and meta-analysis. Clinical Journal of the American Society of Nephrology
2019; 14(7): 1011-20.
110. Wesson DE, Mathur V, Tangri N, et al. Veverimer versus placebo in patients with metabolic
acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled,
phase 3 trial. The Lancet 2019; 393(10179): 1417-27.
111. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular
outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345(12): 861-9.
112. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor
antagonist irbesartan in patients with nephropathy due to type 2 diabetes. New England Journal of
Medicine 2001; 345(12): 851-60.
113. Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of
diabetic nephropathy. N Engl J Med 2013; 369(20): 1892-903.
114. Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for
type 2 diabetes. N Engl J Med 2012; 367(23): 2204-13.
115. Investigators O, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk
for vascular events. N Engl J Med 2008; 358(15): 1547-59.
116. Bakris GL, Agarwal R, Anker SD, et al. Effect of Finerenone on Chronic Kidney Disease
Outcomes in Type 2 Diabetes. N Engl J Med 2020; 383(23): 2219-29.
117. Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ. Change in proteinuria after adding
aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review.
American Journal of Kidney Diseases 2008; 51(2): 199-211.
118. Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and
progression of nondiabetic renal disease: a meta-analysis of patient-level data. Annals of internal
medicine 2001; 135(2): 73-87.
119. Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and
renal outcomes: updated systematic review and meta-analysis. Lancet 2016; 387(10017): 435-43.
120. Jafar TH, Stark PC, Schmid CH, et al. Progression of chronic kidney disease: the role of blood
pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-
analysis. Ann Intern Med 2003; 139(4): 244-52.
121. Malhotra R, Craven T, Ambrosius WT, et al. Effects of intensive blood pressure lowering on
kidney tubule injury in CKD: a longitudinal subgroup analysis in SPRINT. American Journal of Kidney
Diseases 2019; 73(1): 21-30.
54
122. Obi Y, Kalantar-Zadeh K, Shintani A, Kovesdy CP, Hamano T. Estimated glomerular filtration
rate and the risk-benefit profile of intensive blood pressure control amongst nondiabetic patients: a
post hoc analysis of a randomized clinical trial. J Intern Med 2018; 283(3): 314-27.
123. Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and
possibilities. Clinical Journal of the American Society of Nephrology 2017; 12(12): 2032-45.
124. Perkovic V, Heerspink HL, Chalmers J, et al. Intensive glucose control improves kidney
outcomes in patients with type 2 diabetes. Kidney international 2013; 83(3): 517-23.
125. Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. Role of intensive glucose control in
development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis
intensive glucose control in type 2 diabetes. Arch Intern Med 2012; 172(10): 761-9.
126. Heerspink HJL, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin slows
progression of renal function decline independently of glycemic effects. Journal of the American
Society of Nephrology 2017; 28(1): 368-75.
127. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in
type 2 diabetes. New England Journal of Medicine 2016; 375(4): 323-34.
128. Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2
diabetes: results from the CANVAS Program randomised clinical trials. The lancet Diabetes &
endocrinology 2018; 6(9): 691-704.
129. Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and
progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE–TIMI
58 randomised trial. The lancet Diabetes & endocrinology 2019; 7(8): 606-17.
130. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and
nephropathy. New England Journal of Medicine 2019; 380(24): 2295-306.
131. Heerspink HJL, Stefansson BV, Chertow GM, et al. Rationale and protocol of the Dapagliflozin
And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled
trial. Nephrology Dialysis Transplantation 2020; 35(2): 274-82.
132. Wheeler DC, Stefansson BV, Jongs N, et al. Effects of dapagliflozin on major adverse kidney
and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a
prespecified analysis from the DAPA-CKD trial. The lancet Diabetes & endocrinology 2021; 9(1): 22-
31.
133. Herrington WG, Preiss D, Haynes R, et al. The potential for improving cardio-renal outcomes
by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for
the EMPA-KIDNEY study. Clinical kidney journal 2018; 11(6): 749-61.
134. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major
cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the
CARMELINA randomized clinical trial. Jama 2019; 321(1): 69-79.
135. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with
GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of
cardiovascular outcome trials. The lancet Diabetes & endocrinology 2019; 7(10): 776-85.
136. Floege J, Barbour SJ, Cattran DC, et al. Management and treatment of glomerular diseases
(part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies
Conference. Kidney international 2019; 95(2): 268-80.
137. Rauen T, Eitner F, Fitzner C, et al. Intensive supportive care plus immunosuppression in IgA
nephropathy. New England Journal of Medicine 2015; 373(23): 2225-36.
138. Lv J, Zhang H, Wong MG, et al. Effect of oral methylprednisolone on clinical outcomes in
patients with IgA nephropathy: the TESTING randomized clinical trial. Jama 2017; 318(5): 432-42.
139. Barratt J, Rovin B, Diva U, Mercer A, Komers R. Implementing the Kidney Health Initiative
Surrogate Efficacy Endpoint in Patients With IgA Nephropathy (the PROTECT Trial). Kidney
international reports 2019; 4(11): 1633-7.
140. Zipfel PF, Wiech T, Rudnick RB, Afonso S, Skerka C, Person FJ. Complement inhibitors in
clinical trials for glomerular diseases. Frontiers in immunology 2019; 10: 2166.
55
141. Beck Jr LH, Bonegio RGB, Lambeau G, et al. M-type phospholipase A2 receptor as target
antigen in idiopathic membranous nephropathy. New England Journal of Medicine 2009; 361(1): 11-
21.
142. Beck LH, Fervenza FC, Beck DM, et al. Rituximab-induced depletion of anti-PLA2R
autoantibodies predicts response in membranous nephropathy. Journal of the American Society of
Nephrology 2011; 22(8): 1543-50.
143. Hofstra JM, Beck LH, Beck DM, Wetzels JF, Salant DJ. Anti-phospholipase A2 receptor
antibodies correlate with clinical status in idiopathic membranous nephropathy. Clinical journal of
the American Society of Nephrology 2011; 6(6): 1286-91.
144. Polanco N, Gutiérrez E, Covarsí A, et al. Spontaneous remission of nephrotic syndrome in
idiopathic membranous nephropathy. Journal of the American Society of Nephrology 2010; 21(4):
697-704.
145. Van Den Brand JAJG, Ruggenenti P, Chianca A, et al. Safety of rituximab compared with
steroids and cyclophosphamide for idiopathic membranous nephropathy. Journal of the American
Society of Nephrology 2017; 28(9): 2729-37.
146. Praga M, Barrio V, Juárez GF, Luno J. Tacrolimus monotherapy in membranous nephropathy:
a randomized controlled trial. Kidney international 2007; 71(9): 924-30.
147. Cattran DC, Appel GB, Hebert LA, et al. Cyclosporine in patients with steroid-resistant
membranous nephropathy: a randomized trial. Kidney international 2001; 59(4): 1484-90.
148. Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or cyclosporine in the treatment of
membranous nephropathy. New England Journal of Medicine 2019; 381(1): 36-46.
149. Trivin-Avillach C, Beck LH. Management of Membranous Nephropathy after MENTOR.
Clinical Journal of the American Society of Nephrology 2020; 15(3): 415-7.
150. Levey AS, Gansevoort RT, Coresh J, et al. Change in albuminuria and GFR as end points for
clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney
Foundation in collaboration with the US Food and Drug Administration and European Medicines
Agency. American Journal of Kidney Diseases 2020; 75(1): 84-104.
151. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant
polycystic kidney disease. New England Journal of Medicine 2012; 367(25): 2407-18.
152. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in later-stage autosomal dominant
polycystic kidney disease. New England Journal of Medicine 2017; 377(20): 1930-42.
153. Thomas B, Matsushita K, Abate KH, et al. Global cardiovascular and renal outcomes of
reduced GFR. Journal of the American Society of Nephrology 2017; 28(7): 2167-79.
154. Shlipak MG, Matsushita K, Arnlov J, et al. Cystatin C versus creatinine in determining risk
based on kidney function. N Engl J Med 2013; 369(10): 932-43.
155. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and
cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 2013; 382(9889): 339-52.
156. Watson CL, Gold MR. Effect of intracellular and extracellular acidosis on sodium current in
ventricular myocytes. Am J Physiol 1995; 268(4 Pt 2): H1749-56.
157. Silswal N, Touchberry CD, Daniel DR, et al. FGF23 directly impairs endothelium-dependent
vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability. Am J Physiol
Endocrinol Metab 2014; 307(5): E426-36.
158. Yilmaz MI, Sonmez A, Saglam M, et al. FGF-23 and vascular dysfunction in patients with
stage 3 and 4 chronic kidney disease. Kidney Int 2010; 78(7): 679-85.
159. Lv J, Chen J, Wang M, Yan F. Klotho alleviates indoxyl sulfate-induced heart failure and
kidney damage by promoting M2 macrophage polarization. Aging (Albany NY) 2020; 12(10): 9139-
50.
160. Cozzolino M, Dusso AS, Slatopolsky E. Role of calcium-phosphate product and bone-
associated proteins on vascular calcification in renal failure. J Am Soc Nephrol 2001; 12(11): 2511-6.
56
161. Rubinger D, Friedlaender MM, Silver J, Kopolovic Y, Czaczkes WJ, Popovtzer MM. Progressive
vascular calcification with necrosis of extremities in hemodialysis patients: a possible role of iron
overload. Am J Kidney Dis 1986; 7(2): 125-9.
162. Lioufas N, Toussaint ND, Pedagogos E, et al. Can we IMPROVE cardiovascular outcomes
through phosphate lowering in CKD? Rationale and protocol for the IMpact of Phosphate Reduction
On Vascular End-points in Chronic Kidney Disease (IMPROVE-CKD) study. BMJ Open 2019; 9(2):
e024382.
163. Sarnak MJ, Amann K, Bangalore S, et al. Chronic Kidney Disease and Coronary Artery
Disease: JACC State-of-the-Art Review. J Am Coll Cardiol 2019; 74(14): 1823-38.
164. ’
advanced kidney disease. New England Journal of Medicine 2020; 382(17): 1608-18.
165. Wanner C, Amann K, Shoji T. The heart and vascular system in dialysis. The Lancet 2016;
388(10041): 276-84.
166. Konstantinidis I, Nadkarni GN, Yacoub R, et al. Representation of patients with kidney
disease in trials of cardiovascular interventions: an updated systematic review. JAMA internal
medicine 2016; 176(1): 121-4.
167. ’
Journal of the American College of Cardiology 2018; 71(24): 2802-10.
168. Q ention of
Analysis. Journal of the American Heart Association 2020; 9(3): e014908.

169. Trialists CT. Impact of renal function on the effects of LDL cholesterol lowering with statin-
based regimens: a meta-analysis of individual participant data from 28 randomised trials. The Lancet
Diabetes & Endocrinology 2016; 4(10): 829-39.
170. Authors/Task Force M, Rydén L, Grant PJ, et al. ESC Guidelines on diabetes, pre-diabetes,
and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes,
pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed
in collaboration with the European Association for the Study of Diabetes (EASD). European heart
journal 2013; 34(39): 3035-87.
171. ’
2018. A consensus report by the American Diabetes Association (ADA) and the European Association
for the Study of Diabetes (EASD). Diabetologia 2018; 61(12): 2461-98.
172. Palmer SC, Di Micco L, Razavian M, et al. Effects of antiplatelet therapy on mortality and
cardiovascular and bleeding outcomes in persons with chronic kidney disease: a systematic review
and meta-analysis. Annals of internal medicine 2012; 156(6): 445-59.
173. Ha JT, Neuen BL, Cheng LP, et al. Benefits and harms of oral anticoagulant therapy in chronic
kidney disease: a systematic review and meta-analysis. Annals of internal medicine 2019; 171(3):
181-9.
174. Ray KK, Nicholls SJ, Buhr KA, et al. Effect of Apabetalone Added to Standard Therapy on
Major Adverse Cardiovascular Events in Patients With Recent Acute Coronary Syndrome and Type 2
Diabetes: A Randomized Clinical Trial. JAMA 2020.
175. Kalantar-Zadeh K, Schwartz GG, Nicholls SJ, et al. Effect of apabetalone on major adverse
cardiovascular events in patients with chronic kidney disease, type-2 diabetes mellitus and recent
acute coronary syndrome: Results from the BETonMACE randomized controlled trial. Clin J Am Soc
Neph 2021 [in press].
176. Ware JE, Jr., Richardson MM, Meyer KB, Gandek B. Improving CKD-Specific Patient-Reported
Measures of Health-Related Quality of Life. J Am Soc Nephrol 2019; 30(4): 664-77.
177. Kovesdy CP, Naseer A, Sumida K, et al. Abrupt Decline in Kidney Function Precipitating
Initiation of Chronic Renal Replacement Therapy. Kidney Int Rep 2018; 3(3): 602-9.
178. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a
systematic review and meta-analysis. Kidney Int 2012; 81(5): 442-8.
57
179. Rifkin DE, Coca SG, Kalantar-Zadeh K. Does AKI truly lead to CKD? J Am Soc Nephrol 2012;
23(6): 979-84.
180. Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S. Concurrent use of diuretics, angiotensin
converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-
inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ 2013; 346:
e8525.
181. Gaipov A, Molnar MZ, Potukuchi PK, et al. Acute kidney injury following coronary
revascularization procedures in patients with advanced CKD. Nephrol Dial Transplant 2019; 34(11):
1894-901.
182. Grams ME, Sang Y, Coresh J, et al. Acute Kidney Injury After Major Surgery: A Retrospective
Analysis of Veterans Health Administration Data. Am J Kidney Dis 2016; 67(6): 872-80.
183. Wyld M, Morton RL, Hayen A, Howard K, Webster AC. A systematic review and meta-analysis
of utility-based quality of life in chronic kidney disease treatments. PLoS Med 2012; 9(9): e1001307.
184. Murtagh FEM, Marsh JE, Donohoe P, Ekbal NJ, Sheerin NS, Harris FE. Dialysis or not? A
comparative survival study of patients over 75 years with chronic kidney disease stage 5. Nephrology
Dialysis Transplantation 2007; 22(7): 1955-62.
185. Saeed F, Ladwig SA, Epstein RM, Monk RD, Duberstein PR. Dialysis Regret: Prevalence and
Correlates. Clinical Journal of the American Society of Nephrology 2020.
186. Murtagh FEM, Burns A, Moranne O, Morton RL, Naicker S. Supportive care: comprehensive
conservative care in end-stage kidney disease. Clinical Journal of the American Society of Nephrology
2016; 11(10): 1909-14.
187. Siriwardana AN, Hoffman AT, Brennan FP, Li K, Brown MA. Impact of Renal Supportive Care
on Symptom Burden in Dialysis Patients: A Prospective Observational Cohort Study. Journal of Pain
and Symptom Management 2020.
188. Crail SU, Walker R, Brown M, Renal Supportive Care Working G. Renal supportive and
palliative care: position statement. Nephrology 2013; 18(6): 393-400.
189. Cheigh JS, Kim H, Stenzel KH, et al. Systemic lupus erythematosus in patients with end-stage
renal disease: long-term follow-up on the prognosis of patients and the evolution of lupus activity.
Am J Kidney Dis 1990; 16(3): 189-95.
190. Saadi G, Kalantar-Zadeh K, Almasio P, et al. Hepatitis C virus infection and global kidney
health: the consensus proceedings of the International Federation of Kidney Foundations. Afr J
Nephrol 2020; 23(1): 159-68.
191. Ladino M, Pedraza F, Roth D. Hepatitis C Virus Infection in Chronic Kidney Disease. J Am Soc
Nephrol 2016; 27(8): 2238-46.
192. Molnar MZ, Alhourani HM, Wall BM, et al. Association of hepatitis C viral infection with
incidence and progression of chronic kidney disease in a large cohort of US veterans. Hepatology
2015; 61(5): 1495-502.
193. Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus elbasvir in treatment-naive and
treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic
kidney disease (the C-SURFER study): a combination phase 3 study. Lancet 2015; 386(10003): 1537-
45.
194. Su G, Iwagami M, Qin X, et al. Kidney disease and mortality in patients with respiratory tract
infections: a systematic review and meta-analysis. Clinical Kidney Journal 2020.
195. McDonald HI, Thomas SL, Millett ERC, Quint J, Nitsch D. Do influenza and pneumococcal
vaccines prevent community-acquired respiratory infections among older people with diabetes and
does this vary by chronic kidney disease? A cohort study using electronic health records. BMJ open
diabetes research & care 2017; 5(1): e000332.
196. Corbett RW, Blakey S, Nitsch D, et al. Epidemiology of COVID-19 in an Urban Dialysis Center.
J Am Soc Nephrol 2020; 31(8): 1815-23.
58
197. Kalantar-Zadeh K, Moore LW. Renal Telenutrition for Kidney Health: Leveraging Telehealth
and Telemedicine for Nutritional Assessment and Dietary Management of Patients With Kidney
Disorders. J Ren Nutr 2020; 30(6): 471-4.
198. Sise ME, Baggett MV, Shepard JO, Stevens JS, Rhee EP. Case 17-2020: A 68-Year-Old Man
with Covid-19 and Acute Kidney Injury. N Engl J Med 2020; 382(22): 2147-56.
199. Batlle D, Soler MJ, Sparks MA, et al. Acute Kidney Injury in COVID-19: Emerging Evidence of a
Distinct Pathophysiology. J Am Soc Nephrol 2020; 31(7): 1380-3.
200. Zamai L. The Yin and Yang of ACE/ACE2 Pathways: The Rationale for the Use of Renin-
Angiotensin System Inhibitors in COVID-19 Patients. Cells 2020; 9(7).
201. Stanifer JW, Muiru A, Jafar TH, Patel UD. Chronic kidney disease in low- and middle-income
countries. Nephrol Dial Transplant 2016; 31(6): 868-74.
202. Chang TI, Lim H, Park CH, et al. Association Between Income Disparities and Risk of Chronic
Kidney Disease: A Nationwide Cohort Study of Seven Million Adults in Korea. Mayo Clin Proc 2020;
95(2): 231-42.
203. Moosa MR, Norris KC. Sustainable social development: tackling poverty to achieve kidney
health equity. Nat Rev Nephrol 2021; 17(1): 3-4.
204. Ene-Iordache B, Perico N, Bikbov B, et al. Chronic kidney disease and cardiovascular risk in
six regions of the world (ISN-KDDC): a cross-sectional study. Lancet Glob Health 2016; 4(5): e307-19.
205. Liyanage T, Ninomiya T, Jha V, et al. Worldwide access to treatment for end-stage kidney
disease: a systematic review. The Lancet 2015; 385(9981): 1975-82.
206. Engelgau MM, Karan A, Mahal A. The Economic impact of Non-communicable Diseases on
households in India. Global Health 2012; 8: 9.
207. Kovesdy CP, Norris KC, Boulware LE, et al. Association of Race With Mortality and
Cardiovascular Events in a Large Cohort of US Veterans. Circulation 2015; 132(16): 1538-48.
208. Derose SF, Rutkowski MP, Crooks PW, et al. Racial differences in estimated GFR decline,
ESRD, and mortality in an integrated health system. Am J Kidney Dis 2013; 62(2): 236-44.
209. Norris KC, Williams SF, Rhee CM, et al. Hemodialysis Disparities in African Americans: The
Deeply Integrated Concept of Race in the Social Fabric of Our Society. Semin Dial 2017; 30(3): 213-
23.
210. Ahmed S, Nutt CT, Eneanya ND, et al. Examining the Potential Impact of Race Multiplier
Utilization in Estimated Glomerular Filtration Rate Calculation on African-American Care Outcomes. J
Gen Intern Med 2020.
211. Norris KC, Eneanya ND, Boulware LE. Removal of Race From Estimates of Kidney Function:
First, Do No Harm. JAMA 2021; 325(2): 135-7.
212. Kazory A. Fluid overload as a major target in management of cardiorenal syndrome:
Implications for the practice of peritoneal dialysis. World J Nephrol 2017; 6(4): 168-75.
213. Kajbafzadeh AM, Sabetkish N, Sabetkish S. Establishment of colonic dialysis model in uremic
rats by right nephrectomy and left partial nephrectomy. J Pediatr Urol 2018; 14(2): 159 e1- e8.
214. Dai S, Dai Y, Peng J, Xie X, Ning J. Simplified colonic dialysis with hemodialysis solutions
delays the progression of chronic kidney disease. QJM 2019; 112(3): 189-96.
215. Keller RW, Jr., Kopple JD, Kalantar-Zadeh K. Perspiration interventions for conservative
management of kidney disease and uremia. Curr Opin Nephrol Hypertens 2020; 29(1): 57-63.
216. Hanafusa N, Lodebo BT, Shah A, Kopple JD. Is There a Role for Diaphoresis Therapy for
Advanced Chronic Kidney Disease Patients? J Ren Nutr 2017; 27(5): 295-302.
217. Keller RW, Bailey JL, Wang Y, Klein JD, Sands JM. Urea transporters and sweat response to
uremia. Physiol Rep 2016; 4(11).
218. Robinson-Cohen C, Littman AJ, Duncan GE, et al. Physical activity and change in estimated
GFR among persons with CKD. Journal of the American Society of Nephrology 2014; 25(2): 399-406.
219. MacKinnon HJ, Wilkinson TJ, Clarke AL, et al. The association of physical function and
physical activity with all-cause mortality and adverse clinical outcomes in nondialysis chronic kidney
disease: a systematic review. Therapeutic advances in chronic disease 2018; 9(11): 209-26.
59
220. Afsar B, Siriopol D, Aslan G, et al. The impact of exercise on physical function, cardiovascular
outcomes and quality of life in chronic kidney disease patients: a systematic review. International
Urology and Nephrology 2018; 50(5): 885-904.
221. Zhang L, Wang Y, Xiong L, Luo Y, Huang Z, Yi B. Exercise therapy improves eGFR, and reduces
blood pressure and BMI in non-dialysis CKD patients: evidence from a meta-analysis. BMC
nephrology 2019; 20(1): 398.
222. Mallamaci F, Pisano A, Tripepi G. Physical activity in chronic kidney disease and the EXerCise
Introduction To Enhance trial. Nephrology Dialysis Transplantation 2020; 35(Supplement_2): ii18-
ii22.
223. Xia J, Wang L, Ma Z, et al. Cigarette smoking and chronic kidney disease in the general
population: a systematic review and meta-analysis of prospective cohort studies. Nephrology
Dialysis Transplantation 2017; 32(3): 475-87.
224. Staplin N, Haynes R, Herrington WG, et al. Smoking and adverse outcomes in patients with
CKD: The Study of Heart and Renal Protection (SHARP). American Journal of Kidney Diseases 2016;
68(3): 371-80.
225. Saran R, Padilla RL, Gillespie BW, et al. A randomized crossover trial of dietary sodium
restriction in stage 3–4 CKD. Clinical Journal of the American Society of Nephrology 2017; 12(3): 399-
407.
226. Jardine MJ, Li N, Ninomiya T, et al. Dietary sodium reduction reduces albuminuria: a cluster
randomized trial. Journal of Renal Nutrition 2019; 29(4): 276-84.
227. McMahon EJ, Bauer JD, Hawley CM, et al. A randomized trial of dietary sodium restriction in
CKD. Journal of the American Society of Nephrology 2013; 24(12): 2096-103.
228. Luzardo L, Noboa O, Boggia J. Mechanisms of salt-sensitive hypertension. Current
hypertension reviews 2015; 11(1): 14-21.
229. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a
nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19(5): 576-85.
230. Navaneethan SD, Yehnert H, Moustarah F, Schreiber MJ, Schauer PR, Beddhu S. Weight loss
interventions in chronic kidney disease: a systematic review and meta-analysis. Clinical journal of the
American Society of Nephrology 2009; 4(10): 1565-74.
231. Lambert K, Beer J, Dumont R, et al. Weight management strategies for those with chronic
kidney disease: A consensus report from the A sia P acific S ociety of N ephrology and A ustralia and
N ew Z ealand S ociety of N ephrology 2016 renal dietitians meeting. Nephrology 2018; 23(10): 912-
20.
232. Kistler BM, Moore LW, Benner D, et al. The International Society of Renal Nutrition and
Metabolism Commentary on the National Kidney Foundation and Academy of Nutrition and
Dietetics KDOQI Clinical Practice Guideline for Nutrition in Chronic Kidney Disease. J Ren Nutr 2020
[in press]; 30(4).
233. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular
disease and death: a systematic review and meta-analysis. The Lancet 2016; 387(10022): 957-67.
234. Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and
renal outcomes: updated systematic review and meta-analysis. The Lancet 2016; 387(10017): 435-
43.
235. Lv J, Ehteshami P, Sarnak MJ, et al. Effects of intensive blood pressure lowering on the
progression of chronic kidney disease: a systematic review and meta-analysis. Cmaj 2013; 185(11):
949-57.
236. Cheung AK, Rahman M, Reboussin DM, et al. Effects of intensive BP control in CKD. Journal
of the American Society of Nephrology 2017; 28(9): 2812-23.
237. Malhotra R, Nguyen HA, Benavente O, et al. Association between more intensive vs less
intensive blood pressure lowering and risk of mortality in chronic kidney disease stages 3 to 5: a
systematic review and meta-analysis. JAMA internal medicine 2017; 177(10): 1498-505.
60
238. Muntner P, Shimbo D, Carey RM, et al. Measurement of blood pressure in humans: a
scientific statement from the American Heart Association. Hypertension 2019; 73(5): e35-e66.
239. Brenner BM, Cooper ME, De Zeeuw D, et al. Effects of losartan on renal and cardiovascular
outcomes in patients with type 2 diabetes and nephropathy. New England journal of medicine 2001;
345(12): 861-9.
240. Balamuthusamy S, Srinivasan L, Verma M, et al. Renin angiotensin system blockade and
cardiovascular outcomes in patients with chronic kidney disease and proteinuria: a meta-analysis.
American heart journal 2008; 155(5): 791-805.
241. Ohkuma T, Jun M, Rodgers A, et al. Acute increases in serum creatinine after starting
angiotensin-converting enzyme inhibitor-based therapy and effects of its continuation on major
clinical outcomes in Type 2 diabetes mellitus: The ADVANCE Trial. Hypertension 2019; 73(1): 84-91.
242. Haynes R, Lewis D, Emberson J, et al. Effects of lowering LDL cholesterol on progression of
kidney disease. Journal of the American Society of Nephrology 2014; 25(8): 1825-33.
243. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin
plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a
randomised placebo-controlled trial. The Lancet 2011; 377(9784): 2181-92.
244. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for
hypertriglyceridemia. New England Journal of Medicine 2019; 380(1): 11-22.
245. Charytan DM, Sabatine MS, Pedersen TR, et al. Efficacy and safety of evolocumab in chronic
kidney disease in the FOURIER trial. Journal of the American College of Cardiology 2019; 73(23):
2961-70.
246. Tuñón J, Steg PG, Bhatt DL, et al. Effect of alirocumab on major adverse cardiovascular
events according to renal function in patients with a recent acute coronary syndrome: prespecified
analysis from the ODYSSEY OUTCOMES randomized clinical trial. European Heart Journal 2020.
247. Herrington W, Emberson J, Mihaylova B, et al. Impact of renal function on the effects of LDL
cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from
28 randomised trials. Lancet Diabetes and Endocrinology 2016; 4(10).
248. Zoungas S, Arima H, Gerstein HC, et al. Effects of intensive glucose control on microvascular
outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from
randomised controlled trials. The lancet Diabetes & endocrinology 2017; 5(6): 431-7.
249. Giorgino F, Home PD, Tuomilehto J. Glucose control and vascular outcomes in type 2
diabetes: is the picture clear? Diabetes Care 2016; 39(Supplement 2): S187-S95.
250. Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure
in patients with type 2 diabetes: a systematic review and meta-analysis. The Lancet Diabetes &
Endocrinology 2019; 7(11): 845-54.
251. Gansevoort RT, Matsushita K, van der Velde M, et al. Lower estimated GFR and higher
albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general
and high-risk population cohorts. Kidney Int 2011; 80(1): 93-104.
61

Kalantar Zadeh Etal 2021 Preserving Kidney Function in People

Uploaded by

Copyright:

Available Formats

Kalantar Zadeh Etal 2021 Preserving Kidney Function in People

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Kalantar Zadeh Etal 2021 Preserving Kidney Function in People

Uploaded by

Copyright:

Available Formats

Seminar Article, THELANCET- D-20-17156-A1

Preserving Kidney Function in People with Chronic Kidney Disease

(Running Head: Kidney Preserving Care)

Brendon L Neuen, MD,9 and Vlado Perkovic, MD10

Irvine, Orange, California, USA

General Hospital, 5Duke-Global Health Institute, Durham, NC, USA

Kamyar Kalantar-Zadeh, MD, MPH, PhD

Division of Nephrology, Hypertension and Kidney Transplantation

University of California Irvine Medical Center

101 The City Drive South, Orange, California 92868-3217

Tel: (714) 456-5142, Fax: (714) 456-6034. Email: [email protected]

Vlado Perkovic, MBBS, PhD, FRACP, FASN, FAHMS

Faculty of Medicine, University of New South Wales

Sydney, New South Wales, Australia

Abstract Word Count: 250

Main Text Word Count: 6,371

Suggested online Appendix: 5 supplemental figures and 2 supplemental tables

Ethics and consent to participate

Not applicable, this is a Seminar article

Authors have granted consent to publish this work in Lancet

Availability of data and materials

Not applicable, this is a Seminar paper

Competing interests (see attached disclosure forms)

Alexion, Amgen, Astra-Zeneca, Aveo, Chugai, DaVita, Fresenius, Genentech, Haymarket

Vifor, UpToDate, and ZS-Pharma.

investigating aspects of kidney disease in Sub-Saharan Africa.

Metavant, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, Pharmalink,

Relypsa, Retrophin, Sanofi, Servier, Vifor, Vitae, UptoDate, and Tricida.

philanthropic grants from Harold Simmons and Joseph Lee.

THJ is supported by Singapore National Medical Research Council.

ABSTRACT (250 words)

pharmacologic strategies, including dietary adjustments, and CKD-targeted and kidney

disease specific pharmacologic interventions. Plant-dominant low-protein and low-salt diet

Pharmacotherapies that alter intrarenal hemodynamics including angiotensin pathway

by mechanisms in addition to improving blood pressure and glucose control such as by

reducing intraglomerular pressure, while novel agents such as nonsteroidal mineralocorticoid

receptor antagonists may protect the kidney through anti-inflammatory or anti-fibrotic

replacement therapy becomes inevitable, an incremental transition to dialysis may be

health-related quality of life, additional studies on preexisting interventions and development

of innovative strategies are warranted as reviewed here.

Kidney preservation, dialysis freedom, plant-dominant low-protein diet, angiotensin pathway

1. Chronic Kidney Disease

Chronic kidney disease (CKD) is a progressive condition characterized by structural

typically defined as a reduction in kidney function, estimated glomerular filtration rate

[eGFR] <60 ml/min/1.73m2, or markers of kidney damage, such as albuminuria, hematuria or

abnormalities detected on imaging, present for at least 3 months (supplemental Figure S1 in

controversial as to whether hypertension is a cause or consequence of CKD.5 As another

those with obesity, diabetes mellitus and hypertension.8,9

death if left untreated.10

function in people with or at high risk of CKD.

2. Approach to preserving kidney function

patients with CKD.17 Kidney preserving care is a life-sustaining type of conservative

renal comorbidities and their associated symptoms.18,19

Given that conservative management is defined as CKD care without dialysis or a

kidney transplantion,20 misconceptions of dialysis-free management as “no care” or

preserving management of CKD across its full spectrum.12,18 Notwithstanding heterogeneity

in definitions, provision of or access to care, and patient demographics or socioeconomic

kidney preserving strategies.21-33

of CKD and underlying etiology, encompassing a range of pharmacological and non-

pharmacological approaches as shown in Figure 1 and supplemental Figures S2 and S3