Emerging Preventive Strategies in Chronic Kidney Disease: Recent Evidence and Gaps in Knowledge

Abstract

Purpose of Review

Chronic kidney disease (CKD) is increasingly prevalent worldwide and is associated with increased cardiovascular risk. New therapeutic options to slow CKD progression and reduce cardiovascular morbidity and mortality have recently emerged. This review highlights recent evidence and gaps in knowledge in emerging CKD preventive strategies.

Recent Findings

EMPA-Kidney trial found that empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i) led to 28% lower risk of progression of kidney disease or death from cardiovascular causes, compared to placebo. This reinforced the previous findings from DAPA-CKD and CREDENCE trials and led to inclusion of SGLT2i as the cornerstone of CKD preventive therapy in both diabetic and non-diabetic CKD. Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, slowed diabetic kidney disease progression by 23% compared to placebo in a pool analysis of FIDELIO-DKD and FIGARO-DKD trials. Non-pharmacological interventions, including low protein diet, and early CKD detection and risk stratification strategies based on novel biomarkers have also gained momentum. Ongoing efforts to explore the wealth of molecular mechanisms in CKD, added to integrative omics modeling are well posed to lead to novel therapeutic targets in kidney care.

Summary

While breakthrough pharmacological interventions continue to improve outcomes in CKD, the heterogeneity of kidney diseases warrants additional investigation. Further research into specific kidney disease mechanisms will facilitate the identification of patient populations most likely to benefit from targeted interventions.

Introduction

Chronic kidney disease (CKD) afflicts 9.1% of the world population [1, 2••], and it doubles the risk of death compared to those without CKD [3]. Progression of CKD to End Stage Kidney Disease (ESKD) has an ominous prognosis, with over 55% mortality within 5 years of initiating dialysis therapy [3]. Though ESKD patients represent less than 1.5% of Medicare beneficiaries, the total Medicare spending on ESKD patients accounted for 6.1% of the overall Medicare paid claims in 2020 [3]. Chronic kidney disease is a well-recognized accelerator of cardiovascular disease and a predictor of reduced survival. While cardiovascular medicine has experienced steep progress in the general population, these advances have been slow in CKD patients, who continue to have high mortality rates [4, 5].

In addition to time honored therapies such as tight glycemic control, adequate blood pressure control and renin angiotensin aldosterone system blockade, the past decade has added groundbreaking new therapies such as sodium glucose transporter 1 inhibitors (SGLT2i) and nonsteroidal mineralocorticoid receptor antagonists (Finerenone) to the nephrologists’ armamentarium. Glucagon-like peptide-1 (GLP-1) receptor agonists in CKD care are also gaining traction. Knowledge continues to accrue regarding the role of dietary interventions and gut microbiota manipulation in altering CKD trajectories. Recent years have also seen improvements in the identification of biomarkers for early CKD detection, novel antifibrotic therapies, and the application of artificial intelligence for CKD risk stratification. Additionally multi-omics approaches, including the potential of epigenetic modifications have the potential to offer an integrated approach to CKD prevention and care. The purpose of this review is to describe the current and emerging strategies in preventive measures in CKD, with a focus on new therapeutic approaches and gaps in knowledge.

Traditional Preventive Strategies in CKD

Blood Pressure Control

Hypertension is closely linked to CKD through common mechanisms, including endothelial dysfunction, salt retention, sympathetic overactivity and renal angiotensin aldosterone system activation [6]. There is a positive feedback loop between high blood pressure and CKD. Chronic elevation in systemic arterial pressure causes remodeling and loss of autoregulation properties of the afferent arteriole. With loss of autoregulation, high arterial pressure transmitted to the kidney leads to nephrosclerosis, and ultimately loss of kidney function [7]. The landmark Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure below 120 mmHg in individuals with and without CKD resulted in lower risk of cardiovascular events and mortality, although no difference in CKD progression was found [8, 9]. These findings informed the updated 2017 AHA/ACC guidelines recommending a < 130/80 mmHg blood pressure target for patients with CKD given the cardiovascular benefits [10]. However, the appropriate blood pressure target for patients with CKD who do not fit the SPRINT inclusion criteria (specifically those with diabetes mellitus, advanced CKD and heavy proteinuria) remains unclear. Combined analyses from SPRINT and ACCORD-BP trial [11] demonstrated a similar reduction in the primary composite cardiovascular outcome [11] and served as the basis for the 2021 updated KDOQI guidelines for management of BP in CKD that recommends a new systolic blood pressure target of < 120 mmHg for most patients with CKD [2••]. Though this generated a lot of controversy in the medical community[12], general agreement remains regarding accurate measurement of blood pressure, and the addition of out-of-office blood pressure measurements in the decision making [2••]. Large discordance exists between the assessments of BP in clinical trials vs. routine clinical practice.[13] Home or ambulatory blood pressure measurement is now considered essential for both the diagnosis of hypertension and confirmation of blood pressure control [10, 14].

Glycemic Control

Hyperglycemia contributes to a host of complications, including insulin resistance, obesity, hypercholesterolemia, risk of development of cardiovascular and renal disease [15]. Control of hyperglycemia is considered key in reducing the risk of development and progression of microvascular complications in type 2 diabetes. The American Diabetes Association recommends an HbA1c target of less than 7% for most adults with diabetes [16]. This includes diabetics with CKD, for whom strict glycemic control can delay the onset and slow the progression of diabetic nephropathy [17].

Physical Activity & Lifestyle Modifications

Lifestyle modification is an important aspect of CKD prevention. A recent meta-analysis showed that being physically active versus sedentary is associated with lower odds of CKD (OR, 0.82; 95% CI, 0.69 to 0.98). In addition, current and former smokers had significantly increased odds of CKD compared with never smokers (OR, 1.18; 95% CI, 1.10 to 1.27) [18]. In individuals with all stages of CKD, including hemodialysis, being physically active in feasible and associated with improved outcomes [19-21]. In the LANDMARK III (Longitudinal Assessment of Numerous Discrete Modifications of Atherosclerotic Risk Kidney disease) trial, a nurse led multidisciplinary 3-year lifestyle intervention doubled the percentage of CKD patients meeting physical activity guidelines, improved exercise capacity, and ameliorated losses in neuromuscular and cardiorespiratory fitness [22].

Kidney Function Surveillance and Monitoring

Routine screening to include urine albumin-to-creatinine ratio and eGFR (estimated Glomerular Filtration Rate) are the cornerstone of early detection and management, especially in high-risk populations with diabetes, hypertension, or family history of kidney disease. [17] Adherence to this is somewhat underwhelming with less than 50% of diabetics being screened for CKD. [23] In addition to clinically validated risk prediction equations [24], an area of active research in CKD involves machine learning methods integrating novel biomarkers [tumor necrosis factor receptor 1 and 2 (TNFR1 and TNFR2), kidney injury molecule 1 (KIM-1)] to identify those patients at the highest risk of kidney function decline [25].

Recent Pharmacological Advances

Sodium-Glucose Cotransporters 2 Inhibitors (SGLT2i)

Glucose transport through the rat kidney tubules initially discovered in the 1980s led to the detection of two proteins called sodium-glucose cotransporters SGLT1 and SGLT2. While SGLT1 is found in multiple organs, SGLT2 is specific to the kidney and is implicated in the reabsorption of sodium and about 90 percent of the total filtered glucose (approximately 180 g/d) in the proximal tubule. Originally developed to manage hyperglycemia in type 2 diabetes mellitus, the evidence for renoprotective effects of SGLT2i, continue to be re-affirmed through multiple rigorously designed clinical trials both in diabetic and nondiabetic individuals [26-28]. CREDENCE was the first landmark trial to show a 30% lower risk of the composite kidney outcome in albuminuric diabetic patients with eGFR ≥ 30 ml/min/1.73m² treated with Canagliflozin (Table 1) [26]. Subsequently, the benefits of SGLT2i were observed in non-diabetic patients (32% of DAPA-CKD trial population) with albuminuria and eGFR ≥ 25 ml/min/1.73 m² who had 39% lower risk of kidney events (50% decline in eGFR, onset of ESKD or death from renal or cardiovascular causes) after treatment with Dapagliflozin [27]. EMPA-KIDNEY expanded the eligible CKD patient population to eGFR as low as 20 ml/min/1.73m² irrespective of the albuminuria level and diabetes status, and showed consistent reduction in risk of kidney and cardiovascular events with empagliflozin [28]. The “real-world” kidney protective effects were confirmed in CVD-REAL 3 cohort study [29]. It was estimated that SGLT2i treatment started early in CKD (eGFR 56 ml/min/1.73m²) would delay progression to ESKD by as much as 15 years in an average 63 year old patient [30].

Table 1.

Landmark clinical trials of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in CKD

Trial name/Year	Intervention	Design	Population	Outcomes	Key findings
EMPA-KIDNEY/ 2023 [28]	Empagliflozin 10 mg daily vs. placebo	Multi-center, randomized, parallel group, double-blind, placebo-controlled	6609 adults with or without T2DM (54%); eGFR 45–20 ml/min/1.73m 2 regardless of albuminuria. or eGFR 45–90 ml/min/1.73 m 2 with UACR ≥ 200 mg/g, on stable dose of RAAS blockade	Primary outcome: composite first occurrence of progression of kidney disease or death from cardiovascular causes Key secondary outcome: composite of hospitalization for heart failure or death from cardiovascular causes	- Empagliflozin reduced the risk of primary outcome by 28% [HR 0.72, 95% CI (0.64–0.82)]. This was consistent in subgroups by diabetes status and eGFR -Risk of hospitalization from any cause was 14% lower with empagliflozin [HR 0.86, 95% CI (0.78–0.95)] -No significant between group differences with respect to composite outcome of hospitalization for heart failure or death from cardiovascular causes
DAPA-CKD/2020 [27]	Dapagliflozin 10 mg daily vs. placebo	Multi-center, randomized, double-blind, placebo-controlled	4304 adults with or without T2DM (32%) with eGFR 25–75 ml/min/1.73 m2 and UACR 200–5000 mg/g on stable dose of RAAS blockade	Primary outcome: composite decline of at least 50% in the eGFR, ESKD or death from renal or cardiovascular causes Secondary outcome: sustained decline in eGFR of at least 50%, ESKD or death from renal causes	- Dapagliflozin reduced the risk of primary outcome by 29% [HR 0.61, 95% CI (0.51–0.72)] compared to placebo - Risk of secondary composite kidney outcome was 44% lower with dapagliflozin [HR 0.56, 95% CI (0.45–0.68)] compared to placebo
CREDENCE/2019 [26]	Canagliflozin 100 mg daily vs. placebo	Multi-center, randomized, double-blind, placebo-controlled	4401 adults over 30 years old, with T2DM, glycated hemoglobin 6.5–12%; eGFR 30–90 ml/min/1.73 m2 and UACR 300–5000 mg/g on stable dose of RAAS blockade	Primary outcome: composite ESKD, doubling of serum creatinine sustained > 30 days or death from renal or cardiovascular causes Key hierarchical secondary outcomes: composite of cardiovascular death or heart failure hospitalization; composite of ESKD, doubling of creatinine or renal death	- Canagliflozin reduced the risk of primary composite outcome by 30% [HR 0.70, 95% CI (0.59–0.82)] compared to placebo - Risk of cardiovascular death or heart failure hospitalization was 31% lower with canagliflozin [HR 0.69, 95% CI (0.57–0.83)] compared to placebo - Risk of ESKD, doubling of creatinine or renal death was 34% lower with canagliflozin [HR 0.66, 95% CI (0.53–0.83)] compared to placebo

CI confidence interval, ESKD end stage kidney disease, eGFR estimated glomerular filtration rate, HR hazard ratio, RAAS, renin angiotensin aldosterone system; T2DM type 2 diabetes, UACR urine albumin creatinine ratio

Mechanistically, the benefits of SGLT2i are thought to extend beyond glycemic control and involve the modulation of renal hemodynamics, reduction of renal inflammation, hypoxia, oxidative stress, endothelial dysfunction and possibly amelioration of podocyte injury and loss [31••]. These unexpected benefits of SGLT2i led to a change in paradigm from glucose centricity to cardiovascular and renal risk reduction focus, an resulted in the updated clinical guidelines from the American Diabetes Association(ADA)/European Society for the Study of Diabetes (EASD) [32], and the European Society of Cardiology (ESC) [33]. The initial eGFR dip observed post SGLT2i initiation, which may lead to inappropriate discontinuation of therapy, does not portend poor renal outcomes [34], and may in fact be an indication of a possible kidney protective effect [35]. Due to a reduction in hyperkalemia without causing hypokalemia [36], SGLT2i may enable continuation or up titration of RAASi therapy for optimal medical management in CKD.

Though the side effect profile of SGLT2i seems safe and mainly related to genitourinary infections and ketoacidosis [37], their effects in advanced CKD after prolonged use remains to be determined. Due to their known effect to trigger the FGF23/1,25-dihydroxyvitamin D/parathyroid hormone (PTH) axis [38], it is reasonable to assume that they may result in worsening metabolic bone disease in CKD. However, at this time, the increased fracture risk observed earlier with canagiflozin [39] was not replicated in subsequent rigorously designed randomized trials [40] or in a large recent observational study [41]. Similarly, the Food and Drug Administration (FDA) 2018 warning related to the risk of Fournier’s gangrene with the use of SGLT2i was not substantiated by a subsequent meta-analysis of 42,415 patients enrolled in 84 randomized trials [42]. It is speculated that Fournier’s gangrene is under-reported in diabetic patients not on SGLT2i leading to a perceived association with SGLT2i use [42].

Whether SGLT2i offer additive renal protection when combined with non-steroidal mineralocorticoid antagonist finerenone is an area of active investigation [43]. In a pooled analysis of three randomized trials, the estimated gain in survival free from kidney outcomes was nearly 7 years with the combination treatment of SGLT2i and Finerenone [44]. The kidney benefits of dual SGLT blockade are also unclear as the SCORED trial with Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor was terminated early [45].

Glucagon-Like Peptide-1 Receptor Agonists (GLP1)

Glucagon like peptide 1 (GLP1), a peptide produced by enter-oendocrine L cells within the terminal ileum and colon and within the solitary nucleus in the brainstem, is believed to cause natriuresis, by inhibition of the Na/H exchanger 3 at the brush border of proximal tubular cells, which may account for it’s effect on lowering blood pressure [46], and may also modulate inflammation and fibrosis at various sites. GLP 1 physiologically has a short half life due to degradation by the peptidase enzyme DiPeptyl Peptidase 4 (DPP-4). In addition to improved glycemic control, the newer glucose lowering drugs which act as GLP 1 receptor agonists as well as DPP-4 inhibitors were noted to have added beneficial effects on kidney outcomes in patients with diabetic kidney disease. The GLP-1 agonists compared to placebo, resulted in a combined 15–35% relative reduction in the secondary composite renal outcome [47] in trials with liraglutide [48], dulaglutide [49] and semaglutide [50]. A recent meta-analysis of six large randomized controlled trials with injectable GLP-1 agonists also showed a 17% reduction in the risk of kidney events [51], mainly driven by decrease in macroalbuminuria; the effects on eGFR and renal replacement therapy may have been difficult to discern due to a low renal risk trial population and short observation times. In the AWARD-7 study, patients with type 2 diabetes and moderate to severe kidney disease randomized to once-weekly dulaglutide showed a lesser decline in eGFR at 52 weeks as compared to those on insulin glargine, despite similar reduction in HbA1c [52]. In contrast, a similar effect on renal outcome was not observed with DPP-4 inhibitors [53]. Given the potential kidney protection of GLP-1 agonists, FLOW trial designed to assess the role of semaglutide on primary composite kidney events or death from kidney or cardiovascular causes is currently underway [54].

Mineralocorticoid Receptor Antagonists

Acting via the mineralocorticoid receptor (MR) in the kidneys, aldosterone exerts a pro-inflammatory and pro-fibrotic action, leading to podocyte injury, mesangial cell proliferation, arteriolar hyalinosis and interstitial inflammation and fibrosis [55]. In patients with CKD, higher serum aldosterone levels were independently associated with increased risk of progression of CKD irrespective of diabetes status [56]. However, in a recent Cochrane review which included 5,745 participants with diabetic and non-diabetic kidney disease, aldosterone antagonists more than doubled the risk of hyperkalemia and failed to demonstrate an effect on kidney failure, death and cardiovascular events [57]. This underscored the need for more selective MR antagonists, with a better side effect profile. Finerenone, a non-steroidal MR antagonist leads to inhibition of recruitment of transcriptional cofactors implicated in the expression of hypertrophic, proinflammtory and profibrotic genes [58••]. Preclinical studies showed that finerenone administration was associated with less kidney hypertrophy and protection against glomerular, tubulointerstitial and vascular damage along with decreased albuminuria and regression of cardiac hypertrophy, even at doses without significant hemodynamic effects. These actions were more potent compared to equinatriuretic doses of eplerenone and with a minimal impact on serum potassium [58••].

Following the promising results in animal studies, the phase II ARTS program [59-61] was designed to test the safety, tolerability and efficacy of finerenone in patients with HFrEF and mild to moderate CKD. The ARTS program showed that finerenone was as effective as eplerenone in lowering albuminuria and NT-proBNP and with significantly smaller increases in serum potassium levels [62]. The subsequent phase III program consisted of two complementary clinical trials (Table 2) [63, 64]. FIDELIO-DKD showed 18% relative risk reduction in adverse kidney outcomes with finerenone compared to placebo [64]. Though risk of hyperkalemia related adverse events was twice as high (18.3% vs 9%) in the finerenone compared to placebo group, the rate of drug discontinuation was fairly low at 2.3% [64]. FIGARO-DKD extended these findings and showed that finerenone lowered the risk of primary composite cardiovascular outcomes, primarily driven by reduced incidence of hospitalization for heart failure [63]. A larger magnitude of effect on kidney outcomes with finerenone was observed in patients with severely increased albuminuria compared with moderately increased albuminuria (HR: 0.74; 95% CI: 0.62–0.90 and HR: 1.16; 95% CI: 0.91–1.47, respectively; Pinteraction = 0.02 for the eGFR ≥ 57% kidney composite end point) [65]. The benefits of finerenone were independent of the baseline use of SGLT2i [66]. This adds evidence to the complementary cardiorenal protective mechanisms of action of SGLT2i and finerenone, and supports the need for ongoing trials [43]. Whether finerenone has an effect on reducing adverse cardiorenal outcomes in non-diabetic, proteinuric kidney disease is an area of active investigation (NCT05047263; NCT04435626).

Table 2.

Landmark clinical trials of selective non-steroidal mineralocorticoid receptor inhibitors (Finerenone) in CKD

Trial name/Year	Intervention	Design	Population	Outcomes	Key findings
FIGARO-DKD/2021 [63]	Finerenone 10 mg or 20 mg daily vs. Placebo	Multicenter, international, randomized, double-blind, placebo-controlled	7437 adults with T2DM on maximal tolerated RAS blockade with serum potassium ≤ 4.8 mEq/L and UACR 30–300 mg/g with eGFR 25–90 ml/min/1.73m2 or UACR 300–5000 mg/g and eGFR ≥ 60 ml/min/1.73m2	Primary outcome: composite of death from CV causes, nonfatal MI, nonfatal stroke or hospitalization for heart failure First secondary outcome: composite of first occurrence of kidney failure, sustained decrease of at least 40% in eGFR from baseline or death from renal causes	- Finerenone reduced the risk of primary composite outcome by 13% [HR 0.87, 95% CI (0.76–0.98)] compared to placebo - Risk of secondary composite kidney outcome was 13% lower with finerenone [HR 0.87, 95% CI (0.76–1.01)] compared to placebo
FIDELIO-DKD/2020 [64]	Finerenone 10 mg or 20 mg daily vs. Placebo	Multicenter, international, randomized, double-blind, placebo controlled	5734 adults with T2DM on maximal tolerated RAAS blockade with serum potassium ≤ 4.8 mEq/L and UACR 30 −300 mg/g with eGFR 25–60 ml/min/1.73 m2 and diabetic retinopathy or UACR ≥ 300 mg/g and eGFR 25–75 ml/min/1.73m2	Primary outcome: composite of kidney failure, sustained eGFR decline of at least 40% or death from renal causes Secondary outcome: composite of CV death, nonfatal MI, nonfatal stroke or hospitalization for heart failure	- Finerenone reduced the risk of primary composite outcome by 18% [HR 0.82, 95% CI (0.73–0.930] compared to placebo -Risk of secondary outcomes was 14% lower with finerenone [HR 0.86, 95% CI (0.75–0.99)] compared to placebo
ARTS-DN/2015 [60]	Finerenone at different doses (1.25, 2.5, 5, 7.5, 10, 15, 25 mg) vs. Placebo	Multicenter, international, randomized, double-blind, placebo controlled, parallel-group	821 adults with T2DM, UACR ≥ 30 mg/g and eGFR > 30 ml/min/1.73 m2 on at least minimum dose of RAS blocker with serum potassium ≤ 4.8 mEq/L	Primary outcome: Ratio of UACR at day 90 vs. at baseline	-Dose-dependent, incremental reduction in UACR: Finerenone 7.5 mg/day: HR 0.79, 90% CI (0.68–0.91) Finerenone 10 mg/day HR 0.76, 90% CI (0.65–0.88) Finerenone 15 mg/day HR 0.67, 90% CI (0.58–0.77) Finerenone 20 mg/day HR 0.62, 90% CI (0.54–0.72)

CI confidence interval; estimated glomerular filtration rate, HR hazard ratio, RAS renin angiotensin system, T2DM type 2 diabetes, UACR urine albumin creatinine ratio

Non-Pharmacological Approaches

Dietary Interventions in CKD

The recommended protein intake for the general population is 0.8 gm/kg/day, much lower than the average 1.2—1.4 g/kg/day in the U.S.population [67]. High protein intake may accelerate the progression of kidney disease in individuals with CKD. The association between high dietary protein intake and mortality in uremic animals had been discovered almost a century ago [68]. The proposed deleterious effects of high protein diet in CKD may be mediated by induction of renal hyperfiltration leading to proteinuria and glomerular sclerosis [69]. Other putative mechanisms include interstitial fibrosis due to increased mesangial cell signaling as well as indirect effects from harmful metabolic consequences such as increased dietary acid load [70]. Trials of low protein diets, defined as 0.6 g/kg/day or very low protein diets (0.38–0.43 g/kg/day) supplemented with ketoanalogues in patients with non-diabetic, non-proteinuric CKD have shown halting or slowing CKD progression [71, 72]. Given the accumulating data on safety and efficacy of low protein diets in CKD, the updated Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice guideline for nutrition in CKD [73] recommends dietary restrictions to 0.55–0.6 g/kg/day or 0.28–0.43 g/kg/day protein supplemented with keto acids or amino acid in non-diabetic non-dialysis CKD patients to reduce the risk of progression to ESKD and improve the quality of life. For diabetics with non-dialysis CKD, the guidelines recommend between 0.6 to 0.8 g/kg per day [73].

Observational studies have shown that intake of plant based protein may be associated with lower risk of incident CKD and slower progression of established CKD [74, 75]. Several mechanisms have been proposed, including improved glomerular hemodynamics, reduction of proteinuria, shifting the gut microbiome from a proteolytic to saccharolytic profile, thus decreasing the production of uremic toxins, bacterial translocation and inflammation and by reducing dietary acid production [76].

Some of the observed beneficial effects of plant-based diets may be related to higher fiber content of plant-based foods. However, observational studies have found conflicting results in CKD patients [77]. Additionally, benefits of plant based diet may be accrued due to presence of high levels of beneficial micronutrients such has vitamins, minerals and other bioactive phytochemicals like carotenoids, lignans and beta-glucans as well as due to other healthy behaviors that usually accompany a plant based diet [78]. Thus, the paradigm has rightly shifted from emphasizing a single nutritional component to emphasizing healthy dietary patterns such as the DASH (Dietary Approaches to Stop Hypertension) diet and the Mediterranean diet [73].

However, though various plant-based diets have shown beneficial effects, it is important to note that these are all not low protein diets, and strict vegetarians do exceed the minimum recommended amount of protein intake. Care also needs to be taken to avoid ultraprocessed foods as a part of plant based diet (ex. plant based meat alternatives), given mounting evidence regarding adverse renal effects of such foods [79]. Thus, the “optimal” diet for slowing progression of CKD is proposed to be the PLADO diet (PLAnt DOminant) low protein diet consisting of dietary protein intake of 0.6–0.8 g/kg/day from 50% plant based sources and caloric intake of 30–35 kcal/kg/day [80].

Following a plant-based low protein diet requires profound dietary changes for the patient and often proves difficult to achieve. Thus, it would be helpful to elucidate the stage of CKD at which initiation of such dietary modification would be most impactful (late stages vs. early stage); such data is currently lacking. Similarly, there is dearth of data on the safety and efficacy of such diets in special populations such as diabetics with kidney disease and the very old population, which represent areas of active research (NCT05514184).

Therapies with Unclear Efficacy in CKD

Anti-Inflammatory and Anti-Fibrotic Agents

Bardoxolone is an inducer of the NrF2 pathway which inhibits NF-kB, leading to antioxidant and anti-inflammtory effects. In a phase 2 randomized double-blind trial of patients without cardiovascular disease, inulin measured GFR increased by 5.95 (2.29–9.6) ml/min/1.73 m² after 16 weeks of treatment [81]. A phase 3 randomized controlled trial of 1013 patients with diabetic kidney disease [eGFR 15 to 60 ml/min/1.73 m² and spot albumin/creatinine ≤ 3500 mg/g] is currently underway [82]. Atrasentan, a selective endothelin A receptor antagonist was shown to reduce the risk of renal events in diabetic CKD patients the SONAR trial [83]. However due to the risk of sodium retention and heart failure, it’s role in the management of diabetic kidney disease remains unclear.

The efficacy of direct antifibrotic therapy in CKD is unknown. Trials with drugs commonly used to treat idiopathic pulmonary fibrosis (pirfenidone, nintedanib, PRM-151), antagomirs (lademirsen), or drugs targeting interleukin 11 or NKD2 (WNT signaling pathway inhibitor) are ongoing. They would need to prove efficacy beyond the current standards of care involving SGLT2i and MR blockade added to the classic renin angiotensin system inhibition.

Kidney Precision Medicine for CKD Prevention and Future Therapeutic Interventions

The field of medicine is currently moving towards personalized care and nephrology is no exception [84]. Knowledge and understanding of the mechanisms of kidney diseases is important not only to diagnose genetic forms of kidney disease, but also to discover genetic variants and epigenetic regulators with roles in CKD onset, progression, and responses to therapy.

Apolipoprotein A-1 (APOL1), probably the most studied gene in CKD, was found to be implicated in the higher risk of kidney disease progression in people of West African descent [85, 86]. The ongoing, multicenter APOLLO (APOL1 Long-Term Kidney Transplantation Outcomes Network) study aims to prospectively assess the effects of APOL1 risk variants in kidney donors and recipients [87]. Mechanistic trials targeting APOL1 are underway [88], and may establish APOL1 as a potential therapeutic target. In a genome-wide association study, four single-nucleotide polymorphisms with a minor allele frequency of > 0.03 were associated with CKD progression at the genome-wide threshold of P ≤ 5 × 10⁻⁸, and 14 gene regions reached nominal significance (P < 10⁻⁶); specifically, LINC00923, an RNA gene expressed in glomeruli and kidney endothelial cells, was associated with decline in kidney function in people without diabetes [89]. Additionally, the AGT and RENBP genes involved in RAAS and RAAS pathway, were found to be associated with CKD progression [90]. Though the field of nephrogenetics is quite young, the future of CKD prevention and management will imply to elucidate genetic, epigenetic, transcriptomic and proteomic characteristics linked with progressive kidney function decline. Identification of therapeutic targets based on better understanding of genetic determinants of various CKD etiologies are on the horizon and may include the development of novel therapies aimed at activation of endogenous pathways that inhibit the kidney diseases onset and progression.

Integration of genetic testing with biomarkers assessment [91] in daily clinical practice, as a screening tool to identify individuals at risk, who would benefit for more aggressive therapies may become the norm in the future. Treatment of such high-risk patients may involve a multifaceted approach including lifestyle modifications, exercise, plant-based therapy, added to the current best clinical practice therapeis. Other emerging themes based on transcriptomic and epigenetic data and gut immune modulation strategies may become available in the future. Figure 1 presents a schematic of medical decision support to integrate patient related, provider related and environmental factor analysis in creation of a personalized approach to CKD management.

Fig. 1.

Kidney precision medicine approach to decision support in CKD. (Adapted from: Susanne Oparil presentation at the American College of Cardiology, May 2021, with permission)

Conclusion

Preventing CKD requires a multi-faceted approach that includes risk factor identification, lifestyle and dietary modifications, highly effective therapeutics, regular surveillance, and patient education and involvement in own care. Emerging technologies, based on disease mechanisms and genetic discoveries in CKD may provide avenues for targeted therapies. The shift in paradigm from generalized to personalized care show promise in reducing the global burden of this debilitating condition.