Upcoming drug targets for kidney protective effects in chronic kidney disease

PLAIN ENGLISH SUMMARY

 

People with chronic kidney disease (CKD) are at a high risk of heart disease and end-stage kidney disease. This review describes how new medications, such as glucagon-like peptide-1 receptor agonists (GLP1RA), aldosterone synthase inhibitors (ASi), soluble guanylate cyclase (sGC) and endothelin receptor antagonists (ERA), can lower heart–kidney risk in people with CKD. GLP1RA are already recommended for managing blood sugar in people with CKD and type 2 diabetes and have been shown to lower the risk of developing end-stage kidney disease. GLP1RA will likely soon be included in clinical guidelines, but further research is needed to understand how these medications protect the kidneys. ASi are another new medication that lower the protein found in urine. Larger trials are being done to see how well these medications work in slowing CKD. Lastly, both sGC agonists and ERAs have been shown to relax blood vessels to improve blood flow in the kidney, and reduce the amount of protein found in urine, both of which are critical to protecting kidneys. Larger clinical trials are being done to see if these medications prevent CKD from getting worse. In summary, this review describes the new and promising treatments for CKD. These therapies hold the potential to slow kidney disease and improve the wellbeing of patients. Further research of these new treatments is important for improving CKD care.

ABSTRACT

Despite recent advancements in the treatment of chronic kidney disease (CKD), identifying novel therapies beyond guideline-directed therapies that reduce residual cardiorenal risk remains imperative. In this review, we highlight the clinical evidence supporting emerging therapies for CKD, including glucagon-like peptide-1 receptor agonists (GLP1RA) and other incretin-based therapies, aldosterone synthase inhibitors (ASI), endothelin receptor antagonists (ERA), soluble guanylate cyclase (sGC) agonists and anti-inflammatory drugs. Long-acting GLP1RA are already recommended for glycemic control in patients with CKD and type 2 diabetes and the large, dedicated kidney outcome trial FLOW was recently stopped early for efficacy. Emerging clinical trial evidence supports the concept that ASI also provide additional benefit on top of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, which remain a cornerstone of CKD treatment. Next, we consider the use of sGC agonists, which target nitric oxide bioavailability and thereby reduce albuminuria. Finally, we explore the therapeutic potential of ERA, which act through hemodynamic and anti-fibrotic mechanisms, thereby addressing a common final pathway in the development of CKD. Accordingly, our review highlights the changing therapeutic landscape for CKD with promising agents to further prevent the progression of kidney disease.

INTRODUCTION

Chronic kidney disease (CKD) affects 800 million people worldwide and is associated with substantial morbidity and mortality [1, 2]. For decades, the first-line treatment for kidney protection in people with CKD was limited to blockade of the renin–angiotensin–aldosterone system (RAS), using angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers [3]. While effective at lowering the rate of kidney function decline and proteinuria, individuals remained at high risk for progression to end-stage kidney disease (ESKD) [4–6]. More recently, kidney outcome trials employing composite endpoints that include substantial, sustained declines in estimated glomerular filtration rate (eGFR), ESKD and death due to kidney disease have demonstrated that sodium-glucose cotransporter 2 (SGLT2) inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRA) delay CKD progression, with ∼38% and 23% relative risk reductions in kidney outcomes with these drug classes, respectively [7, 8]. Hence, the current treatment paradigm, based on KDIGO 2024 guidelines, supports initiation of RAS inhibitors and SGLT2 inhibitors as first-line therapies for CKD, with nsMRAs as second-line adjunctive therapies for residual proteinuria in individuals who have diabetic kidney disease (DKD) [9].

Despite these advancements in CKD treatments, the risk for CKD progression is not fully attenuated (Fig. 1). Thus, identifying novel therapies aimed at reducing residual cardiorenal risk associated with CKD has been an active area of investigation. The current review summarizes recent evidence of emerging therapies for CKD and DKD beyond current guideline-recommended treatments. This includes glucagon-like peptide-1 receptor agonists (GLP1RA) and other incretin-based therapies, aldosterone synthase inhibitors (ASI), endothelin receptor antagonists (ERA), soluble guanylate cyclase (sGC) activators, and monoclonal antibodies targeting inflammatory pathways (Table 1).

Figure 1.

Effect of combination drug therapy on eGFR decline in a prototypical patient with CKD. On average, compared with the gradual aging-associated decline in eGFR of 1.0–1.2 mL/min/1.73 m² per year, a patient with CKD would have precipitous loss of 6 mL/min/1.73 m² every year. With current guideline-directed therapies for CKD, the addition of SGLT2 inhibitors and nsMRA to RASi, following an initial eGFR dip, would minimize the rate of eGFR decline to >2.0 mL/min/1.73 m² per year. Additional therapies that can provide a clinically significant in annual eGFR loss (>0.75 mL/min/1.73 m²/year) in patients with CKD are under evaluation, including GLP1RA, ASI, ERA, sGC activators and anti-inflammatory agents. RASi: RAS inhibitor; SGLT2i: SGLT2 inhibitor. Created with BioRender.com.

Table 1:

Summary of key kidney outcome randomized control trials for drug targets beyond RAS/SGLT2/MRA.

Target	Study and trial phase	Patient cohort	Study design	Study findings
GLP1RA	AWARD-7 [30] • Phase 3 trial • Randomized, open-label, parallel-arm	• T2DM-CKD; n = 577 • eGFRa: 15–60 • Stable (≥4 weeks) RASi • Stable (≥4 weeks) insulin and/or oral antihyperglycemic agent	• 1:1:1 randomization • Dulaglutide 0.75 mg weekly • Dulaglutide 1.5 mg weekly • Insulin glargine • Duration: 52 weeks	↓ Decline in eGFRa slope ↔ UACR ↔ Serious adverse events ↑ Treatment-emergent adverse events (nausea)
	FLOW [28] • Phase 3b trial • Randomized, double-blind, parallel, placebo-controlled	• T2DM-CKD; n = 3534 • eGFRa: 50–75, UACR: 300–5000 • eGFRa: 25–50, UACR: 100–5000 • Stable (≥4 weeks) RASi • 15.5% prescribed SGLT2i	• 1:1 randomization • Semaglutide 1.0 mg weekly • Placebo • Duration: 3–5 years	↓ Composite renal outcome (kidney failure, eGFRa <15, kidney replacement therapy, ≥50% eGFRa decline, renal or CV death)
	REMODEL • Phase 3b trial • Randomized, double-blind, parallel, placebo-controlled	• T2DM-CKD; n = 105 • Non-biopsy: eGFRa: 30–75 • Biopsy: eGFRa: 40–75 • UACR: 20–5000 • Stable (≥4 weeks) RASi	• 2:1 randomization • Semaglutide 1.0 mg weekly • Placebo • Duration: 52 weeks	• Data pending (NCT04865770) • Primary outcome: change in renal cortical and medullary oxygenation and inflammation
ASI	Tuttle et al. [48] • Phase 2 trial • Randomized, double-blind, parallel, placebo-controlled	• CKD; n = 586 • eGFRa: 30–90 • UACR 200–5000 • Stable (≥4 weeks) RASi	• 1:1 randomization by SGLT2i • 1:1:1:1 randomization • BI 690517 3 mg q.d. • BI 690517 10 mg q.d. • BI 690517 20 mg q.d. • Placebo • Duration: 14 weeks	↓ Decline in eGFRa slope ↓ UACR ↔ SGLT2i treatment interaction effect ↔ Serious adverse events ↑ Hyperkalemia event in 20 mg group
	EASi-Kidney • Phase 3 trial • Randomized, double-blind, parallel, placebo-controlled	• CKD; target n = 11 000 • Stable (≥4 weeks) RASi	• 1:1 randomization on top of 10 mg empagliflozin • BI 690517 q.d. • Placebo	• Data pending • Primary outcome: kidney disease progression, hospitalization for heart failure or death from cardiovascular disease
sGC	Hanrahan et al. [62] • Phase 2 trial • Randomized, double-blind, parallel, placebo-controlled	• T2DM-DKD; n = 156 • eGFRa: 30–75, UACR: 200–5000 • Stable (≥4 weeks) RASi and antihyperglycemic therapy • 7% prescribed SGLT2i	• 1:1:1 randomization • Praliciguat 20 mg q.d. • Praliciguat 40 mg q.d. • Placebo • Duration: 12 weeks	↔ Decline in eGFRa slope ↔ UACR ↑ Treatment-emergent adverse events with 40 mg
	Cherney et al. [63] • Phase 1b trial • Randomized, double-blind, parallel, placebo-controlled	• T1DM or T2DM; n = 74 • eGFRa: 20–75, UACR: 200–3500 • Stable (≥4 weeks) RASi	• 1:1:1:1 randomization • BI 685509 1 mg q.d. • BI 685509 3 mg q.d. • BI 685509 3 mg t.i.d. • Placebo • Duration: 4 weeks	↔ patients with ≥20% reduction in UACR ↔ Decline in eGFRa slope ↔ Adverse events related to drug
	CONCORD • Phase 2 trial • Randomized, double-blind, parallel, placebo-controlled	• T2DM; n = 243 • Established ASCVD or HF • eGFRa: 25–60, UACR: 30–3000 • Stable (≥3 months) RASi • Stable (≥3 months) SGLT2i	• 3:1 randomization • Runcaciguat 120 mg q.d. • CKD • T2DM-CKD • T2DM-CKD with SGLT2i • Placebo • Duration: 8 weeks	• Data pending (NCT04507061)• Primary outcome: change in UACR
	NCT04736628 • Phase 2 trial • Randomized, double-blind, parallel, placebo-controlled	• CKD; n = 240 • eGFRa: 20–90 • UACR: 200–3500 • Stable (≥4 weeks) RASi if UACR >300 • Stable (≥4 weeks) SGLT2i or ERA	• 1:1 randomization • BI 685509 t.i.d. • Three doses • Placebo • Three doses • Duration: 20 weeks	• Data pending • Primary outcome: change in UACR • Secondary outcome: ≥20% reduction in UACR
	NCT04750577 • Phase 2 trial • Randomized, double-blind, parallel, placebo-controlled	• T1DM or T2DM; n = 243 • eGFRa: 20–90 • UACR: 200–3500 • Stable (≥4 weeks) RASi • Stable (≥4 weeks) SGLT2i or ERA	3:1 randomization • BI 685509 t.i.d. (low dose) • BI 685509 t.i.d. (medium dose) • BI 685509 t.i.d. (high dose) • Placebo • Duration: 20 weeks	• Data pending • Primary outcome: change in UACR • Secondary outcome: ≥20% reduction in UACR
ERA	ASCEND [66] • Phase 3 trial • Randomized, double-blind, parallel, placebo-controlled	• T2DM; n = 1392 • UACR ≥309 mg/g • Stable (≥6 months) RASi	• 1:1:1 randomization • Avosentan 25 mg q.d. • Avosentan 50 mg q.d. • Placebo • Duration: 6 months	↔ Occurrence of composite of doubling of serum creatinine, ESKD, or death ↔ Decline in eGFRa slope ↓ UACR ↑ Adverse event related to drug (fluid overload)
	Kohan et al. [67] • Phase 2a trial • Randomized, double-blind, placebo-controlled	• T2DM-CKD; n = 89 • eGFRb: 20–60, UACR: 100–3000 • Stable (≥2 weeks) RASi	• 1:1:1:1 randomization • Atrasentan 0.25 mg q.d. • Atrasentan 0.75 mg q.d. • Atrasentan 1.75 mg q.d. • Placebo • Duration: 8 weeks	↔ Decline in eGFRa slope ↔ UACR ↑ Adverse event related to drug (peripheral edema)
	RADAR [68] • Phase 2b trial • Randomized, double-blind, parallel, placebo-controlled	• T2DM-CKD; n = 211 • eGFRa: 30–75, UACR: 300–3500 • Stable (≥4 weeks) RASi	• 1:1:1 randomization • Atrasentan 0.75 mg q.d. • Atrasentan 1.25 mg q.d. • Placebo • Duration: 12 weeks	↔ Decline in eGFRa slope ↓ UACR ↔ Adverse events related to drug
	SONAR [69] • Phase 3 trial • Randomized, double-blind, parallel, placebo-controlled	• T2DM-CKD; n = 5107 • eGFRa: 25–75, UACR: 300–5000 • Stable (≥4 weeks) RASi	• 1:1 randomization • Atrasentan 0.75 mg q.d. • Placebo • Duration: 2.2 years	↓ Incidence of renal composite endpoint (doubling of serum creatinine and ESKD) ↓ Incidence of CV composite endpoint (CV death, non-fatal MI and stroke) ↓ Proportion of patients with eGFRa decline ≥50% ↓ UACR ↑ Adverse event related to drug (fluid overload and anemia)
	FCRD01 [70] • Phase 2 trial • Randomized, double-blind, placebo-controlled crossover	• CKD; n = 27 • eGFRa ≥15 • Proteinuria >300 mg/day • Stable (≥3 months) RASi	• 1:1:1 randomized crossover • Sitaxsentan 100 mg q.d. • Nifedipine 30 mg q.d. • Placebo • Duration: 6 weeks	↓ 24-h proteinuria ↓ 24-h protein:creatinine ratio ↔ Decline in eGFRa slope ↔ Adverse events related to drug
	ZENITH-CKD [71] • Phase 2b trial • Randomized, double-blind, parallel, active-controlled	• CKD; n = 449 • eGFRb ≥15, UACR: 150–1500 • Stable (≥4 weeks) RASi	• 2:1:2 randomization on top of dapagliflozin 10 mg • Zibotentan 0.5 mg q.d. • Zibotentan 0.25 mg q.d. • Placebo • Duration: 12 weeks	↓ UACR ↔ Decline in eGFRa slope ↑ Adverse event related to drug (fluid retention-related events)
Other	IL-6 monoclonal antibody RESCUE [82] • Phase 2 trial • Randomized, double-blind, parallel, placebo-controlled	• CKD; n = 264 • eGFRa: 10–60 • hsCRP ≥2 mg/L	• 1:1:1:1 randomization • Ziltivekimab 7.5 mg qmonth • Ziltivekimab 15 mg qmonth • Ziltivekimab 30 mg qmonth • Placebo • Duration: 24 weeks	↔ Decline in eGFRa slope ↔ UACR ↓ hsCRP ↔ Treatment-emergent adverse events
	IL-6 monoclonal antibody ZEUS • Phase 3 trial • Randomized, double-blind, parallel, placebo-controlled	• CKD-ASCVD; n = 6200 • eGFRa: 15–60 • eGFRa ≥60, UACR: ≥200 • hsCRP ≥ 2 mg/L	• 1:1:1:1 randomization • Ziltivekimab B 15 mg qmonth • Placebo • Ziltivekimab C 15 mg qmonth • Placebo • Duration: 48 months	• Data pending (NCT05021835) • Primary outcome: CV composite endpoint (CV death, non-fatal MI, non-fatal stroke and hospitalization) • Secondary outcome: renal composite endpoint (≥40% eGFRa decline, kidney failure) and UACR
	IL-1β monoclonal antibody CANTOS [78] • Phase 2 trial • Randomized, double-blind, parallel, placebo-controlled	• CVD; n = 741 • hsCRP ≥2 mg/L	• 1:1:1:1.5 randomization • Canakinumab 50 mg q3month • Canakinumab 150 mg q3month • Canakinumab 300 mg q3month • Placebo • Duration: 48 months	↓ hsCRP ↔ IL-6 ↔ Major cardiovascular event ↑ Adverse events related to drug (neutropenia, thrombocytopenia)

^aIndicates eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula.

^bIndicates eGFR was calculated using the Modification of Diet in Renal Disease formula.

Note: eGFR is expressed in mL/min/1.73 m² and UACR is expressed in mg/g.

ASCVD: atherosclerotic cardiovascular disease; CV: cardiovascular; CVD: cardiovascular disease; HF: heart failure; MI: myocardial infarction; RASi: RAS inhibitor; SGLT2i: SGLT2 inhibitor; T1DM: type 1 diabetes mellitus.

GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS

GLP1RA are analogs of the incretin hormone glucagon-like peptide-1 (GLP1), and were initially developed as glucose-lowering medications for people with type 2 diabetes mellitus (T2DM) [10]. While the therapeutic use of GLP1RA was initially limited by rapid degradation by dipeptidyl peptidase-4 (DPP-4) enzyme in the circulation, the discovery of the DPP-4-resistant homolog exendin-4 allowed for development of long-acting GLP1RA. Currently available formulations of GLP1RA increase insulin secretion in a glucose-dependent manner and decrease glucagon secretion, resulting in a 0.6%–1.6% reduction in hemoglobin A1c (HbA1c) that is independent of baseline eGFR [11]. These agents have also gained traction as therapies for obesity, as substantial weight loss occurs predominantly through central effects in the hypothalamus and through delaying gastric emptying to induce satiety [12–15]. GLP1RA are also metabolized directly by target tissues and thus do not require dose adjustment in CKD [16–19].

Meta-analyses of large cardiovascular outcome trials in diabetic or obese non-diabetic individuals have demonstrated that GLP1RA reduce the rate of major adverse cardiovascular events by 12%–14% [20, 21]. From a nephrology perspective, secondary analyses from several of these cardiovascular outcome trials (ELIXA, LEADER, SUSTAIN-6, EXSCEL, REWIND and AMPLITUDE-O) have also reported reduced incidence of composite kidney outcomes (progression of macroalbuminuria, worsening kidney function or need for kidney replacement therapy) [22–27]. However, salutary effects on kidney outcomes were largely driven by the reduction in macroalbuminuria progression, rather than worsening eGFR or requirement for kidney replacement therapy. This was likely due to low event rates in non-CKD populations highlighting the need for trials in the CKD population.

To address this key knowledge gap, the FLOW trial was the first dedicated kidney outcome trial to evaluate semaglutide in 3534 adults with CKD and T2DM with eGFR 50–75 mL/min/1.73 m² and urinary albumin-to-creatinine ratio (UACR) of 300–5000 mg/g, or eGFR 25–50 mL/min/1.73 m² and UACR of 100–5000 mg/g on a background of RAS inhibitor [28]. Semaglutide led to a 24% lower incidence of the primary renal composite endpoint of kidney failure, sustained 50% decline in eGFR, and cardiovascular and renal death [28].

The kidney protective effects from the FLOW trial will require subsequent studies to unravel the mechanisms underpinning these clinical benefits (Fig. 2). Whether kidney protection is mediated indirectly by improvements in traditional cardiovascular risk factors (i.e. HbA1c reductions, weight loss, blood pressure reduction, improved lipid profile) or via direct actions in the kidney remain unknown [29]. The observation that the favorable effects of dulaglutide on eGFR over a 26-week period were unrelated to improvement in glycemic control or weight loss supports the notion that mechanisms beyond modulation of traditional cardiorenal risk factors play a significant role [30, 31]. Direct effects on the kidney are possible since the GLP1 receptor has been identified in the kidney, with the greatest expression in vascular smooth muscle cells [32]. However, acute infusion of GLP1RA in overweight patients with T2DM had no impact on renal hemodynamics or measured GFR [33], despite increasing proximal tubular sodium excretion [33, 34]. These findings suggest that GLP1RA-related natriuresis has negligible effects on tubuloglomerular feedback, which is distinct from the tubular protective mechanisms induced by SGLT2 inhibition. Other postulated mechanisms for GLP1RA benefits on kidney function include a reduction in oxidative stress and alterations in pro-inflammatory signaling [16]. Accordingly, several ongoing studies [REMODEL (NCT04865770) and TREASURE-CKD (NCT05536804)] are investigating whether GLP1RA therapies can improve kidney oxygenation using blood oxygen level–dependent magnetic resonance imaging, and kidney mechanistic studies are also underway in patients with type 1 diabetes mellitus [REMODEL-T1D (NCT05822609)].

Figure 2.

Putative mechanisms of action of drug therapies under evaluation to mitigate CKD progression. Several metabolic, hemodynamic and inflammatory mediators are currently being investigated as potential targets for therapeutics approaches to delay CKD progression. ACE: angiotensin-converting enzyme; AGE: advanced glycation end product; ARB: angiotensin receptor blocker; ER: endoplasmic reticulum; RAGE: receptor for advanced glycation end product. Created with BioRender.com.

An important area of future work will be to determine the additive effect of combined GLP1RA and SGLT2 inhibitors in patients with CKD and DKD, due to their distinct mechanisms of action on kidney function, as described above. The agents also have different cardioprotective clinical benefits, with GLP1RA reducing the risk of stroke with a lesser impact on heart failure hospitalization [35]. However, GLP1RA use in SGLT2 inhibitor kidney outcome trials have been limited (DAPA-CKD, 2.8%; CREDENCE, 4.2%; EMPA Kidney, 13%). Furthermore, only 15.5% of participants recruited in the FLOW trial were on a background SGLT2 inhibitor at baseline [28]. Despite these statistical limitations, secondary analyses from the EXSCEL trial reported that combined exenatide and SGLT2 inhibitors modestly improved the eGFR slope, in comparison with placebo or exenatide alone [36]. Actuarial analyses, combining SGLT2 inhibitors, GLP1RA and nsMRA trial data anticipated that a 50-year-old individual with T2DM and moderate albuminuria would derive a 5.5-year delay in CKD progression to ESKD [37]. Given the kidney benefits demonstrated from cardiovascular outcome trials, the KDIGO 2024 CKD guidelines recommend long-acting GLP1RA as the preferred agent for glycemic control following metformin or SGLT2 inhibitors in patients with CKD and T2DM [9]. Pending the outcome of the FLOW trial, future iterations of the KDIGO guidelines will have to consider how to incorporate GLP1RA for prevention of DKD progression as well.

Beyond GLP1RA, a multitude of other dual or poly-agonist agents combining GLP1 agonism with glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin and peptide YY are being studied for treatment of obesity. The underlying hypothesis is that targeting multiple receptors may potentially lead to a greater magnitude of weight loss and clinical benefit [35]. The most well-established dual agonist is the GLP1/GIP dual agonist tirzepatide, which induces greater weight loss and HbA1c-lowering than semaglutide [38]. While kidney-related trials with tirzepatide are still in progress, a post hoc analysis of SURPASS-4 showed that tirzepatide slowed the annual rate of eGFR decline by 2.2 mL/min/1.73 m² and reduced albuminuria when compared with insulin glargine [39]. Furthermore, cagrilintide, a dual GLP1 and amylin agonist, and retatrutide, a triple GLP1, GIP and glucagon agonist, were both associated with significant weight loss in phase 2 trials [40, 41]; the translation of these findings into cardiorenal benefit is not yet known. Taken together, the field of incretin biology and clinical trials is rapidly evolving and GLP1RA agents—especially semaglutide—have the strong potential to be used for their kidney protective properties, thereby becoming a part of the nephrologist's toolkit for the management of residual kidney risk in DKD.

ALDOSTERONE SYNTHASE INHIBITION

Aldosterone is critical in the maintenance of electrolyte and volume homeostasis. Under normal conditions, aldosterone is produced in the zona glomerulosa of the adrenal gland and binds to the mineralocorticoid receptor in the principal cells of the distal nephron. This stimulates sodium reabsorption and potassium excretion, which ultimately regulates intravascular volume and blood pressure. However, aldosterone also contributes to CKD progression in certain disease states [42], via aldosterone overproduction or upregulation of the mineralocorticoid receptor, leading to hypertension, as well as kidney inflammation and fibrosis (Fig. 2) [43, 44]. In patients with DKD on background RAS inhibitors, antagonism of the mineralocorticoid receptor using the nsMRA finerenone in the FIDELIO-DKD and FIGARO-DKD trials has provided strong evidence supporting the use of this therapy to delay CKD progression and reduce cardiovascular risk [45, 46].

While concomitant use of RAS inhibitors and nsMRAs provides additive kidney and cardiovascular protection in patients with DKD and they are an established component of clinical practice guidelines and clinical care, alternative approaches to mitigate deleterious effects of aldosterone on cardiorenal risk are emerging in ASI trials. These medications are small molecule inhibitors of aldosterone synthase, an enzyme that is responsible for the final rate-limiting step in aldosterone production [47]. However, due to the similarities in amino acid sequence between aldosterone synthase and cortisol synthase, ASI have been designed to be highly selective to avoid inducing adrenal insufficiency.

In a phase 2 trial for ASI, 586 people with CKD, eGFR of 30–90 mL/min/1.73 m², UACR 200–5000 mg/g, serum potassium <4.8 mmol/L and on maximally tolerated dose of RAS inhibitors were first randomized to empagliflozin versus placebo during an 8-week run-in period and subsequently sub-randomized to 14 weeks of treatment with once daily BI 690517 (3, 10 or 20 mg) or placebo [48]. Participants with an indication for MRA treatment were excluded. The primary outcome was change in UACR from baseline between participants prescribed concomitant BI 690517 and empagliflozin versus BI 690517 and placebo. BI 690517 monotherapy caused a 35% reduction in the UACR compared with placebo, with a similar magnitude response in participants prescribed concomitant BI 690517 and empagliflozin [48], suggesting complementary mechanisms by which ASI and SGLT2 inhibitors reduce kidney risk. BI 690517 also reduced plasma aldosterone in a dose-dependent fashion with placebo-corrected increases in serum potassium ranging from 0.25 to 0.33 mmol/L [48]. The phase 3 randomized control trial, EASi-Kidney, will randomize 11 000 people with CKD, with or without T2DM to treatment with BI 690517 versus placebo. The findings will provide a definitive assessment of the efficacy and safety of BI 690517, when added to standard of care including empagliflozin.

The relative merits and drawbacks of ASI remain to be delineated. Given that these agents have overlapping mechanisms of action, as well as experience with dual RAS inhibition trials showing added risk of side effects, combined use is unlikely to be examined. In addition, head-to-head trials with nsMRA versus ASI therapies are unlikely to be prioritized, even though important between-class differences may be present. For instance, ASI may provide more complete suppression of the effects of aldosterone. In addition, ASI may have a more pronounced blood pressure–lowering effect compared with nsMRA. Nevertheless, it remains to be established whether or not physiological differences impact safety or efficacy.

SOLUBLE GUANYLATE CYCLASE ACTIVATORS

sGC is a key enzyme in the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling axis that contributes to vascular homeostasis. The binding of NO to the heme moiety activates sGC, subsequently upregulating synthesis of cGMP from the precursor guanosine triphosphate [49]. In the kidney, elevated intracellular concentrations of cGMP and increased NO bioavailability decrease vascular tone via afferent arteriole vasodilation, thereby potentially preserving glomerular filtration, and attenuating tubulointerstitial fibrosis [49, 50]. Notably in CKD, oxidative damage and inflammation that cause the uncoupling of NO-cGMP signaling, and decreased NO and cGMP synthesis are pathophysiological processes that contribute to endothelial dysfunction and CKD progression. Thus, sGC agonists represent novel therapies that enhance cGMP concentrations, independent of NO bioavailability [51]. Two types of sGC agonists have been developed: sGC stimulators, which sensitize sGC to low levels of NO due to the presence of a reduced heme moiety, and sGC activators, which activate the enzyme in its oxidized, heme-free state, offering potential benefits under conditions of persistent oxidative stress [51]. In people with heart failure, sGC increases pulmonary and systemic vasodilation to reduce left ventricular afterload [52]. In a large cardiovascular outcome trial, the sGC stimulator vericiguat reduced the incidence of death from cardiovascular causes or hospitalization for heart failure compared with placebo [53]. Given the established feature of endothelial dysfunction in CKD, recent work is emerging to investigate whether sGC agonists can also be employed as a therapy for CKD [49, 51, 54].

The majority of evidence to support the notion of a kidney protective effect of sGC agonists arises from pre-clinical models of diabetic and non-diabetic CKD. sGC agonists in pre-clinical models improve renal blood flow, and mitigate interstitial inflammation and fibrosis, glomerulosclerosis, and albuminuria [55–59]; these beneficial effects were sustained with combined sGC agonists and RAS inhibition [56, 59]. Early phase clinical trials in humans have found favorable safety and tolerability of acute (2–4 weeks) administration of the sGC agonists in healthy adults [60] and with T2DM [61]. These favorable findings were also replicated in patients with DKD in longer-term trials (4–12 weeks), and also caused 19%–56% reductions in albuminuria [62, 63], a trend that persisted in patients on background RAS inhibition [63]. Additional results from phase 2 trials investigating sGC agonists in the setting of DKD and CKD (NCT04507061, NCT04736628, NCT04750577) will provide further evidence around the effects on kidney function. Based on existing efficacy and safety studies, larger-scale trials are warranted to comprehensively investigate potential kidney protective effects of sGC agonists in the setting of CKD.

ENDOTHELIN RECEPTOR ANTAGONISTS

The endothelin system is implicated in the pathogenesis of CKD progression [64, 65]. Endothelin-1 (ET-1) can bind to two receptor isoforms, ET_A and ET_B, which elicit distinct end-organ responses. ET_A stimulation increases afferent arteriole vasoconstriction and interstitial fibrosis, while ET_B stimulation increases natriuresis in the thick ascending limb and collecting duct. During the pathophysiological progression of CKD, upregulation of ET-1 increases ET_A stimulation, which can promote inflammation and vascular injury to cause podocytopathy and fibrosis, clinically manifesting as proteinuria [65]. A detailed review of the role of the endothelin system in renal physiology and pathophysiology is beyond the scope of this manuscript but has been discussed extensively elsewhere [64, 65].

ERA have been studied in CKD for over a decade. Early-phase studies demonstrated that ET_A antagonism can increase renal blood flow and reduce proteinuria in the setting of CKD while ET_B antagonism induced renal microcirculatory vasoconstriction, suggesting that ET_A selective ERAs may particularly represent a promising CKD treatment strategy. The first major effort to investigate an ERA in CKD was the ASCEND kidney outcome trial. ASCEND evaluated the ERA avosentan (25 mg and 50 mg) versus placebo in participants with DKD on the composite primary outcome of time to doubling of serum creatinine, ESKD or death [66]. This trial demonstrated a neutral effect on the primary outcome although the trial was terminated early after a median of 4 months due to increased rates of fluid retention and heart failure hospitalizations [66]. Although avosentan has an ET_A:ET_B specificity of 50–300:1, greater reductions in fractional sodium excretion at doses above 5 mg were observed, possibly reflecting increasing activation of ET_B. Subsequent studies of ERAs have since employed agents designed to preferentially target ET_A to an even greater extent over ET_B, with dosing guided by phase 2 trials.

Based on potent albuminuria-lowering effects in phase 2 trials of the ERA atrasentan (ET_A:ET_B blockade specificity of 1200:1) [67, 68], atrasentan was subsequently evaluated in the SONAR kidney outcome trial. SONAR was the largest trial of ERAs, demonstrating that atrasentan on top of RAS inhibition significantly lowered the risk of doubling serum creatinine or ESKD by 35% compared with placebo in 2648 participants with T2DM and proteinuric CKD [69]. SONAR was designed to account for sodium and volume retention, and 574 participants were excluded during the enrichment period of the trial for a prespecified excessive increase in weight or B-type natriuretic peptide. Whether due to these or other study design considerations, or the degree of ET_A:ET_B selectivity, rates of heart failure hospitalization were much lower in SONAR compared with ASCEND.

Despite the limitations around ERAs in the setting of DKD, the therapeutic potential for ERAs in CKD remains an area of active investigation. Participants with non-diabetic CKD are at lower risk of heart failure and may therefore derive kidney benefits with less concern regarding the risks of sodium and fluid retention. There is a strong rationale to evaluate these agents in non-diabetic CKD considering that inflammation and subsequent fibrosis are integral mechanisms in CKD progression irrespective of etiology. Selective ET_A antagonist induced a 30% reduction in proteinuria in non-diabetic CKD patients following 6 weeks of treatment with sitaxsentan [70]. Furthermore, the combination of these agents with SGLT2 inhibition is particularly interesting considering the natriuresis and protection against heart failure outcomes associated with SGLT2 inhibition. Using the highly selective ET_A ERA zibotentan, the ZENITH-CKD phase 2 trial demonstrated that concomitant zibotentan and dapagliflozin decreased proteinuria compared with dapagliflozin monotherapy [71]. Only 50% of people with CKD had a history of T2DM in the ZENITH-CKD trial, and thus similar phase 2 trials using concomitant zibotentan and dapagliflozin treatment are underway in participants with DKD [ZODIAC (NCT05570305)]. Definitive kidney outcome trials in various CKD populations, particularly in the era of SGLT2 inhibition/MRA/GLP1RA, are required before ERAs can be incorporated into guideline-directed medical therapy for CKD.

Lastly, supporting use of ERA in CKD etiologies beyond DKD, atrasentan is currently being investigated in the setting of immunoglobulin A (IgA) nephropathy and focal segmental glomerulosclerosis in the AFFINITY (NCT04573920) and ALIGN (NCT04573478) trials. Evidence of effectiveness with respect to albuminuria reduction has also been demonstrated with sparsentan, a dual ET_A receptor and angiotensin II subtype 1 receptor antagonist, in the setting of IgA nephropathy (PROTECT trial) and focal segmental glomerulosclerosis (DUPLEX trial) [72, 73].

INFLAMMATORY PATHWAYS

Infiltration of innate immune cells (i.e. monocytes and macrophages) and subsequent upregulation of pro-inflammatory cytokines, chemokines, adhesion molecules and growth factors are prominent features in the etiology of CKD [74]. Proteomic analyses have identified distinct signatures of circulating inflammatory proteins that are linked to the development of ESKD [75]. Renal inflammation can impair perfusion, glomerular filtration and tubular reabsorption through injury to podocytes, epithelial cells and endothelial cells, as well as causing tubulointerstitial fibrosis (Fig. 2) [76]. Although multiple emerging therapeutic strategies have attempted to target inflammatory pathways [77], therapeutic targets identified in pre-clinical models have failed to demonstrate clinical utility in early-phase clinical trials. For example, baricitinib, a JAK1/JAK2 inhibitor, showed dose-dependent reductions in albuminuria without any changes to serum creatinine or eGFR. No further trials with baricitinib in the setting of CKD are anticipated based on information in publicly available databases. Furthermore, bardoxolone methyl, a Nrf2 activator, showed no effect on CKD progression, resulting in the discontinuation of clinical development. While selective pro-inflammatory cytokine inhibitors have been effective for autoimmune rheumatological conditions, the multifactorial, heterogenous nature of CKD pathophysiology have rendered selective anti-inflammatory therapies less effective in this setting.

One promising therapeutic pathway is the NLRP3–interleukin (IL)-1β–IL-6 cascade, with recent evidence demonstrating that it is implicated in the development of atherosclerosis and may play a role in the pathogenesis of CKD. For instance, the CANTOS trial demonstrated that canakinumab, a human monoclonal antibody directed at IL-1β, reduced the recurrence of cardiovascular events in patients with previous myocardial infarction and persistent inflammation, defined by an elevated high-sensitivity C-reactive protein (hs-CRP) [78]. Importantly, CKD and persistent inflammation were both associated with heightened risk of atherosclerotic cardiovascular disease [79], suggesting that inflammatory targeting may be beneficial for cardiovascular risk reduction in the setting of CKD [80, 81]. Subsequently, the phase 2 RESCUE trial in patients with CKD stages 3–5 and elevated hs-CRP demonstrated that ziltivekimab, a human monoclonal antibody directed against the IL-6 ligand, reduced hs-CRP compared with placebo [82]. Furthermore, the reduction in hs-CRP in the RESCUE trial was approximately 2-fold larger than observed in CANTOS trials. However, it remains unknown whether it will have an impact on kidney function, although it is hypothesized that reduction in pro-inflammatory signalling may have beneficial effects on CKD. The upcoming phase 3 ZEUS trial (NCT05021835) represents the next major step to evaluate the impact of ziltivekimab on cardiovascular outcomes amongst 6200 patients with stages 3–4 CKD and elevated hs-CRP. Importantly, key secondary outcomes will include effects on CKD progression (eGFR, UACR reduction and ESKD), with anticipated study completion in October 2025.

SUMMARY

Despite significant advancements in guideline-directed treatment, patients with CKD have elevated residual kidney risk. The identification of additional therapies that mitigate risk associated with cardiorenal disease, and that act through different, non-overlapping mechanisms, remains of critical importance. GLP1RA and other incretin-based treatments consistently improve glycemia and promote weight loss, with emerging evidence demonstrating kidney protection in DKD. While results from the FLOW trial may result in incorporation of GLP1RA into guidelines for DKD, more work is required to determine the physiological mechanisms underpinning possible favorable kidney outcomes. Likewise, phase 2 studies of ASI have demonstrated early evidence of kidney protective benefits including albuminuria lowering, which will be subsequently examined in the phase 3 EASi-Kidney trial. In addition, therapies including ERA and sGC agonists may provide additional kidney protective effects in certain CKD etiologies targeting maladaptive physiological dysregulation in the vasculature and kidney tubular compartments. Finally, selectively targeting pro-inflammatory processes including the NLRP3–IL-1β–IL-6 signalling cascade may help to suppress pathophysiologic inflammation associated with CKD, with ongoing phase 3 trials investigating their effects on kidney outcomes and ESKD progression as secondary outcomes. Examination of these therapeutic strategies in people with CKD may provide further opportunity to attenuate kidney disease progression.

FUNDING

This paper was published as part of a supplement financially supported by Bayer AG; the scientific content has not been influenced in any way by the sponsor. M.N. is supported by a Banting and Best Diabetes Centre Postdoctoral fellowship at the University of Toronto. V.S.S., K.Y. and A.O. are supported by the University of Toronto Department of Medicine Eliot Phillipson Clinician Scientist Training Program. V.S.S. is also supported by the Banting and Best Diabetes Centre Postdoctoral fellowship at the University of Toronto, and the Canadian Institute of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Research Award. K.Y. and A.O. are supported by Kidney Foundation of Canada Kidney Research Scientist Core Education and National Training (KRESCENT) Postdoctoral Fellowships. The KRESCENT program is co-sponsored by the Kidney Foundation of Canada, the Canadian Society of Nephrology and CIHR. K.Y. is also supported by the Clarence Henry Trelford Clinician Scientist Award in Diabetes. A.O. is also supported by the Ted Rogers Centre for Heart Research, the University of Toronto Provost Post-Doctoral Fellowship Program, the Black Research Network and the Canadian Institute for Health Research, Research Excellence, Diversity, and Independence (REDI) Grant. L.K. is supported by the Canadian Heart Function Alliance, Cardiovascular Sciences Collaborative Specialization Queen Elizabeth II/Heart & Stroke Foundation studentship in Science and Technology, and Banting and Best Diabetes Centre-Novo Nordisk studentship. D.Z.I.C is supported by a Department of Medicine, the University of Toronto Merit Award, and receives support from the Canadian Institutes of Health Research, Diabetes Canada, and the Heart & Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research. D.Z.I.C is also the recipient of a 5-year CIHR-Kidney Foundation of Canada Team Grant award.

DATA AVAILABILITY STATEMENT

No new data were generated or analyzed in support of this research.

CONFLICT OF INTEREST STATEMENT

D.Z.I.C. has received consulting fees or speaking honorarium, or both, from AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim-Lilly, Bristol-Myers Squibb, Janssen, JNJ, MAZE, Merck & Co., Inc., Mitsubishi-Tanabe, Novo Nordisk, Otsuka, Prometic and Sanofi; has received operating funds from AstraZeneca, Boehringer Ingelheim-Lilly, Janssen, Merck & Co., Inc., Novo Nordisk and Sanofi; and has served as a scientific advisor or member of AstraZeneca, Boehringer Ingelheim, Janssen, Merck & Co., Inc., Novo Nordisk and Sanofi.