The Expanding Therapeutic Landscape in Chronic Kidney Disease

Key Takeaways

• SGLT2 inhibitors marked a turning point in CKD treatment, demonstrating outcome benefits in patients with and without diabetes and shifting clinical trials toward CKD-centric design.

• Mechanism layering is reshaping CKD drug development, with mineralocorticoid receptor antagonists and endothelin pathway agents targeting defined patient populations.

• Fibrosis represents a structural target in CKD progression, driving ongoing antifibrotic research focused on modifying underlying renal architecture.

• CKD therapy now includes complication management, such as anemia treatment in dialysis-dependent patients, reflecting a broader systemic view of kidney disease.

Chronic kidney disease (CKD) remains one of the most consequential noncommunicable diseases worldwide. A 2025 global analysis reports that stage 1–3 CKD carries a combined prevalence of 13.9%, and that in 2023 CKD ranked as the ninth leading cause of death globally, accounting for 1.48 million deaths.¹

CKD is defined as abnormalities of kidney structure or function present for at least three months, with implications for health.² That temporal threshold distinguishes transient injury from chronic pathology and anchors the diagnosis in sustained dysfunction rather than episodic change. The definition also reflects the dual nature of the disease: structural alteration and functional decline. Both dimensions influence prognosis and therapeutic strategy.

The current staging architecture reinforces this multidimensional view. CKD is classified according to cause, glomerular filtration rate (GFR) category (G1–G5), and albuminuria category (A1–A3), often referred to as the CGA framework.² Rather than relying on a single laboratory value, CGA integrates etiology, filtration capacity, and protein leakage as interlocking indicators of risk. This structure acknowledges that two patients with the same estimated GFR may face different trajectories depending on albuminuria burden or underlying cause.

As the therapeutic landscape expands, this classification system becomes more than descriptive. When new mechanisms of action target specific biological pathways, patient selection and risk stratification gain practical importance. A therapy with demonstrated benefit in one segment of the CKD population may not apply uniformly across causes or albuminuria strata. Conversely, treatments validated across diabetes status in CKD populations reflect a shift toward broader applicability.

CKD is common, lethal, and structurally heterogeneous, illustrating an acute need for therapeutic expansion. However, as the disease spans early asymptomatic stages to advanced renal impairment, intersects with cardiovascular risk, and manifests across diverse etiologies, any meaningful evolution in treatment must account for that complexity.

For decades, therapeutic progress in CKD was closely tied to diabetes management. Kidney protection often entered the conversation as a downstream benefit of glycemic control rather than as a primary objective. That began to shift with the emergence of sodium–glucose cotransporter 2 (SGLT2) inhibitors as disease-modifying agents studied directly in CKD populations.

The DAPA-CKD trial marked a pivotal moment. The primary composite outcome occurred in 9.2% of patients receiving dapagliflozin compared with 14.5% receiving placebo, corresponding to a hazard ratio of 0.61.³ Importantly, the reported effects were similar in participants with type 2 diabetes and those without. This finding expanded the relevance of SGLT2 inhibition beyond a glucose-lowering context and repositioned it as a therapy for CKD itself.

A subsequent study, EMPA-KIDNEY, reinforced that shift. In that study, the primary composite outcome occurred in 13.1% of patients treated with empagliflozin versus 16.9% in the placebo group, with a hazard ratio of 0.72.⁴ Results were described as consistent among patients with or without diabetes. The inclusion of patients across diabetes status and the consistency of outcomes signaled that CKD could serve as the defining condition for therapeutic intervention.

These trials altered more than prescribing patterns. They influenced how CKD studies are designed and justified. Rather than positioning renal endpoints as secondary to metabolic control, investigators and sponsors demonstrated that CKD progression and related outcomes could function as primary targets. The populations enrolled were defined by kidney disease parameters, not just diabetes status.

The result was a structural inflection point. CKD began to be treated in its own right. SGLT2 inhibitors became the first broadly validated class to demonstrate outcome effects in CKD populations regardless of diabetes diagnosis, shifting attention toward kidney-centric trial design. In doing so, they opened the door for subsequent mechanism-driven therapies to be evaluated within CKD-defined cohorts rather than as adjuncts to glucose control.

The expansion of CKD therapeutics did not stop with SGLT2 inhibition. Once outcome-driven, CKD-centric trials became feasible, researchers began layering additional mechanisms that address complementary biological pathways. The field moved beyond hemodynamic modulation toward more specific pathway intervention, often with dual renal and cardiovascular considerations.

Non-steroidal mineralocorticoid receptor antagonism illustrates this next phase. In the FIDELIO-DKD trial, finerenone resulted in lower risks of CKD progression and cardiovascular events compared with placebo in patients with CKD and type 2 diabetes.⁵ Renal and cardiovascular endpoints were evaluated together, reflecting the interconnected risk profile of this population.

Following that success, the FIGARO-DKD study extended this perspective. In that trial, finerenone therapy improved cardiovascular outcomes versus placebo in patients with type 2 diabetes and CKD.⁶ While the evidence base here is specific to CKD with type 2 diabetes, the broader implication is clear: targeting mineralocorticoid receptor signaling can influence both kidney-related and cardiovascular outcomes within defined CKD cohorts.

These data reinforce the concept of layered therapy. As SGLT2 inhibitors established a kidney-centric baseline, additional pathway-directed agents have been evaluated as complementary interventions. The therapeutic strategy evolves from monotherapy to rational combination, as long as safety and population specificity are clearly delineated.

The endothelin pathway offers a parallel example of targeted intervention with more complex development dynamics. In the SONAR trial evaluating atrasentan, the primary endpoint occurred in 6.0% of patients in the treatment group compared with 7.9% in the placebo group, which corresponded to a hazard ratio of 0.65.⁷ The study achieved its primary endpoint but was terminated early.

The SONAR experience highlights two recurring themes in CKD drug development: patient selection and safety balance. Demonstrating benefit within a defined subgroup requires careful enrollment criteria and endpoint selection. At the same time, early termination underscores how safety considerations can shape interpretation and regulatory trajectory.

CKD therapeutics are no longer defined by a single dominant mechanism. Instead, they increasingly rely on matching biological pathway intervention to clearly characterized patient populations. Mechanism without population precision risks dilution of effect or safety compromise; population selection without mechanistic clarity risks therapeutic ambiguity. The expanding landscape therefore depends on aligning both.

If the defining feature of CKD progression is cumulative structural damage, fibrosis is a central therapeutic target. Functional decline, measured through estimated glomerular filtration rate, reflects an underlying biological process that often unfolds within the renal interstitium. Once injury in a CKD patient reaches a certain threshold, an apparently irreversible decline in kidney function may follow, and the tubulointerstitium is a potential common pathway in this progression process.⁸ This understanding shifts attention from isolated hemodynamic shifts to sustained architectural remodeling.

Targeting fibrosis means attempting to intervene directly in the structural evolution of CKD. Connective tissue growth factor (CTGF) has been described as critically involved in progressive fibrosis processes, including diabetic kidney disease.⁹ A phase I study evaluating FG-3019, a human monoclonal antibody directed against CTGF, assessed safety, pharmacokinetics, and potential effects on albuminuria and proteinuria in patients with diabetic kidney disease. While early-stage, such programs reflect a strategy grounded in pathway biology rather than downstream consequence management.

Pirfenidone offers another example of antifibrotic exploration. In a randomized study conducted in diabetic nephropathy, among completers, mean estimated glomerular filtration rate increased in the pirfenidone 1200 mg/day group and decreased in the placebo group.¹⁰ These findings do not establish antifibrotics as standard CKD therapy, but they provide evidence of signal within a structural framework.

The development of antifibrotic approaches should not be interpreted as a singular breakthrough moment. Instead, it reflects a biologically coherent extension of the CKD paradigm. If progressive fibrosis underlies irreversible decline, then intervening upstream of functional collapse represents a structural strategy rather than symptomatic management. As the field advances, the challenge lies in translating mechanistic rationale into durable clinical outcomes without overextending early signals.

The expansion of CKD therapeutics has not followed a straight path. For every validated mechanism, there have been programs that generated early optimism but did not withstand outcome-based scrutiny. The BEACON trial provides a clear example.

In BEACON, which enrolled patients with type 2 diabetes and stage 4 CKD, bardoxolone methyl did not reduce the risk of end-stage renal disease or cardiovascular death. The trial was terminated because of a higher rate of cardiovascular events in the treatment group.¹¹ The combination of lack of benefit on hard renal endpoints and emergent cardiovascular safety concerns altered the trajectory of that development program.

The BEACON experience underscores several realities in CKD drug development. First, improvements in intermediate measures or mechanistic plausibility do not substitute for validated clinical endpoints. Second, cardiovascular safety cannot be considered secondary in a population already at elevated cardiovascular risk. CKD is tightly linked with cardiovascular morbidity and mortality, and interventions must be evaluated within that systemic context.

As the therapeutic landscape broadens to include increasingly specific pathway interventions, the standards for evidence remain high. Demonstrating benefit requires robust endpoint definition and durable follow-up. Demonstrating safety requires particular attention to cardiovascular outcomes.

Expansionhas involved both success and recalibration. The field’s evolution reflects not only the identification of effective mechanisms but also the refinement of development strategies in response to safety signals. Cardiovascular vigilance is not an adjunct consideration in CKD trials; it is central to responsible therapeutic advancement.

The therapeutic expansion in CKD is not limited to slowing structural progression. CKD alters hematologic, metabolic, and cardiovascular physiology, and its complications often shape quality of life and clinical outcomes as much as filtration decline itself. Recognizing this broader disease footprint has widened the scope of what qualifies as CKD-directed therapy.

Anemia represents one of the most significant CKD complications, particularly in advanced stages requiring dialysis. In 2023, the U.S. Food and Drug Administration (FDA) approved daprodustat (Jesduvroq) for the treatment of anemia of CKD in adults on dialysis.¹² Similarly, vadadustat (Vafseo) is approved for anemia due to CKD in adults who have been receiving dialysis for at least three months.¹³ These approvals underscore regulatory recognition that managing CKD-related anemia constitutes a core component of disease care.

The inclusion of such therapies within the CKD landscape reinforces an important conceptual shift. CKD is not solely a progressive decline in glomerular filtration rate. It is a systemic condition with downstream consequences that require targeted intervention. Addressing anemia does not reverse fibrosis or restore nephron mass, but it directly influences patient experience and clinical stability in advanced disease.

From a development perspective, complication-focused therapies broaden the regulatory and commercial framework of CKD treatment. They acknowledge that disease management extends beyond primary renal endpoints and that therapeutic value can be defined through meaningful impact on CKD-associated conditions.

As the field continues to evolve, expansion should be understood in this broader sense. It includes disease-modifying agents that alter progression trajectories, but it also encompasses supportive interventions that manage the systemic consequences of kidney dysfunction. These approaches reflect a more comprehensive understanding of CKD as a multi-organ, multi-domain disease.

As the number of mechanisms under investigation increases, classification becomes more than a staging convention. The CGA framework was designed to standardize CKD assessment, but it increasingly functions as a practical decision matrix.² By integrating etiology, filtration level, and albuminuria burden, CGA captures dimensions of risk that are directly relevant to therapeutic evaluation.

CKD is defined as abnormalities of kidney structure or function present for at least three months. Within that definition, however, the population is heterogeneous. Causes vary from diabetic kidney disease to other etiologies. GFR categories range from early-stage preservation to advanced impairment. Albuminuria spans minimal to severely elevated levels. As new therapies target specific biological pathways, these distinctions influence both expected benefit and safety considerations.

The trials described above illustrate this dynamic. SGLT2 inhibitors demonstrated outcome effects in CKD populations that included participants with and without diabetes,^3,4 suggesting applicability across broader CKD definitions. In contrast, finerenone trials enrolled patients with CKD and type 2 diabetes,^5,6 underscoring phenotype-specific targeting. Endothelin pathway evaluation in SONAR further reflected the importance of carefully defined populations.⁷ These patterns highlight how classification intersects with mechanism.

For drug developers, CGA provides more than descriptive labeling. It offers a framework for trial design, inclusion criteria, endpoint stratification, and regulatory positioning. Broad CKD enrollment may be appropriate when prior data demonstrate consistent effects across diabetes status. Mechanism-driven programs may require tighter phenotype definition. In either case, aligning biological rationale with clearly characterized CKD strata becomes central to development strategy.

As the therapeutic landscape expands, CGA serves as development architecture. It translates heterogeneity into operational structure, guiding how mechanisms are matched to populations and how evidence is generated. In a field defined by both commonality and diversity, classification supports precision rather than abstraction.

Expansion in chronic kidney disease therapeutics does not rest on a single breakthrough or a sweeping redefinition of care. It reflects a series of practical advances that have reshaped how CKD is studied, classified, and treated.

First, disease-modifying therapy now extends across diabetes status. In DAPA-CKD, the primary composite outcome occurred in 9.2% of patients receiving dapagliflozin versus 14.5% in the placebo group, with effects reported as similar in participants with and without type 2 diabetes.³ EMPA-KIDNEY reported a primary composite outcome of 13.1% in the empagliflozin group compared with 16.9% in placebo, with results described as consistent among patients with or without diabetes.⁴ These data support a CKD-centric treatment approach that is not confined to glycemic indication.

Second, layered mechanism-based strategies have entered the landscape. Finerenone demonstrated lower risks of CKD progression and cardiovascular events in patients with CKD and type 2 diabetes in FIDELIO-DKD, and improved cardiovascular outcomes in FIGARO-DKD.^5,6 The endothelin pathway has also shown signal under defined conditions, with SONAR reporting a primary endpoint event rate of 6.0% in the treatment group versus 7.9% in placebo.⁷ These developments illustrate that CKD therapy increasingly involves matching biological pathway intervention to clearly characterized populations.

Third, structural targeting remains an active area of development. The tubulointerstitium has been identified as a potential common pathway in CKD progression, with progression described as potentially reaching an apparently irreversible threshold.⁸ CTGF has been described as critically involved in progressive fibrosis processes, and antifibrotic approaches, such as FG-3019 and pirfenidone, have been evaluated in diabetic kidney disease contexts.^9,10 While these programs represent exploration rather than established standard of care, they reflect a structural strategy aimed at modifying the architecture of disease progression.

Fourth, safety complexity remains central. The BEACON trial did not demonstrate reduction in end-stage renal disease or cardiovascular death and was terminated due to a higher rate of cardiovascular events in the treatment group.¹¹ This experience reinforces that cardiovascular vigilance is intrinsic to CKD drug development, particularly in populations already at elevated cardiovascular risk.

Fifth, expansion includes integrated complication management. The FDA approval of daprodustat for anemia of CKD in adults on dialysis and the approval of vadadustat for anemia due to CKD in adults receiving dialysis for at least three months illustrate regulatory recognition that CKD therapy encompasses management of systemic consequences.^12,13

In 2026, expansion does not mean more drugs; it means more precise architecture for who receives which mechanism and why. It can be defined in operational terms: CKD-focused outcome trials across diabetes status, mechanism layering guided by classification, structural targeting in development, safety discipline anchored in cardiovascular outcomes, and recognition that complication management forms part of comprehensive care.

This evolution unfolds against a backdrop of substantial global burden. The scale of disease ensures that therapeutic refinement is not optional. Expansion, in this context, represents measured progress toward addressing a common, lethal, and biologically complex condition.

1. Mark, Patrick B, et al. “Global, regional, and national burden of chronic kidney disease in adults, 1990–2023, and its attributable risk factors: a systematic analysis for the Global Burden of Disease Study 2023.” The Lancet. 406: P2461-2482 (2025).

2. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Official Journal of the International Society of Nephrology. Apr. 2024.

3. Heerspink, Hiddo JL, et al. “Dapagliflozin in Patients with Chronic Kidney Disease.” The New England Journal of Medicine. 383: 1436–1446 (2020).

4. The EMPA-KIDNEY Collaborative Group. “Empagliflozin in Patients with Chronic Kidney Disease.” The New England Journal of Medicine. 388: 117–127 (2022).

5. Bakris, George L, et al. “Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes.” The New England Journal of Medicine. 383: 2219–2229 (2020).

6. Pitt, Bertram, et al. “Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes.” The New England Journal of Medicine. 385: 2252–2263 (2021).

7. Cahn, Avivit, Simona Cernea, and Itamar Raz. “The SONAR study—is there a future for endothelin receptor antagonists in diabetic kidney disease?” Ann. Transl. Med. 7 (Suppl 8): S330 (2019).

8. Hodgkins, Kavita S, and H William Schnaper. “Tubulointerstitial injury and the progression of chronic kidney disease.” Pediatr. Nephrol. 27: 901–909 (2011).

9. Adler, Sharon G, et al. “Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria.” Clin. J. Am. Soc. Nephrol. 5: 1420–1428 (2010).

10. Sharma, Kumar, et al. “Pirfenidone for diabetic nephropathy.” J. Am. Soc. Nephrol. 22: 1144–1151 (2011).

11. De Zeeuw, Dick, et al. “Bardoxolone Methyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease.” The New England Journal of Medicine. 369: 2492–2503 (2013).

12. Jesduvroq (daprodustat) approved by US FDA for anemia of chronic kidney disease in adults on dialysis. GSK. 1 Feb. 2023.

13. Vafseo NDA Approval Letter. 27 Mar. 2024.