New Therapeutic Agents and Clinical Trials for Preventing Progression to End-Stage Kidney Disease: An In-Depth Review 

 
Dr. Ashutosh Mishra 
MBBS, MD (Medicine), IMS BHU 
 
Chronic kidney disease (CKD) is a growing public health challenge, affecting more than 850 million people worldwide and resulting in substantial morbidity, mortality, and health care expenditures (Jha et al., 2013). While hypertension, diabetes, and glomerulopathies remain the primary culprits in CKD progression, a confluence of socio-demographic factors and global disparities in health care exacerbate these trends. Over time, untreated or inadequately managed CKD inexorably leads to end-stage kidney disease (ESKD), a state necessitating dialysis, kidney transplantation, or palliative care—each with high individual and societal cost (Jha et al., 2013; Lewis et al., 1993). For decades, the clinical strategy for delaying CKD progression relied heavily on controlling hypertension, optimizing glycaemic control, and implementing conventional renoprotective measures. This included the universal use of renin-angiotensin system (RAS) blockade, particularly angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), which marked the first significant advance in reducing the rate at which CKD inexorably progresses to ESKD (Lewis et al., 1993; Brenner et al., 2001). 

Despite this progress, the overall incidence of ESKD has not declined, highlighting the need for more robust, multi-targeted therapeutic approaches (Heerspink & de Zeeuw, 2021). The limitations of conventional RAS inhibition are evident—residual proteinuria, ongoing glomerular injury, and high rates of cardiovascular events persist in many treated patients. In response, the last decade has witnessed the emergence of new classes of pharmacotherapy, each developed on the foundations of molecular insight, clinical trial validation, and an improved understanding of CKD pathobiology. In particular, sodium-glucose cotransporter 2 (SGLT2) inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs) stand at the vanguard of this new era, demonstrating independent renoprotective effects in both diabetic and non-diabetic CKD (Perkovic et al., 2019; Bakris et al., 2020). These newer agents do not simply retard kidney function decline; they also confer cardiovascular benefit and reduce proteinuria through mechanisms that transcend their original therapeutic categories (Cherney & Cooper, 2022). 

Beyond these front-runners, a rich pipeline of investigational therapies—ranging from endothelin receptor antagonists, selective aldosterone synthase inhibitors, and glucose-dependent therapies to regenerative approaches and gene editing—offers further hope for tailored renoprotection (Heerspink & de Zeeuw, 2021). A new era of multicenter, international clinical trials has shed light not just on efficacy, but also on nuanced safety profiles, patient selection, and optimal timing for intervention (Agarwal et al., 2021; Heerspink et al., 2020). 

In parallel, ongoing advances in artificial intelligence (AI) and digital health are expected to revolutionize both trial design and risk stratification, promising earlier identification of rapid progressors for timely and individualized therapy (Topol, 2019; Heinz College, 2024). The combination of evidence-based pharmacotherapy and AI-driven prediction heralds a future in which fewer patients progress to ESKD, and more receive optimized, individualized care. This chapter provides an in-depth review of the origins, mechanisms, landmark clinical trials, real-world experience, and future directions for novel therapeutic agents in CKD, with special attention to the implementation realities and outstanding research questions that remain. 

 

Historical Overview of Renoprotective Therapy  

The introduction of pharmacological RAS blockade marked a pivotal milestone in nephrology. Early randomized trials established that angiotensin-converting enzyme inhibitors (ACEi), and later angiotensin receptor blockers (ARBs), profoundly slow CKD progression, particularly among individuals with diabetic nephropathy and proteinuric non-diabetic kidney diseases (Lewis et al., 1993; Brenner et al., 2001). These agents exert their effect by reducing efferent arteriolar resistance, diminishing intraglomerular pressure, suppressing angiotensin II–mediated fibrosis, and lowering proteinuria—a key surrogate for renal risk. The addition of tight glycaemic control in diabetes and optimal blood pressure management through lifestyle modification and antihypertensive therapy further double-locked the foundations of contemporary CKD care (UKPDS, 1998). 

However, a sizable proportion of patients on maximal renin-angiotensin system (RAS) inhibition continue to lose renal function and progress to ESKD, particularly those with persistent proteinuria, advanced age, or established cardiovascular disease (Brenner et al., 2001). Additionally, some evidence has challenged the efficacy of dual RAS blockade (ACEi plus ARB), owing to unacceptable hyperkalaemia and hypotension risk without substantial benefit. Thus, while ACEi and ARBs remain the gold-standard first line, persistent risk and disease heterogeneity necessitated the exploration of alternative and synergistic mechanisms for kidney protection (Heerspink & de Zeeuw, 2021). As our understanding evolved, it became clear that multifactorial mechanisms—encompassing metabolic, inflammatory, and fibrotic drivers—required expanded therapeutic innovation, giving birth to this new era of renoprotective drugs. 

 
 
 

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors  

First developed as oral hypoglycaemic agents, SGLT2 inhibitors have rapidly become foundational in the quest to delay CKD progression. By inhibiting glucose and sodium reabsorption in the proximal tubule, they restore tubuloglomerular feedback, mitigate maladaptive glomerular hyperfiltration, and reduce albuminuria (Cherney & Cooper, 2022; Perkovic et al., 2019). The CREDENCE trial established canagliflozin’s renoprotective benefit in diabetic CKD, showing a 30% risk reduction for ESKD, doubling of serum creatinine, or renal/cardiovascular death among patients already on standard RAS inhibition (Perkovic et al., 2019). 

Subsequent trials, notably DAPA-CKD, expanded this benefit to non-diabetic CKD, suggesting a class effect that transcends glycaemic modulation (Heerspink et al., 2020). Importantly, SGLT2 inhibitors also appear to confer protection against heart failure and major cardiovascular events—aligning the interests of nephrologists and cardiologists in a single agent. Mechanistically, they reduce inflammation and tubular fibrosis and may enhance erythropoiesis, mitigating anaemia (Cherney & Cooper, 2022). Recent meta-analyses reinforce robust effect sizes for both eGFR preservation and reduction of adverse renal outcomes, even with declining kidney function (Neuen et al., 2021). 

International guidelines have rapidly incorporated SGLT2 inhibitors as first-line therapy for CKD patients with eGFR above 20–25 mL/min/1.73m². These agents are now recommended in both diabetic and non-diabetic CKD, representing a significant paradigm shift. Ongoing questions focus on their use in advanced CKD (eGFR <20), potential for combination with other Reno protective drugs, and long-term safety in vulnerable populations. 

 

Non-Steroidal Mineralocorticoid Receptor Antagonists (nsMRAs)  

Mineralocorticoid receptor antagonists have long been recognized for their anti-inflammatory, anti-fibrotic properties in the kidney, but traditional steroidal MRAs (e.g., spironolactone, eplerenone) are limited by hyperkalaemia risk, especially in CKD. The advent of finer none, a potent non-steroidal selective MRA, is a transformative advance in diabetic CKD management (Bakris et al., 2020; Pitt et al., 2021). 

Two landmark multicentre trials—FIDELIO-DKD and FIGARO-DKD—definitively demonstrated that finerenone significantly lowers the composite risk of CKD progression, kidney failure, and cardiovascular events when added to standard care in type 2 diabetes (Bakris et al., 2020; Pitt et al., 2021). Meta-analyses further support its role as an additive therapy, particularly for high-risk individuals with albuminuria and residual proteinuria on RAS/SGLT2i background (Agarwal et al., 2021). 

Finer none works by selectively blocking aldosterone-mediated pro-inflammatory and pro-fibrotic gene transcription, thus reducing proteinuria and eGFR loss, with less impact on serum potassium than older MRAs. Safety data show manageable adverse effects, although mild hyperkalaemia remains more common than placebo. Finerenone’s use is presently established in diabetic kidney disease, with phase III data anticipated for its benefit in broader CKD populations. 

Integration into routine practice often hinges on sequence after RAS and SGLT2i, availability, and cost. Its efficacy in non-diabetic CKD, benefit of combination with newer drugs, and head-to-head comparisons with other MRAs are topics of ongoing research. 

 

Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs)  

The recognition of type 2 diabetes as a major driver of CKD has naturally highlighted agents that can target hyperglycemia while exerting cardiovascular and renal protection. GLP-1 receptor agonists such as liraglutide and semaglutide, primarily used for glycemic control and weight loss, are now recognized for their kidney-protective potential (Zelniker et al., 2019). 

Meta-analyses of large cardiovascular outcomes trials, including LEADER and SUSTAIN-6, have shown that GLP-1 RAs reduce macroalbuminuria and slow eGFR decline (Zelniker et al., 2019). While their effect size for hard renal outcomes is less pronounced than SGLT2i, patients with concurrent obesity, established cardiovascular disease, or persistent proteinuria may especially benefit from their adjunctive use (Agarwal et al., 2021). 

The FLOW trial, prospectively evaluating semaglutide’s impact on clinically meaningful renal endpoints, will provide further clarification on this drug class’s definitive role (Reusch & Matthaei, 2021). At present, GLP-1 RAs are strongly considered for diabetic CKD patients at cardiovascular risk or requiring additional metabolic benefits. They are well-tolerated, with the added advantage of weight loss and minimal hypoglycemia risk, although gastrointestinal intolerance may limit up-titration in some. Their combination with SGLT2i and nsMRAs represents an area of active clinical research aimed at achieving comprehensive cardiorenal-risk reduction. 

 

Endothelin Receptor Antagonists (ERAs)  

Endothelin-1 is a potent vasoconstrictor and pro-fibrotic peptide implicated in glomerular hypertension, proteinuria, and progressive renal scarring. Endothelin receptor antagonists, particularly those targeting the ETA receptor, aim to mitigate this cycle of injury (D’Agati & Kaskel, 2020). 

The SONAR trial evaluated atrasentan—a selective ETA receptor antagonist—in type 2 diabetic nephropathy, showing a significant reduction in the composite endpoint of doubling serum creatinine or progression to ESKD (Heerspink et al., 2019). However, adverse effects such as fluid retention, peripheral edema, and potential increase in heart failure hospitalization rates have tempered enthusiasm for broad application. 

Current research focuses on improved selectivity, dose optimization, and patient selection (e.g., those with persistent proteinuria despite maximal standard therapy but low cardiovascular risk profile). New ERA compounds are in development, seeking enhanced safety while maintaining efficacy. 

Despite limitations, ERAs may represent valuable adjunctive therapy for a subset of proteinuric CKD patients resistant to other interventions. The translation of these agents into clinical guidelines awaits further large-scale validation. 

 

Other Emerging Therapies  

Building on these advances, several new therapeutic classes are under active investigation. Bardoxolone methyl, an oral Nrf2 pathway activator, was initially promising for improving eGFR in diabetic CKD. However, early termination of the BEACON trial due to cardiovascular toxicity (notably fluid overload and heart failure) curtailed enthusiasm and redirected research towards safer agents (de Zeeuw et al., 2013). 

Aldosterone synthase inhibitors, designed to more selectively and completely block aldosterone biosynthesis, are being evaluated in phase II/III trials. These may afford more precise regulation of mineralocorticoid activity—balancing efficacy with a reduced risk of hyperkalaemia—though their therapeutic window and long-term data remain to be clarified (Arampatzis & Agharazii, 2022). 

On the biological therapy front, regenerative and cellular strategies—including stem cell infusions and exosomal therapies—aim to accentuate inherent repair mechanisms within the nephron, improve microvascular function, and delay ESKD (Tögel & Westenfelder, 2016). Although preclinical data are promising, translation to human trials has been slow and remains in early stages. Over the next decade, advances in gene editing, cellular reprogramming, and personalized regenerative medicine platforms may further enhance these frontiers. 

 

Recent and Ongoing Clinical Trials (2022–2025)  

Multiple ongoing global trials continue to shape the evolving landscape of CKD therapeutics. The FLOW trial (NCT03819153) is specifically studying semaglutide, a GLP-1 receptor agonist, to clarify its independent effect on renal outcomes in type 2 diabetes with CKD (Reusch & Matthaei, 2021). Similarly, the EMPA-KIDNEY trial is evaluating the efficacy and safety of empagliflozin in a broad spectrum of CKD patients, including both diabetic and non-diabetic etiologies (Herrington et al., 2022). 

The ZENITH-CKD study seeks to test novel ERA compounds and combinations for personalized management of proteinuric nephropathies, while several ongoing trials of dual GLP-1/GIP agonists (e.g., tirzepatide) are exploring their multifaceted renoprotective effects in diabetes (Frias et al., 2021). 

Other studies focus on targeted anti-inflammatory and antifibrotic agents, as well as approaches with small interfering RNAs and antisense oligonucleotides designed to suppress pathologic gene expression. Results from these ongoing investigations will be critical for expanding the KDIGO and international treatment guidelines and may herald the arrival of a new generation of highly targeted, precision renal therapy. 

 

Implementation and Precision Medicine  

Embracing innovation in CKD treatment demands not only therapeutics, but also a paradigm shift in implementation. Precision medicine approaches, integrating pharmacogenomics, proteomics, and electronic health record (EHR) analytics, now allow for refined patient stratification and optimized therapy selection (James et al., 2021). 

Artificial intelligence and machine learning applications are rapidly improving the prediction of at-risk and rapid progressor subpopulations, guiding earlier intervention (Heerspink & de Zeeuw, 2021; Topol, 2019). Biomarker panels for fibrosis, inflammation, and tubular injury may soon supplement eGFR and albuminuria in identifying the appropriate timing for therapy initiation, therapy intensification, or even switching drugs. 

Real-world implementation also requires navigating barriers such as drug cost, insurance coverage, patient education, and health system readiness—particularly critical in low- and middle-income settings with disproportionate CKD burden (Jha et al., 2013). Partnership between clinicians, policymakers, patients, and industry is vital to realize the promise of these therapies for all CKD patients. 

 

Future Directions and Unmet Needs  

While the progress in preventing progression to ESKD is undeniable, significant unmet needs persist. The applicability of new therapies to non-diabetic glomerular and hereditary kidney diseases, their efficacy and safety in advanced and pediatric CKD, and the management of polypharmacy in multimorbid patients all warrant dedicated research (Jha et al., 2013). Health systems must also focus on equitable access and culturally adapted implementation strategies to ensure broad benefit. 

Additionally, the durability of effect, long-term safety, cost-effectiveness, and simplification of treatment regimens remain paramount, as does the need for ongoing post-marketing surveillance to monitor safety signals missed in clinical trials. A future in which early, personalized intervention forestalls the need for dialysis or transplantation for the majority of patients with CKD represents not only a clinical aspiration but also a public health imperative. 

 

 
Conclusion: 

The last decade has witnessed an unprecedented transformation in the management of chronic kidney disease, with the introduction of highly efficacious and complementary therapies beyond traditional RAS blockade. Sodium-glucose cotransporter 2 inhibitors, non-steroidal MRAs, GLP-1 receptor agonists, and endothelin receptor antagonists have shifted the landscape from static risk reduction to dynamic, multifaceted risk modification. Supported by the evidence from landmark clinical trials and meta-analyses, the paradigm in CKD therapeutics is now one of continuous improvement—offering renewed hope to millions facing or at risk for ESKD (Agarwal et al., 2021; Bakris et al., 2020; Pitt et al., 2021). 

Each new agent comes with a unique mechanism, efficacy, and safety profile, expanding the clinician’s toolbox for complex and treatment-resistant cases. Particularly promising is the combination of SGLT2 inhibitors and newer MRAs for robust cardio-renal protection. The demonstration that many of these benefits extend to non-diabetic CKD populations, and possibly to advanced kidney disease, marks a universalization of therapy that was previously unthinkable. 

A parallel revolution is underway in the realms of implementation science, digital health, and precision medicine. Artificial intelligence promises to improve patient identification, risk stratification, and treatment personalization, while also accelerating drug discovery. Genomic, proteomic, and multi-omics platforms are poised to materialize the long-envisioned goal of tailored nephroprotection. 

Yet, the journey from trial to bedside is incomplete. Unsolved challenges in long-term safety, application in pediatric and advanced CKD, drug-drug interactions, and real-world effectiveness remain. Health system barriers—most notably drug cost and disparities in delivery—will require coordinated policy, clinical advocacy, and international partnership to overcome. Equitable access to effective therapies is a moral and structural imperative. 

Ultimately, this era has shifted the clinical vision for CKD from the inevitability of ESKD to the possibility of indefinite delay, rationalized treatment, and improved quality of life for a global patient population. With the ongoing pipeline of trials and innovations, and with the support of predictive analytics and pragmatic health system design, nephrology stands on the threshold of a new standard of care—one that focuses on proactive, effective, and just treatment for all. The journey, however, is unfinished: continued innovation, commitment to equity, and a focus on patient-centered outcomes will ensure that the next decade delivers on the promise now visible for all at risk of progressive kidney disease. 

 

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