Rajiv Agarwal, MD, MS, is a Professor Emeritus of Medicine at Indiana University School of Medicine and VA Medical Centre in Indianaoplis.

Rajiv Agarwal, MD, MS

Pentoxifylline reduced albuminuria by 31% in 

, but the estimate was highly heterogeneous, and only 3% of the evidence needed to assess kidney failure or death has accrued, according to a systematic review, meta-analysis, and trial sequential analysis presented at 

Rajiv Agarwal, MD, MS, of the Richard L. Roudebush VA Medical Center and Indiana University School of Medicine, discussed the findings with 

Is Pentoxifylline Effective for Diabetic Kidney Disease? Rajiv Agarwal, MD, MS

Pentoxifylline, an inexpensive oral anti-inflammatory agent, has been tested in DKD for 4 decades, and 7 prior meta-analyses reported reduced albuminuria.¹ Agarwal explained none of those analyses reported a prediction interval or assessed whether enough evidence had accrued to answer the question definitively. Most pentoxifylline trials were also conducted before 2019, before the widespread use of SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists.

What Did the Pentoxifylline Meta-Analysis Show for Albuminuria and GFR?

Investigators searched 7 databases through June 2026 for randomized trials of oral pentoxifylline in DKD. Of 34 included studies, 32 contributed data. Co-primary outcomes were albuminuria and GFR change, with end-stage kidney disease (ESKD) or death as the primary hard outcome, and each estimate was paired with a 95% prediction interval and trial sequential analysis.¹

Albuminuria fell 31% with pentoxifylline (ratio of means, 0.69; 95% CI, 0.50–0.94; 22 studies), but heterogeneity was 97% and the prediction interval ranged from 0.15 to 3.10.¹ Agarwal noted this range means the next trial could show an 85% reduction or a 3.1-fold increase in albuminuria. Only 53% of the required information had accrued.¹

GFR favored pentoxifylline (mean difference, 4.49 mL/min/1.73 m²; 95% CI, 0.84–8.14; five studies), with 11% of required information accrued.¹ In the 2 comparisons at low or some-concerns risk of bias, the difference was 2.96 mL/min/1.73 m² (95% CI, −15.34 to 21.26). No monitoring boundary was crossed for any outcome.¹

Does Pentoxifylline Reduce Kidney Failure or Death in Diabetic Kidney Disease?

For ESKD or death, 29 events across 6 studies yielded a risk ratio of 0.90 (95% CI, 0.46–1.77), representing 3% of the required information.¹ Gastrointestinal adverse events were tripled with pentoxifylline (risk ratio, 3.00; 95% CI, 1.94–4.64), while serious adverse events were not increased (risk ratio, 0.83; 95% CI, 0.56–1.22). The investigators described gastrointestinal intolerance as the firmest finding.¹

“Inconclusive doesn’t mean it’s ineffective,” Agarwal said. He noted proving efficacy or futility requires a much larger trial, which led to the design of the Veterans Affairs PTXRx Cooperative Study.²

PTXRx is a pragmatic, randomized, placebo-controlled trial testing whether pentoxifylline added to usual care reduces time to kidney failure or death in patients with type 2 diabetes and DKD.² Agarwal said the trial includes approximately 2376 patients followed for about 8 years, with kidney failure defined strictly by dialysis or transplant. More than half of participants were receiving an SGLT2 inhibitor at baseline, and about a third were receiving a GLP-1 receptor agonist.

“We are asking not just the question, ‘Does it work?’ but we are answering the question, ‘Does it work over and above the existing therapies?’” Agarwal said. He added an effective, decades-old generic agent could expand access globally, with results expected as early as next year.

Editors’ note: Agarwal reports relevant disclosures with Akebia, Alexion, Bayer, BI, Novartis, Vertex, and others.

Agarwal R, Leehey DJ, Navaneethan SD, et al. Pentoxifylline for diabetic kidney disease: a systematic review, meta-analysis, and trial sequential analysis. Presented at: ASN Kidney Week 2026; October 21-25, 2026; Denver, CO. doi:10.1681/ASN.2026a95qg8cn

Leehey DJ, Carlson K, Reda DJ, et al. Pentoxifylline in diabetic kidney disease (VA PTXRx): protocol for a pragmatic randomised controlled trial. BMJ Open. 2021;11(8):e053019. doi:10.1136/bmjopen-2021-053019

Videos

Rajiv Agarwal, MD, MS, explains why decades of pentoxifylline data in DKD remain inconclusive and how the VA PTXRx trial aims to settle the question.

Pentoxifylline in Diabetic Kidney Disease: What the Evidence Shows

FIND-CKD Trial Poses Finerenone as a "Third Pillar" for Nondiabetic CKD

Finerenone (Kerendia), a nonsteroidal mineralocorticoid receptor antagonist (MRA) already approved for 

 slowed the rate of kidney function decline in adults with CKD who did not have diabetes, according to results of the phase 3 FIND-CKD trial published in the New England Journal of Medicine.

Rajiv Agarwal, MD, professor emeritus of medicine at Indiana University School of Medicine and staff physician at the Richard L. Roudebush VA Medical Center, frames finerenone as completing a trio of complementary mechanisms: RAS inhibitors work hemodynamically, SGLT2 inhibitors act on tubular and metabolic pathways, and finerenone targets inflammation and fibrosis. Together, he said, they may now function as 3 distinct pillars of CKD care.

 Nondiabetic CKD, phase 3 FIND-CKD (n=1584)

 22% reduction in heart failure hospitalization, 18% reduction in CV death

While you’re here, check out part 1 of our conversation with Agarwal:

https://www.hcplive.com/view/find-ckd-expands-finerenone-evidence-beyond-diabetic-ckd-with-rajiv-agarwal-md

How Much Did Finerenone Slow Kidney Decline?

Agarwal and colleagues randomly assigned 1584 adults with CKD and albuminuria who were already taking a renin–angiotensin system (RAS) inhibitor to finerenone, 10 or 20 mg daily, or placebo.

At baseline, participants had an eGFR of 25 to less than 90 mL/min/1.73 m² and a urinary albumin-to-creatinine ratio of 200 to 3500, with a similar mean baseline eGFR between groups, at roughly 47 mL/min/1.73 m².

Over 32 months, the mean annual rate of change in eGFR, the trial's primary outcome, was −3.3 mL/min/1.73 m² with finerenone compared with −4.0 mL/min/1.73 m² with placebo, a difference of 0.7 mL/min/1.73 m² (95% CI, 0.3-1.1; 

A prespecified hierarchical analysis also showed a reduced risk of a composite kidney or cardiovascular outcome, defined as a sustained eGFR decline of at least 57%, kidney failure, heart failure hospitalization, or cardiovascular death, with finerenone versus placebo (hazard ratio, 0.77; 95% CI, 0.60-0.99; P = .04).

Does Finerenone Reduce Cardiovascular Events? What the Pooled Infinity Analysis Adds

In FIND-CKD alone, the cardiovascular composite trended favorably but did not reach statistical significance on its own (hazard ratio, 0.60; 95% CI, 0.27-1.33). A larger pooled analysis, Infinity, combining FIND-CKD with finerenone's prior diabetic CKD trials, filled in that picture: heart failure hospitalization and cardiovascular death were each independently, statistically significant, with reductions of 22% and 18%, respectively.

Notably, cardiovascular death reached nominal significance in the pooled analysis after narrowly missing it in an earlier pooled analysis limited to diabetic CKD trials (

= .076). Agarwal said this pattern, along with a parallel signal for all-cause mortality, represents a mortality benefit worth continued follow-up, since both cardiovascular and all-cause mortality comparisons were nominally significant across the pooled cohort.

Agarwal said the Infinity data support positioning finerenone as a foundational therapy to be layered in early alongside RAS and SGLT2 inhibitors, rather than reserved as a later-line option.

Finerenone selectively blocks the mineralocorticoid receptor, a pathway implicated in inflammation and fibrosis across multiple kidney disease etiologies, independent of glycemic status. 

The agent was first approved by the FDA in 2021 for adults with CKD associated with type 2 diabetes, based on the FIDELIO-DKD trial, which showed reduced risk of CKD progression and cardiovascular events compared with placebo in that population. 

FIND-CKD extends that evidence base to CKD without diabetes, a population that historically has had fewer disease-modifying options despite representing a substantial share of overall CKD cases.

What's Next: The SGLT2 Combination Question

Only about 17% of FIND-CKD participants were using an SGLT2 inhibitor at baseline, leaving the finerenone–SGLT2 inhibitor combination in nondiabetic CKD an open question. 

Of the roughly 14,500 participants in the Infinity pooled analysis, only about 1500 came from FIND-CKD itself, meaning the hard-outcome evidence in nondiabetic CKD still leans heavily on the diabetic trials within the pool. Agarwal pointed to a need for prospective combination data, including potassium and volume effects, adequately powered biopsy-confirmed studies in IgA nephropathy and FSGS, longer-term safety and durability data, and biomarker work to identify which patients benefit most.

Editor’s Note: Agarwal reports relevant disclosures with Alexion Pharmaceuticals, Inc. AstraZeneca, Bayer HealthCare Pharmaceuticals Inc., Boehringer Ingelheim, and others.

Heerspink HJL, Neuen BL, Agarwal R, et al. Finerenone in persons with chronic kidney disease without diabetes. N Engl J Med. Published online June 4, 2026. doi:10.1056/NEJMoa2604625

Neuen BL, Heerspink HJL, Perkovic V, et al. Efficacy and safety of finerenone in patients with chronic kidney disease: an individual participant data pooled analysis (INFINITY). Lancet. 2026;407(10546):2375-2386. doi:10.1016/S0140-6736(26)01009-3

Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383:2219-2229. doi:10.1056/NEJMoa2025845

Bayer. Phase III FIND-CKD results show Bayer's Kerendia (finerenone) improved eGFR slope and reduced risk of a composite kidney-cardiovascular outcome in adults with non-diabetic chronic kidney disease. Press release. June 5, 2026. 

https://www.bayer.com/en/us/news-stories/kerendia-for-non-diabetic-chronic-kidney-disease

Phase 3 FIND-CKD data show finerenone slows kidney decline and reduces CV events in adults with nondiabetic CKD, Rajiv Agarwal, MD, adds his perspective. 


FIND-CKD Expands Finerenone Evidence Beyond Diabetic CKD, With Rajiv Agarwal, MD

Finerenone (Kerendia) slowed the rate of estimated glomerular filtration rate (eGFR) decline and reduced kidney and cardiovascular events among adults with 

without diabetes, according to late-breaking phase 3 FIND-CKD data presented at the 63rd 

European Renal Association (ERA) Congress

The findings represent the first randomized placebo-controlled evidence evaluating finerenone in adults with CKD without diabetes, “It really removes the need to extrapolate from diabetic trials,” Rajiv Agarwal, MD, professor emeritus of medicine at Indiana University School of Medicine and staff physician at the Richard L. Roudebush VA Medical Center, told HCPLive.

In FIND-CKD, the mean annual rate of change in eGFR from baseline to month 32 was −3.3 mL/min/1.73 m² with finerenone compared with −4.0 mL/min/1.73 m² with placebo, corresponding to a 0.7 mL/min/1.73 m² slower decline with finerenone (95% Confidence Interval [CI], 0.3-1.1; 

Finerenone Proves CKD Benefit Extends Beyond Diabetes in FIND-CKD

Expanding the Role of Finerenone in CKD Care, With Brendon Neuen, MBBS, PhD

Finerenone is a selective nonsteroidal mineralocorticoid receptor antagonist that reduces mineralocorticoid receptor overactivation, a pathway associated with inflammation, fibrosis, and kidney injury.

Previous phase 3 trials demonstrated kidney and cardiovascular benefits with finerenone among adults with CKD associated with type 2 diabetes. FIND-CKD was designed to determine whether those benefits extended to adults with CKD without diabetes.

Although diabetes is a leading cause of CKD, a substantial proportion of patients with CKD do not have diabetes and historically have had fewer disease-modifying treatment options.

“Diabetic patients are not a niche group,” Agarwal said, noting that approximately 50% to 70% of CKD cases occur in adults without diabetes.

Beyond RAS blockade and SGLT2 inhibitors, these patients have had limited therapies with demonstrated kidney outcome benefits.

“The nonsteroidal MRA mechanism is not diabetes specific,” Agarwal said.

The phase 3 international, double-blind trial enrolled 1584 adults with CKD receiving maximally tolerated RAS blockade. Participants were randomized to finerenone (n = 793) or placebo (n = 791).

At baseline, mean eGFR was approximately 47 mL/min/1.73 m² in both groups.

After an initial increase in eGFR during the first 3 months, participants receiving finerenone experienced a slower chronic decline in kidney function.

At month 32, mean eGFR was 39.4 mL/min/1.73 m² with finerenone and 38.1 mL/min/1.73 m² with placebo.

Although the difference in annual eGFR slope was 0.7 mL/min/1.73 m², Agarwal emphasized that sustained changes in eGFR slope can be clinically meaningful because eGFR slope is a validated surrogate marker for kidney disease progression.

The composite kidney-cardiovascular outcome occurred in 13.9% of participants receiving finerenone compared with 16.9% receiving placebo (HR, 0.77; 95% CI, 0.60-0.99; P = .04).

Supporting Evidence Across CKD Populations

Agarwal noted that findings from FIND-CKD were further supported by an individual patient-level meta-analysis published in 

, which pooled data from FIND-CKD and previous phase 3 finerenone trials in adults with type 2 diabetes and CKD.

Across more than 14,500 participants, finerenone reduced the composite kidney outcome by 24% and the composite cardiovascular outcome by 20%, strengthening the evidence that mineralocorticoid receptor blockade provides benefits beyond diabetic CKD.

Safety findings were consistent with previous studies of finerenone.

Hyperkalemia occurred more frequently with finerenone, but few participants discontinued treatment or required hospitalization due to hyperkalemia. Rates of acute kidney injury were between groups.

FIND-CKD provides randomized evidence that finerenone may slow CKD progression among adults without diabetes, expanding the potential role of mineralocorticoid receptor antagonism across a broader CKD population.

FIND-CKD demonstrated reduced eGFR decline in patients with nondiabetic CKD, providing new data for a population of >50% of CKD cases. 

Who Benefits Most From CKD Combination Therapy? Breaking Down CONFIDENCE Trial Findings

The treatment paradigm for chronic kidney disease (CKD) is rapidly evolving, as clinicians move from a single-drug approach to a more complex, multi-therapy strategy. Over the past several years, the introduction of SGLT2 inhibitors, finerenone, and semaglutide alongside traditional RAAS blockade has created both new opportunities and new uncertainty around how best to deploy these therapies.

In an interview with HCPLive at World Congress of Nephrology (WCN) in Yokohama, Japan, Rajiv Agarwal, MD, MS, said this expanding toolkit has raised a critical question as to whether therapies should be introduced sequentially or started together. While clinicians have historically taken a stepwise approach titrating one agent at a time, he notes that this process can take up to a year, time during which ongoing kidney and cardiovascular damage may continue.

In response, the CONFIDENCE trial was designed to evaluate whether simultaneous initiation of combination therapy could accelerate benefit without compromising safety. He explains that this was the first adequately powered study to assess starting therapies such as finerenone and SGLT2 inhibitors at the same time. While prior studies evaluated add-on strategies, they did not address the safety and efficacy of concurrent initiation.

Concerns going into the trial included the potential for hypotension, acute kidney injury, and hyperkalemia, particularly given the hemodynamic effects of these agents. The findings, however, demonstrated that combination therapy could achieve meaningful reductions in albuminuria both safely and effectively.

A pair of additional analyses from CONFIDENCE presented at WCN offer further insight into patient response. The first examined differences by sex and age, revealing that women experienced approximately 20% greater reductions in urinary albumin-to-creatinine ratio compared with men. Agarwal noted that older patients also demonstrated enhanced responses, with each decade of age associated with a roughly 10% greater likelihood of benefit. Of note, these gains were not accompanied by increased safety concerns, challenging assumptions about treating higher-risk populations.

The second analysis addressed early declines in estimated glomerular filtration rate (eGFR), a common concern when initiating these therapies. Agarwal emphasizes that these initial dips are typically reversible and not predictive of long-term harm. Rather than discontinuing treatment, clinicians should monitor patients closely, particularly if eGFR declines exceed 30%, and adjust contributing factors such as volume status or concomitant medications.

Ultimately, he underscores that multimodal therapy represents the future of CKD management. Early and sustained use of combination treatment, he suggests, has the potential to significantly reduce cardiovascular events and extend patient survival.

Editors’ note: Relevant disclosures for Agarwal include Akebia Therapeutics, Alnylam, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Intercept, Novartis, and others.

Campbell P. CONFIDENCE: SGLT2i and Finerenone Effective, Safe to Initiate Simultaneously in CKD. HCPLive. June 5, 2025. Accessed April 2, 2026. 

https://www.hcplive.com/view/confidence-sglt2i-and-finerenone-effective-safe-to-initiate-simultaneously-in-ckd

Agarwal R. Effect of Simultaneous Initiation of Finerenone and Empagliflozin on Urinary Albumin-to-creatinine Ratio by Age and Sex in the CONFIDENCE Trial. Presented at World Congress of Nephrology (WCN) in Yokohama, Japan, March 28-31, 2026.

Agarwal R. Estimated Glomerular Filtration Rate, Systolic Blood Pressure, and Urinary Albumin-to-creatinine Ratio — Unravelling the Interplay in Combination: Findings From the CONFIDENCE Trial. Presented at World Congress of Nephrology (WCN) in Yokohama, Japan, March 28-31, 2026.

Further CONFIDENCE analyses support safe combination therapy in CKD, with improved responses in key patient subgroups.

Rajiv Agarwal, MD, MS

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