Pentoxifylline in Diabetic Kidney Disease: What the Evidence Shows

Pentoxifylline reduced albuminuria by 31% in diabetic kidney disease (DKD), 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 ASN Kidney Week 2026 in Denver, Colorado.¹

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

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.

References

1. 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

2. 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