Repurposing Pentoxifylline for Diabetic Kidney Disease in VA PTXRx

Veterans with diabetic kidney disease (DKD) are receiving pentoxifylline or placebo on top of newer kidney-protective therapies in a trial asking whether a peripheral vascular disease drug can prevent kidney failure or death.¹

Baseline characteristics from the Veterans Affairs Pentoxifylline in Diabetic Kidney Disease (VA PTXRx) study were presented at American Society of Nephrology (ASN) Kidney Week 2026 in Denver, Colorado. David J. Leehey, MD, study chair, of Edward Hines Jr. VA Hospital in Hines, Illinois, discussed the trial in an interview with HCPLive.

Why Test Pentoxifylline for Diabetic Kidney Disease?

Pentoxifylline (PTX), a nonspecific phosphodiesterase inhibitor, was approved by the US Food and Drug Administration (FDA) in 1984 for peripheral vascular disease. It has been linked to reduced proteinuria and preserved kidney function in animal models.² Clinical studies in DKD, however, enrolled small numbers of patients, ran for short periods, and relied on surrogate endpoints such as proteinuria and estimated glomerular filtration rate (eGFR).²

“We didn’t know whether this drug really prevented kidney failure, prevented death, [the] two most important things for patients,” Leehey said.

The idea for the trial came in 2015, after a fellow presented the Spanish PREDIAN trial at a journal club. In PREDIAN, PTX reduced eGFR loss and urinary albumin excretion in patients with diabetes and stage 3–4 chronic kidney disease (CKD), with mild digestive symptoms as the main safety signal.² A systematic review and meta-analysis presented at the same meeting found that only 3% of the information needed to assess end-stage kidney disease (ESKD) or death had accrued across prior trials.³

VA PTXRx Design: Pentoxifylline vs Placebo Added to Usual Care

VA PTXRx is a pragmatic, randomized, placebo-controlled trial run through the VA Cooperative Studies Program.² It enrolled patients with type 2 diabetes and an eGFR of 15 to <60 mL/min/1.73 m² in the highest-risk categories of the Kidney Disease: Improving Global Outcomes (KDIGO) heat map:²

• eGFR 15 to <30
• eGFR 30 to <45 with a urine albumin-to-creatinine ratio (UACR) >30 mg/g
• eGFR 45 to <60 with a UACR >300 mg/g

Participants received PTX 400 mg extended release once daily or a matching placebo. At about 5 weeks, the dose was increased to twice daily as tolerated.² The primary outcome is time to ESKD, defined as chronic dialysis or transplant, or all-cause death.² The trial will stop once 646 primary events have occurred.²

Standard care was not protocolized, so treating physicians could add any therapy other than open-label PTX.² Leehey noted that since enrollment began, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and finerenone have entered DKD care. The trial now asks whether PTX adds benefit beyond those agents.

PTXRx Baseline Characteristics: Older Veterans, High SGLT2 Inhibitor Use

Enrollment reached its target of 2376 participants about a year ago, and the trial is now in follow-up.⁴ Leehey said 97% of participants are men, most are older, and minority patients are well represented. [INSERT BASELINE FIGURES FROM POSTER: mean age, race/ethnicity, eGFR, UACR, KDIGO risk group distribution]

About 50% of participants were receiving an SGLT2 inhibitor at baseline, according to Leehey. He said this is greater than SGLT2 inhibitor use across the broader US health system. He attributed the gap to evidence-based VA care, physician accountability for guideline adherence, and fewer insurance barriers to costlier agents such as finerenone.

The trial protocol acknowledged that the male predominance could limit how well the findings generalize to women.² Leehey said there is no scientific reason to expect women to respond differently to PTX.

What a Positive PTXRx Result Could Mean for DKD Care

Outcome results are not yet available. Leehey said a positive trial would add a low-cost option to the DKD treatment arsenal.

“It would mean that we would have a readily available, inexpensive agent that’s been used for 40 years,” Leehey said. “We know it’s a very safe agent. The only issue with PTX is it can cause GI side effects [in] about 10 to 20 percent of patients.”

In the meta-analysis, gastrointestinal adverse events were tripled with PTX, while serious adverse events were not increased.³

Editor’s Note: Leehey reported no relevant disclosures.

References

1. Leehey DJ, Agarwal R, Xing B, et al. The Veterans Affairs Pentoxifylline in Diabetic Kidney Disease (VA PTXRx) Study: baseline characteristics. Abstract presented at: American Society of Nephrology Kidney Week 2026; October 21-25, 2026; Denver, CO.

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

3. 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

4. CSP #2008 – Pentoxifylline in Diabetic Kidney Disease. ClinicalTrials.gov. NCT03625648. Accessed October 29, 2026. https://clinicaltrials.gov/study/NCT03625648