The 11th #NephJC was conducted on Tuesday September 23, 2014 at 9 PM EDT. We discussed this intriguing paper from JASN on the use of Pentoxifilline for diabetic nephropathy.

PMID 24970885: Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease: The PREDIAN Trial.

Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, Chahin J, Méndez ML, Gallego E, Macía M, Del Castillo N, Rivero A, Getino MA, García P, Jarque A, García J.

We had two storify curations, one by Kristina Fiore who also did a nice write up on MedPageToday.

Pre-NephJC Background Summary

Get the skinny on pentoxifylline in renal disease at PBFluids, courtesy of Christos Argyropoulos.

Saiyed Muddasser, a first year nephrology fellow at Saint John Hospital and Medical Center in Detroit, prepared the following article summary.

Summary

Background & Objectives:

Diabetic kidney disease (DKD) is the most frequent form of CKD and ESRD. Renin-angiotensin-aldosterone system (RAAS) inhibition withACEIs or ARBs, is the standard of care to reduce the risk of developing ESRD (Collaborative Study Group, IDNT, RENAAL studies). However, these therapies do not provide complete renal protection, and patients with DKD continue to progress through CKD toward ESRD despite maximal RAAS inhibition.

Inflammation is recognized as a cardinal factor in the pathogenesis and progression of DKD. Pentoxifylline is a methylxanthine derivative and nonspecific phosphodiesterase inhibitor, clinically used to treat peripheral vascular disease. Pentoxifylline has anti-inflammatory, anti-proliferative, and anti-fibrotic activity. The investigators set out to determine if adding pentoxifylline to maximal RAAS inhibition would provide additional renal protection in DKD.

Design, Setting, Participants, & Measurements:

  • Single-center

  • Open-label

  • Prospective

  • Randomized controlled clinical trial

  • Spain

Enrollment criteria:

  • Patients age greater than 40 years

  • Type 2 diabetes for more than 8 years

  • CKD stage 3-4

  • Urine albumin excretion (UAE) > 30mg/24 hours

Patients with type 1 diabetes, non diabetic kidney disease, treatment with combination of ACEI/ARBs, aldosterone antagonists or direct renin inhibitors, uncontrolled hypertension (systolic BP > 180, diastolic BP >110 mmHg), uncontrolled diabetes (glycated haemoglobin >10%) were excluded from the study.

There were total 169 patients randomly assigned to the control and treatment groups. Mean duration of follow-up for 23.6+/- 1.7 months. All patients received ACEi or ARB therapy. The treatment group received pentoxifylline 600mg daily for a month that was then titrated up to 600mg bid. Participants were followed every 3 or 6 months with 24-hour urine collections every 6 months.

The primary outcome was the change in MDRD GFR from baseline. Secondary outcomes were:

  • fraction of of patients with a reduction in eGFR of more than 25%

  • changes in albuminuria

  • change in urinary excretion of TNF alfa

Results:

The eGFR fell by 2.1±0.4 ml/min per 1.73m2 in patients treated with pentoxifylline versus 6.5±0.4 ml/min per 1.73 m2 in the control group. This was a significant mean difference of 4.3ml/min per m2 (95% CI), (P<0.001) in favour of pentoxifylline. Albuminuria fell from 1100 to 973 mg/d (p<0.001) in the pentoxifylline group while it increased from 1000 to 1117 (IQR 584 – 1762) mg/d in the control group.

Median urinary TNF alfa concentration at baseline was 16 (IQR 11-20.1) ng/g, which decreased to 14.3 ng/g in patients treated with PTF (P<0.01), with no significant change in the control group. 

Conclusions:

PTF as an add-on to standard therapy (ACEI /ARB), slowed the progression of nephropathy, with significant mean reduction of eGFR in favour of PTF group. PTF in addition has anti-proteinuric and anti inflammatory effect with only minimal gastrointestinal side effect.

The difference in the reduction of eGFR between the groups showed a trend at 6 months and reached statistical significance after 1 year, suggesting that a long period of treatment is necessary for renal protection.

In the United States maximum PTF dose available is 400mg, so as to get the maximum effect dosing regimen should be TID rather then BID.