Pentoxifylline for diabetic kidney disease

Kidney disease develops in 25% to 40% of diabetic patients, usually 20 to 25 years after the onset of diabetes. Approximately one third of those with diabetic kidney disease (DKD) will progress to end-stage kidney disease (ESKD) and will require long-term dialysis or possibly receive a kidney transplant. Many patients however may die from associated coronary artery disease or other cardiovascular causes before the onset of ESKD. Pentoxifylline has been described as offering properties that may be beneficial for patients with DKD. We reviewed 17 randomised controlled studies, enrolling 991 patients with DKD, which compared pentoxifylline with placebo, routine treatment or antihypertensive drugs.

Compared with placebo, pentoxifylline significantly reduced serum creatinine (SCr), albuminuria, and overt proteinuria, but not creatinine clearance (CrCl). When compared with routine treatment alone, pentoxifylline did not reduce SCr or blood pressure, but did significantly reduce albuminuria and proteinuria. Compared to captopril or clonidine/methyldopa there was no significant difference in SCr, albuminuria, proteinuria or blood pressure for patients with type 1 and type 2 DKD. CrCl was significantly increased when pentoxifylline was compared to clonidine/methyldopa but not with captopril. No data were available on the incidence of ESKD, time to ESKD, quality of life, or all-cause mortality. The adverse events of pentoxifylline were mild; no serious adverse events were reported in any of the included studies.

Pentoxifylline seemed to have some beneficial effects in improving kidney function and reducing albuminuria and proteinuria (which can indicate kidney health) for patients with DKD, and was not associated with any major adverse effects. However, the current evidence on the effects of pentoxifylline for patients with DKD was insufficient to formulate therapeutic recommendations. More large, high-quality randomised studies are needed to better inform clinical decision making about the use pentoxifylline for patients with DKD.

Authors' conclusions: 

From the available evidence, pentoxifylline seems to offer some beneficial effects in renal function improvement and reduction in albuminuria and proteinuria, with no obvious serious adverse effects for patients with DKD. However, most studies were poorly reported, small, and methodologically flawed. Evidence to support the use of pentoxifylline for DKD was insufficient to develop recommendations for its use in this patient population. Rigorously designed, randomised, multicentre, large scale studies of pentoxifylline for DKD are needed to further assess its therapeutic effects.

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Background: 

Diabetic kidney disease (DKD) is associated with increased morbidity and mortality, mostly relating to cardiovascular complications. The relevance of inflammation in the pathogenesis of DKD has been investigated in recent years, and it has been shown that inflammatory markers are higher in people with DKD compared with the wider population. Pentoxifylline is a methylxanthine phosphodiesterase inhibitor with favourable anti-inflammatory effects and immunoregulatory properties. The anti-inflammatory effects conferred by pentoxifylline may be beneficial in the management of DKD.

Objectives: 

To assess the benefits and harms of pentoxifylline for treating people with DKD.

Search strategy: 

We searched the Cochrane Renal Group's specialised register (January 2012), CENTRAL (Issue 12, 2011), MEDLINE, EMBASE and four Chinese biomedical literature databases (CBM-disc, 1979 to July 2009), Chinese Science and Technique Journals Database (VIP, until July 2009), China National Knowledge Infrastructure (CNKI, until July 2009) and WanFang database (until July 2009).

Selection criteria: 

All randomised controlled trials (RCTs) and quasi-RCTs studying the benefits and harms of pentoxifylline for DKD.

Data collection and analysis: 

Data were extracted independently by two authors. Meta-analyses were performed when more than one study provided data on a comparable outcome in sufficiently similar patients. Results of dichotomous outcomes were expressed as risk ratios (RR) with 95% confidence intervals (CI). Mean differences (MD) were calculated to assess the effects of treatment where outcomes were expressed on continuous scales, and standardised mean differences (SMD) calculated where different scales were used. Data was pooled using the random effects model. Adverse effects were assessed using descriptive techniques and where possible, risk differences (RD) with 95% CI.

Main results: 

We identified 17 studies that included a total of 991 participants with DKD which met our inclusion criteria. Overall, the methodological quality of included studies was low: 4/17 reported the method of randomisation, 13/17 did not; no study described the method of random allocation; 4/17 studies were considered to be at high risk of bias and 13/17 were considered to have unclear risk for incomplete outcome data reporting; 9/17 studies were at low risk bias and in 8/17 the risk of bias was unclear for selective outcome reporting.

Compared with placebo, pentoxifylline significantly reduced serum creatinine (SCr) (MD -0.10 mg/dL, 95% CI -0.17 to -0.03), albuminuria (SMD -2.28, 95% CI -3.85 to -0.70) and overt proteinuria (MD -428.58 µg/min, 95% CI -661.65 to -195.50), but there was no difference in creatinine clearance (CrCl) (MD -5.18 mL/min, 95% CI -15.55 to 5.19). When compared with routine treatment alone, pentoxifylline did not significantly reduce SCr (MD 0.00 mg/dL, 95% CI -0.06 to 0.07) or blood pressure (systolic (SBP): MD -0.28 mm Hg, 95% CI -2.20 to 1.63; diastolic (DBP): MD -0.15 mm Hg, 95% CI -1.44 to 1.14), but did significantly reduce albuminuria (SMD 0.62, 95% CI 0.18 to 1.07) and proteinuria (MD 0.46 g/24 h, 95% CI 0.17 to 0.74). There was no significant difference in SCr (MD 0.00 mg/dL, 95% CI -0.08 to 0.07), albuminuria (MD -8.79 µg/min, 95% CI -27.18 to 9.59), proteinuria (MD -0.01 g/24 h, 95% CI -0.03 to 0.01) or blood pressure (SBP: MD 1.46 mm Hg, 95% CI -0.57 to 3.50; DBP: MD 1.37 mm Hg, 95% CI -0.23 to 2.98) between pentoxifylline and the active comparator (captopril or clonidine/methyldopa) for patients with type 1 and type 2 DKD. CrCl was significantly increased when pentoxifylline was compared to clonidine/methyldopa (MD 10.90 mL/min, 95% CI -1.40 to 20.40) but not with captopril (MD 3.26 mL/min, 95% CI -1.05 to 7.59). No data were available on the incidence of end-stage kidney disease (ESKD), time to ESKD, quality of life, or all-cause mortality. The adverse events of pentoxifylline were mild; no serious adverse events were reported in any of the included studies.

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