Pentoxifylline For Diabetic Nephropathy: A Systematic Review Of Randomized Controlled Trials

Background: Diabetic nephropathy (DN) is one of the major chronic microvascular complications with high disability and mortality in patients with diabetic mellitus, and may finally progress to end-stage renal disease (ESRD) with poor quality of life and high economic burden. So far, there are no definitely effective approaches for preventing, delaying or treating DN. Currently the basic managements for DN are represented by diet control, strict glycemic control and maintenance of blood pressure. However, above-mentioned measurements for treating DN are only partially effective. Some clinical trials in patients with DN have shown that PTF can improve renal blood circulation, attenuates proteinuria and reduces the progression rate to renal failure. But most of these trials have only enrolled small numbers of patients. Whether the existing evidence is scientifically rigorous and can be recommended for routine use of these agents in DN is still unknown. Reviewing these data is the aim of our study.Objectives: This review aims to look at the benefits and harms of pentofylline for treating diabetic nephropathy. Methods: We searched Cochrane Controlled Trial Register (CCTR) (The Cochrane Library Issue 4, 2006), MEDLINE (1966 to January 2007), EMbase (1980 to January 2007)) and Chinese Biomedical Database (CBMdisc, 1977 to January 2007). We also handsearched some key Chinese journals and checked reference lists of all papers identified for further trials. Two review authors independently selected trials for inclusion, assessed quality, extracted and cross-checked the data. Outcome measures included incidence of end stage renal disease (ESRD), the change in renal functional measures(e.g. creatinine clearance, glomerular filtration rate(GFR), serum creatinine(Scr), proteinuria), all-cause mortality, quality of life, change of Blood pressure (BP), incidence of cardiovascular disease(CVD) and adverse events.Results: Thirteen trials (694 patients) met the inclusion criteria. Methodological quality was considered inadequate in most of trials with small number of patients. The overall estimates from 13 included trials showed that PTF was not superior to placebo on the improvement of serum creatinine (Scr),urine albumin excretion rate (UAER), systolic blood pressure(SBP) and diastolic blood pressure(DBP) in patients with DN, while better on the control of mean arterial blood pressure(MAP) [WMD=-3.75, 95%CI(-7.31,-0.19), p=0.04]; PTF was better than no treatment on attenuating 24 hour urinary protein, UAER and controlling SBP in DN; PTF had similar effects on the improvement of Scr, creatinine clearance (Ccr), 24-hr urinary protein, UAER , SBP and DBP compared with captopril in patients with DN ; PTF was better than clonidine/methyldopa on the improvement of Ccr in type 1 diabetes[WMD=10.90, 95%CI (1.40, 20.40), P=0.02]. No data on incidence of ESRD, all-cause mortality, quality of life were available. Seven out of 13 trials reported adverse events with headache, dizziness, dyspepsia, nausea and vomiting predominantly occurred to PTF groups. No severe adverse events or allergic reactions were reported. It was not possible to perform sub-group analysis, sensitivity analysis and a funnel plot for checking publication bias in this systematic review because of limited number of trials for each outcome.Conclusions: Pentoxifyline might be relatively effective and safe for diabetic nephropathy in some aspects. However, because the most included trials were insufficent in methodological quality and small in the number of patients, this systematic review does not provide evidence to support the routine use of PTF for patients with diabetic nephropathy. Large, high-quality randomized controlled trials were needed to confirm or refuse the available evidence.