Probably, the most paradigmatic example of diabetic complication is diabetic nephropathy, which is the largest single cause of end-stage renal disease and a medical catastrophe of worldwide dimensions. Metabolic and hemodynamic alterations have been considered as the classical factors involved in the development of renal injury in patients with diabetes mellitus. However, the exact pathogenic mechanisms and the molecular events of diabetic nephropathy remain incompletely understood. Nowadays, there are convincing data that relate the diabetes inflammatory component with the development of renal disease. This review is focused on the inflammatory processes that develop diabetic nephropathy and on the new therapeutic approaches with anti-inflammatory effects for the treatment of chronic kidney disease in the setting of diabetic nephropathy.

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.

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

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).

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

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.

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.

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.

Activation of innate immunity with the subsequent development of a chronic low-grade inflammatory response is now recognized as a critical factor in the pathogenesis of diabetes mellitus and diabetic complications, including diabetic nephropathy. In the setting of diabetic nephropathy, there is now evidence of the relevant contribution of pro-inflammatory cytokines, with special participation of tumor necrosis factor-alpha (TNF-alpha). This new pathogenic perspective leads to new therapeutic implications derived from modulation of inflammation and inflammatory cytokines. Experimental studies have shown the beneficial renal actions derived from TNF-alpha inhibition with the use of soluble TNF-alpha receptor fusion proteins, chimeric monoclonal antibodies and pentoxifylline (PTF). Clinical application of this strategy is nowadays limited to PTF administration, which has demonstrated significant beneficial effects in patients with diabetic nephropathy. Overall, these studies indicate that inhibition of TNF-alpha might be an efficacious treatment for renal disease secondary to diabetes mellitus.

Inflammation and oxidative stress are main culprits behind atherosclerosis in diabetes mellitus. This study explores the effect of add-on Pentoxifylline on inflammatory burden and oxidative stress in hypertensive diabetic patients.

60 hypertensive type 2 diabetic, aged > or = 45 years were evaluated for anthropometry, clinical parameters, C-reactive protein, total leukocyte count, erythrocyte sedimentation rate, serum albumin, plasma malondialdehyde, blood reduced glutathione, platelet aggregation and clot retraction profile. With informed consent and randomization, Pentoxifylline (400 mg) was prescribed to 30 patients orally twice daily with meals as add-on therapy to the standard therapeutic regimen for one month. The particular parameters were repeated in 26 patients in control group and 25 patients in Pentoxifylline group who completed the follow up. The study was a randomized, open, add-on clinical trial with parallel controls.

At one-month follow-up, in the Pentoxifylline group, there was 20.9% decrease (p<0.001) in C-reactive protein, 18% reduction (p<0.001) in erythrocyte sedimentation rate, 11.1% reduction (p<0.001) in total leukocyte count and 5.8% increase (p=0.003) in serum albumin. Pentoxifylline showed 20.2% reduction in plasma malondialdehyde and 4.6% increase in blood reduced glutathione level. In therapeutic dose range, Pentoxifylline exerted a significant anti-aggregatory effect and a dose dependent decrease in clot retraction in-vitro but there was no significant change in ex-vivo clot retraction. The control group showed no statistically significant change in parameters assessed.

This study reveals improvements in inflammatory markers, oxidative stress and platelet-aggregation by Pentoxifylline, thus preventing atherosclerosis in diabetes mellitus.

Despite the beneficial effects of blockade of the renin-angiotensin system in diabetic nephropathy (DN), albuminuria and progression of renal disease are not completely halted by these agents. Therefore, it is necessary to explore potential antiproteinuric and renoprotective effects of innovative therapeutic approaches. This study tested the hypothesis that the combination of pentoxifylline (PTF) with angiotensin II receptor blockers in normotensive patients with type 2 diabetes produces an additive antiproteinuric effect. Sixty-one patients with DN and residual albuminuria despite treatment with the recommended doses of ARB for >1 yr were randomly assigned to receive the addition of 1200 mg of PTF daily (n = 30) or to a control group (n = 31). Baseline characteristics were similar between groups, and correlation analysis showed a significant association between urinary albumin excretion (UAE) and urinary TNF-alpha (R = 0.53, P < 0.001). After 4 mo, albuminuria showed a significant decrease in patients who received PTF, from 900 mg/24 h (466 to 1542 mg/d) to 791 mg/24 h (309 to 1400 mg/d; P < 0.001), whereas no significant changes were observed in the control group: 920 mg/24 h (450 to 1489 mg/d) at baseline, and 900 mg/24 h (428 to 1800 mg/d) at the end of the study. The mean percentage variation of UAE in the treatment and control groups was -16.7 and 5.5%, respectively (between-group comparison, P < 0.001). This additive antiproteinuric effect was not dependent on changes in BP or metabolic control. However, both serum and urinary levels of TNF-alpha also decreased in patients who received PTF, from 6.4 pg/ml (2.1 to 9.7) and 16 pg/mg (8 to 29) at baseline to 4.6 pg/ml (0.4 to 9) and 14.2 pg/mg (3 to 26) at the end of the study, respectively (P < 0.01), without significant variations in control patients. Moreover, regression analysis at the end of the study showed a correlation between the change in UAE and the change in urinary TNF-alpha in patients who were treated with PTF (R = 0.49, P < 0.001). In conclusion, administration of PTF to patients who have type 2 diabetes and are under long-term treatment with an ARB produces a significant additive antiproteinuric effect associated with a reduction of urinary TNF-alpha excretion.

The aim of the study was to investigate the effects of pentoxifylline on the renal growth, the epidermal growth factor receptor expression, and renal total nitric oxide content in streptozotocin-induced diabetic rats. Adult male Wistar albino rats were randomly divided into three groups: normal control (the N group), diabetic nephropathy (the DN group), and diabetic nephropathy treated with pentoxifylline at the dosage of 20 mg x kg(-1) x d(-1), intraperitoneally (the group DNP). Diabetes was induced by injection of streptozotocin intraperitoneally. The kidney wet weight (KWW) and dry weight (KDW), fractional kidney weight (FKW), glomerular volume (VG), renal tissue protein (RTP) contents, and renal tissue total nitric oxide (NO) production were determined after the rats were sacrificed on 10th day. There was a significant increase in KWW and KWD in the DNP and DN groups when compared to the N group (p=0.000 for the DNP group, p = 0.000 and p < 0.01 for the DN group). In the DN group, FKW was increased for both wet and dry kidney weight (p<0.05 and p=0.001, respectively) while in the DNP group there was increase in FKW only for dry kidney weight. VG was increased in both two diabetic groups (p<0.05), but this increase was less prominent in the rats treated with pentoxifylline. RTP was significantly decreased in the DNP group when compared with the values in the DN group (p < 0.05). Immunohistochemically epidermal growth factor receptor expression was increased in diabetic rats, and it was not affected by pentoxifylline treatment. In diabetic rats renal content of total NO was decreased (p<0.05 for the DNP group, p<0.01 for the DN group). In conclusion, the results provide that pentoxifylline may have some beneficial effects on renal changes in streptozotocin-induced diabetic rats.

To compare the relative efficacy of pentoxifylline (PTX) and angiotensin-converting enzyme (ACE) inhibitor, captopril in the treatment of proteinuria of type 2 diabetic patients.

A randomized open, crossover, clinical trial conducted from October 2000 to March 2001.

39 patients with type 2 diabetes age 34-75 years were randomly allocated to the two treatment groups. The first group received PTX (400 mg three times a day) orally for a total of 2 months. The second group received captopril (25 mg three times a day) for 2 months. Response to treatment was assessed at 1, 2, 4, and 8 weeks after start of therapy.

Captopril appeared to be equivalent in efficacy and safety to PTX. A significant decrease in proteinuria occurred in both groups. Of the 20 patients treated with PTX, the mean (SD) of 24 h urinary protein decreased from 1.4 (0.7) to 1.0 (0.7) g/24 h (p < 0.05). Correspondingly, in the 19 patients treated with captopril, the mean (SD) of 24 h urinary protein decreased from 1.3 (0.7) to 0.8 (0.7) g/24 h (p < 0.01).

This study demonstrates that treatment with PTX and captopril both significantly reduce overt proteinuria in patients with type 2 diabetes. This effect of ACE inhibition has previously been shown to slow progression to renal failure and we postulate that treatment with PTX may have a similar benefit.

Tubulointerstitial injury is a major feature of diabetic nephropathy and an important predictor of renal dysfunction. In 45 patients with type 2 diabetes mellitus (DM), we prospectively analyzed urinary excretion of N-acetyl-beta-glucosaminidase (NAG), a marker of tubular renal damage; the potential relationship with urinary protein excretion; and effects of pentoxifylline (PTF) administration.

Forty-five patients with type 2 DM initially were compared with 15 healthy controls matched for age and sex. After randomization, PTF (1,200 mg/d) was administered for 4 months to 30 patients and results were compared with data from a control group (n = 15).

Proteinuria and urinary NAG excretion were significantly greater in patients with DM with respect to healthy controls. Before PTF administration, baseline parameters were similar in both groups of patients with DM. At the end of the study, urinary protein excretion and NAG-creatinine ratios decreased in the active group from 920 +/- 522 mg/d and 14.3 +/- 16.9 U/g to 803 +/- 523 mg/d (P < 0.001) and 10.5 +/- 9.3 U/g (P < 0.05), respectively. Conversely, proteinuria and urinary NAG excretion did not change in the control group. Regression analysis showed that urinary NAG excretion was significantly associated with duration of DM (r = 0.61; P < 0.001) and proteinuria (r = 0.51; P < 0.001).

Urinary NAG excretion is elevated in patients with type 2 DM compared with healthy individuals and increases as nephropathy progresses. PTF administration is effective in reducing proteinuria and urinary NAG excretion in these patients. These findings suggest that PTF may have beneficial effects on tubulointerstitial damage in diabetic kidney disease.

To investigate the anti proteinuric effect of pentoxifylline in diabetic patients, we prospectively studied in 25 hypertensive type 2 diabetic patients with persistent microalbuminuria and normal renal function the impact of combining pentoxifylline with an angiotensin converting enzyme inhibitor, lisinopril, on urinary albumin excretion and compared the results with those obtained in a control group of 25 type 2 diabetic patients treated with lisinopril only.

Fifty hypertensive type 2 diabetic patients with persistent microalbuminuria (31 males and 19 females, aged between 47-73 years) were randomly assigned to two groups. Group A received lisinopril 10 mg/day, while group B was given lisinopril 10 mg/day and pentoxifylline 600 mg/day for nine months. There were no significant differences between serum creatinine, HbA1c, blood pressure and urinary albumin excretion in both groups (p > 0.05).

Serum creatinine, creatinine clearance, blood pressure, HbA1c levels did not change significantly during the study. Urinary albumin excretion decreased from 228 +/- 28 to 148 +/- 15 mg/day in group A (p < 0.05). In group B urinary albumin excretion decreased from 219 +/- 26 to 128 +/- 12 mg/day (p < 0.05). Pentoxifylline and lisinopril combination caused a significant additional reduction in urinary albumin excretion when compared to lisinopril regimen (p < 0.05).

Our findings suggest that the combination of pentoxifylline with an angiotensin converting enzyme inhibitor in hypertensive type 2 diabetic patients with persistent microalbuminuria causes a significant reduction in urinary albumin excretion and this effect seems independent from blood pressure and glycemic control.

In 24 diabetic patients with advanced renal failure (creatinine clearance [C(Cr)] < 35 mL/min), we prospectively studied serum tumor necrosis factor-alpha (TNF-alpha) levels, the possible relationship with urinary protein excretion, and the effects of pentoxifylline (PTF) administration. PTF (400 mg daily) was administered for 6 months to 14 patients, and the results were compared with data from a control group (n = 10). Baseline parameters were similar in both groups. At the end of the study, urinary protein excretion and serum TNF-alpha decreased in the active group from 2.7 (1.2 to 5.8) g/d and 569 +/- 285 pg/mL to 1.1 (0.3 to 4.0) g/d and 329 +/- 232 pg/mL, respectively (P < 0.001). By contrast, proteinuria and TNF-alpha did not change in the control group. Regression analysis showed a significant correlation between proteinuria and serum TNF-alpha both at basal (r = 0.55) and at the sixth month (r = 0.57). Furthermore, the reduction of urinary protein excretion was strongly correlated with the decrease of TNF-alpha (r = 0.72, P < 0.01). Serum Cr and C(Cr) remained stable in both groups during the study. Our findings suggest that cytokines might play a role in renal damage in diabetic nephropathy. PTF is effective in reducing proteinuria in diabetic patients with advanced renal failure. The anticytokine activity of PTF may be a further explanation for this antiproteinuric effect.

Impaired microcirculatory perfusion appears to be crucial to the pathogenesis of both neuropathy and retinopathy in diabetics. This in turn reflects a hyperglycemically mediated perturbation of vascular endothelial function that entails overactivation of protein kinase C, reduced availability of nitric oxide, increased production of superoxide and endothelin, impaired insulin function, diminished synthesis of prostacyclin/PGE1, and increased activation and endothelial adherence of leukocytes. These dysfunctions may be addressed with a supplementation program that includes high-dose antioxidants, fish oil, gamma-linolenic acid, chromium, arginine, carnitine, and ginkgolides. Pharmaceuticals likely to be of benefit in this regard include pentoxifylline, probucol, replacement estrogens, and inhibitors of angiotensin converting enzyme and aldose reductase.

Renal disorders attributed to diabetes mellitus are increasingly recognized as the dominant feature of long-term management. Renal failure in diabetic patients is the most commonly recognized cause of irreversible uremia in the United States, Europe, and Japan. Treating hypertension and normalizing hyperglycemia slows the previously thought inexorable progress of renal insufficiency in diabetes. Once end-stage renal disease has developed, either dialytic therapy or a renal transplant affords life extension, often with excellent rehabilitation.