Pentoxifylline reduces proteinuria in insulin-dependent and non insulin-dependent diabetic patients. [Effect of pentoxifylline on the evolution of diabetic nephropathy]. Effects of pentoxifylline on the urinary protein excretion profile of type 2 diabetic patients with microproteinuria: a double-blind, placebo-controlled randomized trial. Effects of pentoxifylline administration on urinary N-acetyl-beta-glucosaminidase excretion in type 2 diabetic patients: a short-term, prospective, randomized study. Pentoxifylline, albumin excretion rate and proteinuria in type I and type II diabetic patients with microproteinuria. Results of a short-term randomized study. Pentoxifylline, total urinary protein excretion rate and arterial blood pressure in long-term insulin-dependent diabetic patients with overt nephropathy. Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: a short-term, randomized, controlled trial. Comparison of the effect of pentoxifylline and captopril on proteinuria in patients with type 2 diabetes mellitus. Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration. Beneficial hemorheologic therapy of chronic peripheral arterial disorders with pentoxifylline: results of double-blind study versus vasodilator-nylidrin. Combination of pentoxifylline with angiotensin converting enzyme inhibitors produces an additional reduction in microalbuminuria in hypertensive type 2 diabetic patients.
Pentoxifylline is a drug with hemorheological actions used in the management of microcirculatory abnormalities, such as those usually seen in diabetic patients. The drug has been successfully used in improving peripheral and central circulation, as well as proteinuria of long-term diabetes. With the hypothesis that pentoxifylline reduces proteinuria in patients with IDDM and NIDDM, with a wide range of urinary protein excretion, 86 diabetic patients were studied. Forty-one patients with IDDM were stratified in 2 subgroups: one of 18 patients with microalbuminuria, and the other of 23 patients with overt proteinuria. In the same way, 45 patients with NIDDM were divided in 2 subgroups: one of 23 patients with microalbuminuria, and the other of 22 patients with proteinuria. Patients in each subgroup were randomized to receive either placebo or pentoxifylline 1,200 mg/d, during 4 months, using a double blind design. At the beginning of the study and after treatment, 24-hour urinary albumin excretion was measured by nephelometry in each patient.(ABSTRACT TRUNCATED AT 250 WORDS) Diabetic nephropathy (DN) is the principal cause of end-chronic kidney disease. Metabolic and hemodynamic components are directly involved. However, convincing data have shown that inflammation participates in the diabetic complications. The aim of this study was to investigate whether the inhibition of the inflammation and pro-inflammatory cytokines with pentoxifylline (PXF) attenuate the progression of the DN.
                In a prospective, randomized, double-blind, placebo- controlled study, we evaluated the effect of PXF (1200 mg daily) during 12 months, in 34 patients with incipient or established DN. Evaluated parameters were inflammation, pro-inflammatory cytokines and urinary albumin excretion (UAE).
                PXF treatment had a reno-protective effect determined by a significant reduction in the UAE in both incipient and established (p<0,01) DN patient. This effect was attributed to a reduction in the C-reactive protein, interleukin-6, tumor necrosis factor-alpha and leptin serum levels (p<0,01).
                PXF treatment caused regression and prevented the progression of renal damage. Thus, PXF should be used in the preventive treatment of DN. These results showed that inflammation and pro-inflammatory cytokines are related to the progression of diabetic nephropathy. The purpose of this study was to identify the effect of pentoxifylline on the urinary protein excretion profile in type 2 diabetic patients.
                40 type 2 nonhypertensive diabetic patients were randomly allocated to receive either pentoxifylline 400 mg t.i.d. or placebo daily for 16 weeks. Eligible subjects were those with urinary albumin excretion between 20 and 200 microg/min. Subjects receiving angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium antagonists, and diuretics as well as those with reduced renal function, pregnancy, urinary tract infection, and smoking were not included. A 6-month pretreatment stabilization phase aimed to reduce and stabilize fasting serum glucose levels was carried out. Urinary proteins were identified by electrophoresis, and immunodetection was identified by Western blot. Electrophoretic analysis was performed using molecular weight markers of 150, 132, 77, and 66 kDa to identify high-weight proteins, and 54, 41, 36, 27, 21, 14.3, and 12 kDa to identify low-weight proteins.
                At baseline, subjects in both groups who showed a glomerular tubular pattern did not differ in their urinary excretion profile. The urinary proteins identified were immunoglobulin G, ceruloplasmin, transferrin, and albumin (glomerular pattern) as well as alpha1-antitrypsin, alpha1-acid glycoprotein, collagenase inhibitor, alpha1-microglobulin, trypsin inhibitor, lysozyme, and beta2-microglobulin (tubular pattern). Subjects who received pentoxifylline had reduced urinary excretion of high- and low-molecular weight proteins.
                Urinary protein excretion in type 2 diabetic subjects shows a mixed, glomerular and tubular, pattern. Pentoxifylline reduces the excretion of both high and low molecular-weight urinary proteins. 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. An association between renal microvascular complications and hemorheological alterations has been suggested in diabetes mellitus. Therefore, a hemorheologic approach in the treatment of diabetic microproteinuria has been proposed. Eighty-two type I and type II diabetic patients with microproteinuria were randomized and assigned to two different protocols: protocol A, patients treated with pentoxifylline (Trental 400); protocol B, patients without hemorheologic treatment, in whom hypoglycemic therapy was just more strictly enforced. A significant improvement of the hemorheologic pattern and a significant marked reduction of albumin excretion rate and proteinuria was found in diabetic patients treated with pentoxifylline, independently of the degree of metabolic control. These results were readily achieved and were confirmed throughout the study. Moreover, these results were comparable to those obtained in diabetic patients of protocol B. Pentoxifylline might therefore be considered as the first useful therapeutic agent in the treatment of diabetic microproteinuria. A specific hemorheologic treatment might reduce urinary protein excretion and the decline in kidney function in diabetic patients with overt clinical nephropathy. Twenty-one insulin dependent (type I) diabetic patients were randomized and assigned to a treatment with conventional antihypertensive therapy (protocol I) or with pentoxifylline (Trental 400) (protocol II). A marked improvement of blood rheology pattern, together with a reduction of urinary albumin excretion rate and total urinary protein excretion rate, was demonstrated throughout a 1-year follow-up study with pentoxifylline. Furthermore a decrease of systolic and diastolic blood pressure levels was found during the treatment. The modification of these parameters was followed by a significant increase of creatinine clearance in each of the patients studied. The results obtained during pentoxifylline therapy were comparable to those obtained in patients treated with conventional antihypertensive drugs. Pentoxifylline may therefore be used in the treatment of advanced nephropathy in diabetic patients. 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. 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. 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. Pentoxifylline (Trental 400 mg coated tablets) and nylidrin HCl 3 mg were compared for clinical efficacy and safety in an 8-week randomized double-blind trial. The study was conducted in patients with peripheral arterial disease (Fontaine stage II or III), with 30 patients receiving pentoxifylline (23 returned for follow-up), and 30 patients receiving nylidrin HCl (24 returned for follow-up). Efficacy was assessed objectively in terms of walking performance (absolute walking time and walking distance on a treadmill ergometer) and by acral plethysmography. The clear improvement shown for both variables was greater and statistically significant (p less than or equal to 0.05) after treatment with pentoxifylline. Laboratory data provided no evidence to suggest any adverse effect of either treatment. Subjective side effects were reported by six patients in the pentoxifylline group and by three patients in the nylidrin HCl group. 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.
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.