Additive Antiproteinuric Effect of Pentoxifylline in Patients with Type 2 Diabetes under Angiotensin II Receptor Blockade

Abstract

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-␣ (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-␣ 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-␣ 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-␣ excretion.

Pentoxifylline Attenuates Proteinuria in Anti-Thy1 Glomerulonephritis via Downregulation of Nuclear Factor-κB and Smad2/3 Signaling

“…The antiproteinuric effect of this drug is largely ascribed to its inhibitory action on TNF-α and/or TGF-β pathways (20,27,28). In agreement with these reports, the present study shows that PTX can reduce proteinuria in association with attenuation of nephrinuria, downregulation of glomerular NF-κB and Smad signals and restoration of podocyte-related filtration barrier proteins.…”

“…PTX is a clinically available phosphodiesterase inhibitor that has been shown to reduce proteinuria in various human kidney diseases, including mesangial proliferative glomerulonephritis and IgA nephropathy (19)(20)(21)(22)(23)(24). The antiproteinuric effect of this drug is largely ascribed to its inhibitory action on TNF-α and/or TGF-β pathways (20,27,28).…”

“…Our data show that the pathogenesis of proteinuria in anti-Thy1 glomerulonephritis involves TNF-α and TGF-β/activin pathways, and the evolution of this process can be attenuated by pentoxifylline via downregulation of NF-κB and Smad signals and restoration of the podocyte component of the glomerular filtration barrier. the potential mechanisms whereby proteinuria developed in anti-Thy1 disease and the modulation of which by selective signal transduction inhibitors, including the known antiproteinuric agent pentoxifylline (PTX) (19)(20)(21)(22)(23)(24).…”

“…We then examined whether PTX, an agent capable of inhibiting both pathways (20,27,28), might exert a more complete control of proteinuria. Our results showed that treatment with PTX attenuated proteinuria ( Figure 4C) and nephrinuria (Figure 5A) through the course of the disease.…”

Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease

“…18,19 We previously reported that PTF administration to diabetic patients resulted in the reduction of clinical markers of glomerular and tubulointerstitial injury. 20,21 In addition, recent meta-analyses indicate that PTF may reduce proteinuria and that this drug could offer some beneficial effects on renal function in patients with DKD. 22,23 Therefore, we conducted the present randomized trial to prospectively test the hypothesis that add-on PTF to maximized ACEI or ARB treatment provides additional benefits against renal disease progression in patients with type 2 diabetes who have stages 3-4 CKD.…”