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

Abstract

Diabetic kidney disease (DKD) is the leading cause of ESRD. We conducted an open-label, prospective, randomized trial to determine whether pentoxifylline (PTF), which reduces albuminuria, in addition to renin-angiotensin system (RAS) blockade, can slow progression of renal disease in patients with type 2 diabetes and stages 3-4 CKD. Participants were assigned to receive PTF (1200 mg/d) (n=82) or to a control group (n=87) for 2 years. All patients received similar doses of RAS inhibitors. At study end, eGFR had decreased by a mean6SEM of 2.160. patients with a rate of eGFR decline greater than the median rate of decline (0.16 ml/min per 1.73 m 2 per month) was lower in the PTF group than in the control group (33.3% versus 68.2%; P,0.001). Percentage change in urinary albumin excretion was 5.7% (95% CI, 20.3% to 11.1%) in the control group and 214.9% (95% CI, 220.4% to 29.4%) in the PTF group (P=0.001). Urine TNF-a decreased from a median 16 ng/g (interquartile range, 11-20.1 ng/g) to 14.3 ng/g (interquartile range, 9.2-18.4 ng/g) in the PTF group (P,0.01), with no changes in the control group. In this population, addition of PTF to RAS inhibitors resulted in a smaller decrease in eGFR and a greater reduction of residual albuminuria. 26: 220-229, 201526: 220-229, . doi: 10.1681 Diabetic kidney disease (DKD) is the most frequent cause of CKD, and ESRD in type 2 diabetes is considered a medical catastrophe. 1 Strong evidence supports the blockade of the renin-angiotensin system (RAS), most commonly with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptors blockers (ARBs), as an established standard of care in these patients to reduce the risk of developing ESRD. 2 However, these therapies do not provide complete renal protection, 3 and diabetic patients continue to show a high renal risk, which is positively associated with residual albuminuria. 4 Unfortunately, recent studies evaluating new strategies to delay the progression of diabetic nephropathy (DN) have had little success. Trials with pyridoxamine or sulodexide failed to detect a renoprotective effect in patients with type 2 diabetes and renal impairment. 5,6 Meanwhile, studies with the endothelin antagonist avosentan, 7 J Am Soc Nephrol

Effects of pentoxifylline on inflammatory markers and blood pressure

“…The lack of effect of pentoxifylline on systemic arterial blood pressure seen in this study supports previous observations with pentoxifylline [49] and other phosphodiesterase inhibitors [15] where little or no effect on blood pressure was observed. It is important to note that in all but one of the studies which measured the effect of pentoxifylline on blood pressure, the participants were normotensive at baseline.…”

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

“…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).…”

Stop chronic kidney disease progression: Time is approaching

“…Pentoxifylline dose in this trial is 1200 mg/d. After 24 mo of follow-up, treatment with pentoxifylline was associated with a slower rate of eGFR loss together with the significant reduction in urine protein excretion [157] . An inverse relationship was observed between serum level of 25(OH) vitamin D and the rate of GFR decline in children suffering CKD.…”