TNF-a/TNF-a Receptor System as Therapeutic Target

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Over the last decade a number of new ways to inhibit the actions of TNF-α have been developed including monoclonal antibodies (e.g., infliximab), circulating receptor fusion proteins (e.g., etanercept), and small molecule inhibitors (e.g., pentoxyphyline, bupropion, 5-HT2a agonists). Among them pentoxifylline (PTF) is a methyl xanthine derivative that functions in vivo as a phosphodiesterase inhibitor with anti-TNF-a properties. Specifically, PTF inhibits both TNF-a gene transcription and TNF-a mRNA accumulation [58, 59]. Small intervention studies have shown that PTF significantly decreases proteinuria in both type 1 and type 2 diabetic patients [59, 60] and this antiproteinuric effect was associated with a reduction in circulating TNF-a levels. A recent meta-analysis reviewing all randomized controlled trials has shown that PTF is an efficacious anti-proteinuric agent in patients with DN [61]. Finally, an open-label, randomized, 2-year-intervention trial (PREDIAN) has recently demonstrated that addition of PTF to RAS blockade reduces eGFR decline and residual albuminuria in patients with type 2 diabetes and stages 3-4 CKD [62]. However, these are small studies and additional research is needed to determine whether PTF could be a pharmacologic option for delaying or preventing the development of DN. Given that the primary role of TNF-a is the regulation of immune cells, any therapy targeting this axis would need to be extensively tested to define any side effect.