Diabetic nephropathy -- a multifaceted target of new therapies.

Diabetic nephropathy (DN) remains the most common cause for end stage renal disease (ESRD) as the burden of diabetes increases worldwide. Nearly one-third of patients with diabetes develop nephropathy making early diagnosis critical in preventing long term kidney loss. Microalbuminuria is the earliest clinical manifestation of DN and is associated with substantial risk for progressive kidney damage. Hyperglycemia activates various inflammatory pathways both directly and via gene transcription to induce oxidative stress, reactive oxygen species, fibrotic factors TGF-β, renin-angiotensin- aldosterone system (RAAS), and advanced glycation end-products, leading collectively to podocyte injury, malfunction, apoptosis, and protein deposition in extracellular matrix of the nephron with albumin leak. Furthermore elevated glucose may also induce epigenetic metabolic memory with continued complications leading to diabetic complications. In addition, other clinical factors including genetic predisposition, obesity, blood pressure, high lipids, and smoking add to the rate of progression in DN. Thus early diagnosis and normalizing glycemic control in addition to careful blood pressure, weight, lipid control, and smoking cessation remain important in decreasing DN progression particularly for those with higher genetic risk.With evolution in the understanding of mechanistic processes leading to DN, targeted therapies such as RAAS blockers, thiazolidinediones, statins, and fibric acid derivatives are being utilized. However the optimal treatment for DM continues to evolve as newer therapies including inhibitors of sodium glucose transport and preglycated proteins as well as antifibrotic agents are being actively investigated in decreasing DN progression.