Improvements in the Management of Diabetic Nephropathy

Abstract

The burden of diabetes mellitus is relentlessly increasing. Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) worldwide and a major cause of morbidity and mortality in patients with diabetes. The current standard therapy of diabetic nephropathy involves intensive treatment of hyperglycemia and strict blood pressure control, mainly via blockade of the renin-angiotensin system (RAS). Attention has been drawn to additional beneficial effects of oral hypoglycemic drugs and fibrates on other aspects of diabetic nephropathy. On the other hand, antiproteinuric effects of RAS combination therapy do not seem to enhance the prevention of renal disease progression, and it has been associated with an increased rate of serious adverse events. Novel agents, such as bardoxolone methyl, pentoxifylline, inhibitors of protein kinase C (PKC), sulodexide, pirfenidone, endothelin receptor antagonists, vitamin D supplements, and phosphate binders have been associated with controversial outcomes or significant side effects. Although new insights into the pathogenetic mechanisms have opened new horizons towards novel interventions, there is still a long way to go in the field of DN research. The aim of this review is to highlight the recent progress made in the field of diabetes management based on the existing evidence. The article also discusses novel targets of therapy, with a special focus on the major pathophysiologic mechanisms implicated in the initiation and progression of diabetic nephropathy.

Figure 1. Proposed pathophysiological mechanisms implicated in the pathogenesis of diabetic nephropathy

Hyperglycemia may induce mesangial expansion via the stimulation of cytokines and vascular growth factors or glycation of matrix proteins. Hyperglycemia-induced activation of protein kinase C and upregulation of heparanase expression result in increased glomerular permeability. Intraglomerular hypertension and subsequent stimulation of vasoactive hormones cause glomerulosclerosis. Substantial overlap exists between these different pathways.

Figure 2. Key elements in the management of diabetic nephropathy with established and potential novel therapeutic agents

Specific classes of oral hypoglycemic and hypolipidemic agents are associated with renoprotective effects. RAS blockade remains the mainstay of treatment. Novel agents that target different pathophysiologic pathways in diabetic nephropathy are being investigated.