Endothelin A receptor antagonists in diabetic kidney disease

Purpose of review: Despite optimal therapy of diabetic nephropathy with agents blocking the renin–angiotensin–aldosterone system, the residual risk of nephropathy progression to end-stage renal disease (ESRD) remains high. The purpose of this review is to discuss the potential role of endothelin antagonism as a therapeutic tool to reduce residual proteinuria and delay kidney injury progression among patients with diabetic nephropathy. Recent findings: Preclinical studies have shown that endothelin receptor antagonists (ERAs) exert proteinuria lowering and nephroprotective actions in experimental models of diabetic nephropathy. ERAs reduce proteinuria in phase 2 trials that included therapy with renin–angiotensin–aldosterone system blockers. Safety of these agents and protection from ESRD needs to be demonstrated in phase 3 trials. Excess risk of fluid retention and heart failure risk remains. Summary: The hypothesis that the antiproteinuric effect of endothelin antagonism may be translated into a slower progression of diabetic nephropathy to ESRD is investigated in ongoing randomized trials assessing 'hard' renal endpoints. ERAs may represent a promising tool toward renoprotection in diabetic nephropathy by individualizing therapy and mitigating the risk of heart failure, if these trials are positive.

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