Georgianos Panagiotis I, Agarwal Rajiv
aDivision of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece bDepartment of Medicine, Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA.
Curr Opin Nephrol Hypertens. 2017 Sep;26(5):338-344. doi: 10.1097/MNH.0000000000000342.
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.
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.
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.
尽管使用阻断肾素 - 血管紧张素 - 醛固酮系统的药物对糖尿病肾病进行了最佳治疗，但肾病进展至终末期肾病（ESRD）的残留风险仍然很高。本综述的目的是讨论内皮素拮抗作用作为一种治疗手段在降低糖尿病肾病患者残留蛋白尿和延缓肾损伤进展方面的潜在作用。
临床前研究表明，内皮素受体拮抗剂（ERA）在糖尿病肾病实验模型中具有降低蛋白尿和肾脏保护作用。在包括肾素 - 血管紧张素 - 醛固酮系统阻滞剂治疗的2期试验中，ERA可降低蛋白尿。这些药物的安全性以及对ESRD的保护作用需要在3期试验中得到证实。液体潴留风险和心力衰竭风险仍然存在。
在正在进行的评估“硬”肾脏终点的随机试验中，研究了内皮素拮抗作用的抗蛋白尿效应是否可转化为糖尿病肾病向ESRD进展减缓的假设。如果这些试验结果为阳性，ERA可能通过个体化治疗和降低心力衰竭风险，成为糖尿病肾病肾脏保护的一种有前景的工具。
