Endothelin-1 is a potent vasoconstrictor that has diverse physiological functions in the kidney, including in the regulation of blood flow and glomerular filtration, electrolyte homeostasis and endothelial function. Overexpression of endothelin-1 contributes to the pathophysiology of both diabetic and non-diabetic chronic kidney disease (CKD). Selective endothelin receptor antagonists (ERAs) that target the endothelin A (ET_A) receptor have demonstrated benefits in animal models of kidney disease and in clinical trials. In patients with type 2 diabetes and CKD, the selective ET_A ERA, atrasentan, reduced albuminuria and kidney function decline. Concerns about the increased risks of fluid retention and heart failure with ERA use have led to the design of further trials to optimize dosing and patient selection. More recent studies have shown that the dual ET_A receptor and angiotensin receptor blocker, sparsentan, preserved kidney function with minimal fluid retention in patients with IgA nephropathy. Moreover, combined administration of a low dose of the ET_A-selective ERA, zibotentan, with the sodium–glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, enhanced albuminuria reduction and mitigated fluid retention in patients with CKD. Notably, sparsentan and aprocitentan have received FDA approval for the treatment of IgA nephropathy and treatment-resistant hypertension, respectively. This Review describes our current understanding of the use of ERAs in patients with CKD to guide their optimal safe and effective use in clinical practice.

内皮素-1 是一种有效的血管收缩剂，在肾脏中具有多种生理功能，包括调节血流和肾小球滤过、电解质稳态和内皮功能。内皮素-1 的过表达有助于糖尿病和非糖尿病慢性肾脏病 （CKD） 的病理生理学。靶向内皮素 A （ET_A） 受体的选择性内皮素受体拮抗剂 （ERA） 已在肾脏疾病的动物模型和临床试验中显示出益处。在 2 型糖尿病和 CKD 患者中，选择性 ET_A ERA、atrasentan 减少了尿白蛋白和肾功能下降。由于担心使用 ERA 会增加体液潴留和心力衰竭的风险，因此设计了进一步的试验来优化剂量和患者选择。最近的研究表明，双重 ET_A 受体和血管紧张素受体阻滞剂 sparsentan 可保留 IgA 肾病患者的肾功能，且液体潴留最小。此外，低剂量 ET_A 选择性 ERA zibotentan 与钠-葡萄糖协同转运蛋白 2 （SGLT2） 抑制剂达格列净的联合给药可增强 CKD 患者的白蛋白尿减少并减轻液体潴留。值得注意的是，sparsentan 和 aprocitentan 已分别获得 FDA 批准用于治疗 IgA 肾病和难治性高血压。本综述描述了我们目前对 CKD 患者使用 ERAs 的理解，以指导它们在临床实践中的最佳安全和有效使用。