J. David Smeijer, Donald E. Kohan, Neeraj Dhaun, Irene L. Noronha, Adrian Liew, Hiddo J. L. Heerspink
{"title":"Endothelin receptor antagonists in chronic kidney disease","authors":"J. David Smeijer, Donald E. Kohan, Neeraj Dhaun, Irene L. Noronha, Adrian Liew, Hiddo J. L. Heerspink","doi":"10.1038/s41581-024-00908-z","DOIUrl":null,"url":null,"abstract":"<p>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<sub>A</sub>) 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<sub>A</sub> 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<sub>A</sub> 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<sub>A</sub>-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.</p>","PeriodicalId":19059,"journal":{"name":"Nature Reviews Nephrology","volume":"20 1","pages":""},"PeriodicalIF":28.6000,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Reviews Nephrology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41581-024-00908-z","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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 (ETA) receptor have demonstrated benefits in animal models of kidney disease and in clinical trials. In patients with type 2 diabetes and CKD, the selective ETA 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 ETA 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 ETA-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.
期刊介绍:
Nature Reviews Nephrology aims to be the premier source of reviews and commentaries for the scientific communities it serves.
It strives to publish authoritative, accessible articles.
Articles are enhanced with clearly understandable figures, tables, and other display items.
Nature Reviews Nephrology publishes Research Highlights, News & Views, Comments, Reviews, Perspectives, and Consensus Statements.
The content is relevant to nephrologists and basic science researchers.
The broad scope of the journal ensures that the work reaches the widest possible audience.