Endothelin Receptor Antagonists in Chronic Kidney Disease

Endothelin-1 (ET-1) is a potent vasoconstrictor with diverse physiologic actions in the kidney, including regulation of blood flow and glomerular filtration, electrolyte homeostasis, and endothelial function. Overexpression of ET-1 contributes to the pathophysiology of both diabetic and non-diabetic chronic kidney disease (CKD). Selective endothelin receptor antagonists (ERAs) targeting the endothelin A (ETA) receptor have demonstrated benefits in animal models of kidney disease and clinical trials. In patients with type 2 diabetes and CKD, the selective ETA ERA, atrasentan, reduced albuminuria and kidney function decline. Although all ERAs have shown benefits on kidney parameters and clinical outcomes, their widespread use in nephrology practices has been limited due to increased risks of fluid retention and heart failure in clinical trials in patients with type 2 diabetes and CKD. More recent trials incorporated optimal dose and patient selection for the safe and effective use of ERAs. The PROTECT trial enrolled patients with IgA nephropathy, inherently at lower heart failure risk than patients with type 2 diabetes, and demonstrated that the dual ETA-angiotensin receptor blocker sparsentan preserved kidney function with minimal fluid retention side effects. The ZENITH-CKD trial demonstrated that combining a low dose of the selective ETA ERA zibotentan with the SGLT2i dapagliflozin enhances albuminuria reduction and mitigates fluid retention. Notably, sparsentan and aprocitentan have received FDA approval for the treatment of IgA nephropathy and treatment-resistant hypertension, respectively. This review describes the current knowledge on the use of ERAs in patients with CKD to guide optimal safe and effective use in clinical practice.