Endothelin receptor antagonists in chronic kidney disease.
Selective endothelin A receptor antagonists reduce albuminuria and slow kidney function decline in chronic kidney disease, with sparsentan and aprocitentan now FDA-approved for IgA nephropathy and treatment-resistant hypertension respectively. Fluid retention and heart failure risk remain the central safety constraint, and combining a low-dose ERA with an SGLT2 inhibitor has been shown to mitigate it.
Background
Endothelin-1 is a potent vasoconstrictor with diverse physiological functions in the kidney, including 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, making the endothelin A (ETA) receptor a therapeutic target.
Key findings
Selective ERAs targeting the ETA receptor have demonstrated benefit in animal models of kidney disease and in clinical trials. In patients with type 2 diabetes and CKD, the selective ETA antagonist atrasentan reduced albuminuria and kidney function decline. More recent studies show that the dual ETA receptor and angiotensin receptor blocker sparsentan preserved kidney function with minimal fluid retention in patients with IgA nephropathy. Combined administration of a low dose of the ETA-selective antagonist zibotentan with the SGLT2 inhibitor dapagliflozin enhanced albuminuria reduction while mitigating fluid retention in patients with CKD. Sparsentan and aprocitentan have received FDA approval for IgA nephropathy and treatment-resistant hypertension, respectively.
Safety
Concerns about increased risks of fluid retention and heart failure with ERA use have driven the design of further trials aimed at optimising dosing and patient selection. The sparsentan and zibotentan-plus-dapagliflozin experience indicates that fluid retention can be limited by agent choice, lower dosing and co-administration with an SGLT2 inhibitor.
Clinical implications
This Review describes the current understanding of ERA use in patients with CKD in order to guide their optimal safe and effective use in clinical practice — in particular, matching agent and dose to patient risk so that the albuminuria and kidney-function benefit is obtained without incurring fluid overload.
Category
Regulatory
Source
Nat Rev Nephrol
More from ASNRT News
Browse the latest news, society announcements, KDIGO guideline updates, and AJNT issue releases on the ASNRT newsroom.