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Endothelin receptor antagonists in chronic kidney disease
J David Smeijer1, Donald E Kohan2, Neeraj Dhaun3
1Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Insights
Endothelin receptor antagonists (ERAs) show promise in managing chronic kidney disease (CKD) by reducing albuminuria and preserving kidney function. Optimizing ERA use requires careful patient selection and dosing to minimize side effects like fluid retention.
Area of Science:
- Nephrology
- Pharmacology
- Cardiovascular Medicine
Background:
- Endothelin-1 (ET-1) plays a key role in kidney physiology and its overexpression contributes to chronic kidney disease (CKD) pathophysiology.
- Selective endothelin receptor antagonists (ERAs) targeting the endothelin A (ETA) receptor have shown therapeutic potential in preclinical and clinical studies for kidney diseases.
Purpose of the Study:
- To review the current understanding of endothelin receptor antagonist (ERA) use in patients with chronic kidney disease (CKD).
- To guide the optimal, safe, and effective clinical application of ERAs in managing CKD.
Main Methods:
- Review of existing literature on ERAs in CKD, including clinical trials and preclinical data.
- Analysis of the efficacy and safety profiles of various ERAs, such as atrasentan, sparsentan, and aprocitentan.
- Examination of combination therapies involving ERAs and other agents like SGLT2 inhibitors.
Main Results:
- Selective ETA ERAs, like atrasentan, have reduced albuminuria and slowed kidney function decline in patients with type 2 diabetes and CKD.
- Dual-acting agents like sparsentan have preserved kidney function with reduced fluid retention in IgA nephropathy.
- Combination therapy with ERAs and SGLT2 inhibitors enhanced albuminuria reduction and mitigated fluid retention.
Conclusions:
- ERAs represent a valuable therapeutic class for managing chronic kidney disease (CKD).
- Optimizing ERA therapy involves careful patient selection and dosing strategies to balance efficacy and minimize adverse effects like fluid retention and heart failure.
- Emerging data support the use of novel ERAs and combination therapies for improved CKD management.
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.
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