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Review
. 2021 Jul 1;30(4):456-465.
doi: 10.1097/MNH.0000000000000716.

Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease

J David Smeijer  1 , Donald E Kohan  2 , David J Webb  3 , Neeraj Dhaun  3   4 , Hiddo J L Heerspink  1
Affiliations
Review

Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease

J David Smeijer et al. Curr Opin Nephrol Hypertens. .

Abstract

Purpose of review: To summarize new clinical findings of endothelin receptor antagonists (ERA) in various etiologies of kidney disease targeted in clinical trials.

Recent findings: Endothelin-1 is a multifunctional peptide with potential relevance to glomerular and tubulointerstitial kidney diseases. The phase 3 SONAR trial demonstrated a significant reduction in clinically relevant kidney outcomes for patients with diabetic kidney disease (DKD) after long-term treatment with the ERA, atrasentan, in addition to blockade of the renin-angiotensin-aldosterone system. Promising preclinical disease models and small clinical trials in non-DKD resulted in the initiation of phase 3 trials investigating the effects of long-term treatment with ERA in patients with immunoglobulin A (IgA) nephropathy and focal segmental glomeruloscelerosis (FSGS). The mechanisms by which ERA protects the kidneys have been extensively studied with evidence for the protection of tubule cells, podocytes, mesangial cells, the endothelial glycocalyx, and a reduction in glomerular perfusion pressure. The occurrence of fluid retention during ERA treatment, particularly in susceptible populations, necessitates strategies to support safe and effective treatment.

Summary: Treatment with ERA induces long-term kidney protection in DKD. Phase 3 trials are underway to investigate ERA effects in patients with IgA nephropathy and FSGS.

Trial registration: ClinicalTrials.gov NCT04724837.

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References

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    1. Kohan DE, Rossi NF, Inscho EW, Pollock DM. Regulation of blood pressure and salt homeostasis by endothelin. Physiol Rev 2011; 91:1–77.
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    1. Dolinina J, Rippe A, Öberg CM. Sustained, delayed, and small increments in glomerular permeability to macromolecules during systemic ET-1 infusion mediated via the ETA receptor. Am J Physiol Renal Physiol 2019; 316:F1173–F1179.

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