J David Smeijer1, Donald E Kohan2, David J Webb3, Neeraj Dhaun3,4, Hiddo J L Heerspink1. 1. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 2. Division of Nephrology, University of Utah Health, Salt Lake City, Utah, USA. 3. University of Edinburgh/British Heart Foundation Centre of Research Excellence, Centre for Cardiovascular Science, Queen's Medical Research Institute. 4. Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK.
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.
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.