Aldosterone and Residual Cardiorenal Risk: Pathophysiology and Emerging Therapeutic Strategies.

Authors

Mehmet Kanbay, Rama AlShiab, Ermeena Shah, Anas Abdo, Alberto Ortiz, Francesca Mallamaci, Carmine Zoccali

Published in

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. Oct 16, 2026. Epub Oct 16, 2026.

Abstract

Aldosterone, the terminal effector of the renin-angiotensin-aldosterone system, regulates sodium retention, potassium excretion, and blood pressure. Beyond these classical effects, aldosterone-associated and mineralocorticoid receptor (MR)-mediated signaling is implicated in inflammation, oxidative stress, fibrosis, albuminuria, and progressive cardiorenal injury, while its synthesis is regulated by factors beyond angiotensin II. This is particularly relevant in chronic kidney disease (CKD), where persistent renin-angiotensin system (RAS) activation, impaired potassium handling, reduced Klotho, altered aldosterone clearance, and incomplete suppression may sustain aldosterone exposure and MR activation despite conventional RAS blockade. These mechanisms may contribute to residual cardiorenal risk despite standard-of-care therapy. Mineralocorticoid receptor antagonist (MRA) outcome trials establish MR signaling as a therapeutic target in defined CKD populations, but therapeutic benefit from MR blockade should not be interpreted as evidence of biochemical aldosterone excess in all treated patients. This review distinguishes aldosterone excess from MR activation and proposes a nephrology-focused clinical framework separating established MRA indications, evaluation for primary aldosteronism, and the unestablished cardiorenal outcome role of aldosterone synthase inhibitors (ASIs). We discuss aldosterone-associated and MR-mediated kidney injury, the cardiorenal axis, albuminuria as a downstream marker of injury and treatment response, and current and emerging therapeutic strategies, including steroidal and non-steroidal MRAs, ASIs, and combinations with SGLT2 inhibitors. Whereas MRA therapy has established outcome benefits in defined CKD populations, cardiorenal outcome benefit from ASIs remains unestablished; EASi-KIDNEY was discontinued early after independent Data Monitoring Committee review, with detailed results pending.

PMID:
42886065
Bibliographic data and abstract were imported from PubMed on 16 Oct 2026.

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