Targeting Aldosterone in Chronic Kidney Disease: from Mineralocorticoid Receptor Antagonism to Synthase Inhibition

Abstract

Chronic kidney disease (CKD) remains a major cause of morbidity and mortality despite advances in renin–angiotensin system blockade and sodium–glucose cotransporter-2 inhibitors. Persistent aldosterone production and mineralocorticoid receptor (MR) overactivation may contribute to residual cardiorenal risk through sodium retention, hypertension, oxidative stress, inflammation, endothelial dysfunction, and fibrosis. This narrative review summarizes the biological rationale and clinical evidence for aldosterone-targeted therapies in CKD, including steroidal MR antagonists, finerenone, and emerging aldosterone synthase inhibitors (ASIs). Steroidal MR antagonists reduce albuminuria but are limited by hyperkalemia and endocrine adverse effects. Finerenone has the most mature outcome evidence among nonsteroidal MR antagonists, reducing kidney and cardiovascular events in CKD with type 2 diabetes. Recent trials also support greater albuminuria reduction when finerenone is combined with empagliflozin and extend anti-albuminuric evidence to type 1 diabetes. Selective ASIs, including vicadrostat, baxdrostat, and lorundrostat, directly suppress aldosterone synthesis and have shown promising effects on albuminuria or blood pressure. However, hyperkalemia, adrenal safety, and the absence of definitive long-term kidney and cardiovascular outcome data remain important limitations. Current evidence supports a layered approach to CKD therapy, while ASIs remain investigational pending larger outcome trials. The objective of this narrative review is to critically summarize the role of aldosterone and mineralocorticoid receptor activation in CKD progression, compare steroidal and nonsteroidal mineralocorticoid receptor antagonists, and evaluate the emerging efficacy, safety, and clinical positioning of aldosterone synthase inhibitors within contemporary layered CKD therapy.