Mineralocorticoid Receptor Antagonists in Dialysis

Aldosterone regulates genes controlling fluid and electrolyte balance through mineralocorticoid receptor (MR) activation. Sustained MR activation promotes inflammation, fibrosis, sodium retention, and myocardial remodeling. MR antagonists (MRAs) block aldosterone binding in the kidney, heart, and vasculature and are classified as steroidal or nonsteroidal. Although large, randomized trials have confirmed the benefits of steroidal MRAs in heart failure and of finerenone in diabetic kidney disease, these pivotal studies systematically excluded patients with kidney failure receiving dialysis. Over the past decade, several phase 2 and 3 trials have evaluated MRAs in dialysis, yielding heterogeneous and sometimes conflicting results. This review summarizes the biological rationale, evolving clinical evidence, and future directions for MR blockade in dialysis.

Pharmacokinetic studies indicate that spironolactone and eplerenone are highly protein-bound, hepatically metabolized, and not dialyzable, supporting cautious use in dialysis with potassium monitoring. Early randomized trials from East Asia suggested potential cardiovascular benefit with spironolactone 25 mg daily; however, these studies were underpowered and reported relatively few outcome events. More definitive evidence is now available from two large multicenter randomized controlled trials. In ALCHEMIST (n = 644), spironolactone 25 mg daily did not reduce major adverse cardiovascular events compared with placebo over a median follow-up of 2.7 years [hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.73-1.36]. Similarly, in ACHIEVE (n = 2,538), spironolactone failed to reduce the composite of cardiovascular death or hospitalization for heart failure (HR 0.92, 95% CI: 0.78-1.09) over 1.8 years and was associated with higher rates of hyperkalemia. A contemporary meta-analysis incorporating these trials confirmed neutral efficacy but higher rates of asymptomatic hyperkalemia and gynecomastia.

Current evidence indicates that steroidal MRAs confer no cardiovascular or survival benefit in maintenance dialysis and modestly increase the risk of hyperkalemia and endocrine adverse effects.