Background
Patients with kidney failure requiring dialysis suffer from an extraordinarily high burden of cardiovascular morbidity and mortality. This population represents a challenging clinical subset in which to manage cardiovascular risk factors due to altered physiology and heightened vulnerability. Mineralocorticoid receptor antagonists (MRAs), primarily steroidal agents such as spironolactone and eplerenone, have demonstrated benefits in reducing cardiovascular events and mortality in patients with heart failure and mild to moderate chronic kidney disease (CKD). However, the safety and efficacy of MRAs in end-stage kidney disease (ESKD) patients on maintenance dialysis remain unclear, as these patients were largely excluded from earlier landmark cardiovascular trials. Understanding the therapeutic potential and risks of MRAs in this group is critical, given the high levels of aldosterone-driven pathology, but concerns persist regarding adverse effects such as hyperkalaemia and hypotension.
Study Design
The referenced systematic review and meta-analysis comprehensively evaluated randomized controlled trials (RCTs) comparing steroidal MRAs to placebo or standard care in adults aged 18 or older receiving maintenance dialysis. The literature search spanned databases including MEDLINE, Embase, Cochrane Central, and CINAHL, covering inception until March 18, 2025. Included trials reported clinically relevant endpoints: cardiovascular mortality, heart failure hospitalization, all-cause mortality, all-cause hospitalization, hyperkalaemia, gynecomastia or breast pain, and hypotension. The quality of included studies was rigorously assessed using the Cochrane risk-of-bias tool, allowing stratified analyses. The primary outcome was cardiovascular mortality, evaluated via empirical Bayes random-effects meta-analysis models. Study registration on PROSPERO (CRD420251008119) ensured methodological transparency.
Key Findings
Nineteen trials encompassing 4675 patients met inclusion criteria, all assessing steroidal MRAs. When stratified by study quality, four trials with low risk of bias included 3562 participants. Within these, cardiovascular deaths occurred similarly in the MRA and control arms—264 of 1785 patients on MRAs versus 276 of 1777 controls. The pooled odds ratio was 0.98 (95% CI, 0.80 to 1.20) with no heterogeneity (I2=0%), suggesting no statistically significant effect on cardiovascular mortality. This translates into an absolute risk reduction of 1 fewer cardiovascular death per 1000 patients per year (95% CI 14 fewer to 11 more), a clinically negligible result.
In terms of safety, concerns around hyperkalaemia—a known consequence of mineralocorticoid receptor blockade—were evaluated. Though this adverse event was reported across studies, its incidence did not rise substantially or consistently enough to outweigh potential benefits, indicating a manageable safety profile in controlled settings. Other side effects such as gynecomastia or hypotension were reported variably but did not imply major safety concerns.
Notably, the evidence on subgroups of dialysis patients (such as those differentiated by dialysis modality or comorbid conditions) was insufficient to draw definitive conclusions. Moreover, no data were available regarding the newer class of non-steroidal MRAs, which may offer better safety and efficacy profiles in this population.
Expert Commentary
This meta-analysis addresses a crucial evidence gap for cardiovascular risk management in dialysis patients. While MRAs reduce cardiovascular events in earlier stages of CKD and heart failure, these findings highlight that such benefits do not clearly extend to the dialysis-dependent population, possibly due to different disease mechanisms or altered drug responses. The minimal effect size and moderate-certainty evidence caution against routine MRA use for cardiovascular mortality prevention in dialysis patients at present. The safety profile is reassuring but requires careful monitoring, especially for hyperkalaemia.
Limitations include variability in trial designs and duration, and a lack of robust data on patient-centered outcomes beyond mortality. The exclusion of non-steroidal MRAs remains a substantial knowledge gap, emphasizing the need for prospective trials evaluating these novel agents potentially better suited to this high-risk group.
From a mechanistic perspective, aldosterone-mediated pathophysiology might contribute less prominently to cardiovascular events in established kidney failure, or its blockade insufficient to alter outcomes. This biological reasoning supports the clinical findings and suggests a differential therapeutic approach may be warranted.
Conclusion
Steroidal mineralocorticoid receptor antagonists do not confer a meaningful reduction in cardiovascular mortality among patients requiring maintenance dialysis. While generally safe under monitored conditions, their routine use for cardiovascular risk reduction in this population is not supported by current high-quality evidence. Future research should focus on identifying patient subgroups most likely to benefit and on evaluating the efficacy and safety of non-steroidal MRAs. Trial designs must realistically account for modest treatment effects and integrate mechanistic disease understanding.
Funding and Trial Registration
No funding was declared for this review. The systematic review protocol is registered with PROSPERO under number CRD420251008119.
Reference
Pyne L, Rossignol P, Giles C, Junek M, Mark PB, Gallagher M, de Zoysa JR, Devereaux PJ, Walsh M. Safety and efficacy of steroidal mineralocorticoid receptor antagonists in patients with kidney failure requiring dialysis: a systematic review and meta-analysis of randomised controlled trials. Lancet. 2025 Aug 23;406(10505):811-820. doi: 10.1016/S0140-6736(25)01153-5. Epub 2025 Aug 18. PMID: 40840478.
