Treatment-resistant hypertension (TRH) often coexists with chronic kidney disease (CKD), and the presence of both conditions increases the risk of adverse cardiovascular outcomes. Patients with TRH and CKD exhibit enhanced aldosterone and mineralocorticoid receptor expression, which promote inflammation and fibrosis in cardiac and renal tissues, contributing to the development and progression of cardiorenal diseases. Both achieving optimal blood pressure (BP) control and mitigating the risk of aldosterone-related adverse events are cornerstones in the management of patients with TRH and CKD. Mineralocorticoid receptor antagonists (MRAs) are recommended for the treatment of TRH. To date, the efficacy has been investigated in populations with mostly normal renal function. However, the potential risk of hyperkalaemia limits the use of MRAs, particularly in patients with CKD. Non-steroidal MRAs and sodium glucose cotransporter-2 inhibitors have slowed renal function decline and shown cardiorenal benefits. Additionally, aldosterone synthase inhibitors may emerge as a therapeutic option for patients with TRH. Clinical trials for TRH primarily centred on assessing BP-lowering effects; however, merely lowering BP might not be a sufficient target to prevent a risk of cardiorenal disease progression. This paper presents evidence and potential benefits of aldosterone-targeted therapy in the treatment of TRH and CKD and re-consider the treatment strategies in clinical practice and trial design.

Aims: A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated. Methods and results: In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642–1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213–1.434). The safety profile for eplerenone was as expected. Conclusion: The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power.

Kidney disease frequently coexists with cardiovascular (CV) diseases, and this dual presence significantly amplifies the risk of adverse clinical outcomes. Shared pathophysiological mechanisms and common CV risk factors contribute to the increased expression of mineralocorticoid receptors, which in turn can drive the progression of chronic CV–kidney disorders. The steroidal mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone have demonstrated efficacy in improving patient outcomes in cases of heart failure with reduced ejection fraction or after a myocardial infarction, but have limited value in patients with chronic kidney disease. The non-steroidal MRA finerenone has now established itself as a foundational guideline-recommended therapy in patients with diabetic kidney disease. To date, these pharmacological agents have been developed in distinct patient populations. The consequences of their distinct pharmacological profiles necessitate further consideration. They have not undergone testing across the entire spectrum of cardiorenal scenarios, and the evidence base is currently being complemented with ongoing trials. In this review, we aim to synthesize the existing body of evidence and chart the future trajectory for the use of spironolactone, eplerenone and finerenone in improving clinical outcomes across the diverse spectrum of cardiorenal diseases. By consolidating the current state of knowledge, we seek to provide valuable insights for informed decision making in the management of patients with these complex and interconnected conditions.