Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, characterized by the overproduction of aldosterone from the adrenal glands, leading to sodium retention, potassium excretion, and elevated blood pressure (BP). If left untreated, PA can result in significant kidney damage, as well as cardiovascular complications, including left ventricular hypertrophy, heart failure, and an increased risk of myocardial infarction [1]. Standard treatments for PA typically include surgical resection of the adrenal gland in cases of unilateral adenomas or the use of mineralocorticoid receptor antagonists (MRAs) in cases of bilateral adrenal hyperplasia [2]. Spironolactone and eplerenone are well-established steroidal MRAs that have been used for decades. In PA patients, these agents have shown significant benefits in reducing albuminuria [3, 4], a key marker of kidney damage, as well as improving cardiovascular outcomes [5]. However, the use of steroidal MRAs is often associated with notable side effects, such as hyperkalemia and endocrine-related adverse events like gynecomastia, which has driven the need for more selective and safer alternatives for long-term management of PA.

Recent clinical trials on a nonsteroidal MRA, esaxerenone, have demonstrated its antihypertensive impact on essential hypertension [6] as well as its combined antihypertensive and antialbuminuric benefits in hypertension associated with type 2 diabetes [7]. However, despite its established benefits in treating hypertension, there is limited real-world evidence evaluating the efficacy of nonsteroidal MRAs specifically in PA patients. Moreover, few studies have investigated how these agents impact PA-specific outcomes, particularly patient-reported outcomes like quality of life (QOL).

The study by Yoshida et al. in this issue [8] investigated the effect of MR antagonism with esaxerenone, a nonsteroidal MRA, in a cohort of 25 PA patients over a 6-month treatment period, and evaluated various parameters including BP, urinary albumin to creatinine ratio (UACR), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), which reflects decreased myocardial stress or remodeling. The treatment resulted in significant and consistent reductions in both systolic and diastolic BP. Along with its effects on BP, the intervention reduced UACR levels. Decreased NT-proBNP levels were also observed over the treatment period.

Furthermore, Yoshida et al. uniquely examined how the effects of esaxerenone were influenced by factors such as dietary salt intake and BP control over time. No significant correlation was observed between estimated NaCl intake change and other parameters. Additional correlation analyses showed significant inverse correlation between DBP and NT-proBNP changes at 3 months after treatment, but this correlation disappeared at 6 months after treatment. In addition, changes of SBP and DBP did not significantly correlate with those of UACR or NT-proBNP at both 3 and 6 months after treatment.

QOL is another important factor when evaluating long-term therapies for chronic conditions like PA. In the study, Yoshida et al. [8] evaluated QOL using the SF-36 Health Survey, which measures both physical and mental health domains. The treatment not only maintained but also improved QOL scores over 6 months, particularly in areas related to physical functioning, vitality, and social interactions. This indicates that nonsteroidal MR antagonism is useful to effectively manage PA without compromising, and even improving, overall well-being of patients—an important factor in ensuring patient adherence to therapy.

Fujimoto et al. [9] specifically investigated the antihypertensive effects of nonsteroidal MRA over 1–3 months in PA patients. However, no significant changes were found in UACR or BNP, and QOL was not evaluated. These limitations highlight the need for further exploration of the effects of nonsteroidal MRAs in PA, particularly with regard to longer-term outcomes and patient-reported measures.

The study by Yoshida et al. in this issue [8] evaluated the treatment effect of esaxerenone in PA patients. The treatment significantly reduced BP under conditions of aldosterone excess. This study also implies that MRAs may exert intrinsic protective effects on both the kidney and heart beyond their BP-lowering capacity. The observed improvements in UACR and NT-proBNP levels, independent of BP reduction, indicate the potential of nonsteroidal MR antagonism to provide both cardioprotective and renoprotective benefits through mechanisms beyond simple BP control. While aldosterone excess is well known to induce harmful processes such as fibrosis, inflammation, and structural remodeling in the heart and kidneys [10], the ability of MRAs to mitigate these processes indicates the importance of MR overactivation.

Recent studies have further explored the molecular pathways involved in MR overactivation, independent of its primary ligand aldosterone, which may explain these broader protective effects [11]. One such mechanism is mediated by the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1), leading to kidney damage [12]. Also, diabetic kidney disease (DKD) model mice displayed Rac1-mediated MR activation, where treatment with finerenone, another nonsteroidal MRA, effectively reduced both BP and kidney damage [13]. These findings suggest the importance of MR antagonism in kidney protection, regardless of aldosterone excess.

In recent years, there has been increasing interest in understanding the cellular and molecular mechanisms by which MR overactivation contributes to kidney damage at a more detailed level. Advances in technology, such as single-cell transcriptomics and chromatin accessibility profiling, have allowed researchers to investigate the impact of MR activation on specific kidney cell populations. A recent study utilized these advanced techniques in a rat model to uncover the kidney-protective mechanisms of nonsteroidal MRAs [14]. The study identified that MR activation primarily affects principal and connecting tubule cells, influencing chromatin accessibility and gene expression. Finerenone, a nonsteroidal MRA, demonstrated pronounced efficacy in reducing albuminuria and modulating gene expression in podocytes and proximal tubule cells. This protective effect, observed beyond its BP-lowering actions, involved key genes linked to fibrosis and inflammation, such as Spp1, Il34, and Pdgfb, highlighting its targeted renal benefits.

Yoshida et al. revealed that esaxerenone was well-tolerated throughout the 6-month study period, with no significant adverse events related to hyperkalemia or renal dysfunction [8]. This safety profile is critical when considering long-term treatment options for PA patients, especially those with concomitant renal insufficiency or electrolyte imbalances. Compared to steroidal MRAs like spironolactone, the absence of serious side effects makes nonsteroidal MRA a more suitable option for patients requiring chronic MRA therapy.

In conclusion, the study by Yoshida et al. [8] provides valuable evidence supporting the use of nonsteroidal MRA in managing PA. The findings suggest its efficacy in reducing BP and improving renal and cardiac markers, such as UACR and NT-proBNP, as well as QOL of PA patients (Fig. 1). These results highlight its potential not only as an effective antihypertensive agent but also as a compound with broader renoprotective, cardioprotective, and systemic benefits. However, several important questions remain. As the authors acknowledge, the study’s small cohort size, single-center design, and non-randomized design limit the generalizability of the findings. While the short-term benefits are clear, the 6-month follow-up may still be insufficient to fully assess long-term efficacy, particularly in preventing cardiovascular and renal remodeling. Future studies with larger, more diverse patient populations and extended follow-up periods will be critical in confirming whether the early improvements observed in this study translate into sustained clinical outcomes.

Fig. 1
figure 1

Therapeutic effects of Esaxerenone on MR pathway and associated outcomes in PA patients. This figure illustrates the therapeutic effects of esaxerenone, a nonsteroidal MRA, on patients with PA. PA patients experience overactivation of the MR, contributing to pathological changes in the kidneys and heart. Esaxerenone binds to MR, blocking its harmful activation. This leads to significant improvements in renal function (e.g., reduced UACR), cardiac function (e.g., reduced NT-proBNP), and overall QOL. PA primary aldosteronism, MR mineralocorticoid receptor, MRA, mineralocorticoid receptor antagonist, UACR urinary albumin-to-creatinine ratio, NT-proBNP N-terminal prohormone of brain natriuretic peptide, QOL quality of life

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Moreover, the underlying molecular mechanisms by which nonsteroidal MR antagonism confers organ protection, independent of its BP-lowering effects, remain to be fully elucidated. While these findings are promising, more research is needed to confirm its the broader applications in PA and related conditions. Exploring these pathways could reveal new therapeutic opportunities and provide a deeper understanding of how MRAs mitigate the harmful effects of aldosterone excess. Expanding this research into other hypertensive and cardiovascular disease models could further broaden our understanding of its potential applications in clinical practice.