Primary aldosteronism (PA) is associated with a higher risk of cardiovascular and chronic kidney diseases than essential hypertension. Therefore, screening for PA in hypertensive patients and treating them according to their pathophysiology with either adrenalectomy or medical therapy with mineralocorticoid receptor antagonists (MRAs) has been actively recommended [1]. Patients with idiopathic aldosteronism due to bilateral adrenocortical hyperplasia or unilateral adrenocortical adenoma who do not wish to undergo surgical resection require lifelong MRA therapy [2]. The goal of PA treatment is not only to decrease blood pressure and correct serum potassium levels but also to reduce the risk of cardiovascular events and mortality.

Until now, the correction of blood pressure and serum potassium levels has primarily been a therapeutic milestone [3], but this perception is beginning to change with the findings on the relationship between renin activity and cardiovascular events reported by Hundemer et al. in 2018 [4]. In their report, they compared the risk of cardiovascular events and death in PA patients treated with MRAs to that in patients with essential hypertension. The hazard ratio for cardiovascular events was 2.83 (95% confidence interval [CI], 2.11-3.80) and that for death was 1.78 (95% CI, 1.14-2.80) in PA patients whose plasma renin activity (PRA) was still suppressed (<1.0 μg/L/h) compared with essential hypertension patients. However, these risks in patients with PA whose PRA was not suppressed (≥1 μg/L/h) were similar to those of patients with essential hypertension. In other words, increasing renin activity is now considered an important milestone in PA treatment with MRAs. This perspective has already been mentioned in the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019) [5] and clearly stated in the Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism, which recommends that treatment should proceed according to PRA levels in addition to blood pressure and serum potassium levels [6]. Renin activity is thought to be a sensitive indicator of mineralocorticoid receptor (MR) activity, and continued suppression of renin activity suggests residual MR activity [7]. Thus, to prevent cardiovascular events in patients with PA, mainly due to excessive aldosterone signaling, it may be necessary to titrate MRAs using renin activity as an indicator of MR activity.

In this issue of the journal, Yoshida et al. discuss the correlation between the change in the active renin concentration (ARC) and the change in estimated dietary salt intake in 26 PA patients undergoing MRA treatment [8]. They divided patients into two groups: those with an ARC ≥ 5 pg/mL (corresponding to PRA ≥ 1 μg/L/h) after 6 months of MRA treatment in whom renin activity was not suppressed and those with an ARC < 5 pg/mL in whom renin activity was still suppressed. Interestingly, a statistically significant negative correlation was observed between changes in the ARC and estimated salt intake in patients with an ARC < 5 pg/mL, whose blood pressure was not improved after MRA treatment. Therefore, the authors concluded that suppressed renin activity after the initiation of MRA therapy indicates possible residual salt sensitivity, in other words, incomplete suppression of MR activity in patients with an ARC < 5 pg/mL. As shown above, this may be an additional insight that supports the concept that renin activity is clinically useful as a milestone in MRA treatment. Furthermore, the authors emphasized the importance of reducing dietary salt consumption in PA patients by mentioning the estimated salt intake during MRA treatment.

Dietary salt intake tends to increase in PA patients due to an impaired threshold of salt taste perception caused by hyperaldosteronism, and salt intake also remains high during MRA treatment [1]. Furthermore, the organ damage associated with hyperaldosteronism is enhanced in a high-salt environment. Catena et al. [9] reported that the left ventricular mass index (LVMI) prior to MRA treatment or adrenalectomy was associated with urinary sodium excretion and the plasma aldosterone concentration in patients with PA. Moreover, the LVMI was more improved in the group that achieved at least a 10% reduction in urinary sodium excretion 1 year after MRA initiation or adrenalectomy than in the group that did not achieve this reduction. In several in vitro studies, the high-salt environment itself promoted left ventricular hypertrophy, regardless of blood pressure control. Ras-related C3 botulinum toxin substrate 1 (Rac1)-mediated aldosterone-independent MR activation has been postulated to have detrimental effects in high-salt environments [10]. These findings suggest that dietary salt reduction is essential for PA patients even during MRA treatment, and Yoshida et al. [8] also emphasized the need for salt restriction prior to increasing the MRA dose in PA patients with low renin activity with reference to medical costs.

However, this approach of salt reduction without MRA titration may not be sufficient to prevent cardiovascular events because the residual salt sensitivity of patients with PA is assumed to be due to inadequate suppression of MR activity. In patients with PA, aldosterone secretion is renin-independent and autonomous [1]; therefore, salt reduction itself cannot suppress MR activity sufficiently, while it is effective in lowering blood pressure. Importantly, appropriate suppression of MR activity by titrating the MRA dose in addition to salt reduction may be the principle of PA medical treatment, possibly contributing to the cardiovascular event risk reduction (Fig. 1). Unfortunately, the interaction of dietary salt intake, renin activity, and MRA dose was not observed in the study by Yoshida et al. [8], and the burden of salt intake did not change after 6 months of MRA therapy. Further studies are therefore needed to determine the impact of salt reduction on renin activity, MR activity, and the risk of cardiovascular events in patients with PA undergoing MRA treatment.

Fig. 1
figure 1

Possible pathophysiology of primary aldosteronism and the effects of mineralocorticoid receptor antagonists and dietary salt restriction. The blue letters and arrows indicate pathways related to salt intake. MR mineralocorticoid receptor, MRA mineralocorticoid receptor antagonist

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Although PA is a well-established disease entity, evidence is still accumulating on which measures of treatment improve prognosis in PA patients undergoing MRA therapy. Yoshida et al. [8] allowed us to reconsider the role of MR activity and salt reduction, which may be important milestones in PA treatment. We believe their work could provide a novel perspective on better clinical management and pharmacotherapy for PA, which may contribute to improved cardiovascular outcomes in this patient population.