Macrolide-induced aldosterone suppression as a functional marker of KCNJ5-mutated aldosterone-producing adenoma: a proof-of-concept clinical and experimental study (MAPA study).
Rossi G, Caroccia B, et al. • European journal of endocrinology • 2026
Roxithromycin selectively suppressed plasma aldosterone concentration in patients with KCNJ5-mutated aldosterone-producing adenomas but not in wild-type APA or non-PA patients, representing a potential functional marker of KCNJ5 mutations for precision subtyping of primary aldosteronism.
Key Findings
Results
Roxithromycin reduced plasma aldosterone concentration (PAC) selectively in patients with KCNJ5-mutated APA but not in those with wild-type APA or non-PA hypertension.
Among 373 challenged patients, 18 had KCNJ5 (G151R or L168R)-mutated APA, 25 had wild-type APA, and 307 had no PA.
PAC reduction was statistically significant only in the KCNJ5-mutated APA group (P < .001).
The pharmacologic challenge used a single oral dose of roxithromycin.
Wild-type APA patients showed no significant aldosterone suppression in response to roxithromycin.
Results
Roxithromycin did not lower blood pressure in patients with KCNJ5-mutated APA despite suppressing aldosterone.
Despite significant PAC reduction in KCNJ5-mutated APA patients, BP values were not lowered.
This finding suggests that a single-dose acute aldosterone suppression is insufficient to produce measurable antihypertensive effects.
The study used a single oral dose as a pharmacologic challenge rather than a chronic dosing regimen.
Results
Roxithromycin produced a small blood pressure decrease in non-PA hypertensive patients through an aldosterone-independent mechanism.
The BP-lowering effect in non-PA patients occurred without significant aldosterone suppression, indicating a distinct mechanism of action.
Mouse studies indicated this effect involved macrolide-induced attenuation of angiotensin II actions.
The antihypertensive mechanism involved enhancement of endothelium- and nitric oxide-dependent vasodilation.
This aldosterone-independent antihypertensive effect was characterized in mouse experimental studies.
Results
Mouse studies demonstrated that macrolide-induced blood pressure lowering involves nitric oxide-dependent vasodilation and attenuation of angiotensin II actions.
Experimental mouse studies were used to characterize the hemodynamic effects of macrolides.
The mechanism involved enhancement of endothelium-dependent vasodilation.
Angiotensin II actions were attenuated by macrolide treatment in mouse models.
These findings provide a mechanistic basis for the observed aldosterone-independent antihypertensive effect seen in non-PA patients.
Discussion
The selective suppression of aldosterone by roxithromycin in KCNJ5-mutated APA aligns with ex vivo mechanistic data and may serve as a functional marker for KCNJ5 mutations.
Prior in vitro studies had shown KCNJ5 mutations render aldosterone synthesis sensitive to macrolides.
The in vivo findings in this prospective within-patient pharmacologic challenge study are consistent with these ex vivo mechanistic data.
The authors propose this approach could help guide precision subtyping of PA patients.
Primary aldosteronism is described as 'the most common curable form of hypertension.'
Methods
The study was a prospective, within-patient pharmacologic challenge conducted at a specialized Hypertension Center at the University of Padua, enrolling 373 consecutive hypertensive patients screened for PA.
Design was prospective with within-patient comparison of pharmacologic challenge outcomes.
Eligible consecutive hypertensive patients were recruited from the University of Padua Hypertension Center.
Outcomes measured included within-patient changes in PAC, active renin, cortisol, and blood pressure.
KCNJ5 mutations examined were specifically G151R and L168R variants.
What This Means
This research suggests that a common antibiotic class called macrolides — specifically roxithromycin — can be used as a diagnostic test to identify a specific genetic subtype of a hormone-producing benign tumor of the adrenal gland. Primary aldosteronism is the most common curable cause of high blood pressure, often caused by these tumors (called aldosterone-producing adenomas or APAs) that release too much of the hormone aldosterone. Some of these tumors carry mutations in a gene called KCNJ5, and laboratory studies had previously shown these mutations make the tumors sensitive to macrolide antibiotics. In this study of 373 patients, a single dose of roxithromycin selectively lowered aldosterone levels only in patients whose tumors carried KCNJ5 mutations — not in patients with tumors lacking these mutations, and not in hypertensive patients without the condition at all.
This finding is important because identifying which patients have KCNJ5-mutated tumors currently requires complex and invasive procedures. A simple single-dose pharmacologic test with roxithromycin could potentially serve as a non-invasive 'functional marker' to help doctors identify which subtype of primary aldosteronism a patient has, enabling more targeted and precise treatment decisions. Notably, despite lowering aldosterone, a single dose of roxithromycin did not lower blood pressure in the tumor patients, suggesting longer treatment would be needed for blood pressure benefits.
The study also discovered that roxithromycin slightly lowered blood pressure in hypertensive patients who did not have primary aldosteronism at all, through a completely different mechanism unrelated to aldosterone. Mouse experiments revealed this effect involves the drug reducing the actions of angiotensin II (a blood pressure-raising molecule) and enhancing blood vessel relaxation through a pathway involving nitric oxide. This suggests macrolide antibiotics may have modest blood pressure-lowering properties independent of their effects on aldosterone, though the clinical significance of this effect would require further study.
Rossi G, Caroccia B, Bressan A, Byiringiro C, García-Redondo A, Ceolotto G, et al.. (2026). Macrolide-induced aldosterone suppression as a functional marker of KCNJ5-mutated aldosterone-producing adenoma: a proof-of-concept clinical and experimental study (MAPA study).. European journal of endocrinology. https://doi.org/10.1093/ejendo/lvag161