Mulatero, Paolo

BACKGROUND: Primary aldosteronism (PA) is a common and treatable cause of hypertension, yet data on the durability of medical treatment response beyond the first year are limited. Using the PA medical treatment outcomes framework, we evaluated long-term biochemical and clinical outcomes and factors associated with treatment response. METHODS: We conducted an international, multicenter, observational cohort study across 27 centers on 4 continents. Adults with PA treated with mineralocorticoid receptor antagonists and/or epithelial sodium channel blockers between 2016 and 2021 were included if follow-up data were available at ≥12 months. Biochemical and clinical responses were classified as complete, partial, or absent using PA medical treatment outcomes criteria. Ordinal logistic regression identified determinants of a favorable treatment response. RESULTS: The cohort included 1292 patients (47.5% women, mean age 52 years) with a median follow-up of 34 months (interquartile range, 21–51). At ≥12 months, 58.3% achieved a complete biochemical response, and 20.8% achieved a complete clinical response, with only 5% showing no response. Determinants of a favorable biochemical response included lower aldosterone and lateralization index, and higher renin and potassium levels at baseline. In those taking spironolactone, a higher daily dose was also associated with a favorable biochemical response. Determinants of a favorable clinical response included female sex, lower body mass index, shorter duration of hypertension, and absence of hypertension-mediated organ damage. CONCLUSIONS: Targeted medical therapy for PA can deliver sustained biochemical and clinical benefits. Early disease detection and adequate dose titration are highly actionable determinants of long-term treatment success.

Abstract Disclosure: A. Prete: HRA Pharmaceuticals, Lundbeck, Diurnal. L. Adbi: None. J.T. Bain: None. F. Shaheen: None. O. Suntornlohanakul: None. E. Deflorenne: None. A. Blanchard: None. M. Nestola: None. C. Pamporaki: None. I. Tizianel: None. E. Nowak: None. J. Bertherat: None. D.A. Vassiliadi: None. I. Bancos: None. C.M. Dennedy: None. D. Kastelan: None. M. Fassnacht: None. P. Mulatero: None. U. Ambroziak: None. A. Tabarin: None. M. Quinkler: None. S. Puglisi: None. J. Deinum: None. G.Å. Ueland: None. L. Lenzini: None. F. Beuschlein: None. M. Reincke: None. F. Ceccato: None. G. Eisenhofer: None. S.M. Corsello: None. L. Amar: None. M. Zennaro: None. N. Karavitaki: None. A.E. Taylor: None. W. Arlt: None. Introduction: Twenty-four-hour urinary free cortisol is used to diagnose Cushing’s syndrome (CS); amongst its limitations is failure to differentiate ACTH-dependent CS (AD-CS) from ACTH-independent CS (AI-CS). We tested the performance of urine steroid metabolomics (USM), the computational analysis of 24-hour urine steroid metabolome data by machine learning, for the diagnosis and differential diagnosis of CS. Given the physiological diurnal rhythm of cortisol secretion and its loss in CS, we also hypothesised that the difference in glucocorticoid excretion between CS and controls should be higher during nighttime, thereby facilitating more sensitive detection of CS. Methods: 264 subjects completed a 24-hour urine collection (40 AD-CS, 103 AI-CS due to adrenocortical adenoma or hyperplasia, 121 healthy subjects). A subset of 52 individuals (13 CS, 39 healthy) provided a nighttime urine collection and a daytime urine collection. Mass spectrometry-based multi-steroid profiling was used to quantify the urinary excretion of 27 steroid metabolites. Data were analysed by generalised matrix learning vector quantisation (a prototype-based supervised machine learning approach), multiple linear regression adjusted for age, sex, and BMI, and multiple logistic regression adjusted for age, sex, and BMI. Results: Twenty-four-hour USM demonstrated very high accuracy in differentiating CS from healthy individuals (AUC-ROC 0.99, 95%CI 0.99-0.99), reflected by higher urinary excretion of glucocorticoid and glucocorticoid precursor metabolites in CS. USM yielded high accuracy in differentiating AD-CS from AI-CS (AUC-ROC 0.91, 95%CI 0.89-0.94), with androgen metabolites being the most discriminatory. We observed significant sex differences in steroid excretion in both healthy individuals and those with CS. Women exhibited markedly lower excretion of both glucocorticoids and mineralocorticoids compared to men: average glucocorticoid excretion was reduced by 43% in healthy women and 30% in CS women, while average mineralocorticoid excretion was 29% lower in healthy women and 51% lower in CS women (results adjusted for age and BMI). Timed steroid excretion in healthy individuals reflected the diurnal pattern of adrenal steroid secretion, with lower nighttime than daytime excretion of glucocorticoid metabolites. Nighttime glucocorticoid metabolite excretion (AUC-ROC 1.00, 95%CI 0.99-1.00) performed better than daytime (AUC-ROC 0.91, 95%CI 0.77-1.00) and 24-hour excretion (AUC-ROC 0.94, 95%CI 0.86-1.00) in separating CS cases from healthy individuals. Conclusions: USM is a non-invasive, one-step candidate test for the accurate diagnosis and differential diagnosis of CS. Timed nighttime urine collection leverages cortisol circadian rhythmicity and improves the diagnostic accuracy of the current reference standard 24-hour collection. Presentation: Sunday, July 13, 2025

Abstract Background Primary aldosteronism (PA), a primary adrenal disorder leading to excessive aldosterone production by one or both adrenal glands, is a common cause of hypertension. It is associated with an increased risk of cardiovascular complications compared with primary hypertension. Despite effective methods for diagnosing and treating PA, it remains markedly underdiagnosed and undertreated. Objective To develop an updated guideline that provides a practical, clinical approach to identifying and managing PA to improve diagnosis rates and encourage targeted treatment. Methods The Guideline Development Panel (GDP), composed of a multidisciplinary panel of clinical experts and experts in systemic review methodology, used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to define 10 questions related to the diagnosis and treatment of PA. Systematic reviews were conducted for each question. The GDP used the GRADE Evidence to Decision (EtD) framework to consider contextual factors, such as stakeholder values and preferences, costs and required resources, cost-effectiveness, acceptability, feasibility, and the potential impact on health equity. Results We suggest that all individuals with hypertension be screened for PA by measuring aldosterone and renin and determining the aldosterone to renin ratio, and that subsequent clinical care be guided by the results. We suggest that individuals with PA receive PA-specific therapy, either medical or surgical. In individuals who screen positive for PA, we suggest (1) commencement of PA-specific medical therapy in individuals who do not desire or are not candidates for surgery and in situations where the probability of lateralizing PA (excess aldosterone produced by one adrenal) is low based on screening results; and (2) aldosterone suppression testing in situations when screening results indicate an intermediate probability for lateralizing PA and individualized decision making confirms a desire to pursue eligibility for surgical therapy. In those who test positive by aldosterone suppression testing, and in those in whom screening results show a high probability of lateralizing PA (obviating the need for aldosterone suppression testing), we suggest adrenal lateralization with computed tomography scanning and adrenal venous sampling prior to deciding the treatment approach (medical vs surgical). In all individuals with PA and an adrenal adenoma, we suggest performing a 1-mg overnight dexamethasone suppression test. We suggest the use of mineralocorticoid receptor antagonists (MRAs) over epithelial sodium-channel (ENaC) inhibitors in the medical treatment of PA. We suggest the use of spironolactone over other MRAs, given its lower cost and greater availability; however, all MRAs, when titrated to equivalent potencies, are anticipated to have similar efficacy in treating PA. Thus, MRAs with greater mineralocorticoid receptor specificity and fewer androgen/progesterone receptor-mediated side effects may be preferred in some situations. In individuals receiving MRA therapy, we suggest monitoring renin and, in those whose hypertension remains uncontrolled and renin is suppressed, titrating the MRA to increase renin. Conclusion These recommendations provide a practical framework for the diagnosis and treatment of PA. They are based on currently available literature and take into consideration outcomes that are important to key stakeholders. The goal is to increase identification of individuals with PA and, by initiating PA-specific medical or surgical therapy, improve blood pressure control and reduce PA-associated adverse cardiovascular events. The guidelines also highlight important knowledge gaps in PA diagnosis and management.

Abstract Primary aldosteronism (PA) is a common form of endocrine hypertension previously believed to account for less than 1% of hypertensive patients. Hypokalemia was considered a prerequisite for pursuing diagnostic tests for PA. Recent studies applying the plasma aldosterone/plasma renin activity ratio (ARR) as a screening test have reported a higher prevalence. This study is a retrospective evaluation of the diagnosis of PA from clinical centers in five continents before and after the widespread use of the ARR as a screening test. The application of this strategy to a greater number of hypertensives led to a 5- to 15-fold increase in the identification of patients affected by PA. Only a small proportion of patients (between 9 and 37%) were hypokalemic. The annual detection rate of aldosterone-producing adenoma (APA) increased in all centers (by 1.3–6.3 times) after the wide application of ARR. Aldosterone-producing adenomas constituted a much higher proportion of patients with PA in the four centers that employed adrenal venous sampling (28–50%) than in the center that did not (9%). In conclusion, the wide use of the ARR as a screening test in hypertensive patients led to a marked increase in the detection rate of PA.