Beyond aldosterone and renin: emerging biomarkers for diagnosing and subtyping primary aldosteronism.

Primary aldosteronism (PA) is the most common endocrine cause of high blood pressure, affecting more than 1 in 10 people with hypertension. Once considered rare, it has become a public health priority because undiagnosed PA confers significantly higher risks of stroke, myocardial infarction, heart failure, chronic kidney disease, and impaired quality of life. As a result, international guidelines now recommend routine screening for PA in all adults with hypertension. Despite this progress, diagnostic challenges remain. Conventional screening with plasma aldosterone, renin, and the aldosterone-to-renin ratio suffers from intra-individual variability and interference by medications, diet, posture, amongst other factors. Even when PA is diagnosed, distinguishing lateralizing from non-lateralizing adrenal disease is difficult. The current gold-standard test, adrenal vein sampling, is invasive, technically demanding, confined to specialized centers, and often yields inconclusive results. Emerging biomarker research offers new opportunities. Novel steroidomic-based approaches, such as steroid profiling, show promise for both diagnosis and subtyping. Circulating and urinary proteomic and metabolomic signatures are beginning to reveal molecular fingerprints of PA and its subtypes, while transcriptomic studies of adrenal tissue, circulating cells, and extracellular vesicles, along with circulating microRNAs, provide insights into pathophysiology and candidate diagnostic markers. Markers of end-organ damage are also emerging as complementary indicators of disease burden and treatment response. This review synthesizes current molecular and clinical biomarker research in PA, with an emphasis on their diagnostic, subtyping, and prognostic potential. By integrating traditional hormone assays with advances in multi-dimensional biomarker discovery, we highlight possibilities that may transform the diagnosis and management of PA.