Opportunistic aldosterone testing during hypokalemia as an alternative confirmatory test for primary aldosteronism

Background Primary aldosteronism (PA) is a common secondary cause of hypertension and confers additional cardiovascular, renal and metabolic risks. While recent guidelines recommend universal screening, screening rates remain low (<2%) even in high-risk groups (hypertension and hypokalaemia). Guidelines recommend correction of hypokalaemia prior to screening tests. We hypothesized that the physiological suppression of aldosterone by hypokalaemia can be an aldosterone suppression test and expedite the diagnostic process. Purpose To evaluate the diagnostic performance of opportunistic aldosterone and renin testing during spontaneous hypokalemia for identifying PA. Methods We conducted an international multicenter retrospective cohort across 19 centers in 15 countries. We included hypertensive patients who underwent aldosterone and renin testing during hypokalaemia from 2010 to 2025. Patients were classified as PA using the Endocrine Society criteria (severe phenotype or positive confirmatory testing). In addition, those with lateralization on adrenal vein sampling (AVS) or complete biochemical success post-adrenalectomy were classified as unilateral PA. Essential hypertension (EH) was defined by normal aldosterone-renin ratio during normokalaemia, or negative confirmatory testing. Diagnostic performance was assessed using ROC analysis, and a multivariable logistic model incorporating plasma aldosterone concentration (PAC) and direct renin concentration (DRC) was developed and internally validated using bootstrap resampling. Results We included 942 patients, mean age 59.9 ± 12.6 years, 42.3% female. There were 81 (8.6%) with EH, and 861 (91.4%) with PA. Among patients with PA, 302 (35.1%) had unilateral PA, 187 (21.7%) bilateral PA, and 372 (43.2%) were indeterminate (AVS failed or not done). Compared with EH, patients with PA had higher blood pressure, higher PAC and lower DRC (p<0.001). Amongst patients with PA, median PAC were lower during baseline hypokalemia (24.8 ng/dL, IQR 17.5-38.5) vs post-potassium replacement (29.3 ng/dL, IQR: 21.2–47.0), p<0.0001. Using PAC alone differentiated PA vs EH (AUROC 0.836, 95% CI: 0.790-0.882), and the model improved when both PAC and DRC (≤10mIU/L) were used (AUROC 0.868, 95% CI: 0.829-0.907), De Long’s test (p<0.0007). Using a threshold of PAC ≥ 14.6 ng/dL, coupled with DRC ≤10mIU/L, 652 of 861 patients with PA were diagnosed, with a specificity of 85.2% and sensitivity of 75.7%. Conclusion Although hypokalemia suppresses aldosterone physiologically, patients with PA maintain persistent aldosterone secretion. Hence, opportunistic testing of aldosterone and renin during presentation with hypokalemia allows an expedited diagnosis of PA. This is particularly useful in individuals with severe disease when potassium normalization is challenging.