PSUN51 Re-Calibrating Aldosterone Assay Interpretations: Immunoassay and Liquid Chromatography-Tandem Mass Spectrometry Measurements Across Multiple Controlled Physiologic Conditions

BACKGROUND: Clinicians frequently rely on aldosterone thresholds derived from older immunoassays to diagnose primary aldosteronism. However, liquid chromatography tandem mass spectrometry (LC-MS/MS) is in increasingly widespread clinical use and has been reported to yield lower aldosterone concentrations. Given that primary aldosteronism is highly prevalent and morbid, yet rarely diagnosed, incorrect interpretations of aldosterone levels can have significant public health impact. To address the potential for incorrect interpretations across the entire dynamic range of aldosterone physiology, we compared aldosterone measurements using LC-MS/MS and immunoassay under controlled physiologic conditions. METHODS: Untreated, normotensive, overweight volunteers (n=48) underwent prospective characterization of aldosterone production during four controlled conditions: oral sodium suppression and dietary sodium restriction (to capture the full range of Angiotensin II-mediated aldosterone production) and dexamethasone suppression and cosyntropin stimulation (to capture the full range of ACTH-mediated aldosterone production). Serum aldosterone from each condition (n=188 samples) was measured by both immunoassay and LC-MS/MS. RESULTS: Serum aldosterone concentrations by LC-MS/MS and immunoassay had a Pearson correlation of 0.69 (p<0.001), with good agreement (intraclass correlation coefficient 0.76 [95% CI 0.52-0.87]). Overall, aldosterone was 37.2% lower by LC-MS/MS than immunoassay (median 10.5 [IQR 3.8, 21.9] vs. 19.6 [9.5, 28.0] ng/dL; p<0.001) with an average bias of 7.2 (SD 12.0) ng/dL by Bland-Altman analysis. The most notable discrepancy was observed in the clinically discriminatory range below 20 ng/dL: 9.9 [7.1, 13.8] ng/dL by immunoassay corresponded to 5.5 [1.4, 8.9] ng/dL by LC-MS/MS (p<0.001), a median difference of 49.6% [20.6, 75.2%] higher by immunoassay. Following oral sodium suppression testing, the aldosterone-to-renin ratio was 4-fold higher by immunoassay than by LC-MS/MS (27.2 [19.7, 62.4] vs. 6.4 [3.5, 19.1] ng/dL per ng/mL/h; p<0.001). CONCLUSIONS: Aldosterone measurements are systematically lower by LC-MS/MS than by immunoassay across the entire physiologic spectrum of aldosterone production; this effect was especially pronounced – up to 50-65% lower – when aldosterone levels were less than 20 ng/dL, meaning that clinicians should be careful to verify the assay used and the clinical context before excluding the diagnosis of primary aldosteronism. Our findings highlight the risk for false negative interpretations with increasingly common LC-MS/MS assays, thereby underscoring the urgent need to raise awareness among clinicians that interpretations of circulating aldosterone and aldosterone-to-renin ratio values need to be re-calibrated to include much lower values than previously recommended. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.