2016 Endocrine Society guidelines update for the diagnosis of primary aldosteronism: are the proposed aldosterone-to-renin ratio cut-off values relevant in the era of fully automated immunoassays?

The Endocrine Society guidelines for the management of primary aldosteronism (PA) have been updated recently. ¹ As before, determination of the aldosterone-renin ratio (ARR) is advocated as the most reliable tool to screen for PA in high-risk groups of hypertensive patients; this recommendation echoes a widely held view.^2,3 The guidelines provide a list of ARR cut-off values, reflecting the use of plasma renin activity (PRA) or direct renin concentration (DRC), and on multiple different units respectively for PRA, DRC and plasma aldosterone concentration (PAC).

The proposed ARR cut-off values are a useful starting point. However, it is essential that individual laboratories carefully select the appropriate ARR cut-off value. This varies substantially (by as much as two-fold), depending on the analytical methods used; for example, aldosterone methods with or without extraction provide one source of variation.^4–6 This problem affects renin methods to a lesser extent. Variation between methods should prompt examination of the clinical validity of the proposed ARR cut-off values in terms of test performance parameters like sensitivity and specificity.

The ARR cut-off values proposed in the current guidelines ¹ are similar to those previously advocated in the 2008 guidelines. ² However, in the interim, several methods have been developed, including liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoassays. The proposed ARR cut-off values require clinical validation against these new methods. In particular, two new fully automated chemiluminescent assays for DRC and PAC on, respectively, Liaison (Diasorin, Dartford, UK) and iSYS (IDS, Tyne & Wear, UK) platforms are now being promoted on the basis of their technical feasibility, high throughput and lower cost in comparison with LC-MS/MS. A method-specific ARR cut-off with direct, automated chemiluminescence immunoassays for PAC and DRC has recently been validated in a large cohort of hypertensive patients, allowing discrimination between PA and essential hypertension. ⁷ In this study, an ARR cut-off of 1.12 (with PAC in ng/dL and DRC in mIU/L) was reported to offer 99% sensitivity and 79% specificity for diagnosis of PA; the corresponding cut-off proposed in the recent guidelines is 3.7 ng/dL/mIU/L. ¹ With the Liaison automated chemiluminescent immunoassay system, an ARR cut-off of 2.7 ng/dl/mIU/L has been reported to offer 78% sensitivity and 100% specificity for the diagnosis of PA. ⁸

The findings of these studies demonstrate the risk of false negative classification if laboratories using these automated methods apply the proposed ARR cut-off of 3.7 ng/dL/mIU/L. ¹ Individual laboratories should select an ARR cut-off value (for their combination of renin and aldosterone methods) that is based on the literature, on method comparison studies and, ideally, on validation in their local population.