Novel Approach to Establishing an Aldosterone: Renin Ratio Cutoff for Primary Aldosteronism

Abstract

P rimary aldosteronism (PA) is a common form of remediable hypertension. The aldosterone:renin ratio (ARR) is the recommended screening test for PA in individuals with hypertension with or without hypokalemia. [1][2][3] Elevations in the ratio are predominantly dependent on renin measurements, 2 thus any alteration to the renin assay will have an impact on the resulting ARR. 4 Plasma renin activity (PRA) has traditionally been used to calculate the ARR; however, measurement of direct renin concentration (DRC) has become increasingly popular because the assay procedure is less labor and time intensive. Although numerous conversion factors have been proposed in an effort to generate clinically meaningful and stable cutoffs between assays, 1 it remains uncertain whether an interchangeable relationship exists, especially as PRA and DRC are biologically distinct entities. Head-to-head comparisons are often performed by simultaneously measuring PRA and DRC, looking for correlations to establish stable conversion factors. Such studies are generally small thus limiting their general applicability. [5][6][7][8][9][10][11] Moreover, the Endocrine Society has advised that the correlation between PRA and DRC is poor at lower renin levels, the domain of greatest importance for PA screening. 1 Indeed, differences in analytical method can result in as much as a 2-fold variation in ARR cutoffs and classification error.12 On a population level, this may result in significant downstream consequences with tremendous clinical and public health implications.Addressing this, we developed a novel yet easily generalizable approach to determining ARR cutoffs using population-based data without relying on direct assay comparisons or conversion factors. The specific aim of our study was to produce a new DRC-based ARR threshold consistent with an established PRA-based ARR cutoff, thus providing diagnostic congruity with established thresholds used in routine practice. Our approach is based on 2 inter-related assumptions: first, in a defined healthcare system with a relatively static population pool, screening is performed in similar types of patients; and second, of those who are screened, the prevalence of PA has remained stable over time.Abstract-Direct renin concentration is replacing plasma renin activity in many laboratories for the investigation of primary aldosteronism, which may have a significant impact on the resulting aldosterone:renin ratios. We sought to develop a population-based approach to establishing an aldosterone:renin ratio cutoff when transitioning between assays. A population-based study was performed in Calgary, Alberta, Canada of 4301 individuals who received testing from January 2012 to November 2015. In 2014, direct renin concentration replaced plasma renin activity in routine testing. We described the prevalence of primary aldosteronism in our population before the change and, using the assumption of disease prevalence stability, determined the corresponding ratio cutoffs after the introduction of the new assay....

Autonomous Aldosterone Secretion as a Subclinical Form of Primary Aldosteronism: Pathogenesis and Clinical Significance

“…Multiple ARR and ADRR thresholds have been applied; the ES guideline mentions ARR cutoffs of 20, 30, and 40 ng/dl per ng/ml/h, while the ESH consensus suggests an ADRR between 11.2 and 27 ng/mIU (further in this review ARR is expressed consistently in ng/dl per ng/ml/h and ADRR in ng/mlU without providing units) [4][5][6][7]. In a large cohort study, an ADRR of 12.6 was observed to correspond to an ARR of 20 [8]. As a rule, following the positive screening, PA diagnosis requires confirmation with one of four tests: 1) captopril suppression test (CST), 2) fludrocortisone suppression test (FST), 3) oral sodium loading test (OSLT), and 4) salt (0.9 % natrium chloride) infusion test (SIT).…”

Dr. Conn Lives on: Insights Into Screening and Genetics of Primary Aldosteronism

“…Nevertheless, it is uncertain whether an interchangeable relationship exists, particularly because PRAs and DRCs are biologically distinct entities. [7][8][9] The correlation between DRC and PRA is generally good, except when PRAs are ,1 ng/ml/hour, which corresponds to the most relevant PA clinical screening scenario. 7 In a recently introduced and already commonly used automated DRC assay, the conversion factor is 12.…”

“…Specifically, DRCs are less laborand time-intensive procedures and have shorter turnaround times, better reproducibility, and greater ease of standardization. 8 The calculation of the ratio of aldosterone-to-direct renin concentration (ADRR) may be employed as a screening test for PA instead of the ARR. The ADRR is also termed the plasma aldosterone-to-direct renin concentration ratio (PAC/DRC).…”

“…Another population-based study was conducted in Canada with the goal of establishing an ARR cutoff during the transition from PRA to DRC assays. 8 In Calgary, DRC testing replaced the PRA for routine testing in 2014; 4301 participants who received testing between January 2012 and November 2015 were included. During the initial portion of the study using PRAs and locally validated cutoff values, 4.9% of screenees were classified as highly probable cases of PA, 10.4% probable, and 28.9% possible.…”

“…This data-driven approach would lead to fewer falsenegative results, i.e., greater sensitivity. 8 In summary, the use of DRCs and ADRRs as opposed to classical PRAs and ARRs remains problematic because standardized conversion methodologies do not work well when renin is suppressed-the clinical scenario most relevant during screening for PA. As feasible, health care providers evaluating patients for possible PA should rely on local experience and continue to order PRAs and ARRs until issues surrounding DRCs and ADRRs are clarified.…”