Age- and Sex-Specific Reference Ranges Are Needed for the Aldosterone/Renin Ratio

Pravik Solanki; Stella May Gwini; James C. G. Doery; Kay Weng Choy; Jimmy Shen; Morag J. Young; Peter J. Fuller; Jun Yang

Disclosures

Clin Endocrinol. 2020;93(3):221-228. 

In This Article

Abstract and Introduction

Abstract

Objective: Current Endocrine Society Clinical Practice Guidelines use a specific aldosterone/renin ratio (ARR) threshold to screen for primary aldosteronism (a treatable disease causing up to 15% of hypertension in primary care) in all patients. We sought to characterize demographic variations in the ARR, hypothesizing a need for age- and sex-specific reference ranges to improve the accuracy of the test.

Design: Retrospective cross-sectional analysis of ARR measurements at a single tertiary hospital from December 2016 to June 2018.

Patients: A total of 442 patients with clinically indicated ARR were included, after excluding those who were on spironolactone or the oral contraceptive pill, were pregnant or had an existing adrenal condition.

Measurements: Aldosterone, renin and the ARR.

Results: Among those aged 20–39 years (n = 74), females had significantly higher median aldosterone (369 vs 244 pmol/L, P = .028), lower median renin (17.0 vs 27.6 mIU/L, P = .034) and higher median ARR (20.7 vs 10.3 (pmol/L)/(mIU/L), P = .001) than males, despite having lower systolic (135 vs 145 mmHg, P = .021) and diastolic (89 vs 96.5 mmHg, P = .007) blood pressure. The ≥ 60-year age group (n = 157) also had significant sex differences in the ARR. With increasing age (20–39 vs ≥ 60 years), there was a significant fall in plasma aldosterone in females (369 pmol/L vs 264 pmol/L, P = .005), with no change observed in males.

Conclusions: For those 20–39 years old, aldosterone and the ARR are significantly higher in females despite a lower systolic and diastolic BP, highlighting the potential for false-positive results. Our findings indicate the need for prospective studies with a control population to define age- and sex-specific ARR reference ranges.

Introduction

Hypertension is a significant risk factor for cardiovascular disease. Although most hypertensive patients have essential hypertension (EH), an estimated 3%-15% of hypertension in primary care is caused by primary aldosteronism (PA), a treatable condition of aldosterone excess.[1,2]

Patients with PA experience greater end-organ complications than patients with EH alone, independent of blood pressure, due to the proinflammatory and profibrotic effects of inappropriate mineralocorticoid receptor (MR) activation by aldosterone.[3] A meta-analysis of 31 studies found that after a median of 8.8 years, prevalence rates were three-and-a-half-fold for atrial fibrillation, two-and-a-half-fold for stroke and double for heart failure among patients with PA compared to those with EH.[4] As such, patients with PA have significantly greater cardiovascular risk and a reduced quality of life.[5] However, PA is highly treatable, either with targeted MR antagonist therapy (such as spironolactone) or adrenalectomy to remove an aldosterone-producing adenoma and potentially cure the hypertension.[5]

The aldosterone/renin ratio (ARR) is the recommended screening test for PA, reflecting the pathophysiology of autonomously produced aldosterone alongside a relatively suppressed renin.[6] It is more accurate for detecting PA than aldosterone or renin measurements alone,[7] with a sensitivity of 73%-93% and specificity of 71%-84%.[8] The Endocrine Society Clinical Practice Guidelines recommend a range of ARR cut-off values to define an abnormal result, depending on the assays used and units of measurement.[9] At our centre, the cut-off is 70 (pmol/L)/(mU/L), with the plasma aldosterone concentration (PAC) in pmol/L and the direct renin concentration (DRC) in mU/L, measured by chemiluminescence. The ARR determines the need for a saline suppression test to formally diagnose PA, followed by adrenal venous sampling to further subtype PA. These tests are invasive and time-consuming, and therefore, the accurate interpretation of an ARR is critically important for the appropriate triage of patients in the PA diagnostic pathway.

While the diagnostic threshold for ARR differs around the world,[6] in all centres, there is a single cut-off for men and women of all ages. However, limited studies suggest underlying age- and sex-based differences in the ARR,[10] which could affect the accuracy of this test for different patient populations, leading to missed diagnoses or unnecessary invasive testing.

Several studies indicate that females have higher aldosterone, lower renin and higher resultant ARR than males, regardless of hypertension or PA status.[11–13] An early study of 96 normotensive volunteers found females to have a 46% higher median ARR than males,[14] while another study that randomly tested 287 individuals from a population register in Italy found 64.9% of those with an elevated ARR to be female.[15]

Studies have also shown that with increasing age, plasma aldosterone decreases,[11] while renin decreases to a greater extent,[16] leading to a higher ARR.[17] Current static ARR thresholds decrease in specificity with increasing age,[16] suggesting the need for higher ARR thresholds to detect PA in elderly populations.[18]

However, there is a paucity of studies of sufficient sample size that stratify the sample population into different sex and age groups. Due to limited evidence, diagnostic thresholds for ARR have not been further stratified by age or sex in current guidelines. To address this knowledge gap, we aim to investigate aldosterone, renin and ARR levels in stratified groups to quantify age- and sex-based differences.

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