The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension

Abstract

Background Primary aldosteronism is recognized as a severe form of “renin-independent aldosteronism” that results in excessive mineralocorticoid receptor (MR) activation. Objective To investigate whether there is a spectrum of subclinical renin-independent aldosteronism among normotensives that increases risk for hypertension. Design Cohort study. Setting National community-based study. Participants 850 untreated normotensive participants in the Multi-Ethnic Study of Atherosclerosis with measurements of serum aldosterone, plasma renin activity (PRA). Measurements Longitudinal analyses investigated whether aldosterone concentrations, in the context of physiologic PRA phenotypes (suppressed: ≤0.50; indeterminate: 0.51–0.99; unsuppressed: ≥1.0 μg/L/h), associated with incident hypertension, defined as SBP≥140, DBP≥90 mmHg, or initiation of anti-hypertensive medications. Cross-sectional analyses investigated associations of aldosterone with MR activity, assessed via serum potassium and urinary fractional excretion of potassium. Results A suppressed renin phenotype was associated with a higher rate of incident hypertension when compared to other PRA phenotypes (85.4 [73.4, 99.3] vs. 53.3 [42.8, 66.4] vs. 54.5 [41.8, 71.0] cases per 1000 person-years of follow-up). With renin suppression, higher aldosterone concentrations were independently associated with an increased risk for incident hypertension; whereas no association between aldosterone and hypertension was observed when renin was not suppressed. Higher aldosterone concentrations were associated with lower serum potassium and higher urinary excretion of potassium, but only when renin was suppressed. Limitations Measurements of sodium and potassium occurred several years before renin and aldosterone. Conclusions Suppression of renin, and higher aldosterone concentrations in the context of this renin suppression, associated with an increased risk for developing hypertension and possibly also with increased MR activity. These findings suggest a clinically-relevant spectrum of subclinical primary aldosteronism (renin-independent aldosteronism) in normotension. Funding National Institutes of Health

Renin‐Angiotensin‐Aldosterone System, Glucose Metabolism and Incident Type 2 Diabetes Mellitus: MESA

“…Second, participants were classified into 3 categories of PRA of ≤0.50, 0.51 to 0.99, and ≥1.0 μg/L per hour, to characterize “suppressed renin phenotype (a state of autonomous aldosterone production),” “indeterminate renin phenotype,” and “unsuppressed renin phenotype” (a state of potentially appropriate mineralocorticoid receptor activation in the setting of physiologic renin‐dependent secretion of aldosterone). The referent category (≥1.0 μg/L per hour) was compared with the 0.51 to 0.99 and ≤0.50 μg/L per hour categories for the association with incident diabetes mellitus 9. Third, participants were classified into 3 categories of PRA of ≤0.50, 0.51 to 0.99, and ≥1.0 μg/L per hour and the association of log‐aldosterone with incident diabetes mellitus was assessed among participants in the 3 PRA classifications 9…”

“…Among blacks in the Jackson Heart Study,6 aldosterone was positively associated with insulin resistance, while higher levels of aldosterone across the spectrum were associated with a dose‐dependent higher risk of the development of type 2 diabetes mellitus over 8 years. Recent observations demonstrate that aldosterone can be produced autonomously from aldosterone producing cell clusters within morphologically normal adrenal glands with a large spectrum and high prevalence of subclinical aldosteronism 7, 8, 9. Thus, we examined the association of aldosterone and PRA with glucose metabolism and incident diabetes mellitus across the spectrum of aldosterone levels in a multiethnic cohort to determine if there are racial/ethnic differences.…”

Diagnostic approach to low‐renin hypertension

“…In another study 60 61 Furthermore, only when renin was suppressed, high aldosterone levels were associated with an increased risk for incident hypertension. 61 The increase in aldosterone secretion, that progressively becomes independent from angiotensin II regulation, results in normotensive aldosteronism. According with a recent study conducted on a cohort of predominantly female individuals, normotensive aldosteronism can be detected (by postfludrocortisone-dexamethasone suppression test) in 13% of the participants.…”

“…Similarly, a prospective longitudinal study recently demonstrated that normotensive individuals with suppressed renin activity (≤0.50 μg/L/h, independently from aldosterone status), display a higher risk of developing hypertension compared with patients with unsuppressed renin phenotype . Furthermore, only when renin was suppressed, high aldosterone levels were associated with an increased risk for incident hypertension . The increase in aldosterone secretion, that progressively becomes independent from angiotensin II regulation, results in normotensive aldosteronism.…”

“…Notably, 6 out of these 29 patients had a concomitant elevated ARR (>20 ng/dL per ng/mL/h) and therefore could be considered as affected by PA according to the current guideline . Similarly, a prospective longitudinal study recently demonstrated that normotensive individuals with suppressed renin activity (≤0.50 μg/L/h, independently from aldosterone status), display a higher risk of developing hypertension compared with patients with unsuppressed renin phenotype . Furthermore, only when renin was suppressed, high aldosterone levels were associated with an increased risk for incident hypertension .…”