The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension: A Cohort Study

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 a spectrum of subclinical renin-independent aldosteronism that increases risk for hypertension exists among normotensive persons.

Design: Cohort study.

Setting: National community-based study.

Participants: 850 untreated normotensive participants in MESA (Multi-Ethnic Study of Atherosclerosis) with measurements of serum aldosterone and plasma renin activity (PRA).

Measurements: Longitudinal analyses investigated whether aldosterone concentrations, in the context of physiologic PRA phenotypes (suppressed, ≤0.50 µg/L per hour; indeterminate, 0.51 to 0.99 µg/L per hour; unsuppressed, ≥1.0 µg/L per hour), were associated with incident hypertension (defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of antihypertensive medications). Cross-sectional analyses investigated associations between aldosterone and 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 than other PRA phenotypes (incidence rates per 1000 person-years of follow-up: suppressed renin phenotype, 85.4 events [95% CI, 73.4 to 99.3 events]; indeterminate renin phenotype, 53.3 events [CI, 42.8 to 66.4 events]; unsuppressed renin phenotype, 54.5 events [CI, 41.8 to 71.0 events]). With renin suppression, higher aldosterone concentrations were independently associated with an increased risk for incident hypertension, whereas no association between aldosterone and hypertension was seen 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.

Limitation: Sodium and potassium were measured several years before renin and aldosterone.

Conclusion: Suppression of renin and higher aldosterone concentrations in the context of this renin suppression are associated with an increased risk for hypertension and possibly also with increased MR activity. These findings suggest a clinically relevant spectrum of subclinical primary aldosteronism (renin-independent aldosteronism) in normotension.

Primary funding source: National Institutes of Health.

Figure 1. Renin-independent aldosteronism and the incidence rate of hypertension

Figures depict the unadjusted incidence rate of hypertension (number of incident cases per 1,000 person-years at risk) by phenotypes of renin and quartiles of aldosterone. Conversion of plasma renin activity (PRA) from SI to conventional units: 1 μg/L/h = 1 ng/mL/h. Conversion of aldosterone from SI to conventional units: 1 pmol/L=0.036 ng/dL. Quartiles of aldosterone in conventional units are: Q1 (<9.23 ng/dL), Q2 (9.23–12.73 ng/dL), Q3 (12.74–17.32 ng/dL), Q4 (≥17.32 ng/dL). A) Participants with a suppressed renin phenotype (PRA ≤ 0.50 μg/L/h); B) Participants with an indeterminate renin phenotype (PRA 0.51–0.99 μg/L/h); C) Participants with an unsuppressed renin phenotype (PRA ≥ 1.0 μg/L/h).

Figure 2. The proposed spectrum of renin-independent aldosteronism

A) The Endocrine Society Clinical Practice Guidelines recommend screening for primary aldosteronism (PA) using the aldosterone-to-renin ratio (ARR) in severe or resistant hypertension. This practice of screening for a very high ARR (>20–30 ng/dL per ng/dL/h in conventional units or >750–830 pmol/L per μg/L/h in SI units) is highly sensitive at detecting patients with severe hypertensive PA: patients with an obvious clinical syndrome of excessive mineralocorticoid receptor (MR) activation (hypertension and/or hypokalemia) who are confirmed to have biochemically “Overt PA,” and likely have an aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia (BAH) as the cause of their disease. B) Using confirmatory testing thresholds recommended by The Endocrine Society (such as oral or intravenous sodium loading, flurdrocortisone suppression, or captopril challenge), it has been observed that a substantial portion of normotensives and mild hypertensives, populations for whom PA screening is not routinely recommended, have biochemically overt PA. These patients have “Unrecognized Yet Biochemically Overt PA.” C) Even below the thresholds of what is currently considered biochemical confirmation of PA, there exists a continuum of renin-independent aldosteronism among healthy normotensives and mild hypertensives, in whom no obvious clinical syndrome of MR overactivation is apparent. These individuals have subtle evidence of renin-independent aldosteronism (renin suppression with inappropriately “normal” or high aldosterone levels) and higher risk for developing incident hypertension (as seen in the current study). This phenotype may best be described as “subclinical primary aldosteronism” or a “syndrome of clinically-relevant renin-independent aldosteronism.” The newly described and prevalent histopathology of aldosterone producing cell clusters (APCCs) may provide one explanation for this expanded continuum of subtle autonomous aldosteronism.