The Spectrum of Dysregulated Aldosterone Production: An International Human Physiology Study

Abstract

Context: Primary aldosteronism is a form of low-renin hypertension characterized by dysregulated aldosterone production.

Objective: To investigate the contributions of renin-independent aldosteronism and ACTH-mediated aldosteronism in individuals with a low-renin phenotype representing the entire continuum of blood pressure.

Design/participants: Human physiology study of 348 participants with a low-renin phenotype with severe and/or resistant hypertension, hypertension with hypokalemia, elevated blood pressure and stage I/II hypertension, and normal blood pressure.

Setting: 4 international centers.

Interventions/main outcome measures: The saline suppression test (SST) to quantify the magnitude of renin-independent aldosteronism; dexamethasone suppression and ACTH-stimulation tests to quantify the magnitude of ACTH-mediated aldosteronism; adrenal venous sampling to determine lateralization.

Results: There was a continuum of nonsuppressible and renin-independent aldosterone production following SST that paralleled the magnitude of the blood pressure continuum and transcended conventional diagnostic thresholds. In parallel, there was a full continuum of ACTH-mediated aldosteronism wherein post-SST aldosterone levels were strongly correlated with ACTH-stimulated aldosterone production (r = 0.75, P < .0001) and nonsuppressible aldosterone production postdexamethasone (r = 0.40, P < .0001). Beyond participants who met the criteria for primary aldosteronism (post-SST aldosterone of ≥10 ng/dL or ≥277 pmol/L), the continuum of nonsuppressible and renin-independent aldosterone production persisted below this diagnostic threshold, wherein 15% still had lateralizing aldosteronism amenable to surgical adrenalectomy and the remainder were treated with mineralocorticoid receptor antagonists.

Conclusion: In the context of a low-renin phenotype, there is a continuum of primary aldosteronism and dysregulated aldosterone production that is prominently influenced by ACTH. A large proportion of individuals with low renin may benefit from aldosterone-directed therapy.

Keywords: ACTH; aldosterone; hypertension; low-renin hypertension; primary aldosteronism.

Figure 1.

Flowchart of participants and patients who underwent assessment of renin-independent aldosterone production and ACTH-mediated aldosterone production.

Figure 2.

Saline suppression testing to interrogate renin- and angiotensin II-independent aldosterone production across the continuum of blood pressure. Postsaline suppression test aldosterone levels in participants with low renin are depicted on the y-axis. Values are ordered from lowest to highest for each individual participant on the x-axis as a waterfall plot. (A) Results for the entire study population with the inset depicting a magnified view of only those participants who had a saline suppression test aldosterone value less than 10 ng/dL (277 pmol/L). (B) Results stratified by blood pressure phenotype. (C) Results stratified by site. Data in table (below the figure) are presented as median and interquartile ranges. Abbreviations: SST, saline suppression test.

Figure 3.

Biochemical continuum of renin-independent aldosterone production transcending conventional diagnostic SST thresholds. The median aldosterone-to-renin ratio for each BP phenotype is depicted as a function of post-SST aldosterone levels. Abbreviations: BP, blood pressure; HTN, hypertension; SST, saline suppression test.

Figure 4.

Lateralization of aldosterone production and treatment decisions as a function of saline suppression testing. (A) Lateralization of aldosterone production: Patients had lateralization assessed, either via AVS or via imaging for a unilateral adrenal mass in the setting of overt PA and hypokalemia; 143/288 (49%) patients were determined to have lateralizing PA. The inset depicts a magnified view of only those participants who had a saline suppression test aldosterone value less than 10 ng/dL (277 pmol/L) wherein 13/89 had lateralizing PA (15%). (B) Treatment decision based on lateralization assessments: 131/288 (45%) underwent unilateral adrenalectomy with biochemical cure or improvement, 152/288 (53%) were treated with MRA, and 5/288 (2%) had unknown treatment as they were lost to follow-up. Abbreviations: AVS, adrenal venous sampling; MRA, mineralocorticoid receptor antagonist; PA, primary aldosteronism; SST, saline suppression test.

Figure 5.

Overview of lateralization assessments in the 288 patients and the treatments prescribed. Abbreviations: MR, mineralocorticoid receptor; PA, primary aldosteronism.

Figure 6.

Interrogation of ACTH-mediated aldosterone production. (A) Waterfall plots depicting the postdexamethasone aldosterone levels ordered from lowest to highest in a waterfall plot, overlayed with post-ACTH stimulation aldosterone levels ordered from lowest to highest. (B) The correlation between postdexamethasone suppression test and post-ACTH stimulation test aldosterone levels. Shown are the mean regression line with the 95% confidence interval of the mean regression line and of the distribution.

Figure 7.

The correlation between renin- and angiotensin II-independent aldosterone production and ACTH-mediated aldosterone production. The correlation between post-SST aldosterone production (x-axis) with ACTH-independent aldosterone production measured via the dexamethasone suppression test (A) and with ACTH-dependent aldosterone production measured via the ACTH stimulation test (B). Shown are the mean regression line with a 95% confidence interval of the mean and the distribution. Abbreviations: SST, saline suppression test.