Primary aldosteronism has traditionally been perceived as a rare cause of hypertension, but recent evidence suggests that its prevalence may be higher than previously believed. This study used gold-standard diagnostic approaches to characterize abnormal renin-independent aldosterone production and biochemically overt primary aldosteronism among patients across a continuum of blood pressures.
Abstract
Background:
Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease.
Objective:
To characterize the prevalence of nonsuppressible renin-independent aldosterone production, as well as biochemically overt primary aldosteronism, in relation to blood pressure.
Design:
Cross-sectional study.
Setting:
4 U.S. academic medical centers.
Participants:
Participants with normotension (n = 289), stage 1 hypertension (n = 115), stage 2 hypertension (n = 203), and resistant hypertension (n = 408).
Measurements:
Participants completed an oral sodium suppression test, regardless of aldosterone or renin levels, as a confirmatory diagnostic for primary aldosteronism and to quantify the magnitude of renin-independent aldosterone production. Urinary aldosterone was measured in participants in high sodium balance with suppressed renin activity. Biochemically overt primary aldosteronism was diagnosed when urinary aldosterone levels were higher than 12 μg/24 h.
Results:
Every blood pressure category had a continuum of renin-independent aldosterone production, where greater severity of production was associated with higher blood pressure, kaliuresis, and lower serum potassium levels. Mean adjusted levels of urinary aldosterone were 6.5 μg/24 h (95% CI, 5.2 to 7.7 μg/24 h) in normotension, 7.3 μg/24 h (CI, 5.6 to 8.9 μg/24 h) in stage 1 hypertension, 9.5 μg/24 h (CI, 8.2 to 10.8 μg/24 h) in stage 2 hypertension, and 14.6 μg/24 h (CI, 12.9 to 16.2 μg/24 h) in resistant hypertension; corresponding adjusted prevalence estimates for biochemically overt primary aldosteronism were 11.3% (CI, 5.9% to 16.8%), 15.7% (CI, 8.6% to 22.9%), 21.6% (CI, 16.1% to 27.0%), and 22.0% (CI, 17.2% to 26.8%). The aldosterone–renin ratio had poor sensitivity and negative predictive value for detecting biochemically overt primary aldosteronism.
Limitation:
Prevalence estimates rely on arbitrary and conventional thresholds, and the study population may not represent nationwide demographics.
Conclusion:
The prevalence of primary aldosteronism is high and largely unrecognized. Beyond this categorical definition of primary aldosteronism, there is a prevalent continuum of renin-independent aldosterone production that parallels the severity of hypertension. These findings redefine the primary aldosteronism syndrome and implicate it in the pathogenesis of “essential” hypertension.
Primary Funding Source:
National Institutes of Health.
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Author, Article, and Disclosure Information
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (J.M.B., G.H.W., A.V.)
University of Alabama at Birmingham, Birmingham, Alabama (M.S., D.A.C.)
University of Virginia Health System, Charlottesville, Virginia (R.M.C.)
University of Utah School of Medicine, Salt Lake City, Utah (P.N.H.)
Acknowledgment: The authors thank Mahabuba Akhter, MBBS; Robin A. Felder, PhD; Katie Schiermeyer, MB; and Peng Xu, PhD, at the University of Virginia and Venkata S. Tekumalla, BS, at the University of Alabama at Birmingham for assistance in conducting and supporting study procedures. They thank Camden Bay, PhD, and Mahyar Heydarpour, PhD, at Brigham and Women's Hospital for providing guidance on statistical methods.
Grant Support: By grants T32 HL007604 (Dr. Brown); 2T32HL007457-36A1 (Dr. Siddiqui); R01 HL113004 (Dr. Calhoun); P01-HL-074940 and R01-HL-128189 (Dr. Carey); 5R01 HL136567, 1R01 HL144779, 1R01 HL114765, RM-07-2002, R01 HL085224, R01 HL086907, and 5 P50 HL55000 (Dr. Williams); and R01 DK115392 and R01 DK107407 (Dr. Vaidya) from the National Institutes of Health, and by grant AHA 5SFRN2390002 from the American Heart Association (Dr. Calhoun).
Disclosures: Dr. Brown reports grants from the National Heart, Lung, and Blood Institute. Dr. Williams reports grants from the National Institutes of Health. Dr. Vaidya reports consultancy for Catalys Pacific, Corcept Therapeutics, HRA Pharma, Orphagen, and Selenity Therapeutics and grants from the National Institutes of Health and Ventus Charitable Foundation. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-0065.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement: Study protocol: See the Supplement). Statistical code: Available from Dr. Vaidya (e-mail, [email protected]
Corresponding Author: Anand Vaidya, MD, MMSc, Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB, Boston, MA 02115; e-mail, [email protected]
Current Author Addresses: Dr. Brown: Division of Cardiovascular Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
Dr. Siddiqui: University of Alabama at Birmingham, 933 19th Street South, Room 115 Community Health Service Building, Birmingham, AL 35209.
Dr. Calhoun: University of Alabama at Birmingham, Division of Cardiology, BMR2 430, Birmingham, AL 35294.
Dr. Carey: PO Box 801414, University of Virginia Health System, Charlottesville, VA 22908.
Dr. Hopkins: Division of Cardiovascular Genetics, University of Utah School of Medicine, 50 North Medical Drive, Room 1160, Salt Lake City, UT 84132.
Drs. Williams and Vaidya: Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB, Boston, MA 02115.
Author Contributions: Conception and design: J.M. Brown, D.A. Calhoun, R.M. Carey, G.H. Williams, A. Vaidya.
Analysis and interpretation of the data: J.M. Brown, M. Siddiqui, D.A. Calhoun, R.M. Carey, A. Vaidya.
Drafting of the article: J.M. Brown, M. Siddiqui, A. Vaidya.
Critical revision of the article for important intellectual content: J.M. Brown, M. Siddiqui, R.M. Carey, P.N. Hopkins, G.H. Williams, A. Vaidya.
Final approval of the article: J.M. Brown, M. Siddiqui, D.A. Calhoun, R.M. Carey, P.N. Hopkins, G.H. Williams, A. Vaidya.
Provision of study materials or patients: M. Siddiqui, R.M. Carey, G.H. Williams, A. Vaidya.
Statistical expertise: P.N. Hopkins, A. Vaidya.
Obtaining of funding: D.A. Calhoun, R.M. Carey, A. Vaidya.
Administrative, technical, or logistic support: P.N. Hopkins, G.H. Williams, A. Vaidya.
Collection and assembly of data: J.M. Brown, M. Siddiqui, D.A. Calhoun, R.M. Carey, P.N. Hopkins, A. Vaidya.
This article was published at Annals.org on 26 May 2020.
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