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Wednesday June 17th, 2020 at 9 pm British Summer Time
The Unrecognized Prevalence of Primary Aldosteronism A Cross-sectional Study
Ann Intern Med 2020 May 26. doi: 10.7326/M20-0065. Online ahead of print
Jenifer M. Brown, MD; Mohammed Siddiqui, MD; David A. Calhoun, MD; Robert M. Carey, MD; Paul N. Hopkins, MD, MSPH; Gordon H. Williams, MD; and Anand Vaidya, MD, MMSc
PMID: 32449886 Full Text at ACPJournals
Annals of Internal Medicine editorial (Funder, Ann Intern Med May 2020)
Introduction
Primary aldosteronism is the most common endocrine cause of hypertension (Monticone et al, Lancet Diab Endoc, 2018) with a presumed prevalence of 5-11% (Rossi et al, Curr HTN Reports, 2010). It is caused by renin-independent aldosterone production, wherein aldosterone is produced despite the suppression of renin and angiotensin II and is not adequately suppressed by sodium loading. This autonomous aldosterone production causes hypertension and hypokalemia and is associated with an increased risk for adverse kidney and cardiovascular outcomes (Hundemer et al, Hypertension, 2018). Recent evidence suggests that the prevalence of primary hyperaldosteronism is higher than previously estimated (Gouli et al, Eur J Clin Invest, 2011), and unfortunately remains significantly underdiagnosed. In the paper we are discussing this week, Brown and colleagues call into question not only the presumed low prevalence of the disease, they also shed light on the shortfalls of the current definitions using specific cutoffs. The current screening guidelines and practice using single spot measurements of plasma aldosterone and renin is also called into question.
Source: NephMadness 2019; the present study questions the validity of this ratio
Primary Aldosteronism has certainly risen up to the discussion platform in recent years. Notably, Nephmadness2019 featured hyperaldosteronism in a diagnosis versus treatment grudge match. Though aldosteronism lost out to the eventual tournament winners, this piece, along with a blog by Dr. Vaidya, senior author of this paper, gave us a glimpse of what was coming.
Current guidelines recommend screening for primary aldosteronism by measuring the aldosterone– renin ratio (ARR) in patients with severe hypertension or hypertension accompanied by hypokalemia, sleep apnea, or an adrenal mass. As is customary, screening is carried with a spot test of renin and aldosterone plasma values and patients with positive screening results then undergo confirmatory testing with oral or IV salt loading. The authors point out the recent evidence suggesting that the spectrum of autonomous aldosterone is much larger than captured by the spot screening test: a spectrum that certainly appears to be clinically relevant (Brown et al, Ann Intern Med, 2018). This continuum appears to even extend to patients without hypertension or hypokalemia, who happen to have an elevated ARR (Vasan et al, N Engl J Med, 2004).
This paper attempts to evaluate the scope of abnormal renin-independent aldosterone production in a cohort of patients without hypertension and those with various degrees of hypertension severity. Given the presumed limitations of spot testing, the authors utilize dynamic confirmatory testing with oral salt loading testing regardless of the ARR screening results.
The Study
Design Cross sectional study design
Study Population
Patients were pooled from 5 study protocols from 4 distinct sites across the United States (Birmingham, Alabama; Boston, Massachusetts; Charlottesville, Virginia; and Salt Lake City, Utah) that recruited participants with specific blood pressure phenotypes.
Inclusion and exclusion criteria varied by the study protocol aimed at a specific hypertension phenotype:
The Salt Sensitivity of Blood Pressure protocol recruited healthy adult volunteers with normotension or hypertension from the greater Charlottesville area to the University of Virginia to study salt sensitivity of blood pressure. Inclusion criteria specified age 18 to 70 years and body mass index of 18 to 30 kg/m2. Patients with known severe or secondary hypertension, renal or cardiovascular disease, or pregnancy were excluded.
The Prospective Phenotyping of Autonomous Aldosterone Secretion protocol recruited overweight normotensive volunteers from the greater Boston area to Brigham and Women's Hospital to study subclinical aldosterone dysregulation. Inclusion criteria were an untreated systolic blood pressure on screening of 120 to 135 mm Hg, an untreated diastolic blood pressure on screening of 75 to 85 mm Hg, a body mass index of at least 25 kg/m2, and a first-degree relative with hypertension before age 60. The study excluded patients with morbid obesity, poorly controlled diabetes, renal or cardiovascular disease, active cancer, use of opioids or glucocorticoids, or pregnancy.
Hypertensive Pathotype Consortium recruited adult volunteers with normotension or hypertension from the greater Boston and Salt Lake City areas to study mechanisms of hypertension. Normotension was defined by both blood pressure and an absence of family history of hypertension in a first-degree relative before age 60 years. Hypertension was defined by blood pressure or use of antihypertensive drugs. Persons with known or suspected secondary hypertension or established renal or cardiovascular disease were excluded.
University of Alabama at Birmingham Resistant Hypertension Clinic recruited patients to study hormonal mechanisms of resistant hypertension, defined as uncontrolled blood pressure despite use of 3 or more antihypertensive medications (including a diuretic) or controlled blood pressure requiring 4 or more antihypertensive medications. The study excluded patients with known congestive heart failure, chronic kidney disease, primary aldosteronism or another secondary form of hypertension, or long-term glucocorticoid use.
Interventions
Every participant completed an oral sodium loading protocol regardless of circulating aldosterone, renin, and ARR values.
Antihypertensive medications were withdrawn over 2 to 12 weeks to minimize confounding of renin and aldosterone measurements.
The exception was the Resistant Hypertension Clinic protocol, where participants stopped receiving mineralocorticoid receptor antagonists and epithelial sodium-channel inhibitors 6 weeks before study assessments. Other antihypertensive medications were continued for safety.
Research volunteer protocols: participants were prescribed a high-sodium diet and standardized potassium intake for 5 to 7 days before completing a 24-hour urine collection.
Resistant Hypertension Clinic, potassium was supplemented to correct hypokalemia to a serum potassium level greater than 3.5 mmol/L. Sodium was supplemented for 3 days only if 24-hour urinary sodium excretion was less than 200 mmol without supplementation.
24-hour urine collections were collected to measure urinary excretion of aldosterone, sodium, and potassium. Blood pressure, plasma renin activity, serum aldosterone, and serum potassium were also measured.
The oral sodium suppression test consists of an oral sodium load, with the goal of achieving a 24-hour urinary sodium balance of at least 180 to 200 mmol, to induce expansion of intravascular volume and physio logic suppression of renin and angiotensin II
Outcomes
Single measurements of circulating aldosterone were variable and unreliable. As such, 24-hour urinary aldosterone excretion was used as a consistent and integrated measurement of renin-independent aldosterone production
Aldosterone production in the context of a high sodium balance and renin suppression was quantified as “renin-independent” aldosterone production.
Biochemically overt primary aldosteronism” was designated when aldosterone excretion rate was at least 12 μg/24 h in the context of both high sodium balance and suppressed renin activity.
Blood pressure was measured on the day of testing to classify untreated participants on the basis of the 2017 hypertension guidelines:
Normotensive (<130/80 mm Hg)
Stage 1 hypertensive (130-139/ 80–89 mm Hg)
Stage 2 hypertensive (≥140/90 mm Hg)
Treated participants with resistant hypertension were kept in their own category.
Statistical analysis
Cross-sectional analyses were done to examine the distribution of renin-independent aldosterone production and prevalence of biochemically overt primary aldosteronism across categories of blood pressure.
Participants with 24-hour urinary sodium excretion less than 190 mmol were excluded
Suppressed renin activity after achieving a high sodium balance (<1.0 μg/L per hour seated or <0.6 μg/L per hour supine) was a requirement to designating renin-independent aldosterone production,
Participants who had unsuppressed renin activity despite achieving a high sodium balance had a physiology that was incompatible with renin-independent aldosteronism and instead exhibited renin-dependent aldosterone production; these participants could not have primary aldosteronism but were still included in the denominator of prevalence estimates.
Mean adjusted rates of aldosterone excretion and adjusted estimates of prevalence were calculated using the PROC GLM procedure and LSMEANS statement in SAS, version 9.4 (SAS Institute).
In secondary analyses, the continuous relationships between urinary aldosterone excretion and biomarkers of mineralocorticoid receptor activation (blood pressure, ratio of urinary potassium–sodium excretion, and serum potassium) were assessed using adjusted linear regression (PROC REG in SAS).
Funding
Work supported by T32 NIH grant and an AHA grant
Results
There were a total of 1846 participants with complete data for aldosterone, renin, and urinary sodium, of which 1015 had a rate of urinary sodium excretion of at least 190 mmol/24h. A subset of 691 had suppressed renin activity and were eligible for the assessment of the magnitude of renin-independent aldosterone production as shown in figure below:
Figure 1 from Brown et al, Annals of IM
The baseline characteristics of the entire study population, and the selected subchorts is shown here:
Supplemental Table 2 from Brown et al, Annals of IM
Supplemental Table 3 from Brown et al, Annals of IM
The study population included 289 untreated normotensive participants, 115 with untreated stage 1 hypertension, 203 with untreated stage 2 hypertension, and 408 with resistant hypertension who were receiving antihypertensive treatment. Participants with more severe hypertension were older, had higher body mass index, were more likely to identify as black, and had a higher frequency of diabetes. See table below.
Table 1 from Brown et al, Annals of IM, 2020
A continuum of renin-independent aldosterone production was observed to parallel the severity of hypertension. The categorical diagnostic threshold of 12 µg/24 h is recommended to designate those with and without primary aldosteronism, the magnitude of renin-independent aldosterone production was progressively higher across blood pressure categories, regardless of this arbitrary designation.
Figure 2 from Brown et al, Annals of IM
The adjusted prevalence of biochemically overt primary aldosteronism ranged from 11.3% (95% CI, 5.9% to 16.8%) in normotensive to 22.0% (CI, 17.2% to 26.8%) in resistant hypertension.
Supplemental Table 2 from Brown et al, Annals of IM
Among participants confirmed to have biochemically overt primary aldosteronism, the sensitivity and negative predictive value of the ARR were poor at a threshold of 832 (Table 3, below) but even at a lower threshold of 555 (supplemental table 4).
Table 3 from Brown et al, Annals of IM
Supplemental Table 2 from Brown et al, Annals of IM
Similarly, among participants with resistant hypertension, where the pretest probability of primary aldosteronism is high, 24.5% of confirmed case patients, i.e. those who did have primary aldosteronism (24 of 98) still had a serum aldosterone concentration less than 277 pmol/L (10 ng/dL).
There was a continuous relationship between the severity of renin-independent aldosterone production and biomarkers of mineralocorticoid activity and serum aldosterone.
Supplemental figure 6 from Brown et al, Annals of IM (panels B and D are insets from panel A and C)
Discussion
This study showed a pervasive spectrum of renin-independent aldosterone production that parallels the severity of human hypertension and correlates with biomarkers of mineralocorticoid receptor activation. The findings of this study indicate a highly prevalent pathologic continuum of renin independent aldosteronism. In PATHWAY-2 (Prevention And Treatment of Hypertension With Algorithmbased therapy number 2), a trial of add-on therapy for uncontrolled resistant hypertension, the efficacy of spironolactone directly correlated with the combination of lower renin levels, higher aldosterone levels within the “normal” range, and higher ARR values thereby demonstrating that the efficacy of mineralocorticoid receptor antagonists in lowering blood pressure was dependent on the magnitude of unrecognized renin-independent aldosterone production. The current study provides mechanistic support for the findings of PATHWAY-2 and suggests that primary aldosteronism may be better considered to be a severity spectrum of renin-independent aldosterone production biomarkers of mineralocorticoid receptor activation.
This study was not designed to determine the underlying cause of the prevalent phenotype of renin-independent aldosterone production.
An important practical clinical implication of this study was that, the classic stereotype of severe hypertension or hypokalemia is not the sine qua non for primary aldosteronism; primary aldosteronism can frequently be detected in normokalemic hypertensive persons of all blood pressure categories, and even among normotensive persons.
Clinicians should strongly emphasize the importance of dietary sodium restriction, not only as a general intervention to improve blood pressure but also as a targeted maneuver to minimize the fuel that feeds primary aldosteronism pathophysiology.
Strengths:
This study provides an insight suggesting primary aldosteronism as a probable and more common diagnosis in resistant hypertension
This study provides mechanistic support to the findings of the PATHWAY-2 trial.
Limitations:
The study population was not a representative nationwide cohort; therefore, the generalizability of the study findings to the U.S. population is uncertain.
The heterogeneity of the site-specific protocols, recruitment of geographically and physically disparate participants, sampling in different postures, and use of multiple laboratory assays may all have imparted bias and variability.
The cross-sectional design of the study means that causality cannot be determined.
Most participants were evaluated while not receiving antihypertensive medications, but patients with resistant hypertension were studied while receiving treatment. This factor probably might have caused potential misclassification of the true prevalence given that the typical effect of renin–angiotensin–aldosterone system inhibitors and diuretics is to raise renin levels.
Role of ACTH was not investigated.
Conclusion
Clinicians should consider screening for primary aldosteronism much more frequently, especially in the general hypertensive population. Reliance on a single ARR is insensitive, even among patients with resistant hypertension.
Clinicians should consider prescribing mineralocorticoid receptor antagonists more liberally for hypertensive patients with suppressed renin.
The study supports the need to redefine primary aldosteronism from a rare and categorical disease to, instead, a common syndrome that manifests across a broad severity spectrum and may be a primary contributor to hypertension pathogenesis.
Summary prepared by
Ali Mehdi MD MEd, Cleveland Clinic, Cleveland, Ohio
Krishna Agrawal MD, DM, Universal College of Medical Sciences, Nepal
NSMC Interns, Class of 2020