GENETICS IN ENDOCRINOLOGY: Impact of race and sex on genetic causes of aldosterone-producing adenomas.

Primary aldosteronism (PA) is a common cause of secondary hypertension. Recent technological advances in genetic analysis have provided a better understanding of the molecular pathogenesis of this disease. The application of next-generation sequencing has resulted in the identification of somatic mutations in aldosterone-producing adenoma (APA), a major subtype of PA. Based on the recent findings using a sequencing method that selectively targets the tumor region where aldosterone synthase (CYP11B2) is expressed, the vast majority of APAs appear to harbor a somatic mutation in one of the aldosterone-driver genes, including KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2. Mutations in these genes alter intracellular ion homeostasis and enhance aldosterone production. In a small subset of APAs, somatic activating mutations in the CTNNB1 gene, which encodes ß-catenin, have also been detected. Accumulating evidence suggests that race and sex impact the somatic mutation spectrum of APA. Specifically, somatic mutations in the KCNJ5 gene, encoding an inwardly rectifying K+ channel, are common in APAs from Asian populations as well as women regardless of race. Associations between APA histology, genotype, and patient clinical characteristics have also been proposed, suggesting a potential need to consider race and sex for the management of PA patients. Herein, we review recent findings regarding somatic mutations in APA and discuss potential roles of race and sex on the pathophysiology of APA as well as possible clinical implications.

Primary aldosteronism and obstructive sleep apnea: A single-center cross-sectional study of the Japanese population.

ABSTRACT: A recent report demonstrated that the prevalence of obstructive sleep apnea (OSA) is 67.6% among Caucasian and Chinese patients with primary aldosteronism (PA). Moreover, the report showed a significant association between plasma aldosterone concentration (PAC) and the severity of OSA in Caucasian patients. However, no studies have examined the prevalence of OSA with PA or the association of its severity with PAC in the Japanese population. We retrospectively evaluated the prevalence and severity of OSA in 71 newly diagnosed Japanese patients with PA. Thirty-nine (55%) of the 71 patients were diagnosed with OSA, and 69% of PA patients with OSA reported snoring. No correlation was found between the respiratory event index (REI), snoring index, and PAC and plasma renin activity (PRA). In contrast, REI correlated significantly with body mass index (BMI), which was significantly correlated with PRA. In conclusion, although the severity of OSA did not correlate with PAC and PRA, there was a high prevalence of OSA among Japanese patients with PA. Moreover, the severity of OSA was strongly affected by BMI. Thus, the examination of OSA in patients with PA and the proper management of OSA might be important for the Japanese population.

A primary aldosteronism-like phenotype identified with the aldosterone-to-angiotensin II ratio in black men: the SABPA study.

INTRODUCTION: Black populations may be more likely to have primary aldosteronism (PA) due to adrenal hyperplasia or other forms of adrenal hyperactivity, with suppressed renin levels and high levels of aldosterone, which may contribute to the development of hypertension. METHODS: This sub-study involved 35 black men matched for age, gender and race, and aged 20-65 years, living in the North West Province of South Africa. RAAS triple-A analysis was carried out with LC-MS/MS quantification. Blood pressure, electrocardiography and other variables were determined with known methods. RESULTS: Hypertensive subjects with higher aldosterone levels showed an increased aldosterone-angiotensin II ratio (AA2 ratio) compared to the hypertensive subjects with low aldosterone levels (10.2 vs 3.0 pmol/l; p = 0.003). The serum potassium concentration was significantly lower in the high-aldosterone group and the serum sodium-potassium ratio was significantly higher compared to the low-aldosterone group (3.9 vs 4.5, p = 0.016, 34.8 vs 31.8, p = 0.032, respectively). Furthermore, aldosterone was positively associated with both left ventricular hypertrophy (Cornell product) (Spearman R = 0.560; p = 0.037) and kidney function [albumin-to-creatinine ratio (ACR) ] (Spearman R = 0.589, p = 0.021) in the hypertensive high-serum aldosterone group. CONCLUSIONS: The AA2 ratio, a novel screening test that is currently being validated for PA case detection, was used to identify a PA-like phenotype in black men. Excess aldosterone was associated with endothelial dysfunction and left ventricular hypertrophy, independent of blood pressure.

Primary Aldosteronism and Obstructive Sleep Apnea: A Cross-Sectional Multi-Ethnic Study.

The association between primary aldosteronism (PA) and obstructive sleep apnea (OSA) has been a matter of debate. 2016 Endocrine Society guideline recommends screening for PA all hypertensive patients with OSA. We designed a multicenter, multiethnic, cross-sectional study to evaluate the prevalence of PA in patients with OSA and the prevalence of OSA in unselected patients with PA. Two hundred and three patients with OSA (102 whites and 101 Chinese) were screened for PA, and 207 patients with PA (104 whites, 100 Chinese, and 3 of African descent) were screened for OSA by cardiorespiratory polygraphy. Eighteen patients with OSA (8.9%) had PA (11.8% of white and 5.9% of Chinese ethnicity). In patients without other indications for PA screening, the prevalence of PA dropped to 1.5%. The prevalence of OSA in patients with PA was 67.6%, consistent in both white and Chinese patients. A correlation between aldosterone levels and apnea/hypopnea index was observed in white patients with PA (R2=0.225, P=0.016) but not in Chinese patients. Multinomial logistic regression confirmed a significant and independent association between plasma aldosterone levels and moderate to severe OSA diagnosis in white patients (odds ratio, 1.002; P=0.002). In conclusion, aldosterone levels may contribute to the severity of OSA in white patients with hyperaldosteronism, but patients with OSA are not at high risk of PA. Results of the present study challenge the current recommendation of the Endocrine Society guideline that all patients with OSA should be screened for PA, irrespective of the grade of hypertension.

Analytical validation and investigation on reference intervals of aldosterone and renin in Chinese Han population by using fully automated chemiluminescence immunoassays.

BACKGROUND: The aldosterone/renin ratio (ARR) is recommended to screen for primary aldosteronism (PA) in hypertension. We estimated fully automated chemiluminescence immunoassays (CLIA) for plasma aldosterone concentrations (PAC) and plasma direct renin concentrations (PRC) and investigated their reference intervals in Chinese Han population. METHODS: PAC and PRC were measured on a fully automated analyzer (LIAISON XL, DiaSorin, Italy). Performance characteristics were estimated according to CLSI approved guidelines. 328 healthy individuals were selected for reference intervals investigation. Results simultaneously tested by CLIA and radioimmunoassays were reviewed from 123 patients with hypertension and/or adrenal space-occupying lesion. PAC/PRC ratio (ARRprc) was compared to PAC/plasma renin activity (PRA) ratio (ARRpra). RESULTS: Within-laboratory imprecision was 5.6%-6.7% for PAC and 3.0%-3.3% for PRC. The LoQ was 72.2 pmol/L for PAC and 1.27 mIU/L for PRC. Linearity was excellent in the range of concentrations between 94 and 2708 pmol/L for PAC and 1.3-461.8 mIU/L for PRC. Interferences of hemoglobin, unconjugated bilirubin and lipaemia could be acceptable, but not of conjugated-bilirubin when renin and aldosterone at low concentrations. The central 95% reference intervals for males: PAC: 76-722 pmol/L, PRC: 3.3-92.7 mIU/L, ARR: 2.2-46.0 pmol/mIU; for females: PAC: 85-1010 pmol/L, PRC: 3.7-99.8 mIU/L, ARR: 3.6-68.4 pmol/mIU. Upper reference limits for ARR of younger and older men were lower than women. ARRprc and ARRpra showed almost perfect agreement (kappa = 0.815) for screening PA. CONCLUSION: The DiaSorin tests are valuable analytical options for PAC and PRC measurements. We recommend sex-specific and age-specific reference intervals of these items should be estimated.

Evaluation of the Saline Infusion Test and the Captopril Challenge Test in Chinese Patients With Primary Aldosteronism.

Context: The aim of this study was to determine whether the diagnosis cutoff values associated with the saline infusion test (SIT) and captopril challenge test (CCT) in the Endocrine Society guidelines are applicable to Chinese subjects. Objective and Design: We performed a head-to-head comparison of the SIT and CCT among Chinese subjects with primary aldosteronism (PA) and essential hypertension (EH). Participants and Setting: One hundred sixty-four hypertensive patients were enrolled. Intervention: All participants underwent both the SIT and CCT. Main Outcome Measures: The plasma aldosterone concentration (PAC) and plasma renin activity were measured before and after the SIT and CCT. The degree of PAC decline after CCT was calculated. Results: This study included 115 PA and 49 EH subjects. The prevalence of hypokalemia was 74.8% in the PA group. Supine PACs in the EH and PA groups were 15.1 ± 4.7 mmol/L and 30.4 ± 12.1 mmol/L. Post-SIT PACs were 8.8 ± 1.7 ng/dL and 22.7 ± 10.2 ng/dL in the EH and PA groups. The degree of PAC decline after CCT was 17.7% and 14.2% in the EH and PA groups; post-CCT PACs were 11.7 ± 3.3 ng/dL and 25.9 ± 10.6 ng/dL. PAC values of 11.2 ng/dL and 16.7 ng/dL after the SIT and CCT represented the optimal cutoff values for PA diagnosis. The post-SIT and post-CCT area under the receiver operating characteristic curve values were 0.972 [95% confidence interval (CI) = 0.934 to 0.991] and 0.933 (95% CI = 0.883 to 0.966). Conclusions: Post-SIT and post-CCT PACs, but not the degree of PAC suppression, were both reliable for PA diagnosis. However, the optimal cutoffs were slightly higher in Chinese subjects than those recommended by the Endocrine Society.

KCNK3 Variants Are Associated With Hyperaldosteronism and Hypertension.

Blood pressure (BP) is a complex trait that is the consequence of an interaction between genetic and environmental determinants. Previous studies have demonstrated increased BP in mice with global deletion of TASK-1 channels contemporaneous with diverse dysregulation of aldosterone production. In humans, genome-wide association studies in ≈100 000 individuals of European, East Asian, and South Asian ancestry identified a single nucleotide polymorphism (SNP) in KCNK3 (the gene encoding TASK-1) associated with mean arterial pressure. The current study was motivated by the hypotheses that (1) association of KCNK3 SNPs with BP and related traits extends to blacks and Hispanics, and (2) KCNK3 SNPs exhibit associations with plasma renin activity and aldosterone levels. We examined baseline BP measurements for 7840 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), and aldosterone levels and plasma renin activity in a subset of 1653 MESA participants. We identified statistically significant association of the previously reported KCNK3 SNP (rs1275988) with mean arterial pressure in MESA blacks (P=0.024) and a nearby SNP (rs13394970) in MESA Hispanics (P=0.031). We discovered additional KCNK3 SNP associations with systolic BP, mean arterial pressure, and hypertension. We also identified statistically significant association of KCNK3 rs2586886 with plasma aldosterone level in MESA and demonstrated that global deletion of TASK-1 channels in mice produces a mild-hyperaldosteronism, not associated with a decrease in renin. Our results suggest that genetic variation in the KCNK3 gene may contribute to BP variation and less severe hypertensive disorders in which aldosterone may be one of several causative factors.

[An evaluation of plasma aldosterone-to-active-renin ratio in different postures in combination with aldosterone concentration in the diagnosis of aldosteronoma].

OBJECTIVE: To investigate the diagnostic value of plasma aldosterone-to-active-renin ratio(ARR)in combination with plasma aldosterone concentration(PAC)in the predication of aldosteronoma(APA). METHODS: A total of 85 APA and 155 essential hypertension(EH)patients from January 2012 to December 2014 in Chinese PLA General Hospital were enrolled. The ROC curve was applied to calculate the optimal cut-off points of ARR for APA. RESULTS: (1)The optimal cut-off point of supine ARR was 1 707.4(pmol/L)/(µg·L(-1)·h(-1))[61.64(ng/dl)/(µg·L(-1)·h(-1))] with the sensitivity, specificity and accuracy of 89.41%, 80.65% and 83.75%, respectively. The specificity and accuracy of the diagnostic value for APA increased (89.03% and 87.5% respectively) when supine ARR cut-off point were used in combination with supine PAC over 329.4 pmol/L. (2) The optimal cut-off point of upright ARR was 741.5 (pmol/L)/(µg·L(-1)·h(-1))[26.77(ng/dl)/(µg·L(-1)·h(-1) )]with the sensitivity, specificity and accuracy of 85.88%, 91.61% and 89.58%, respectively. Similarly, the specificity and accuracy greatly improved (94.84% and 91.67%, respectively) when upright ARR were applied together with upright PAC over 323.1 pmol/L. CONCLUSIONS: Both spine and upright ARR can be used in screening for APA. Moreover, the specificity and accuracy could be improved when ARR and PAC were used together both in the supine and upright position.

ARMC5 mutation analysis in patients with primary aldosteronism and bilateral adrenal lesions.

Idiopathic hyperaldosteronism (IHA) due to bilateral adrenal hyperplasia is the most common subtype of primary aldosteronism (PA). The pathogenesis of IHA is still unknown, but the bilateral disease suggests a potential predisposing genetic alteration. Heterozygous germline mutations of armadillo repeat containing 5 (ARMC5) have been shown to be associated with hypercortisolism due to sporadic primary bilateral macronodular adrenal hyperplasia and are also observed in African-American PA patients. We investigated the presence of germline ARMC5 mutations in a group of PA patients who had bilateral computed tomography-detectable adrenal alterations. We sequenced the entire coding region of ARMC5 and all intron/exon boundaries in 39 patients (37 Caucasians and 2 black Africans) with confirmed PA (8 unilateral, 27 bilateral and 4 undetermined subtype) and bilateral adrenal lesions. We identified 11 common variants, 5 rare variants with a minor allele frequency <1% and 2 new variants not previously reported in public databases. We did not detect by in silico analysis any ARMC5 sequence variations that were predicted to alter protein function. In conclusion, ARMC5 mutations are not present in a fairly large series of Caucasian patients with PA associated to bilateral adrenal disease. Further studies are required to definitively clarify the role of ARMC5 in the pathogenesis of adrenal nodules and aldosterone excess in patients with PA.

Plasma soluble (pro)renin receptor is independent of plasma renin, prorenin, and aldosterone concentrations but is affected by ethnicity.

A soluble (pro)renin receptor (sPRR) circulates in plasma and is able to bind renin and prorenin. It is not known whether plasma sPRR concentrations vary with the activity of the renin-angiotensin system. We measured plasma sPRR, renin, prorenin, and aldosterone concentrations in 121 white and 9 black healthy subjects, 40 patients with diabetes mellitus, 41 hypertensive patients with or without renin-angiotensin system blockers, 9 patients with primary aldosteronism, and 10 patients with Gitelman syndrome. Median physiological plasma sPRR concentration was 23.5 ng/mL (interquartile range, 20.9-26.5) under usual uncontrolled sodium diet. sPRR concentration in healthy subjects, unlike renin and prorenin, did not display circadian variation or dependence on age, sex, posture, or hormonal status. sPRR concentrations were ≈25% lower in black than in white subjects, whereas renin concentrations were ≈40% lower. Patients with diabetes mellitus (average renin-high prorenin levels) and with hypertension only (average renin-average prorenin levels) had sPRR concentrations similar to healthy subjects. Renin-angiotensin system blockade was associated with increase of sPRR concentration by ≈12%. sPRR in patients with primary aldosteronism (low renin-low prorenin) and Gitelman syndrome (high renin-high prorenin) were similar and ≈10% higher than in healthy subjects. There was no correlation between sPRR and renin or prorenin. In conclusion, our results show that plasma sPRR concentrations are dependent on ethnicity and independent of renin, prorenin, and aldosterone concentrations in healthy subjects and in patients with contrasted degrees of renin-angiotensin system activity.

Positive relationship of sleep apnea to hyperaldosteronism in an ethnically diverse population.

OBJECTIVE: Approximately, 50-60% of patients with sleep apnea have hypertension. To explore a mechanism of this relationship, we compared its prevalence in a hypertensive population with and without hyperaldosteronism. METHODS: Using the Kaiser Permanente Southern California database, hypertensive individuals who had plasma aldosterone and plasma renin activity measured between 1 January 2006 and 31 December 2007 were evaluated. Hyperaldosteronism was defined as an aldosterone : renin ratio more than 30 and plasma aldosterone more than 20 ng/dl or an aldosterone : renin ratio more than 50 (ng/dl : ng/ml per h). Hypertension was identified by International Classification of Disease, Ninth Revision (ICD-9) coding and sleep apnea was defined by ICD-9 coding or procedural coding for dispensation of positive airway devices. RESULTS: Of 3428 hypertensive patients, 575 (17%) had hyperaldosteronism. Sleep apnea was present in 18% (105) with hyperaldosteronism vs. 9% (251) without hyperaldosteronism (P < 0.001). Odds ratio for sleep apnea in patients with hyperaldosteronism was 1.8 (95% confidence interval 1.3-2.6) after controlling for other sleep apnea risk factors. No ethnic group was at greater risk for sleep apnea. CONCLUSION: The prevalence of sleep apnea in a diverse hypertensive population is increased in patients with hyperaldosteronism, even when controlling for other sleep apnea risk factors.

Type 2 diabetic patients with resistant hypertension should be screened for primary aldosteronism.

BP control in diabetic patients is often poor. The contribution of secondary hypertension due to undiagnosed PA in hypertensive type 2 diabetic patients is not well studied. We prospectively screened 100 consecutive Asian type 2 diabetic patients with difficult-to-control or resistant hypertension for PA. PAC (pmol/L) to PRA (ng/mL/h) ratio was measured; those with PAC-to-PRA ratio >550 (corresponding PAC >415) underwent intravenous 0.9% SLT. Patients with PAC >/=140 following SLT had CT adrenals and bilateral AVS. Thirteen patients (13%) were confirmed to have PA, and all had resistant hypertension. Eight had a surgically correctable form of PA. Patients with PA had higher mean (SD) systolic [159.0 (10.6) vs. 146.0 (10.7) mmHg, p=0.001] and diastolic BP [94.6 (6.0) vs. 87.6 (5.9) mmHg, p=0.001], lower serum potassium [3.5 (0.6) vs. 4.3 (0.5) mmol/L, p=0.001], and higher PAC [679.3 (291.0) vs. 239.5 (169.4) pmol/L, p=0.001]. Identification and institution of definitive treatment for PA resulted in better BP control and in a reduction in the use of antihypertensive medications. Our findings demonstrate a high prevalence of PA in type 2 diabetic patients with resistant hypertension. Systematic screening for PA in this select group is recommended, as targeted treatment improves BP control.

Hyperaldosteronism: a commonly occurring underlying feature of essential hypertension and the metabolic syndrome?

Individuals with primary aldosteronism make up a substantial proportion of those with hypertension. Less well appreciated is what appears to be inappropriately elevated aldosterone secretion in hypertensive patients who do not meet the criteria for true primary aldosteronism. This finding is particularly true of African-Americans. An additional, recently described, aspect of aldosterone excess is its apparent contribution to insulin resistance as evidenced by the frequent association of primary aldosteronism with the metabolic syndrome. Thus in the management of, not only hypertension, but also certain metabolic conditions, greater consideration should be given to the participation of aldosterone.

Validity of plasma aldosterone-to-renin activity ratio in African American and white subjects with resistant hypertension.

BACKGROUND: Recent reports suggesting that primary aldosteronism (PA) is more common than historically thought have often relied on use of the plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio (ARR) to identify patients with PA. Prior determinations of the validity of the ARR had been generally limited to subjects that could be withdrawn from antihypertensive therapy and to non-African American subjects. METHODS AND RESULTS: The current study was designed to evaluate prospectively the diagnostic value of the ARR in treated African American and white subjects with resistant hypertension. Consecutive subjects referred to a university hypertension clinic for resistant hypertension were evaluated with an early morning ARR and a 24-h urinary aldosterone and sodium. The presence of PA was defined as a suppressed PRA (<1.0 ng/mL/h) and elevated urinary aldosterone excretion (>12 microg/24 h) during high dietary sodium ingestion (>200 mEq/24 h). In 58 subjects, PA was confirmed. The ARR was elevated (>20) in 45 of 58 subjects with PA and in 35 of the 207 patients without PA, resulting in a sensitivity of 78% and specificity of 83% with a corresponding positive predictive value of 56% and a negative predictive value of 93%. Among African American subjects, the ARR was less sensitive than in white subjects (75% v 80%), but it still had a high negative predictive value (92% v 94%). CONCLUSIONS: These data indicate that the ARR is valid as a screening test for PA in African American and white patients on stable antihypertensive treatments, but a high percentage of false-positive results precludes using it for accurate diagnosis of PA.

Hyperaldosteronism and hypertension: ethnic differences.

The purpose of this study is to evaluate the relationship between aldosterone and blood pressure in a total of 220 normotensive and 293 essential hypertensive subjects in 2 genetically distinct populations-blacks and white French Canadians. The 24-hour blood pressure monitoring was performed under standardized conditions after discontinuing antihypertensive medications. Plasma renin activity and plasma aldosterone were measured in the supine position and after standing for 10 minutes. Plasma atrial natriuretic factor was also measured. Supine and standing plasma renin activities were lower (P< or =0.01), plasma aldosterone was higher (P<0.0001), and the aldosterone/renin ratios were higher (P<0.0001) in the hypertensive subjects. Atrial natriuretic factor was also higher in the hypertensive subjects (P<0.0001). Among blacks, blood pressures did not correlate with plasma renin activity. However, both average daytime and nighttime systolic and diastolic blood pressures were correlated with supine and standing plasma aldosterone and with the aldosterone/renin ratio (P<0.005 or less). In French Canadians, blood pressures tended to be positively correlated with standing plasma renin activity and aldosterone, but not with the aldosterone/renin ratio. Correlations of blood pressure with aldosterone were more consistent and more striking in blacks than in French Canadians. In both ethnic groups, there were inconsistent correlations of blood pressure with atrial natriuretic factor. These observations are consistent with the hypothesis that aldosterone-induced volume expansion is an important contributor to hypertension, especially in blacks.

Hyperaldosteronism among black and white subjects with resistant hypertension.

Recent reports suggesting that the prevalence of primary hyperaldosteronism may be higher than historically thought have relied on an elevated plasma aldosterone concentration/plasma renin activity ratio to either diagnose or identify subjects at high risk of having primary hyperaldosteronism and have not included suppression testing of all evaluated subjects. In this prospective study of 88 consecutive patients referred to a university clinic for resistant hypertension, we determined the 24-hour urinary aldosterone excretion during high dietary salt ingestion, baseline plasma renin activity, and plasma aldosterone in all subjects. Primary hyperaldosteronism was confirmed if plasma renin activity was <1.0 ng/mL per hour and urinary aldosterone was >12 microg/24-hour during high urinary sodium excretion (>200 mEq/24-hour). Eighteen subjects (20%) were confirmed to have primary hyperaldosteronism. The prevalence of hyperaldosteronism was similar in black and white subjects. Of the 14 subjects with confirmed hyperaldosteronism who have been treated with spironolactone, all have manifested a significant reduction in blood pressure. In this population, an elevated plasma aldosterone/plasma renin activity ratio (>20) had a sensitivity of 89% and a specificity of 71% with a corresponding positive predictive value of 44% and a negative predictive value of 96%. These data provide strong evidence that hyperaldosteronism is a common cause of resistant hypertension in black and white subjects. The accuracy of these results is strengthened by having done suppression testing of all evaluated subjects.

Screening for primary aldosteronism: implications of an increased plasma aldosterone/renin ratio.

BACKGROUND: The value of the ratio of plasma aldosterone concentration (aldosterone) to plasma renin activity (renin) to identify patients at risk for primary aldosteronism is controversial. We determined the sensitivity, specificity, and predictive value of the ratio to identify combinations of renin and aldosterone compatible with primary aldosteronism. METHODS: The ratio was calculated in 505 adults with essential hypertension (143 black women, 82 black men, 122 white women, and 158 white men). We used a conventional cutpoint for an increased ratio (i.e., 20 mL/dL x h). The primary combination of renin and aldosterone considered compatible with primary aldosteronism was increased aldosterone for the concomitant renin, defined as aldosterone in the highest quartile predicted by linear regression on renin. Renin was considered low if it was in the lowest quartile of the sample distribution. RESULTS: The sensitivity of the ratio to identify individuals with increased aldosterone for the concomitant renin was 66% (80% in blacks and 56% in whites; P = 0.009), and the specificity of the ratio was 67% (46% in blacks and 84% in whites; P <0.0001). In 36% of instances of an increased ratio, it was a measure of low renin alone without increased aldosterone for renin (32% in blacks and 45% in whites; P = 0.072). The positive predictive value of the ratio to identify individuals with increased aldosterone for the concomitant renin was 34% (49% in whites and 27% in blacks; P <0.002). CONCLUSION: The aldosterone/renin ratio lacks sensitivity and specificity and has only a modest predictive value for combinations of renin and aldosterone that are compatible with primary aldosteronism.

Validity of the aldosterone-renin ratio used to screen for primary aldosteronism.

OBJECTIVE: To determine whether the calculated ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA), a proposed screening test for primary aldosteronism, provides a renin-independent measure of circulating aldosterone that is suitable to judge whether PAC is inappropriately elevated relative to PRA. SUBJECTS AND METHODS: This study consisting of 221 black and 276 white subjects with previously diagnosed essential hypertension was conducted between 1996 and 2000. Antihypertensive drugs were withdrawn for at least 4 weeks; PAC and PRA were measured while subjects were supine and then seated after 30 minutes of ambulation. The seated measurements were repeated after 4 weeks of oral diuretic therapy with hydrochlorothiazide (25 mg/d). RESULTS: The variation in the aldosterone-renin ratio was strongly and inversely dependent on PRA (R2=0.71; P<.001). When subjects changed position from supine to seated, the increase in mean +/- SD PRA (from 1.18 +/- 1.06 to 1.31 +/- 1.19 ng x mL(-1) x h(-1); P<.001) was associated with an increase in the mean ratio (from 18.6 +/- 52.8 to 25.8 +/- 38.1 h x 10(2); P<.001), whereas the increase in mean +/- SD PRA in response to diuretic therapy (from 1.31 +/- 1.19 to 2.72 +/- 2.67 ng x mL(-1) x h(-1); P=.007) was associated with a decrease in the mean ratio (from 25.8 +/- 38.1 to 16.4 +/- 31.6 h 10(2); P<.001). CONCLUSION: In patients with previously diagnosed essential hypertension, calculation of the aldosterone-renin ratio does not provide a renin-independent measure of circulating aldosterone that is suitable for determining whether PAC is elevated relative to PRA. Because elevation of the aldosterone-renin ratio is predominantly an indicator of low PRA, its perceived value in screening for primary aldosteronism most likely derives from additional diagnostic tests being done in patients with low-renin hypertension.