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Screening for Primary Aldosteronism: Implications of an Increased Plasma Aldosterone/Renin Ratio

¹ Division of Hypertension, Department of Internal Medicine, and
² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905.

³ Emory University, Atlanta, GA 30320.

⁴ University of Texas Health Sciences Center, Houston, TX 77225.

^aAddress correspondence to this author at: Division of Hypertension, West 9A, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Fax 507-284-1161; e-mail gschwartz{at}mayo.edu.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
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 · 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.

	Introduction

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Primary aldosteronism is recognized as the most common endocrine form of secondary hypertension (1), with prevalence estimates as high as 15% in the hypertensive population (2)(3)(4). Classically, this condition has been characterized by hypokalemia, suppressed plasma renin activity, increased aldosterone production, and nonsuppressible plasma and urine aldosterone. It is now recognized that the most common laboratory abnormality routinely assessed to distinguish primary aldosteronism from essential hypertension, namely hypokalemia, may be absent (2). Thus, there is ongoing interest in using measures of plasma renin activity (renin) and plasma aldosterone concentration (aldosterone) to screen for this disorder.

Although many have questioned the value of the separate measures, calculation of the aldosterone/renin ratio has been promulgated as a convenient and effective method to screen for primary aldosteronism (5). The Mayo Clinic medical laboratory is receiving increasing requests to report the ratio value as a screening test for this disorder. The rationale for the ratio as a screening test is based on the assumption that the usual dependency of aldosterone on renin is lost in primary aldosteronism and aldosterone becomes disproportionately increased relative to the concomitant renin. Moreover, because aldosterone increases renal sodium reabsorption and extracellular volume, renin may become secondarily depressed, increasing the ratio further. Therefore, an increased ratio is believed to identify individuals who have an increased aldosterone for the measured renin (increased aldosterone for the concomitant renin), with or without low renin. However, critics of the ratio point out that an increased value can often arise solely as the consequence of low renin in the absence of an increased aldosterone for the concomitant renin (6)(7), a common finding in essential hypertension, especially in blacks (8)(9)(10). In addition, it is unknown how often combinations of renin and aldosterone compatible with primary aldosteronism are associated with a normal ratio. A better understanding of the information provided by an increased ratio is an important first step in assessing its potential value as a screening test.

The goals of this study were therefore to determine the sensitivity, specificity, and predictive value of the aldosterone/renin ratio to identify combinations of renin and aldosterone compatible with primary aldosteronism. To accomplish these goals, we conducted a prospective cohort study in population-based samples of blacks and whites with previously diagnosed essential hypertension in whom renin and aldosterone were measured at a standard time of day 4 weeks after discontinuation of antihypertensive drug therapy and after stabilization on a standard sodium diet.

	Materials and Methods

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participants
The participants in the present study were community- and population-based samples of 225 unrelated non-Hispanic black adults (143 women, 82 men) from Atlanta, GA, and 280 unrelated non-Hispanic white adults (122 women, 158 men) from Rochester, MN (age range, 30–59.9 years), with previously diagnosed hypertension. These individuals were participants in an ongoing study conducted between 1996 and 2000 to assess genetic predictors of blood pressure response to diuretic therapy. Recruitment methods have been described (11). In brief, participants were ambulatory volunteers who had to be in good general health with a blood pressure <180/<110 mmHg and have no evidence by medical record review, history, physical examination, or screening laboratory studies of secondary hypertension, renal or liver dysfunction, serious heart disease, or diabetes. Individuals who had been taking diuretics and were found to be hypokalemic at the screening visit were allowed to participate as described below; however, because unexplained hypokalemia in a hypertensive individual is associated with a high probability of primary aldosteronism (12), a setting where screening tests are not needed, individuals with unexplained hypokalemia were excluded from participation (a total of seven individuals: six black volunteers and one white volunteer). Participants had to be able to discontinue antihypertensive medications and any drug that could influence the renin-angiotensin-aldosterone axis. However, postmenopausal women were allowed to continue hormone replacement therapy. Participants were required to review and sign a written consent form. The Institutional Review Boards of Emory University and the Mayo Clinic approved all procedures involving study participants in Atlanta, GA, and Rochester, MN, respectively. All study procedures were carried out in each institution’s general clinical research center in accordance with the respective institution’s guidelines.

study protocol
The study protocol has been described (11). Briefly, participants had their antihypertensive medications withdrawn, and other contraindicated drugs were discontinued. If the serum potassium concentration was <3.6 mmol/L at the screening visit and the individual had been receiving diuretic therapy, a potassium supplement (potassium chloride, 20 mmol/day) was prescribed. A dietitian instructed each participant in a diet designed to provide a daily sodium intake of 2 mmol/kg of body weight. After a minimum of 4 weeks without antihypertensive drug therapy, blood was collected at approximately 0800 in the morning with participants in the seated position after a timed ambulatory period of 0.5 h. The plasma renin activities and plasma aldosterone concentrations were analyzed by RIA as described previously (13).

statistical methods
The aldosterone/renin ratio was calculated for each individual. A ratio was defined as increased if it was 20 mL/dL · h (when aldosterone is expressed as ng/dL and renin is expressed as ng · mL^-1 · h^-1), the threshold value frequently used in clinical practice to indicate possible primary aldosteronism (14)(15). The distribution of observed renin activities was determined separately in each race-gender subgroup. Renin was classified as low if it was below the 25th percentile in its respective race-gender-specific distribution (lowest quartile). Linear regression of aldosterone on renin was carried out in each race-gender subgroup, and 50% confidence intervals for a predicted aldosterone observation about the regression were determined. An observed aldosterone was classified as increased for a measured renin (increased aldosterone for the concomitant renin) if it was above the upper bound of the 50% confidence interval for a predicted aldosterone value as a function of the concomitant renin (highest quartile). Using this information, we determined the number of individuals with increased aldosterone for the concomitant renin (compatible with primary aldosteronism) separately in each race-gender subgroup, and these were further subdivided into those with and those without low renin. Likewise, the number of individuals without increased aldosterone for the concomitant renin (compatible with essential hypertension) was determined, and these also were further subdivided into those with and those without low renin. These four categories of combinations of renin and aldosterone, which are mutually exclusive and completely exhaustive, were used to calculate sensitivity, specificity, and predictive values for the ratio to identify combinations of renin and aldosterone compatible with primary aldosteronism.

For quantitative traits, means and SDs were calculated for each race-gender subgroup stratified by ratio status. Student’s t-test was used to assess differences in means between subgroups. For categorical traits, ² analysis was used to assess for differences in proportions between races and between genders within each race.

	Results

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characteristics of study sample
As expected, individuals with increased ratios had lower mean renin and higher mean aldosterone values than individuals with normal ratios. Means for age, body mass index, baseline blood pressure, and serum potassium concentration did not differ significantly by ratio status [see supplemental data available with the online version of this article at Clinical Chemistry Online (http://www.clinchem.org/content/vol48/issue11/)].

Race- and gender-specific cutpoints for the lowest quartile of renin (ng · mL^-1 · h^-1) were <0.4 (<0.11 ng/L · s) in both black women and black men, <0.8 (<0.22 ng/L · s) in white women, and <0.6 (<0.17 ng/L · s) in white men. At these renin activities, cutpoints for the highest quartile of aldosterone (ng/dL) were >19 (527 pmol/L) in black women and >14 (388 pmol/L) in the other three race-gender subgroups. Overall, the correlation coefficient for the regression of aldosterone on renin was 0.22. This did not differ significantly among race-gender subgroups.

Overall, 21% of the participants had combinations of renin and aldosterone compatible with primary aldosteronism (with low renin in 5% and without low renin in 16%), whereas 79% had combinations of renin and aldosterone compatible with essential hypertension (with low renin in 19% and without low renin in 60%). These percentages were similar across race-gender subgroups [see supplemental data available with the online version of this article at Clinical Chemistry Online (http://www.clinchem.org/content/vol48/issue11/)].

frequency of an increased ratio
The frequency of an increased aldosterone/renin ratio in the overall sample was 40%. The frequency was higher in blacks than in whites (60% vs 25%; P <0.001), and this was also true in each gender. In blacks, the frequency was higher in women than in men (67% vs 46%; P = 0.002), whereas in whites the trend was for the ratio to be higher in men than in women, but this did not reach statistical significance [28% vs 20%; P = 0.090 (see supplemental data)].

implications of an increased ratio
Overall, the sensitivity of an increased ratio to identify combinations of renin and aldosterone compatible with primary aldosteronism was 66% (70 of 106; Tables 1 and 2 ). Sensitivity was higher in blacks than in whites (80% vs 56%; P = 0.009), and this was also true in each gender. In blacks, sensitivity was higher in women than in men (89% vs 65%; P = 0.046), whereas in whites, sensitivity was similar in women and men (54% vs 57%; P = 0.842). An increased ratio identified all 27 individuals who had increased aldosterone for the concomitant renin with low renin but only 54% (43 of 79) of individuals who had increased aldosterone for the concomitant renin without low renin [75% (27 of 36) of blacks and 37% (16 of 43) of whites; Table 1 ].

Overall, in 34% (70 of 203) of the individuals with an increased ratio, it was associated with combinations of renin and aldosterone compatible with primary aldosteronism (positive predictive value; Tables 1 and 2 ). The positive predictive value was higher in whites than in blacks [49% (34 of 69) in whites vs 27% (36 of 134) in blacks; P <0.002], and this was also true in each gender. Within race, the positive predictive value was similar in women and men.

Consequently, in 66% (133 of 203) of the individuals with an increased ratio, it was associated with combinations of renin and aldosterone compatible with essential hypertension [with low renin in 36% (32% in blacks and 45% in whites; P = 0.072) and without low renin in 29% (41% in blacks and 6% in whites; P <0.001); Table 1 ].

implications of a normal ratio
Overall, the specificity of a normal ratio to identify combinations of renin and aldosterone compatible with essential hypertension was 67% (266 of 399; Tables 1 and 2 ). Specificity was higher in whites than in blacks (84% in whites vs 46% in blacks; P <0.0001), and this was also true in each gender. In blacks, specificity was higher in men than in women (58% vs 38%; P = 0.009), whereas in whites, the trend was for it to be higher in women than in men, but this did not reach statistical significance (89% vs 80%; P = 0.08). Among participants with combinations of renin and aldosterone compatible with essential hypertension, a normal ratio identified 22% (21 of 95) of those with low renin [7% (3 of 46) of blacks and 37% (18 of 49) of whites] and 81% (245 of 304) of those without low renin [59% (79 of 134) of blacks and 98% (166 of 170) of whites; Table 1 ].

Overall, in 88% (266 of 302) of the participants with a normal ratio, it was associated with combinations of renin and aldosterone compatible with essential hypertension (negative predictive value; Tables 1 and 2 ). The negative predictive value was similar across all race-gender subgroups. Consequently, in 12% of the individuals with a normal ratio, it was associated with combinations of renin and aldosterone compatible with primary aldosteronism [10% of blacks and 13% of whites (P = 0.474); increased aldosterone for renin without low renin in all participants; Table 1 ].

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Because of poor sensitivity and specificity, measures of renin and aldosterone by themselves are considered to have limited value in screening for primary aldosteronism. In contrast, calculation of the aldosterone/renin ratio, which reduces these measures to a single number, is advocated as a useful screening method (5)(14)(15). Proponents suggest that the ratio, which reexpresses aldosterone as a multiple of renin, can identify hypertensive individuals who have an inappropriately high concentration of aldosterone for a measured concentration of renin, with or without low renin. This study determined the likelihood of the ratio being increased in patients with such combinations of renin and aldosterone (sensitivity) and the likelihood of the ratio being normal in patients without such combinations (specificity).

The overall sensitivity of an increased ratio for combinations of renin and aldosterone compatible with primary aldosteronism was low, especially in whites. The complement of sensitivity is the false-negative rate. The ratio test was associated with a high false-negative rate because it failed to identify almost one-half of the individuals who had increased aldosterone for the concomitant renin but who did not have low renin (25% of blacks and 63% of whites). This was the most common (76%) of the two combinations of renin and aldosterone compatible with primary aldosteronism in the study sample.

The overall specificity of a normal ratio for combinations of renin and aldosterone compatible with essential hypertension was also low, especially in blacks. The complement of specificity is the false-positive rate. The ratio test was associated with a high false-positive rate because it was frequently a measure of low renin in the absence of increased aldosterone for the concomitant renin. This was the case for almost one-half of increased ratios among whites and for one-third of increased ratios among blacks. These results corroborate our concern expressed in a previous publication that an increased ratio often might be merely a surrogate measure for low renin (13).

In our sample, the prevalence of combinations of renin and aldosterone compatible with primary aldosteronism was 21%, which is the pretest likelihood. Overall, the effect of an increased ratio on the pretest likelihood was to increase it only modestly, to 34% (positive predictive value). Likewise, the effect of a normal ratio on this pretest likelihood was to decrease it only modestly, to 12% (negative predictive value, 88%).

The results of this study cast doubt on the value of the aldosterone/renin ratio to screen for primary aldosteronism. These results also suggest an alternative reporting method that would provide the clinician with unambiguous information about the rank value of renin and the appropriateness of the aldosterone value for a measured renin value when using these values to screen for primary aldosteronism. The distribution of renin activities in representative samples of the hypertensive population, stratified by race, gender, and age, could be determined. The percentile rank of an observed renin value could then be reported. Similarly, the age-adjusted distribution of aldosterone values for measured values of renin could also be determined. The percentile rank of an observed aldosterone for a measured renin value could then be reported. Joint consideration of renin and aldosterone values in this manner should improve their usefulness in screening for primary aldosteronism.

Inferences from this study are dependent in part on the cutpoints (action limits) used to define specific combinations of renin and aldosterone compatible with primary aldosteronism. The cutpoints used in this study are reasonable because the effect of higher values would be to markedly reduce the frequency of these combinations below the likely prevalence of the disorder in the sample. Inferences from this study are also dependent on the fact that we chose only one of several potential values to define an increased aldosterone/renin ratio. Although some use a higher value to define an increased ratio to improve specificity, this would further reduce its sensitivity. In general, screening tests are designed to maximize sensitivity at the expense of specificity.

A further potential limitation of all screening methods that rely on single measurements of renin and aldosterone arises from the variability in these values, even in individuals with primary aldosteronism (16). Moreover, the dependence of aldosterone on renin is much weaker than conventionally assumed, and among individuals with essential hypertension, much of the variation in aldosterone is independent of the variation in renin (13).

Prospective studies are needed to determine the relative frequencies of the specific combinations of renin and aldosterone identified in this study in patients with confirmed primary aldosteronism. Such studies would be a basis to assess the effectiveness of our proposed method of reporting renin and aldosterone to screen for primary aldosteronism.

	Acknowledgments

 
This study was supported by US Public Health Service Grants RO1-HL53330, MO1-RR00585, and MO1-RR00039 and funds from the Mayo Foundation.

	References

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This Article Abstract Full Text (PDF) Supplemental Data Submit an electronic Letter to the Editor about this paper Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (24) Citing Articles via Google Scholar Google Scholar Articles by Schwartz, G. L. Articles by Turner, S. T. Search for Related Content PubMed PubMed Citation Articles by Schwartz, G. L. Articles by Turner, S. T. Related Collections Laboratory Management Endocrinology and Metabolism