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Screening for Primary Aldosteronism: Implications
of an Increased Plasma Aldosterone/Renin Ratio
Gary L. Schwartz,
1*
Arlene B. Chapman,
3
Eric Boerwinkle,
4
Robert M. Kisabeth,
2
and
Stephen T. Turner
1
Background: The value of the ratio of plasma aldoste-
rone concentration (aldosterone) to plasma renin activ-
ity (renin) to identify patients at risk for primary aldo-
steronism is controversial. We determined the
sensitivity, specificity, and predictive value of the ratio
to identify combinations of renin and aldosterone com-
patible 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 䡠 h). The primary combination of renin and aldo-
sterone considered compatible with primary aldosteron-
ism was increased aldosterone for the concomitant re-
nin, 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 individ-
uals with increased aldosterone for the concomitant
renin was 66% (80% in blacks and 56% in whites; P ⴝ
0.009), and the specificity of the ratio was 67% (46% in
blacks and 84% in whites; P <0.0001). In 36% of in-
stances 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 ⴝ 0.072). The
positive predictive value of the ratio to identify individ-
uals 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 sensitiv-
ity and specificity and has only a modest predictive
value for combinations of renin and aldosterone that are
compatible with primary aldosteronism.
© 2002 American Association for Clinical Chemistry
Primary aldosteronism is recognized as the most common
endocrine form of secondary hypertension (1), with prev-
alence estimates as high as 15% in the hypertensive
population (2–4). Classically, this condition has been
characterized by hypokalemia, suppressed plasma renin
activity, increased aldosterone production, and nonsup-
pressible plasma and urine aldosterone. It is now recog-
nized 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 rela-
tive to the concomitant renin. Moreover, because aldoste-
rone increases renal sodium reabsorption and extracellu-
lar 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
1
Division of Hypertension, Department of Internal Medicine, and
2
De-
partment 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.
*Address 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@mayo.edu.
Received March 7, 2002; accepted August 9, 2002.
Clinical Chemistry 48:11
1919–1923 (2002)
Endocrinology and
Metabolism
1919
hypertension, especially in blacks (8–10). In addition, it is
unknown how often combinations of renin and aldoste-
rone compatible with primary aldosteronism are associ-
ated with a normal ratio. A better understanding of the
information provided by an increased ratio is an impor-
tant 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 aldo-
sterone/renin ratio to identify combinations of renin and
aldosterone compatible with primary aldosteronism. To
accomplish these goals, we conducted a prospective co-
hort 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
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 pre-
dictors 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 dysfunc-
tion, serious heart disease, or diabetes. Individuals who
had been taking diuretics and were found to be hypokale-
mic at the screening visit were allowed to participate as
described below; however, because unexplained hypoka-
lemia 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 participa-
tion (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, respec-
tively. 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 with-
drawn, and other contraindicated drugs were discontin-
ued. 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 antihyper-
tensive drug therapy, blood was collected at approxi-
mately 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 concentra-
tions were analyzed by RIA as described previously (13 ).
statistical methods
The aldosterone/renin ratio was calculated for each indi-
vidual. A ratio was defined as increased if it was ⱖ20
mL/dL 䡠 h (when aldosterone is expressed as ng/dL and
renin is expressed as ng 䡠 mL
⫺1
䡠 h
⫺1
), the threshold value
frequently used in clinical practice to indicate possible
primary aldosteronism (14, 15). The distribution of ob-
served 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 re-
gression 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 aldoste-
ronism) 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 mutu-
ally exclusive and completely exhaustive, were used to
calculate sensitivity, specificity, and predictive values for
the ratio to identify combinations of renin and aldoste-
rone 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.
1920 Schwartz et al.: Screening for Primary Aldosteronism
Results
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 䡠 mL
⫺1
䡠 h
⫺1
) were ⬍0.4 (⬍0.11
ng/L 䡠 s) in both black women and black men, ⬍0.8
(⬍0.22 ng/L 䡠 s) in white women, and ⬍0.6 (⬍0.17 ng/
L 䡠 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 correla-
tion 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 aldoste-
ronism (with low renin in 5% and without low renin in
16%), whereas 79% had combinations of renin and aldo-
sterone 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
Table 1. Distribution of combinations of renin and aldosterone by ratio status in each race-gender subgroup.
a
Combinations
Blacks, n (%)
Pooled
(n ⴝ 225)
Women
(n ⴝ 143)
Men
(n ⴝ 82)
Ratio >20
(n ⴝ 134)
Ratio <20
(n ⴝ 91)
Ratio >20
(n ⴝ 96)
(Ratio <20)
(n ⴝ 47)
Ratio >20
(n ⴝ 38)
Ratio <20
(n ⴝ 44)
Compatible with PA
b,c
With low renin 9 (7%)
d
0 (0%) 5 (5%) 0 (0%) 4 (11%) 0 (0%)
Without low renin 27 (20%) 9 (10%) 20 (21%) 3 (6%) 7 (18%) 6 (14%)
Compatible with EH
e
With low renin 43 (32%) 3 (3%) 29 (30%) 1 (2%) 14 (37%) 2 (5%)
Without low renin 55 (41%)
d
79 (87%) 42 (44%) 43 (92%) 13 (34%) 36 (81%)
Whites, n (%)
Pooled
(n ⴝ 280)
Women
(n ⴝ 122)
Men
(n ⴝ 158)
Ratio >20
(n ⴝ 69)
Ratio <20
(n ⴝ 211)
Ratio >20
(n ⴝ 24)
Ratio <20
(n ⴝ 98)
Ratio >20
(n ⴝ 45)
Ratio <20
(n ⴝ 113)
Compatible with PA
c
With low renin 18 (26%) 0 (0%) 8 (33%) 0 (0%) 10 (22%) 0 (0%)
Without low renin 16 (23%) 27 (13%) 5 (21%) 11 (11%) 11 (24%) 16 (14%)
Compatible with EH
e
With low renin 31 (45%) 18 (9%) 11 (46%) 11 (11%) 20 (44%) 7 (6%)
Without low renin 4 (6%) 166 (78%) 0 (0%) 76 (78%) 4 (10%) 90 (80%)
a
Renin, plasma renin activity; aldosterone, plasma aldosterone concentration.
b
PA, primary aldosteronism; EH, essential hypertension.
c
Increased aldosterone for the concomitant renin.
d
P ⫽ 0.0001 between blacks and whites.
e
Expected aldosterone for the concomitant renin.
Clinical Chemistry 48, No. 11, 2002 1921
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 aldoste-
ronism (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 combina-
tions 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 hyper-
tension, 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 sub-
groups. 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
Because of poor sensitivity and specificity, measures of
renin and aldosterone by themselves are considered to
have limited value in screening for primary aldosteron-
ism. 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 ). Pro-
ponents suggest that the ratio, which reexpresses aldoste-
rone as a multiple of renin, can identify hypertensive
individuals who have an inappropriately high concentra-
tion 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 combi-
nations of renin and aldosterone compatible with primary
aldosteronism was low, especially in whites. The comple-
ment 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 combina-
tions 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
Table 2. Test characteristics for the aldosterone/renin ratio to identify combinations of renin and aldosterone compatible
with primary aldosteronism.
a
Overall
b
Blacks Whites
Women Men Pooled Women Men Pooled
Prevalence,
c
%21 202120 202322
Sensitivity, % 66 89 65 80 54 57 56
Specificity, % 67 38 58 46 89 80 84
PPV,
d
% 34 262927 544749
NPV, % 88 94 86 90 89 86 87
a
Renin, plasma renin activity; aldosterone, plasma aldosterone concentration.
b
Entire study sample.
c
Prevalence of combinations of renin and aldosterone compatible with primary aldosteronism.
d
PPV, positive predictive value; NPV, negative predictive value.
1922 Schwartz et al.: Screening for Primary Aldosteronism
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 aldosteron-
ism. These results also suggest an alternative reporting
method that would provide the clinician with unambig-
uous 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 rep-
resentative samples of the hypertensive population, strat-
ified 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 aldo-
sterone values for measured values of renin could also be
determined. The percentile rank of an observed aldoste-
rone 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 combina-
tions of renin and aldosterone compatible with primary
aldosteronism. The cutpoints used in this study are rea-
sonable 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 sensi-
tivity. In general, screening tests are designed to maxi-
mize 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 indi-
viduals 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 aldoste-
rone is independent of the variation in renin (13).
Prospective studies are needed to determine the rela-
tive frequencies of the specific combinations of renin and
aldosterone identified in this study in patients with con-
firmed 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.
This study was supported by US Public Health Service
Grants RO1-HL53330, MO1-RR00585, and MO1-RR00039
and funds from the Mayo Foundation.
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