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Screening for Primary Aldosteronism in Essential
Hypertension: Diagnostic Accuracy of the Ratio of
Plasma Aldosterone Concentration to Plasma
Renin Activity
Gary L. Schwartz
*
and Stephen T. Turner
Background: The ratio of plasma aldosterone concen-
tration to plasma renin activity (PRA) is considered the
screening test of choice for primary aldosteronism. Un-
certainty exists, however, regarding its diagnostic accu-
racy and the effects of antihypertensive drugs and
dietary sodium balance on test characteristics.
Methods: We measured PRA and aldosterone in 118
white adults [71 men and 47 women; mean (SD) age,
51 (7) years] with previously diagnosed essential hyper-
tension. Measurements were made while individuals
were on antihypertensive drug therapy, after a 2-week
drug-free period, after 4 days of dietary sodium loading,
and after acute furosemide diuresis. We measured 24-h
urine aldosterone excretion and PRA on the 4th day of
dietary sodium loading to establish the diagnosis of
primary aldosteronism. ROC curves were constructed
for ratios measured under each clinical condition, and
likelihood ratios were determined for individuals on or
off antihypertensive drug therapy.
Results: Fifteen patients [13%; 95% confidence interval
(CI), 7–20%] met the reference standard for primary
aldosteronism. The mean (SD) areas under the ROC
curves did not differ significantly across conditions of
measurement [range, 0.80 (0.10) to 0.85 (0.04); P ⴝ 0.72].
When measured on and off antihypertensive drug ther-
apy, the 95% CIs for the optimum cutpoint for the ratio
overlapped. Point estimates of sensitivity on and off
therapy were 73% (95% CI, 50 –96%) and 87% (70–100%),
respectively, and specificities were 74% (65– 83%) and
75% (66–84%). Under either condition, increased ratios
were associated with 2.4- to 13-fold increases of posttest
odds above pretest odds.
Conclusions: The aldosterone:PRA ratio provides only
fair diagnostic accuracy in screening for primary aldo-
steronism, but concomitant antihypertensive drug ther-
apy or acute variation in dietary sodium balance does
not adversely affect test accuracy. Reporting of likeli-
hood ratios associated with ranges of values of the
aldosterone:PRA ratio, rather than use of a single “opti-
mum” cutpoint, may enhance the usefulness of the test.
© 2005 American Association for Clinical Chemistry
Recently published series suggest that primary aldoste-
ronism is the most common secondary form of hyperten-
sion with prevalence estimates as high as 18% (1–8).
Moreover, some experts advocate screening of all hyper-
tensive individuals for this disorder to guide drug selec-
tion and improve treatment success (8, 9).
In 1976, Dunn and Espiner (10 ) first suggested simul-
taneous measurement of plasma aldosterone concentra-
tion and plasma renin activity (PRA)
1
and calculation of
the aldosterone:PRA ratio as a potentially useful screen-
ing test for primary aldosteronism. They reasoned that
because primary aldosteronism is characterized by in-
creased aldosterone with consequent extracellular volume
expansion and suppression of PRA, individuals with the
disorder should have higher values of the ratio than those
with essential hypertension. In 1981, Hiramatsu et al. (11)
proposed the aldosterone:PRA ratio as the screening test
of choice for primary aldosteronism. Currently, the ratio
is widely accepted as a simple and reliable screening test
for this disorder (12, 13 ); however, its sensitivity and
specificity have not been determined in individuals with
Division of Nephrology and Hypertension, Department of Internal Medi-
cine, Mayo Clinic College of Medicine, Rochester MN.
*Address correspondence to this author at: Division of Nephrology and
Hypertension, Department of Internal Medicine, Mayo Clinic College of
Medicine, 200 First Street SW, Rochester MN 55905. Fax 507-284-1161; e-mail
gschwartz@mayo.edu.
Received August 19, 2004; accepted November 16, 2004.
Previously published online at DOI: 10.1373/clinchem.2004.041780
1
Nonstandard abbreviations: PRA, plasma renin activity; GCRC, General
Clinical Research Center; and CI, confidence interval.
Clinical Chemistry 51:2
386–394 (2005)
Endocrinology and
Metabolism
386
presumed essential hypertension, in whom the reference
standard was performed subsequent to the screening test,
regardless of the result of the latter test (14). Moreover,
experts do not agree on the clinical conditions for screen-
ing. In particular, although it is recognized that concom-
itant antihypertensive drug therapy can influence ratio
values (15 ), the effect on the diagnostic accuracy of the
test has not been formally assessed. In addition, the
influence of variation in dietary sodium balance on the
diagnostic accuracy of the ratio is unknown.
The primary objective of this study, therefore, was
to determine the sensitivity and specificity of the aldoste-
rone:PRA ratio to screen a community-based sample of
adults with presumed essential hypertension for primary
aldosteronism based on the results of a urinary aldoste-
rone suppression test as the reference standard. A second
objective was to assess the overall influence of antihyper-
tensive drug therapy and variation in dietary sodium
balance on diagnostic accuracy of the ratio.
Materials and Methods
participants
The sample of 118 individuals for the present study was
recruited from a population-based cohort of 280 unrelated
non-Hispanic white adults (122 women and 158 men; age
range, 30 –59.9 years) from Rochester, MN who had
essential hypertension and had participated in a previous
study to assess genetic predictors of blood pressure re-
sponse to diuretic therapy (16, 17). The present study was
carried out from January 2000 through May 2002 with
recruitment extending from January 2000 through Febru-
ary 2002. The parent cohort of 280 individuals was origi-
nally recruited from a list of all residents of Olmsted
County, MN with the diagnosis of essential hypertension
who had been seen by a healthcare provider in the
previous 3 years before recruitment (18 ). Candidates for
the parent study who responded favorably to an informa-
tive letter about this study were recruited. Essential
hypertension was defined as a blood pressure ⱖ140/90
mmHg or a previous diagnosis of essential hypertension
and current use of prescription antihypertensive medica-
tions. Candidates were considered ineligible for the par-
ent study for the following reasons: known or suspected
secondary hypertension; unexplained hypokalemia; use
of more than three antihypertensive medications for
blood pressure control; allergy to hydrochlorothiazide;
inability to discontinue antihypertensive medications; use
of nonsteroidal antiinflammatory medications, including
daily aspirin ⬎325 mg; congestive heart failure; liver or
renal disease (serum creatinine concentration ⬎15 mg/L);
or diabetes mellitus, defined as fasting blood glucose
⬎1400 mg/L or taking hypoglycemic medications.
Women taking oral contraceptive medications were dis-
qualified, but those receiving postmenopausal hormone
replacement were allowed. Candidates with hypokalemia
while taking diuretics were allowed to participate. Partic-
ipants in the parent study had to have a diastolic blood
pressure ⬎90 mmHg after discontinuing antihypertensive
drug therapy.
All 280 participants from the parent study were sent a
letter providing information about the present study.
Interested candidates who contacted the study center
were considered for recruitment. History, physical exam-
ination, and routine laboratory tests were used in the
parent study to exclude secondary hypertension and were
repeated in the present study. Participants had to be able
to discontinue antihypertensive medications and any
drug that could influence the renin-angiotensin-aldoste-
rone axis. Candidates found to have diuretic-induced
hypokalemia were placed on oral potassium supplements
at the time of enrollment. All participants were required
to review and sign a written consent form. Of the 280
candidates, 140 agreed to participate and 119 completed
the study protocol. One individual was excluded from the
analysis because of noncompliance with the study diet.
The Institutional Review Board of the Mayo Clinic ap-
proved all procedures involving study participants. All
study procedures were carried out in the Mayo Clinic
General Clinical Research Center (GCRC) in accordance
with institutional guidelines.
study protocol
Determination of the aldosterone:PRA ratio to screen for
primary aldosteronism. PRA and aldosterone concentra-
tions for calculation of the ratio were obtained for all
study participants on four separate occasions: (a)atthe
screening and consent visit before discontinuation of
antihypertensive drug therapy; (b) after a minimum
2-week drug-free period; (c) after 4 days of dietary so-
dium loading (urinary aldosterone suppression test); and
(d) after acute furosemide diuresis. Throughout the study,
participants ate their usual diet except for a 1-week period
before acute furosemide diuresis when they were in-
structed in a 90 mmol/day sodium diet. Blood samples
for measurement of PRA and aldosterone were obtained
with individuals in the seated position after 5 min of rest.
All samples were obtained at ⬃0800 except for samples
after acute furosemide diuresis, which were obtained at
⬃1800 (6 h after the last dose of furosemide).
Reference standard for primary aldosteronism. After a mini-
mum 2-week antihypertensive-drug-free period, and in a
potassium-replete state, all study participants underwent
a urinary aldosterone suppression test. They ingested a
diet designed to provide a daily sodium intake of at least
250 mmol over 4 consecutive days. Each day, breakfast
and dinner were eaten at the GCRC and a box lunch was
provided. With breakfast and dinner, participants were
required to also ingest two NaCl tablets (17 mmol sodi-
um/tablet). After 3 days on the diet, participants began a
24-h urine collection for measurement of sodium, potas-
sium, creatinine, and aldosterone excretions. At ⬃0800 the
next morning, blood was obtained after 5 min in the
sitting position for measurement of sodium, potassium,
Clinical Chemistry 51, No. 2, 2005 387
and aldosterone concentrations and PRA. For dietary
sodium loading to be considered sufficient to suppress
aldosterone, 24-h urinary sodium excretion was re-
quired to be ⱖ200 mmol. Under these conditions, a 24-h
urinary aldosterone excretion ⱖ12
g is consistent with
autonomous aldosterone production and primary aldo-
steronism (19 ).
Acute furosemide diuresis. Immediately after the urinary
aldosterone suppression test, all study participants were
instructed to ingest a 90 mmol/day sodium diet. After a
minimum of 1 week on the diet, and in a potassium-
replete state, they were subjected to acute furosemide-
induced diuresis. Furosemide in a dose of 2 mg/kg of
body weight was given orally at 0600, and the dose was
repeated 6 h later at 1200. Before each dose, participants
were weighed (beam balance), and blood pressures were
measured after 5 min of quiet sitting and after 1 min of
standing. Furosemide was given if systolic blood pressure
was ⱖ120 mmHg, the change in systolic blood pressure
from sitting to standing was ⬍30 mmHg, and there were
no complaints of lightheadedness. After each dose of
furosemide, participants were allowed to engage in their
usual daily activities but were instructed not to rest in the
supine position. On the day of the test, all meals were
ingested in the GCRC and fluid intake was restricted to 15
mL water/kg of body weight. Participants returned to the
GCRC 6 h after the second dose of furosemide, at ⬃1800,
when blood was obtained after 5 min in the sitting
position for measurement of PRA and aldosterone, so-
dium, and potassium concentrations.
Laboratory procedures. Plasma and urine aldosterone was
measured by RIA (Diagnostic Products Corporation).
PRA was measured by RIA of angiotensin I in the
presence of reagents that inhibit angiotensin I-converting
enzyme and angiotensinases. The assay was performed
according to the method of Sealy and Laragh (20, 21 ),
using GammaCoat Plasma Renin Activity RIA Kits (Dia-
Sorin).
Each plasma and urine sample was assayed in tripli-
cate, and the means were used in the analyses. For plasma
aldosterone, the mean within- and between-assay CVs
were 3.3% and 8.4%, respectively, for samples between
5.8 and 57.5 ng/dL.
2
For urine aldosterone, the mean
within- and between-assay CVs were ⬍7%. For PRA, the
mean within- and between-assay CVs were 4.8% and
8.4%, respectively, for samples between 0.9 and 5.2
ng 䡠 mL
⫺1
䡠 h
⫺1
.
Electrolyte concentrations were measured by use of an
ion-selective electrode. Serum and urine creatinine con-
centrations were measured by automated spectrophoto-
metric methods implemented on the Hitachi 911 Chemis-
try Analyzer (Roche Diagnostics).
All laboratory measurements were performed after
participants completed the study protocol; therefore,
study personnel were blinded to the results of the screen-
ing test and reference standard until the time of analysis.
statistical methods
The diagnostic criteria for primary aldosteronism, estab-
lished before the study, were a 24-h urine aldosterone
excretion ⱖ12
g after dietary sodium loading (urine
sodium excretion ⱖ200 mmol) and a concomitant PRA
ⱕ1.0 ng 䡠 mL
⫺1
䡠 h
⫺1
. At the end of the study, two indi-
viduals (the author and coauthor) who are trained neph-
rologists and experts in hypertension reviewed the labo-
ratory results and determined who met the diagnostic
criteria for primary aldosteronism without knowledge of
the ratio values. The prevalence of primary aldosteronism
and the 95% confidence intervals (CIs) were determined
(22).
Under each of the four clinical conditions, the aldoste-
rone:PRA ratio was calculated for each participant. The
ratio was calculated using conventional units for PRA
(ng 䡠 mL
⫺1
䡠 h
⫺1
) and aldosterone (ng/dL). To convert
PRA to SI units of ng/L 䡠 s, multiply by 0.2778; to convert
aldosterone to SI units of pmol/L, multiply by 27.74. In
some publications, the ratio is calculated using aldoste-
rone expressed in SI units and PRA expressed in conven-
tional units. Dividing such values by 27.74 converts them
to values used in the present analyses. Using the calcu-
lated aldosterone:PRA ratios, we generated ROC curves
for the ratio under the four clinical conditions. We com-
pared the area under each ROC curve for differences,
using the method of Delong et al. (23 ). The optimum ratio
value for each clinical condition was defined as the value
on the ROC curve that was associated with the minimum
Euclidean distance (Pythagorean theorem) from the curve
to the upper left corner of the graph, using the formula:
公
(1 ⫺ sensitivity)
2
⫹ (1 ⫺ specificity)
2
. Bootstrapping was
used to determine 95% CIs for each optimum ratio value.
The sensitivity and specificity associated with the opti-
mum ratio value for each clinical condition with its
respective 95% CI were determined. Finally, for the two
clinical conditions of screening most often encountered in
clinical practice (on or off antihypertensive drug therapy),
likelihood ratios for a positive test (sensitivity/1 ⫺ spec-
ificity) were determined for various ranges of ratio values.
This is of practical value because it provides diagnostic
information over the entire range of ratio values, rather
than for only a single “optimum” cutpoint.
Results
description of the sample
Of the 280 adults with previously diagnosed essential
hypertension who were candidates for this study, 140
agreed to participate and 118 successfully completed the
urinary aldosterone suppression test. Their median age
was 52 years (range, 29 – 63 years), and 39.8% were
women (n ⫽ 47). Other characteristics of the participants
2
To convert aldosterone to SI units of pmol/L, multiply by 27.74; to
convert PRA to SI units of ng/L 䡠 s, multiply by 0.2778.
388 Schwartz and Turner: Screening for Primary Aldosteronism
are described in Table 1. Of the 118 participants, 113 (96%)
were on antihypertensive drug therapy at study entry. Of
these 113 individuals, 69 (61%) were on monotherapy and
44 (39%) were on combination therapy with two or three
drugs. Sixty-two (55%) were on thiazide diuretics [25 of
62 (40%) on monotherapy]; 42 (37%) were on beta-block-
ers [19 of 42 (45%) on monotherapy]; 39 (35%) were on
angiotensin-converting enzyme inhibitors or angiotensin
receptor blockers [23 of 39 (59%) on monotherapy]; and
11 (10%) were on calcium antagonists [2 of 11 (18%) on
monotherapy]. There were no adverse events associated
with antihypertensive drug withdrawal, the aldosterone
suppression test, or acute furosemide diuresis.
prevalence estimate of primary aldosteronism
Fifteen of the 118 participants [13% (95% CI, 7–20%)] met
the reference standard for diagnosis of primary aldoste-
ronism, i.e., PRA ⱕ1.0 ng 䡠 mL
⫺1
䡠 h
⫺1
and 24-h urinary
aldosterone excretion after dietary sodium loading ⱖ12
g. Among those who met the diagnostic criteria for
primary aldosteronism, median (range) 24-h urinary so-
dium excretion was 290 (201–494) mmol, median PRA
was 0.40 (0.07– 0.97) ng 䡠 mL
⫺1
䡠 h
⫺1
, and median 24-h
urinary aldosterone excretion was 14.9 (12.3–30.7)
g.
Among participants who did not meet the diagnostic
criteria for primary aldosteronism, the median (range)
24-h urinary sodium excretion was 302 (153– 486) mmol,
median PRA was 1.10 (0.06 –4.66) ng 䡠 mL
⫺1
䡠 h
⫺1
, and
median 24-h urinary aldosterone excretion was 8.0 (1.5–
24.7)
g.
distribution of the aldosterone:pra ratio in
the study sample
The distributions of ratio values for participants before
and after discontinuation of antihypertensive drug ther-
apy are shown in panels A and B, respectively, of Fig. 1.
Under both clinical conditions, the ratio distribution was
skewed to higher values among individuals with primary
aldosteronism. In both diagnostic groups, discontinuation
of antihypertensive drug therapy led to a shift of the
distribution to higher values.
diagnostic accuracy of the aldosterone:pra
ratio
The ROC curves for the ratios under each clinical condi-
tion are displayed in Fig. 2. The diagnostic accuracy of the
ratio, defined by the area under the ROC curve, did not
differ significantly across clinical conditions [range of the
mean (SD), 0.80 (0.10) to 0.85 (0.04); P ⫽ 0.72 for compar-
ison].
optimum values of the aldosterone:pra ratio
and associated test characteristics
Optimum values of the aldosterone:PRA ratio ranged
from 8.9 mL/dL 䡠 h when measured after acute furo-
semide diuresis to 14.9 mL/dL 䡠 h when measured when
Fig. 1. Distribution of values for the ratio of plasma aldosterone concentration to PRA in the study sample by diagnosis of essential hypertension
(EH) or primary aldosteronism (PA).
(A), distribution of ratio values in the study sample measured when participants were on antihypertensive drug therapy. (B), distribution of ratio values in the study
sample measured when participants were off antihypertensive drug therapy.
Table 1. Description of the 118 study participants.
a
Characteristic Median
25th
percentile
75th
percentile
P
(for normality)
Age, years 52 48 58 ⬍0.010
Duration HT,
b
years 6 4 12 ⬍0.010
BMI, kg/m
2
30.7 26.8 34.6 0.093
Systolic BP, mmHg 139 129 146 0.025
Diastolic BP, mmHg 91 87 97 ⬎0.150
Sodium, mmol/L 142 140 144 ⬎0.150
Potassium, mmol/L 4.5 4.3 4.7 ⬎0.150
Creatinine,
mol/L 97 88 106 ⬍0.010
a
All measurements were obtained at the screening visit before study entry
except for systolic and diastolic blood pressure, sodium, and potassium, which
were measured when patients were off antihypertensive therapy before the
urinary aldosterone suppression test.
b
HT, hypertension; BMI, body mass index; BP, blood pressure.
Clinical Chemistry 51, No. 2, 2005 389
participants were off antihypertensive drug therapy (Ta-
ble 2). The 95% CIs for these point estimates are shown in
Table 2.
The diagnostic sensitivity of the optimum ratio value
was highest when measured after dietary sodium loading
(93%) and lowest when measured either when partici-
Fig. 2. ROC curves for the aldosterone:PRA ratio determined under the clinical conditions of concurrent antihypertensive drug therapy (A), after a
minimum 2-week antihypertensive-drug-free interval (B), after 4 days of dietary sodium loading (C), and after acute furosemide diuresis (D).
Values of the ratio at various points on the curve are displayed in conventional units of mL/dL 䡠 h. Bold values represent the optimum value of the ratio under each
clinical condition. AUC, area under the ROC curve.
Table 2. Test characteristics of the aldosterone:PRA ratio to screen for primary aldosteronism.
Drug therapy Drug free Sodium loading Acute diuresis
Optimum ratio (95% CI), mL/dL 䡠 h 12.4 (7.1–16.6) 14.9 (14.2–20.9) 13.3 (11.8–25.5) 8.9 (5.2–9.7)
Sensitivity (95% CI), % 73 (50–96) 87 (70–100) 93 (80–100) 73 (50–96)
Specificity (95% CI), % 74 (65–83) 75 (66–84) 71 (62–80) 84 (77–91)
Likelihood ratio
Positive test 2.8 3.4 3.2 4.4
Negative test 0.36 0.18 0.10 0.32
Predictive value, %
Positive test 29 33 32 41
Negative test 95 97 99 96
390 Schwartz and Turner: Screening for Primary Aldosteronism
pants were on antihypertensive drug therapy or after
acute furosemide diuresis (73% under both conditions;
Table 2). Sensitivity was intermediate when measured
when participants were off antihypertensive drug therapy
(87%). Specificity of the optimum ratio value was highest
when measured after furosemide diuresis (84%) and
lower when measured under the other clinical conditions
(71–75%). The 95% CIs for the point estimates of sensitiv-
ity and specificity are shown in Table 2.
For optimum values of the aldosterone:PRA ratio (Ta-
ble 2), the likelihood ratio for a positive test was highest
after acute furosemide diuresis (4.4) and lowest when
measured when participants were on antihypertensive
drug therapy (2.8). The likelihood ratio for a negative test
was lowest for the aldosterone:PRA ratio measured after
dietary sodium loading (0.10) and highest when mea-
sured when participants were on antihypertensive drug
therapy (0.36).
likelihood ratios associated with ranges of
aldosterone:pra ratio values
Because the overall diagnostic accuracy of the ratio did
not differ significantly across clinical conditions, likeli-
hood ratios associated with increasing ranges of values of
the aldosterone:PRA ratio are shown only for the two
clinical conditions most likely to be used in clinical
practice, i.e., on or off antihypertensive drug therapy.
Under either of these conditions, ratio values ⬎15 mL/
dL 䡠 h were associated with 2.4- to 13-fold increases above
the pretest odds for primary aldosteronism (Table 3).
Discussion
The results of our study demonstrate that measurement of
the aldosterone:PRA ratio to screen for primary aldoste-
ronism has only fair diagnostic accuracy that is not
significantly affected by concurrent antihypertensive
drug therapy or acute variation in dietary sodium bal-
ance. This implies that the ratio can be determined with-
out the need for prior discontinuation of antihypertensive
drug therapy or imposition of a controlled sodium diet. In
general, values of the ratio ⬎15 mL/dL 䡠 h were associ-
ated with an increase above the pretest odds for primary
aldosteronism; however, ranges of values of the ratio and
their associated likelihood ratios may be more clinically
useful and informative than a single cutpoint value. The
results of our study also demonstrate that primary aldo-
steronism, as currently defined, is common among adults
with presumed essential hypertension.
Montori and Young (14 ) recently conducted a system-
atic review of prospective studies of the aldosterone:PRA
ratio as a screening test for primary aldosteronism. The
review included 16 studies with ⬎3000 participants. They
noted that none of these studies evaluated the ratio and
the reference standard independently of each other; only
two studies evaluated individuals who had a “negative”
ratio with the reference standard; and only 16.7% of the
participants had both the ratio and the reference standard
performed. In these studies, cutpoint values of the ratio
ranged from 7.2 to 100 mL/dL 䡠 h. Moreover, the origin of
the study samples (primary care, referral, or hospitalized
patients), the clinical conditions of measurement (usual vs
low-salt diet; on or off antihypertensive drug therapy),
and the details of measurement (time of day, body posi-
tion, and specific methods used to measure PRA and
aldosterone) all varied among studies. In most studies, the
rationale for the chosen cutpoint value of the ratio was not
explicitly disclosed. The authors of the review concluded
that: “there are no published valid estimates of the test
characteristics of the aldosterone:PRA ratio when used as
a screening test for primary aldosteronism in patients
with presumed essential hypertension.” Our study over-
comes most of these deficiencies and provides the first
estimate of the diagnostic accuracy of the ratio when used
to screen individuals from the community with presumed
essential hypertension for primary aldosteronism, the
group most commonly considered for this disorder.
Diagnostic sensitivities associated with optimum val-
ues of the ratio were only modest when measured when
participants were either on or off antihypertensive drug
therapy (73– 87%). This is not unexpected because it is
Table 3. Effect of aldosterone:PRA ratio values on pretest odds of primary aldosteronism in the study sample when
measured in patients on or off antihypertensive drug therapy.
Pretest odds
(probability) Ratio value Likelihood ratio
Posttest odds
(probability)
On antihypertensive drug therapy 0.15 (13%) 0–10 0.39 0.06 (6%)
10–15 0.72 0.11 (10%)
15–20 7.0 1.05 (51%)
20–25 13.0 1.95 (66%)
⬎25 3.6 0.54 (35%)
Off antihypertensive drug therapy 0.15 (13%) 0–10 0.12 0.02 (2%)
10–15 0.41 0.06 (6%)
15–20 2.9 0.44 (30%)
20–25 5.0 0.75 (43%)
25–30 13.0 1.95 (66%)
⬎30 2.4 0.36 (26%)
Clinical Chemistry 51, No. 2, 2005 391
known that the ratio can vary greatly and that “normal”
values are not uncommon in individuals with primary
aldosteronism. For example, in a recent study of repeated
measures of the ratio under random and standardized
conditions in 71 patients with confirmed primary aldoste-
ronism attributable to aldosterone-producing adenomas
(24), normal ratio values were observed in 31% of patients
on at least one occasion and in only 37% of patients was
the ratio increased on all occasions of measurement. These
observations support the possibility that modest further
increases in sensitivity might be achieved by obtaining
repeated measures of the ratio, as suggested by Gordon
(9). However, the benefit of this approach would have to
be balanced against its associated added cost and incon-
venience.
Specificities associated with optimum values of the
ratio were also only modest when measured when par-
ticipants were either on or off antihypertensive drug
therapy (74–75%). One explanation for the relatively low
specificity is the frequency of low PRA in hypertensive
patients (9, 25 ). As we have previously pointed out, most
of the variation in the ratio in patients with essential
hypertension is attributable to variation in PRA, and in
many patients, an increased ratio is simply an indicator of
low PRA (26, 27 ). To improve the specificity of the ratio,
some have advocated the addition of a threshold value of
aldosterone as part of the screening criteria (4, 13 ). Al-
though such a strategy increases the specificity of the test
(i.e., decreases the number of false positives), it also
markedly decreases sensitivity (i.e., increases the number
of false negatives). For example, imposition of a threshold
value of aldosterone of ⬎15 ng/dL, as suggested by the
authors in the above-cited studies, to the optimum ratio of
⬎12.4 mL/dL 䡠 h (when screening individuals on antihy-
pertensive drug therapy) increased the specificity in our
sample from 74% to 97% but markedly decreased the
sensitivity from 73% to 33%. Thus, based on our findings,
such a strategy is ill advised in screening for primary
aldosteronism.
Differences in clinical conditions at the time of screen-
ing that influence PRA and aldosterone may also influ-
ence the test characteristics of the ratio. A common and
important clinical condition is concomitant antihyperten-
sive drug therapy. In a sample of 154 adults with known
primary aldosteronism, Mulatero et al. (15 ) reported that
a beta-blocker (atenolol) increased the mean ratio by 62%,
whereas, a calcium antagonist (amlodipine), an angioten-
sin-converting enzyme inhibitor (fosinopril), and an an-
giotensin II receptor blocker (irbesartan) decreased the
mean ratio by 17%, 30%, and 43%, respectively. In a
previous study, we found that a thiazide diuretic (hydro-
chlorothiazide) decreased the mean ratio by 36% (26).
Although these studies clearly demonstrate that antihy-
pertensive drugs may influence ratio values, this is the
first study to assess the overall effects of the presence of
antihypertensive drug therapy on the diagnostic accuracy
of the ratio. As expected, the presence or absence of
antihypertensive drug therapy influenced optimum cutoff
values of the ratio, e.g., 12.4 mL/dL 䡠 h on drug therapy vs
14.9 mL/dL 䡠 h off drug therapy; however, the diagnostic
accuracy of the test defined by the area under the ROC
curves was not significantly affected [0.80 (0.06) vs
0.84 (0.04); P ⫽ 0.49]. Discontinuation of antihypertensive
drug therapy before screening is time-consuming and
potentially dangerous, and our results suggest that it is
not necessary.
Another clinical condition at the time of screening that
could influence the test characteristics of the ratio is
dietary sodium balance. Clearly, dietary sodium restric-
tion is associated with increases in both PRA and aldoste-
rone concentration, whereas dietary sodium loading is
associated with opposite effects. However, the influence
of these changes on the ratio has not been systematically
investigated. In our study, similar to the observed effects
of the presence or absence of antihypertensive drug
therapy, acute changes in dietary sodium balance influ-
enced the optimum cutpoint value of the ratio (e.g., 13.3
mL/dL 䡠 h after sodium loading vs 8.9 mL/dL 䡠 h after
acute diuresis), but did not significantly affect the diag-
nostic accuracy of the test [area under the ROC curve,
0.85 (0.04) vs 0.81 (0.06); P ⫽ 0.51]. These results suggest
that imposition of a controlled sodium diet before screen-
ing is also unnecessary.
A practical problem with application of the ratio in
clinical practice is deciding on which of several published
cutpoint values to use for a positive test (14 ). The tradition
of reporting a single cutpoint value for the ratio does not
take full advantage of the information provided by any
single value obtained during screening. In reality, useful
information for clinical decision-making can be provided
by any value of the ratio. Thus, we display in Table 3 the
likelihood ratios associated with ranges of values of the
ratio that could be used by the clinician to determine the
impact of any measured value on the probability of
disease. In general, higher ranges of ratio values were
associated with correspondingly higher likelihood ratios;
however, this was not the case for the highest ranges (⬎25
mL/dL 䡠 h on drug therapy and ⬎30 mL/dL 䡠 h off drug
therapy). This is likely a consequence of the small number
of individuals in our sample with ratio values in these
highest ranges.
Our study, consistent with several recent reports, indi-
cates that primary aldosteronism is common in patients
with presumed essential hypertension (1–8). In these
recent series, idiopathic hyperaldosteronism attributable
to presumed bilateral adrenal hyperplasia was the most
common subtype, accounting for two thirds of cases, with
a unilateral adrenal cortical adenoma accounting for the
remainder (8 ). All of the participants in our study who
met the diagnostic criteria for primary aldosteronism
underwent high-resolution computed tomography imag-
ing of the adrenal glands, and none was found to have an
adenoma. In part, this may reflect the study sampling
method, which excluded adults with severe hypertension
392 Schwartz and Turner: Screening for Primary Aldosteronism
or unexplained hypokalemia, among whom adrenal cor-
tical adenoma is more common. Controversy exists as to
whether idiopathic hyperaldosteronism represents a state
of true autonomous overproduction of aldosterone, as is
observed in adrenal cortical adenoma, or if it should be
more properly considered a form of low-renin essential
hypertension (28 –30 ).
This study has several limitations. Because we re-
stricted sampling to adults with only mild to moderate
hypertension who did not have unexplained hypo-
kalemia, application of the ratio test characteristics de-
termined in this study to patients referred for severe
hypertension or unexplained hypokalemia is uncertain.
However, we believe that the participants in this study
are representative of patients encountered in a primary
care practice, a setting where use of the ratio has been
advocated (8, 9). Because of the small sample size, we
could not assess the impact of any specific drug class on
the test characteristics of the ratio. Although we did not
demonstrate an overall effect of antihypertensive drug
therapy on test characteristics of the ratio, it is still
possible that the effects of specific drug classes could be
substantial. In addition, none of the patients in our study
were taking aldosterone-receptor-blocking drugs, which
are assumed to impact the test characteristics of the ratio
(9, 13). Finally, the test characteristics of the ratio deter-
mined in this study may not apply if sampling conditions
(blood samples obtained after 5 min in the seated position
at 0800) or the specific laboratory methods used to mea-
sure PRA and aldosterone are not the same as those used
in this study.
In conclusion, the results of this study demonstrate that
primary aldosteronism is common among adults in the
community with presumed essential hypertension. Al-
though determining the aldosterone:PRA ratio is simple
and relatively inexpensive, the ratio has only fair diag-
nostic accuracy in screening for this disorder. Whether
widespread screening for primary aldosteronism is ap-
propriate awaits the results of future studies to determine
the practical impact of making this diagnosis on the
management and control of hypertension. If it is found
that widespread screening for primary aldosteronism is
appropriate, test reporting of likelihood ratios associated
with ranges of ratio values may be more useful than
consideration of a single optimum value.
This study was supported by funds from the Mayo
Foundation and by US Public Health Service Grant R01-
HL53330 and GCRC Grant M01-RR00585.
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