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Departments of Medicine and Surgery (T.O.), Institute of Clinical Endocrinology, Tokyo Women’s Medical University School of Medicine, Tokyo 162-8666, Japan
Address all correspondence and requests for reprints to: Dr. Kaoru Nomura, Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women’s Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: nomurak{at}endm twmu.ac.jp.
Abstract
An aldosterone-producing adenoma causes surgically correctable hypertension. Screening tests should be assessed for their accuracy and ability to detect aldosterone-producing adenoma in an appropriate population. This study aims to validate the accuracy and efficacy of the basal plasma aldosterone concentration (picomoles per liter) to PRA (nanograms per liter/sec) ratio and of combined stimulation of PRA by the furosemide and upright posture test in screening for aldosterone-producing adenoma in hypertensives with PRA less than 0.28 ng/liter·sec (1 ng/ml·h). Thirty-five aldosterone-producing adenoma and 79 nonaldosterone-producing adenoma patients were retrospectively selected from among 159 patients examined with the furosemide and upright posture test between 1989 and 1999. Selection criteria were based on blood pressure, PRA, and plasma aldosterone concentration. Diagnosis was based on surgical outcome, computed tomography scans with adrenal scintigraphy, or venous sampling. The accuracy and efficacy of basal (aldosterone/PRA ratio) and dynamic (postfurosemide and upright posture PRA) screening tests were assessed based on test sensitivity, specificity, likelihood ratio, and receiver operating characteristics.
At a cut-off value of 3,200, the aldosterone/PRA ratio had a high sensitivity of 1.0 and a low specificity of 0.61. The importance was strengthened by using a multilevel likelihood ratio, i.e. positive (aldosterone/PRA ratio >10,000), negative (aldosterone/PRA ratio <3,200), and neutral (intermediate aldosterone/PRA ratio) levels. Patients with a positive level had a likelihood ratio of 7.1 and were likely to have an aldosterone-producing adenoma. The aldosterone/PRA ratio enclosed a larger area under the receiver operating characteristics curve (0.905) than did postfurosemide and upright posture PRA (0.826). In conclusion, the plasma aldosterone concentration to PRA ratio is an effective screening and diagnostic test when a triple level likelihood ratio is applied. The furosemide and upright posture test did not raise the posttest probability over that obtained using the aldosterone/PRA ratio.
PRIMARY ALDOSTERONISM due to an aldosterone-producing adenoma (APA) causes a surgically correctable form of secondary hypertension. Because of the low prevalence of APA in hypertensive patients, screening tests should be able to accurately detect APA. High or normal plasma aldosterone concentration (PAC) with low PRA are characteristics of the disease. Such disparity between increased PAC and suppressed PRA values potentiates the efficacy of the basal PAC to PRA ratio (AR ratio) as a screening test. Previous investigations have agreed, with high sensitivity, on the cut-off value of the AR ratio (1, 2, 3, 4, 5, 6, 7). However, because the main purpose of these studies was to obtain a cut-off value with high sensitivity (or a high true positive rate), and because they did not assess specificity, they did not select the appropriate spectrum of control subjects under the clear definition for controls. Their conclusions were inevitably biased to lower the false positive rate or overestimate the specificity and general applicability of the test. Furthermore, they could not give much information on how high or low the probability of the disease was in a given individual.
A dynamic test is useful when basal hormonal levels are not sufficient to estimate the dysfunction of a target hormone disease. In general, stimulation of hormone secretion is preferable when the target hormone is suppressed. Combined stimulation of PRA by the furosemide and upright posture (FUP) test has been used as a stimulation test for the diagnosis of APA (1, 4, 5, 8, 9). The underlying rationale is that PRA is so intensively suppressed that even potent stimulators could not increase renin release in primary aldosteronism, whereas they would do so in other forms of hypertension. Furosemide is a potent loop diuretic that stimulates renin release, and upright posture also stimulates renin release. The FUP test is thus a combination maneuver that strongly stimulates renin release. A dynamic test is expected to improve the diagnostic performance over that obtained by the basal test (AR ratio). The accuracy of the FUP test, however, remains to be assessed in an appropriate population.
One objective of this study was to assess the accuracy and efficacy of the AR ratio in screening for APA. The study subjects were patients with APA and those with disorders to be differentiated from APA. In our clinic, PRA and PAC were routinely measured in hypertensive subjects. Hypertensive subjects with low PRA are candidates for screening for primary aldosteronism, which may include idiopathic hyperaldosteronism (IHA) or primary hypertension. The selection criteria and reference diagnosis were both conducted as completely and reasonably as possible to obtain accurate results. We also assessed the importance of the AR ratio as a screening test by dividing patients into three groups and by using a likelihood ratio. The accuracy of the FUP test was also validated by receiver operating characteristics (ROC) analysis to clarify whether it could raise the posttest probability of accurately diagnosing APA over that obtained using the AR ratio. An ROC curve is a graph of the pairs of the sensitivity and false positive rate (1 - specificity) that correspond to each possible cut-off for the diagnostic test result. The larger the area under the ROC curve (AUC), the more accurate the test (10).
Subjects and Methods
Subjects and diagnosis
This was a retrospective case-control study. Between January 1989 and December 1999, the FUP test was performed on 159 subjects in our clinic to evaluate disturbances in the renin-angiotensin-aldosterone axis. The main target disorders were primary aldosteronism, hypoaldosteronism, and renovascular hypertension. Subjects were further selected by the following inclusion and exclusion criteria. Subjects were included if they had 1) blood pressure above 140 mm Hg systolic and 90 mm Hg diastolic at repeated out-patient visits or during treatment with an antihypertensive drug(s) (n = 156); 2) PRA less than 0.28 ng/liter·sec (1.0 ng/ml·h) after 30 min in a supine position (n = 119); because 34 APA subjects who had been treated surgically before 1989 had a maximum PRA of 0.17, we judged that PRA less than 0.28 ng/liter·sec was a sufficient cut-off value for screening for APA; and 3) PAC more than 139 pmol/liter (5 ng/dl; n = 116). This last criterion excluded subjects with hyporeninemic hypoaldosteronism. Subjects with other forms of secondary hypertension were excluded (n = 2; 1 with Cushing’s syndrome and 1 with pheochromocytoma). Eventually, 114 subjects were enrolled in this study, and they were diagnosed as either APA or non-APA based on the criteria described below. None of the 114 subjects was being treated with spironolactone or inhibitors of steroid synthesis. Subjects treated with other antihypertensive drugs were not excluded. Seventy-two subjects were treated with either single or multiple antihypertensive drugs, as shown below.
The reference diagnosis of APA or non-APA was principally based on
demonstrating a functioning adenoma. As shown in Table 1
, diagnosis of either APA or non-APA was
made using the following five criteria.
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2) Subjects examined by computed tomography (CT) and adrenal scintigraphy. CT demonstrated an adenoma, and the functional activity of an adenoma was evidenced by the predominant uptake of iodomethylnorcholesterol on dexamethasone suppression adrenal scintigraphy on an adenoma-bearing adrenal gland (n = 3). Seventeen subjects were placed in the non-APA group based on the following: CT demonstrated a normal-looking adrenal gland (n = 3), hyperplasia (n = 4), or adenoma (n = 10). There was, however, no laterality in dexamethasone suppression scintigraphy. Predominant uptake of iodomethylnorcholesterol indicated 2 times higher uptake on the adenoma side than on the other side (11).
3) Subjects examined by CT and selective adrenal vein sampling. No APA subject was present. Eight subjects were judged to be non-APA based on the following: CT demonstrated adrenal hyperplasia (n = 2) or adenoma (n = 6), but no laterality of PAC values on the adrenal veins (12). We defined lateralization of adrenal aldosterone secretion as a ratio of adrenal vein (aldosterone/cortisol levels)/inferior vena cava (aldosterone/cortisol levels) greater than 1.0 from the ipsilateral adrenal vein and 1.0 or less from the contralateral vein, as others have reported (7, 13, 14).
4) Subjects examined by CT only. CT demonstrated normal-looking adrenals (n = 28), hyperplasia (n = 4), or adenoma (n = 7). They were categorized as non-APA, as described in Results and Discussion.
5) Subjects without CT. CT scan was not performed in 14 subjects. They were categorized as non-APA, as described in Results and Discussion. Experienced radiologists evaluated the findings on CT and scintigraphy. The hormonal profiles and FUP test results were not necessarily blind to radiologists, whereas findings on CT, scintigraphy, and adrenal sampling were open to investigators.
Measurements of AR ratio and post-FUP PRA
Informed consent to perform the FUP test was obtained from all subjects. Food and salt intake were neither generally restricted nor estimated. Tests were performed on an out-patient or in-patient basis. Eating, drinking, and medication were prohibited on the day of examination until testing was complete. Examinations started between 0800–0900 h. After patients had been supine for 30 min, blood was taken and measured for PAC and PRA. Subjects were then given an iv bolus of 40 mg furosemide. After 1 h (n = 38) or 2 h (n = 76) in an upright posture, blood was taken to measure post-FUP PRA. There was no significant difference between the 1 and 2 h post-FUP PRA values in APA and non-APA subjects. In 10 APA subjects, the post-FUP PRA was 0.14 ± 0.11 (±SD) ng/liter·sec at 1 h vs. 0.15 ± 0.16 at 2 h. In 11 non-APA subjects, the post-FUP PRA was 0.28 ±0.26 ng/liter·sec at 1 h vs. 0.31 ± 0.29 at 2 h. Therefore, we used the 1 h post-FUP PRA for subjects who had no further measurements taken. The AR ratio was expressed as the value of PAC (picomoles per liter) divided by PRA (nanograms per liter/sec). By dividing this AR ratio by 100, the AR ratio could be expressed as the value of PAC (nanograms per dl) divided by PRA (nanograms per ml/h). A PRA lower than a detectable level (0.028 ng/liter·sec) was set at 0.014 when calculating the AR ratio (n = 4, one APA and three non-APA).
Hormone assays
PAC and PRA were measured by division of the radioassay. Normal
values for PAC and PRA ranged from 61–416 pmol/liter (2.2–15 ng/dl)
and from 0.14–0.83 ng/liter·sec (0.5–3 ng/ml/h), respectively. PAC
was measured using a commercial RIA kit (Dainabot Co., Tokyo, Japan)
(15). The intraassay variations were 4.4%, 4.4%, and
3.2% at a PAC of 233, 419, and 2572 pmol/liter, respectively;
interassay variations were 5.2%, 5.7%, and 4.4% at those same PAC
values. Antiserum cross-reacted 0.0021% with corticosterone; 0.0080%
with 11-deoxycorticosterone; less than 0.0015% with T, cortisone, and
progesterone; less than 0.00015% with cortisol and
dehydroepiandrosterone sulfate; and 0.00097% with
18-hydroxycorticosterone. PRA was measured using a commercial RIA kit
(Renin RIAbeads, Dainabot Co., Tokyo, Japan) (16). Blood
samples were collected in a Vacutainer tube containing EDTA (1
mg/ml) and promptly chilled in an ice bath, followed by immediate
centrifugation. Aliquots of the plasma samples were stored at –20 C
and assayed for PRA within 1 wk. The measurement of PRA involved an
initial enzymatic reaction to generate angiotensin I, followed by
quantitation by RIA. Reagents were chilled and set up in polypropylene
test tubes in an ice bath. Then, 0.02 ml 0.6 M citrate
buffer (70 mM EDTA), 0.2 ml plasma sample, and 0.01 ml
phenylmethylsulfonylfluoride (Sigma, St. Louis, MO) in
ethanol solution (10 mg/ml) were added to each test tube. The samples
were incubated at 37 C for 1 h. The same samples in separate tubes
were also incubated at 4 C for 1 h to determine background
activity. EDTA and phenylmethylsulfonylfluoride inhibited the
activities of both angiotensinase and converting enzyme completely up
to 4 h and, with time, gave good linearity of angiotensin I
generation in low PRA samples, but not in high PRA samples
(16). At the end of angiotensin I generation, the tube was
transferred to an ice bath with an added 0.1 ml
[125I]angiotensin I containing 0.5 mg/ml
pepstatin A (Protein Research Foundation, Osaka, Japan). Pepstatin A
inhibited renin activity completely up to 4 h at 25 C
(16). Antibody-coated balls were then placed in all tubes
and incubated for 3 h at room temperature. Two milliliters of
distilled water were added to each tube, and the solution was removed.
The radioactivity of each ball in each test tube was then counted with
a 
-counter. The intraassay variations were 6.9%, 6.7%, and 5.5%
at PRAs of 0.51, 0.28, and 1.56 ng/liter·sec, respectively;
interassay variations were 8.2%, 3.7%, and 7.4% at those same PRA
values.
The accuracy of the AR ratio greatly depends on PRA measurement for two reasons. First, small changes in low PRA values can greatly affect the AR ratio, as PRA is the denominator in the calculation. Second, because the PRA levels are at the low limit of the RIA standard curve, it may be argued that accurate estimation is difficult. If a more accurate and stable assay procedure was available, it could improve the reliability of the AR ratio. To examine these issues, we conducted studies as follows. First, because angiotensin I was generated at 37 C in a time-dependent manner, prolonged incubation was expected to generate more angiotensin I, resulting in a more reliable PRA value. By comparing the effects on 1- and 3-h incubations, the accuracy of the PRA value in an ordinary assay can be estimated. Second, to examine reproducibility, an epidemiological approach was employed. The AR ratios were reexamined at a different time (second test) under the same conditions as in the first test and compared with the values from the first test.
Analysis and statistics
Sensitivity, specificity, and likelihood ratios were calculated (17). Mean, SD, and 95% confidence intervals (CI) were also expressed. Cross-table and Fisher’s exact tests were conducted. The accuracies of the two tests were compared with a receiver-operating characteristics (ROC) curve (10). Statistics were analyzed using SPSS 10.0J software (SPSS, Inc., Tokyo, Japan).
Results
Subjects: diagnosis and characteristics
One hundred and fourteen hypertensives with PRAs less than 0.28
ng/liter·sec (1.0 ng/ml·h) and PACs greater than 139 pmol/liter (5
ng/dl) were enrolled in this study and were diagnosed (Table 1
). All 35
APA and 26 of 79 non-APA subjects were diagnosed by reference
diagnostic criteria 1–3. The remaining 53 non-APA subjects in
diagnostic criteria 4 and 5 were poorly examined. Reports examining
more than 10 APA subjects showed that subjects with AR ratios below
3200 or 5000 could be excluded from the diagnosis of APA
(3, 4, 5, 6, 7). Of the 53 subjects who did not meet the
reference diagnostic criteria, 36 had AR ratios below 3200 and were
accepted as non-APA subjects. The remaining 17 subjects with AR ratios
over 3200 had normal adrenals on CT scan (n = 11), hyperplastic
adrenals on CT scan (n = 3), an adenoma on CT scan (n =
1), or did not undergo CT examination (n = 2). The validity of
including these 17 subjects in the non-APA group will be assessed
later, using a sensitivity analysis.
There was no significant difference between APA and non-APA subjects
taking any given antihypertensive medication (Table 2). Potassium supplements were, however,
more frequently prescribed (P < 0.001) in the APA
group (20%) than in the non-APA group (1.3%). There was no difference
in either PAC or PRA between subjects taking or not taking
antihypertensive drugs (Table 2). Subjects taking antihypertensive
drugs tended to have higher PACs than those not taking them, although
the difference was not statistically significant.
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. As expected, there was a
significant difference in serum potassium (P < 0.001),
PRA (P < 0.001), and PAC (P < 0.001)
between APA and non-APA subjects. There was no significant difference
in age, gender, or prevalence of diabetes mellitus in the two groups.
Significantly higher AR ratios and lower post-FUP PRA were observed in
the APA group than in the non-APA group (P < 0.001;
Figs. 1 and 2).
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The sensitivity, specificity, and likelihood ratio (LR)
of the AR ratio in screening for APA were estimated. A 2 x 2
table was constructed for the AR ratio. When the cut-off point was set
at 3,200 to permit sensitivity of 1.0 (35 true positives in 35 APA
subjects), the specificity was only 0.61 (48 true negatives in 79
non-APA subjects). Thus, an AR ratio less than 3,200 excluded the
possibility of APA, whereas an AR ratio over 3,200 suggested a
diagnosis of APA with a high false positive rate (0.39). The positive
LR was calculated by dividing sensitivity by (1 - specificity).
The resulting LR of 2.5 only slightly improved the posttest probability
of an accurate diagnosis. Dividing AR ratios into 3 levels gave better
results (Table 4), i.e.
positive (AR ratio, >10,000), negative (AR ratio, <3,200), and
neutral (10,000 > AR ratio > 3,200) level. Of the 35 APA
subjects, 63% (n = 22) had positive level AR ratios, whereas only
9% of non-APA subjects (n = 7) did. This gave an LR of 7.1
(0.63/0.09) and raised the posttest probability. At the neutral AR
ratio level, the LR was 1.2, which failed to raise the posttest
probability. At the negative AR ratio level, the LR was 0, indicating
that subjects with an AR ratio below 3,200 could be excluded from the
diagnosis of APA.
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Eleven samples with low PRA values were processed to generate
angiotensin I for both 1- and 3-h incubations (Table 5). After the 1-h incubation, the
background activity (4 C) was greater than the generated activity (37
C) in two samples (no. 3 and 7). These samples were calculated to have
negative values and were assessed to have PRAs less than 0.028
ng/liter·sec. After the 3-h incubation, PRA reached a detectable
level (0.028 ng/liter·sec) in sample 3, but was still undetectable in
sample 7. After the 3-h incubation, nine samples generated higher PRAs
than they did after 1 h.
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, most of the AR ratios on the second
test remained at the same level as the first test. APA subjects always
had an AR ratio above 3200. The second test gave an LR of 7.09 for
positive, 0.82 for neutral, and 0 for negative levels. These LR values
were within the 95% CI on the first test. Thus, the AR ratio was shown
to be reproducible.
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Statistical analysis of the accuracy of the AR ratio and post-FUP
PRA was performed using ROC curves (Fig. 4). AUC were 0.905 (95% CI,
0.852–0.959) for the AR ratio and 0.826 (95% CI, 0.741–0.852) for
the post-FUP PRA. Even among subjects with a neutral LR, the AUC for
the AR ratio was larger than that for the post-FUP PRA, 0.745 (95% CI,
0.579–0.912) vs. 0.655 (95% CI, 0.461–0.850). The
post-FUP PRA had a 95% CI less than 0.5, which suggests that the
result of the FUP test may reduce the accuracy of the diagnosis of APA.
Thus, the AR ratio was found to be more accurate than the post-FUP PRA
in screening for APA.
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Lastly, we assessed the validity of including in the non-APA group
the 17 subjects who had AR ratios over 3,200 and were poorly examined,
as mentioned above. Data were reconstituted by including these 17
subjects in the APA group. The modified population was composed of 52
APA and 62 non-APA subjects (Table 6). As
expected, there was an increase in specificity at a cut-off value of
3,200 and when the likelihood ratio of the AR ratio was over 10,000.
The AUCs for the AR ratio and post-FUP PRA remained within the 95% CIs
of the original data, suggesting that the uncertainty of diagnosing
these 17 subjects did not affect our conclusions.
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Our clinic operates as a division of both the endocrinology and general internal medicine departments at Tokyo Women’s Medical University Hospital. Therefore, the prevalence of APA in hypertensive patients is probably higher in our clinic (3%; our unpublished observation) than in the general clinics. At the first visit to our clinic, hypertensive patients are carefully examined to determine the etiology of the hypertension. PAC and PRA are routinely measured. Furthermore, most hypertensive patients with low renin profiles have been screened with the FUP test for primary aldosteronism. This enabled us to evaluate the accuracy and efficacy of tests in screening for APA. Because this was a retrospective study, 53 of 79 non-APA subjects did not meet the reference diagnostic criteria. As described in Results, 36 of these 53 subjects could be excluded from a diagnosis of APA because they had AR ratios less than 3,200. Among the 17 remaining subjects whose AR ratios were greater than 3,200, tiny APAs may be present. CT scans reportedly detect adenomas with a sensitivity ranging between 71–82% (18, 19, 20) or 100% (21). In false negative cases, tiny APAs may be hiding in normal-looking or hyperplastic adrenals on CT scan. Several of the 17 subjects might have IHA, although the real prevalence of IHA is uncertain. We placed these 17 subjects in the APA group and compared the modified population with the original one. This sensitivity analysis showed no significant difference in the accuracy or importance of the AR ratio and post-FUP PRA. Therefore, we used data from all 114 subjects enrolled in this study.
Hiramatsu et al. (2) reported in 1981
that diuretics did not affect their conclusions. However, other
hypertensive drugs, such as angiotensin-converting enzyme inhibitors,
calcium channel blockers, and 
- and ß-adrenergic blockers, have
since been used. The use of antihypertensive drugs was not assessed in
this study. There was no evidence that these drugs were prescribed
differently in the APA and non-APA groups or that subjects taking these
drugs had different PACs and PRAs from those not taking them. It is of
interest that high sensitivity was obtained at the same cut-off values
in studies that restricted the use of antihypertensive drugs (5, 7) and those that did not (2). Thus,
antihypertensive drugs are not likely to change our conclusions.
The AR ratio has been generally accepted as an efficient screening tool since Hiramatsu et al. first reported it (2). Their study was conducted with a random blood sampling, was not affected by administration of antihypertensive drugs or varying dietary sodium levels, and obtained the perfect sensitivity of the AR ratio at a cut-off value of 4000 in screening for APA. Other investigators also reported high sensitivity ranging between 0.85–1.00 at cut-off values ranging between 2100–5000. Thus, our finding of a cut-off value of 3200 was consistent with others. It is important to note that an AR ratio of less than 3200 could exclude the diagnosis of APA. The specificity of the AR ratio was also important for the assessment of a false positive rate. Weinberger and Fineberg (5) reported a specificity of 0.91 in the assessment of 14 subjects with IHA and 263 subjects with essential hypertension (EH). Eng et al. (3) reported a specificity of 0.92 in the assessment of 10 patients with EH. On the other hand, Blumenfeld et al. (7) reported an exceptionally low sensitivity of 0.56 in the assessment of 6 IHA and 10 EH subjects. Our study presented a similarly low specificity of 0.61 in the assessment of 79 non-APA subjects. Such an inconsistency in specificity may be attributable to a different spectrum of control subjects and the lack of a reference standard for control or non-APA subjects. Because previous studies did not select an appropriate population for non-APA subjects (3, 7) or did not report the use of control criteria (1, 2, 4, 6, 8), their accuracy could not be validated. Because the goal of our study was to screen for APA among hypertensives with low PRA, the proportion of subjects with false positive results increased. Such a high false positive rate was not attributed to sampling bias, but represented a real proportion. Lim et al. also reported recently that the prevalence of subjects with an AR ratio over 2700 was 18 (14.4%) in 125 hypertensives in a single family physician’s practice (22), suggesting that a significant number of subjects should be differentiated. In our clinic, the prevalence of APA was 3.3% in hypertensives and 13% in hypertensives with PRA less than 0.28 ng/liter·sec (1.0 ng/ml·h; our unpublished observation). These findings were consistent with our finding that the false positive rate of the AR ratio was higher than previously reported.
To improve the APA screening efficacy of the AR ratio, we measured the LR on a 3 x 2 table. Subjects were divided into 3 groups by two cut-off values of the AR ratio (3,200 and 10,000). There were 29 patients whose AR ratio was more than 10,000, i.e. 22 APA and 7 non-APA patients. They had LRs of 7.1. In our clinic, the posttest probability of APA was calculated from the prevalence (pretest probability, 13%) and likelihood ratio (7.1) (17) and was estimated to be 51%. Patients with AR ratios ranging from 3,200–10,000 have an LR of 1.2 and a posttest probability of 15%. Thus, posttest probabilities calculated from the AR ratio could affect a physician’s management. In addition, our study was conducted under random conditions, i.e. no food, salt intake, or drug restrictions. Therefore, our results could be applicable to the general population. The next diagnostic test is an adrenal CT scan, which can show a high positive predictive value for APA (19, 20, 21), but has a false negative rate (23, 24). For subjects with a positive LR level, a diagnosis of APA can be confirmed when a CT scan shows an adrenal adenoma. Further testing, such as adrenal venous sampling, should be performed when a CT scan fails to show an adenoma. For patients with a neutral LR level, a diagnosis of APA can be excluded when a CT scan does not show an adenoma, and the patient should undergo further testing to differentiate between APA and a nonfunctioning adenoma when the CT scan demonstrates an adrenal adenoma. In this last situation, adrenal venous sampling may be more valuable than adrenal scintigraphy for diagnosing APA or non-APA (11).
In terms of the accuracy and reproducibility of the AR ratio for APA screening, accurate measurement of PRA in the low range was important (25). Only 4 of the 114 subjects enrolled in this study had undetectable PRA levels. Because details of assay documents were not preserved, we could not judge whether the PRA values in these 4 samples had higher generated activity (37 C) than background activity (4 C). We could not exclude the possibility that some of the 4 had nonspecific angiotensin I-like radioimmunoactivity higher than angiotensin I generated by renin. The population with such samples was small, however, and most of samples in this study appeared to be correctly measured. We compared the PRA levels from 11 samples obtained after either a 1- or 3-h incubation. As expected, the PRA levels after a 3-h incubation, expressed as nanograms per liter/sec, were higher than those seen after a 1-h incubation in 9 of 11 samples. This suggests that in most cases PRA values after a 1-h incubation could be properly measured. Of 2 samples with background activity greater than generated activity at 1-h incubation, 1 had a detectable PRA level after a 3-h incubation. Thus, the special assay procedure with prolonged generation time may improve the accuracy of low PRA values. Sealey (25) reported that nonspecific substances in background activity could be ignored by prolonged incubation time and proposed that the angiotensin I generation step should last 18-h for samples with low PRA. As the present study was retrospective, we could not reevaluate our data with this improved procedure. We also clarified the reproducibility of the AR ratio with a second test. Epidemiologically, the results indicate the high reproducibility of the AR ratio for screening for APA. Although the special assay protocol that extends angiotensin I generation time is cumbersome for a routine assay, it may be worthwhile for a second estimate of the AR ratio in a limited population. In such a case, as the PRA level changes, cut-off values of the AR ratio should be reevaluated.
The accuracy of the FUP test as a dynamic test was assessed by comparing the AUC of the FUP test with that of the AR ratio test. Because the AR ratio enclosed a larger AUC than did the post-FUP PRA, it was judged to be more accurate for screening for APA than the post-FUP PRA. The FUP test could not give any additional diagnostic information concerning primary aldosteronism.
In conclusion, the validity of screening tests for APA was assessed among hypertensive subjects with PRAs less than 0.28 ng/liter·sec and PACs greater than 139 pmol/liter. The AR ratio for screening for APA had high sensitivity at a cut-off value of 3,200, but it had low specificity. To improve clinical performance, AR ratios were divided into three levels. Subjects with AR ratios over 10,000 had LRs of 7.1 and were likely to be APA. Subjects with AR ratios less than 3,200 were excluded from the diagnosis. The AR ratio was thus used not only as screening test, but also as a diagnostic test for APA. Renin stimulation by the FUP test was not as accurate or effective as the AR ratio in diagnosing APA.
Acknowledgments
We deeply appreciate the kind collaboration of Dr. Emi Odagiri and Ms. Kazuko Jibiki, Division of Radioassay, in testing the PRA assay.
Footnotes
Abbreviations: APA, Aldosterone-producing adenoma; AR ratio, aldosterone/PRA ratio; AUC, area under the ROC curve; CI, confidence intervals; CT, computed tomography; EH, essential hypertension; FUP, furosemide and upright posture; IHA, idiopathic hyperaldosteronism; LR, likelihood ratio; PAC, plasma aldosterone concentration; ROC, receiver operating characteristics.
Received August 28, 2000.
Accepted May 25, 2001.
References
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