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Variability in the Renin/Aldosterone Profile under Random and Standardized Sampling Conditions in Primary Aldosteronism

Department of Medicine, Institute of Clinical Endocrinology (A.T., M.N., S.T., K. Ta.), Kidney Center (K.Ts.), Tokyo Women’s Medical University, Tokyo 162-8666, Japan; and Institute of Gerontology, Nippon Medical School (T.I.), Kawasaki, Kanagawa 211-8533, Japan

Address all correspondence and requests for reprints to: Akiyo Tanabe, M.D., Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjukuku, Tokyo 162-8666, Japan. E-mail: address: akiyotana{at}endm.twmu.ac.jp.

	Abstract

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An increased plasma aldosterone concentration (PAC) with decreased plasma renin activity (PRA) is the abnormal endocrine finding in primary aldosteronism (PA). However, it remains unknown whether this profile is universal when blood samples are obtained in a random manner. We retrospectively evaluated the renin/aldosterone profile in 71 patients with PA due to unilateral adrenal adenoma. Blood samples were obtained randomly at an out-patient clinic and under standardized conditions during hospitalization before surgery. The frequency of PAC above 15 ng/dl, PRA below 0.5 ng angiotensin I/ml·h, and a PAC/PRA ratio greater than 35 was determined. These three variables showed a large intra- and interpatient variation. At least one measurement of PAC, PRA, and PAC/PRA ratio was in the normal range in 39%, 48%, and 31% of patients, respectively. Only 37% of patients always had the characteristic profile associated with PA. The mean values of PAC at the out-patient clinic were slightly, but significantly, lower than those in the hospital. These results clearly demonstrated that the renin/aldosterone profile in PA is not always abnormal due in part to conditions for blood sampling. We conclude that a single normal PAC, PRA, or PAC/PRA ratio does not excluded the diagnosis of PA in a hypertensive patient, but repeated measurements yields one or more abnormal parameters in the vast majority of patients. The PAC/PRA ratio is recommended to use as a screening, but other testing is required to arrive at the correct diagnosis.

	Introduction

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PRIMARY ALDOSTERONISM (PA) is one of the primary causes of endocrine hypertension (1). Recent advances in diagnostic procedures have led to an increase in diagnosis of PA, and it is estimated that PA accounts for approximately 2–30% of essential hypertension (2, 3). The incidence of cardiovascular complications has been reported to be relatively high in PA (4, 5, 6), whereas Sugihara et al. (7) demonstrated that left ventricular hypertrophy is more severe in Cushing’s syndrome than in essential hypertension and PA. We have demonstrated that the prevalence and severity of left ventricular hypertrophy is increased in patients with PA compared with patients with Cushing’s syndrome and pheochromocytoma with comparable blood pressure levels (8). Furthermore, Obara et al. (9) reported that sustained hypertension after surgery was closely related to the age at diagnosis of PA. Taken together these findings indicate that early diagnosis of PA is important not only because the disorder can be cured surgically, but also to prevent the development of cardiovascular lesions.

Although hypertension associated with hypokalemia is the major diagnostic feature of PA, recent studies have shown that about two thirds of patients have normal potassium (K) levels (10). To accurately diagnose PA, evaluation of the renin/angiotensin/aldosterone system is quite important. The core endocrine feature includes an increased plasma aldosterone concentration (PAC) and a decreased plasma renin activity (PRA), whereas recent studies have suggested that the PAC to PRA ratio also has diagnostic value (11, 12, 13). As both PAC and PRA are affected by the conditions of blood sampling, such as posture, time of the day, food and sodium intake, and antihypertensive agents (14), it is generally recommended to measure PAC and PRA under standardized conditions. It is not always possible, however, to standardize conditions of blood sampling at out-patient clinics. As it is presumed that the renin/aldosterone profile remains constant in PA as a result of the autonomy of aldosterone secretion, it is unknown whether blood collection under random conditions affects the renin/aldosterone profile in PA. In the present study we investigated the variation in PAC and PRA measured under both random and standardized conditions in 71 patients with PA.

	Subjects and Methods

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Seventy-one Japanese patients (35 males and 36 females; mean age, 49 ± 12 yr; age range, 28–71 yr) were diagnosed as PA between 1974 and 2002 at the Institute of Clinical Endocrinology, Tokyo Women’s Medical University Hospital. The diagnosis of PA due to unilateral adrenal adenoma was verified histologically after adrenal surgery. All of the patients studied showed normal serum creatinine levels. Data for PAC and PRA determined as a part of the diagnostic procedure before adrenal surgery were retrospectively analyzed. Blood samples at the out-patient clinic have been obtained under random conditions in terms of posture, time of collection, and prior food and sodium intake. In addition, the patients were taking one or more antihypertensive agents that included calcium (Ca) channel blockers, angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor antagonists, and ß-blockers. Those patients taking any kinds of diuretics, including spironolactone, were excluded from the study. Blood samples in the hospital have been collected on several occasions from 64 of the 71 patients under standardized conditions in terms of posture (at least 30 min of recumbence), time of the day (0900 h), food intake (12-h overnight fast), food intake (sodium chloride, 5–7 g/d = 85–120 meq sodium/d; K, 4–5 g/d = 102–128 meq potassium/d), and, if any, antihypertensive medication (Ca channel blocker only). Antihypertensive medications were discontinued or changed to Ca channel blocker alone on the day of admission. A total of 385 blood samples were collected under random and standardized conditions.

Plasma samples were kept at -20 C until assay for PAC and PRA. PAC was determined in duplicate by RIA using commercially available kits. PRA was determined in duplicate by RIA using commercially available kits for angiotensin I (Ang I) after incubation of the plasma at 37 C for 1 h. The within- and between-assay coefficients of variation in the PAC assay were 4.4% and 5.2%, respectively. The within- and between-assay variations in the PRA assay were 2.7% and 4.5%, respectively. The incidence of PAC greater than 15 ng/dl, PRA less than 0.5 ng Ang I/ml·h, and a PAC/PRA ratio greater than 35 (12) was determined in each patient.

Statistical analysis of the combined data are expressed as the mean ± SD, with differences between the groups assessed using the Mann-Whitney U test and t test, as appropriate. Linear regression analyses were used to test the correlation between serum K and PAC. P < 0.05 was considered statistically significant.

	Results

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Variations in PAC, PRA, and PAC/PRA ratio

The serial measurements of PAC, PRA, and PAC/PRA ratio in the individual patients with PA were arranged by increasing maximal PAC in Figs. 1A, 2A, and 3A. A wide variation in PAC, PRA, and PAC/PRA ratio was observed in each patient as well as between patients. The frequency of PAC more than 15 ng/dl (Fig. 1B), PRA less than 0.5 ng Ang I/ml·h (Fig. 2B), and an abnormal PAC/PRA ratio (>35; Fig. 3B) in each patient ranged from 0–100%, respectively. PAC was always within the normal range in one patient (case 1; Fig. 1, A and B), whereas PRA was always normal in four patients (cases 6, 13, 31, and 34; Fig. 2A, 2B). Two patients (cases 13 and 31) had a constantly normal ratio (Fig. 3, A and B).

View larger version (49K): [in this window] [in a new window]   Figure 1. A, Variation in serial measurements of PAC in 71 patients with PA. The patients are arranged in increasing order of maximal PAC. •, Out-patient clinic sample; , hospital sample. B, Frequency of PAC greater than 15 ng/dl in individual patients. The shaded area signifies the normal range of PAC.

View larger version (69K): [in this window] [in a new window]   Figure 2. A, Variation in serial measurements of PRA in 71 patients with PA. The patients are arranged in the same order as in Fig. 1. •, Out-patient clinic sample; , hospital sample. B, Frequency of PRA less than 0.5 ng Ang I/ml·h in individual patients. The shaded area signifies the normal range of PRA.

View larger version (62K): [in this window] [in a new window]   Figure 3. A, Variation in serial measurements of the PAC/PRA ratio in 71 patients with PA. The patients are arranged in the same order as in Fig. 1. •, Out-patient clinic sample; , hospital sample. B, Frequency of PAC/PRA ratio greater than 35 in individual patients. The shaded area signifies the normal range of the ratio.

View larger version (69K): [in this window] [in a new window]   Figure 4. Percentage of patients with consistent abnormal PAC (A), PRA (B), PAC/PRA ratio (C), and consistently abnormal all three variables (D). , Patients without constantly typical profiles; , patients with constantly typical profiles.

For individual patients there was no obvious difference between the values in blood samples collected at the out-patient clinic or during hospitalization (Figs. 1A, 2A, and 3A). To compare the measurements made at the out-patient clinic and hospital, 32 patients who had more than 2 determinations at both locations were selected, and the average of the mean values for each patient was used for paired comparison. PAC (29.9 ± 14.4 ng/dl) was significantly lower in the out-patient blood samples than in blood samples collected those in the hospital (PAC, 35.4 ± 19.8 ng/dl; P < 0.05; Fig. 5A). By contrast, PRA and PAC/PRA ratio did not show any significant difference between the out-patient clinic samples and the hospital samples (Fig. 5, B and C).

View larger version (22K): [in this window] [in a new window]   Figure 5. Comparison of the mean values of PAC (A), PRA (B), and PAC/PRA ratio (C) between 233 blood samples collected from 32 patients either at an out- patient clinic or during hospitalization. *, P < 0.05 vs. out-patient clinic.

Interrelation between PAC and PRA and serum K levels was studied in 18 patients in whom sufficient numbers of simultaneously determined data were available. There was a significant, inverse correlation between PAC (r = 0.624) or the PAC/PRA ratio (r = 0.571) and serum K (Fig. 6, A and B), although there was no significant correlation between PRA and serum K.

View larger version (16K): [in this window] [in a new window]   Figure 6. Correlation between PAC or PAC/PRA ratio and serum K in 18 patients with PA.

Profiles were determined on 385 occasions in the 71 patients. An abnormal pattern (PAC, >15 ng/dl; PRA, <0.5 ng Ang I/ml·h; PAC/PRA ratio, >35) was observed in 237 of 385 (62%) of the measurements. The combination of abnormal PAC and PAC/PRA ratio occurred in 62 of 385 (16%) measurements, whereas the combination of abnormal PRA and PAC/PRA ratio occurred in only 32 of 385 (8%) of the samples. The finding of 1 abnormal variable occurred in only a minority of profiles, with 30 of 385 (8%) having increased PAC and 8 of 385 (2%) having low PRA. No abnormality in any of the variables was measured in 16 of 385 (4%; Fig. 7).

View larger version (21K): [in this window] [in a new window]   Figure 7. Frequency of patterns in the 385 blood samples analyzed. Patterns included all 3 variables abnormal, abnormal PAC, and PAC/PRA ratio, abnormal PRA and PAC/PRA ratio, abnormal PAC only, abnormal PRA only and normal profile, respectively.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Approximately two thirds of patients had a consistently abnormal profile of each endocrine parameter, with only about half of these individuals having all three endocrine parameters abnormal in every blood sample collected. These results indicate that the renin/aldosterone profile may be quite variable in PA, and in approximately two thirds of cases the abnormal endocrine profile associated with the disorder may not be observed consistently.

Although the key pathophysiological mechanism in PA is the autonomous secretion of aldosterone from the tumor, the cause of the variability in renin/aldosterone profile remains unknown. Evidence suggests the cause is likely to be multifactorial. It is well established that aldosterone secretion in PA is sensitive to ACTH (15, 16), showing ACTH-dependent diurnal rhythms. Upright posture modifies PAC in patients with PA due to unilateral adenoma; PAC decreases in most of the patients, but increases in a subset of PA (17). The changes associated with the diurnal rhythm and posture would be expected to be a confounding factor in blood samples collected randomly at an out-patient clinic. Another variable that should be taken into account is serum K, because hypokalemia is known to decrease aldosterone secretion. The inverse correlation between serum K and PAC or PAC/PRA, however, shows that hypokalemia rarely caused falsely normal PAC values in our subjects. Rather, high aldosterone production causes kaliuresis and hypokalemia, and elevated aldosterone production often continues despite concomitant hypokalemia.

In addition, the effects of antihypertensive agents on the renin/aldosterone profile should be taken into account when examining the endocrine profile in PA. Although Ca channel blockers, angiotensin-converting enzyme inhibitors, and AT1 antagonists all decrease PAC and increase PRA (18, 19), the effects of the Ca channel blockers are less marked than the agents acting on the renin/angiotensin system. It is therefore recommended to stop antihypertensive treatment before measurement of the profile, although such an option is often not feasible in patients with severe hypertension. The patients in our study were generally taking one or more antihypertensive agents while attending the out-patient clinic, but were only administered Ca channel blockers, if needed, during hospitalization.

Taking all of these factors into account we suggest that the variability in the renin/aldosterone profile may be attributed at least in part to the conditions of blood sampling. The results of the analyses of the combined data support this, as mean PAC was lower in blood samples from the out-patient clinic compared with those collected during hospitalization. Blood samples were obtained under random conditions in the out-patient clinic and under standardized conditions in the hospital in terms of posture, time of day, food, sodium and K intakes, and antihypertensive regimen. As it is possible that random conditions may obscure the renin/aldosterone profile associated with PA, it is recommended that conditions for blood sampling be standardized. However, the difference in PAC between the out-patient clinic and after hospitalization was less prominent, and no significant change was seen in PRA or PAC/PRA ratio. In addition, it should be noted that variability remained in the renin/aldosterone profile even in blood samples collected under standardized conditions in the hospital. The variable nature of aldosterone secretion from the tumor therefore could be a factor responsible for this diversity in the renin/aldosterone profile.

The significance of a PAC/PRA ratio in the diagnosis of PA was first demonstrated by Hiramatsu et al. (11). After this initial observation, the significance of the ratio has been further emphasized especially in the early stage of the disorder during which the changes in PAC and PRA are relatively minor (20, 21). In our study we selected 35 as the upper limit of normal for the ratio. The percentage of blood samples with a ratio above this value was 69%, which was higher than the 61% that had an increased PAC and the 52% that had a decreased PRA. In addition, 24% of blood samples had an abnormal PAC/PRA ratio despite having normal PAC or PRA. These results may suggest that the ratio is a more sensitive measure to detect PA than either of its determinants. It is important to note, however, that the PAC/PRA ratio was also extremely variable and showed inconsistent trends over time in individual patients. There was no significant difference in the PAC/PRA ratio between the random conditions in the out-patient clinic and the more standardized conditions after hospitalization. In addition, it has been clearly demonstrated by Montori et al. (22) that low PRA, rather than high PAC, predominantly affect elevation of the PAC/PRA ratio. Although the present analysis in surgically proven PA does not provide information about the specificity of the ratio, its variability suggests that clinical significance of the PAC/PRA ratio should be limited as a screening only and that additional tests are essential to arrive at the correct diagnosis.

In conclusion, our study suggests that PA may occur in hypertensive patients despite a normal renin/aldosterone profile. Recent studies have indicated the importance of blocking aldosterone action in the treatment of cardiovascular diseases (23, 24), and early diagnosis of PA is required to minimize cardiovascular complications. The abnormal renin/aldosterone profile was observed consistently only in one third of cases. In addition, an abnormal pattern was observed in 62% of the total measurements. In order that the diagnosis of PA is not overlooked, therefore, it is recommended to repeat assays of PAC and PRA at least three times during long-term treatment in patients with hypertension even if the endocrine profile is normal on limited occasions.

	Footnotes

 
This work was supported in part by research grants for Akiyo Tanabe from the Toshiko Yamakawa Research Award of Tokyo Women’s Medical University and the Japan Association of Women’s Doctors.

Abbreviations: Ang I, Angiotensin I; K, potassium; PA, primary aldosteronism; PAC, plasma aldosterone concentration; PRA, plasma renin activity.

Received September 23, 2002.

Accepted February 16, 2003.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor 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 PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tanabe, A. Articles by Takano, K. Search for Related Content PubMed PubMed Citation Articles by Tanabe, A. Articles by Takano, K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB POTASSIUM