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Aldosterone to Renin Ratio in a Primary Care Setting: The Bussolengo Study

Unit of Internal Medicine, Department of Clinical and Experimental Medicine (O.O., F.P., P.G., C.P., R.C.), and Institute of Clinical Chemistry (A.Co.), University of Verona, 37134 Verona, Italy; and General Practitioner (A.Ci., A.M., C.C.) and Service of Epidemiology, Bussolengo Health District (D.S., S.F., G.B.), 37012 Bussolengo, Italy

Address all correspondence and requests for reprints to: Dr. Oliviero Olivieri, Dipartimento Medicina Clinica e Sperimentale, Cattedra di Medicina Interna, Università di Verona, Policlinico Borgo Roma, 37134 Verona, Italy. E-mail: oliviero.olivieri{at}univr.it.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The aim of the study was to evaluate the prevalence of hypertension associated with an elevated aldosterone to renin activity ratio (ARR) in a sample of adults aged 35–74 yr, randomly selected from the population register of the Bussolengo Health District (northern Italy) and representative of the total population of the district. Subjects (n = 1462) were randomly selected from the population register and examined by their general practitioners. Complete data for 1348 individuals were available for final statistical analysis. Apart from verapamil or -blockers, no hypotensive drugs were allowed during the 4 wk before assay. Direct active renin and aldosterone were measured in the plasma of hypertensive patients after 2 h in the upright posture. Of 412 identified hypertensive patients, 287 subjects agreed to give blood (70% response rate). An aldosterone to active renin ratio (AARR) of 32 pg/ml was taken as the cut-off value, equivalent to an ARR of 50 ng/dl/ng/ml·h. An elevated AARR was observed in 32.4% of the hypertensive patients, with increased prevalence in females and in people aged 55 yr or older. As an elevated AARR is frequent in the general hypertensive population, screening should not be limited to the patients referred to specialist units.

	Introduction

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IN RECENT YEARS, growing evidence has consistently supported the view that arterial hypertension due to primary aldosteronism is much more frequent than was previously suspected (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15). This change in the estimated prevalence has been mainly due to the widespread use of the aldosterone to renin ratio (ARR) as a screening test capable of detecting inappropriately high aldosterone secretion for the degree of renin-angiotensin system activation (16) (see Table 1). By means of this approach, which is generally followed by confirmatory tests, it has also been demonstrated that most of the affected patients are normokalemic and therefore clinically indistinguishable from patients with essential hypertension (16, 17). In addition to its screening function, ARR elevation has been reported to be a useful predictor of patient susceptibility to spironolactone treatment regardless of the established diagnosis of primary aldosteronism (18, 19).

In the present paper we report the results of a study of the prevalence of hypertension associated with elevated ARR in a sample of adults (n = 1,462; aged 35–74 yr) from the general population randomly selected from the population register of a northern Italian health district and representative of the total population of the district (n = 124,991) with regard to age and sex distribution, educational status, and socioeconomic level.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patient selection

The Italian Health System is organized in districts, catering to the whole population in terms of health care needs. On December 31, 2001, a total of 124,991 adults, aged 35–74 yr, were entered in the population register of the Health District of Bussolengo, a small town near Verona in northern Italy. The primary aim of the study was to estimate the prevalence of hypertension associated with high ARR in the general population living in the Bussolengo district, with the collaboration of a substantial number of general practitioners (GPs) who agreed to participate in the project. Considering that about one third (n = 59 of 180) of all GPs working in the district approved and gave their written consent for the proposed protocol, a corresponding number of 41,644 individuals represented the basal reference population of the study. On the basis of a reported prevalence of hypertension in at least 30% in the population of northern Italy (21) and an 8% reliability coefficient, the optimal sample size for the study was estimated to be on the order of 1,500 individuals. Using a simple random method, an equivalent number of subjects was selected from the population register of the district, contacted by mail, and invited to meet their own GPs within 4 wk. The response rate was 97.1%, with a total of 1,462 individuals examined by their GPs. During the visit, a written questionnaire, recording the main personal and clinical data, was completed for both normotensive and hypertensive subjects, with the result that a total of 1,462 records were collected and analyzed by the investigators. In that data were incomplete in 114 cases, a dataset comprising 1,348 individuals was finally validated by the study committee. A schematic representation of the selection procedure is provided in Fig. 1.

View larger version (26K): [in this window] [in a new window]   FIG. 1. A schematic representation of the selection procedure for normotensive and hypertensive subjects.

The inclusion criteria were as follows: 1) systolic BP greater than 140 or diastolic BP greater than 90 mm Hg, measured twice in both arms, with the patient in the sitting position for 5 min, providing that he had not drunk any coffee or smoked during the previous 30 min; a third measurement (or further measurements, if necessary) was obtained in the case of a difference in BP values of more than 5 mm Hg; to establish a firm diagnosis, high BP also had to be confirmed 2 wk later (the same procedure was repeated as described above); or 2) current therapy for a previous diagnosis of hypertension.

Biochemical assays

Hypertensive patients were invited to give blood for biochemical assays on the condition that they complied with the instructions reported here. To avoid possible pharmacological interference with aldosterone and renin secretion, no hypotensive drugs were allowed during the 4 wk after inclusion in the study (wash-out period). If necessary, BP reduction was obtained using agents such as verapamil and -blockers (prazosin or doxazosin) (19, 22). In addition, patients were invited to avoid any relevant changes in their usual diet, including sodium restriction or vitamin/mineral supplementation before blood assay.

Patient blood samples for hormonal and routine parameters were collected after overnight fasting. Samples for aldosterone and renin assay were collected midmorning (i.e. 0900–1000 h) after at least 2 h in the upright posture and a subsequent period of 10 min in the seated position. Tubes were immediately centrifuged at room temperature, separated, frozen, and stored at –20 C until processed. All samples were assayed in one step, using the same batches of reagents, in the laboratory of Verona University Clinical Chemistry Institute.

Aldosterone and renin assay

Plasma aldosterone was measured by a commercially available method, according to the manufacturer’s instructions (Maia Adaltis, Bologna, Italy) and expressed as picograms per milliliter.

Renin was measured as direct active renin (DAR; picograms per milliliter) by the Nichols Diagnostics chemiluminescent immune assay (San Juan Capistrano, CA) performed on the automated Nichols Advantage System. The intra- and interassay variation coefficients were less than 5% and 8%, respectively.

Considering that in a substantial majority of published studies ARR is reported as a function of renin measured as plasma renin activity (PRA; nanograms per milliliter per hour) (for review, see Refs.23, 24, 25), and very few data are available to date for DAR, we first defined the equivalence of these two measures. For this purpose, two different procedures were adopted.

Linear correlation analysis. Both PRA and DAR were assayed on samples of 120 hypertensive patients, examined in the hypertension unit of the University Hospital of Verona during the past year, and linear correlation analysis of the respective measures was then performed. It should be noted that for PRA values less than 0.2 ng/ml·h (i.e. below the detection limit of the method) were taken as 0.2 ng/ml·h.

Comparison of percentile distribution of aldosterone to renin ratios in age- and sex-matched hypertensive patients. Plasma aldosterone and either PRA or DAR were assayed in a total of 474 hypertensive patients, investigated for possible secondary causes of hypertension in the Hypertension Unit of the University Hospital of Verona over the past 5 yr. The patients were matched for age and gender to the hypertensive individuals selected in the Bussolengo population. All patients were on a sodium-controlled diet (NaCl, 110–120 mmol/d) for 3 d before sampling, and the assay was not accepted when urinary sodium excretion was less than 100 mmol on the day before sampling. Over the previous 4 wk, patients took no hypotensive drugs other than verapamil and/or -blockers. PRA was measured in 165 patients, whereas DAR was assayed in the remaining 309 subjects. These two subgroups were matched for age (48 ± 12 vs. 46.4 ± 11 yr) and gender (55% vs. 59% male) and also showed similar values for all of the main clinical features (BP, body mass index, creatinine, plasma electrolytes, and lipids). The ARR was calculated as a function of both PRA and DAR, and the percentile distributions were compared. For the sake of simplicity, the former ratio will now be indicated as ARR, and the latter as aldosterone to active renin ratio (AARR).

	Results

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Reliability of population sampling

To verify whether the population sampling was adequately representative of the entire population, the features of the selected group (n = 1,348) were compared with the demographic data available for the whole population of the Bussolengo district, aged 35–74 yr (n = 124,991). No statistical differences between the selected sample and the total district population were observed for age (the relative distribution by age classes is shown in Fig. 2), sex (male/female, 47/53% vs. 48/52%), socioeconomic level, or educational status (data not shown).

View larger version (25K): [in this window] [in a new window]   FIG. 2. Comparison between selected samples and reference population of Bussolengo: distribution by age.

Relationship between PRA and DAR, and definition of AARR cut-off

Although not yet definitively validated, previous literature findings suggest that an orthostatic ARR value of 50 ng/dl/ng/ml·h or more should have relatively high sensitivity and specificity for the diagnosis of aldosteronism (for a comprehensive review, see Ref.23). Using the above-described procedures, we therefore sought to determine the AARR equivalent of an ARR of 50 in our dataset.

PRA and DAR were closely correlated (r = 0.87; r²= 0.75; P < 0.0001), but the correlation was stronger for the high/normal than for the low range values of the parameters. Patients with PRA values of 1 ng/ml·h (used as the cut-off for low renin hypertension) or less, however, consistently presented DAR concentrations of 15 pg/ml or less. Analysis of the percentile distribution of ARR and AARR in the respective groups indicated that an ARR value of 50 (ratio of aldosterone, expressed as nanograms per deciliter, to PRA, expressed as nanograms per milliliters per hour) corresponded to the 79th percentile and the equivalent in AARR percentiles (ratio of aldosterone, expressed as picograms per milliliter, to DAR, expressed as picograms per milliliter) was a value of 32 (Table 2). In agreement with the results of the correlation analysis, subjects with ARR of 50 or greater showed PRA of 1 ng/ml·h or less, and those with AARR of 32 or greater had DAR of 15 pg/ml or less. An orthostatic AARR of 32 or more was therefore considered the cut-off value capable of identifying patients characterized by inappropriately high aldosterone secretion.

The aldosterone to active renin ratio was 32 or more in 93 hypertensive patients and less than 32 in the remaining 194 individuals, so that about one of three patients (32.4%) had an elevated ratio. In the total hypertensive group (n = 287), upright plasma aldosterone levels above and DAR values below the normal range were 11% and 2.8%, respectively. Table 3 presents the main features of the hypertensive patients, divided into subgroups according to normal or high AARR. Age and gender were differently distributed between the two groups (see Table 3), but all other clinical parameters (including potassium) were similar in patients with both normal and raised AARR. The frequency of elevated AARR increased with age, but remained constant beyond 55 yr (Fig. 3). No relationship was observed between AARR distribution and socioeconomic or educational status (data not shown).

View this table: [in this window] [in a new window]   TABLE 3. Characteristics of hypertensive patients according to normal or high AARR (32)

View larger version (32K): [in this window] [in a new window]   FIG. 3. ARR: distribution by age.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Since Lim et al. (8) published their pioneering paper on the subject, no reports have evaluated the issue on the basis of a specific epidemiological approach. In particular, to the best of our knowledge, ours is the first study to examine a sample of individuals affected by hypertension, randomly selected from the population included in the population register of a certain geographical area, namely, the Bussolengo district of northern Italy. A sample of 1,462 individuals was examined, and these were representative, with regard to age, gender, socioeconomic level, and educational status, of 124,991 adults, aged 35–74 yr, living in the district.

The overall prevalence of hypertension (30.5%) in this population was comparable to the recently reported results of a collaborative international study, including specific data on the northern Italian population (21). Although almost one third of the hypertensive patients refused blood sampling, the gender, age, BP, and socioeconomic and educational status of these patients were very similar to those of the patients who consented. In addition to the random sampling, these commonalities provide an a posteriori demonstration of the validity and accuracy of the selection process.

The main result of the study is that inappropriately elevated levels of aldosterone, in relation to renin activation, characterizes one of three hypertensive individuals randomly selected from the general population. Most of the literature concerning ARR has used the traditional PRA assay, and very few reports have examined direct active renin (15). PRA assay, however, requires particular care to maintain the temperature of the specimen during the assay and a long run-time (31). These conditions could not be guaranteed in our study and thus could represent potential causes of imprecision; for this reason, the DAR assay was chosen as a surrogate measure. The problem inherent in this choice was to identify the corresponding values of DAR for PRA, which, in turn, determine the AARR. Several researchers have found a highly significant correlation between both methods (32, 33), as also confirmed by our results. Weaker correlations between the measures, however, were observed only for the lowest concentrations, i.e. in the range of interest of the study. In view of this fact, we combined the correlation analysis with comparison of the distribution of ARR and AARR divided into percentiles between two age- and sex-matched groups of patients for whom PRA or DAR were available. In this way, an AARR cut-off value of 32 proved to be the equivalent of an ARR value of 50. In addition, subjects with ARR of 50 or greater showed levels of PRA of 1 ng/ml·h or less, and those with AARR of 32 or more had DAR of 15 pg/ml or less. This result was consistent with our correlation analysis data and with the fact that patients with low renin have PRA of 1 ng/ml·h or less (24, 25). Previous reports have used a relatively wide range of cut-off values, with a significant predictive capability claimed for ARR values of 27 or greater (23). The ARR value of 50 (or the corresponding AARR value of 32) should therefore be a sufficiently prudent cut-off.

Although no apparent reason for bias due to inappropriate patient selection, interference of pharmacological or dietary factors, or methodological inaccuracy would appear to limit the validity of the present results, it should be clearly stated that the study does not allow us to quantify the prevalence of primary aldosteronism, but only that of an elevated ARR. In particular, this does not mean that an equal proportion of subjects with raised AARR automatically should be considered as being affected by aldosteronism, because no confirmatory tests of the diagnosis were performed. Moreover, a single elevated ratio does not necessary imply that the patient has primary aldosteronism, and a prudent practice would be to repeat AARR. Although high AARR and aldosteronism are very often concomitantly present, the study aims did not include establishing the extent of this association in our population.

Nevertheless, other implications of AARR that are potentially relevant in terms of human health have to be taken into account. The first is probably the need to extend AARR screening to all hypertensive patients. In this connection, the methodological procedure used in the present study is a suitable model in general practice without major undesirable consequences due to the withdrawal of previous antihypertensive drugs. None of the patients showed a symptomatic elevation of BP or had to be hospitalized during the wash-out period. This may be related to the fact that general practice patients are generally affected by less severe hypertension, but also further emphasizes the fact that AARR screening is particularly recommended and can be performed without danger in this specific setting. The potential impact of such a diagnostic approach in terms of subsequent workup for aldosteronism and possible surgical cure of hypertension due to aldosterone-producing adenomas is relevant. After suppression studies to confirm the presence of primary aldosteronism, further workup generally includes adrenal computed tomography scanning, but this imaging method may underscore a substantial number of surgically curable forms (16). Although not accepted by all, the policy to perform adrenal venous sampling in the totality of patients found to be affected by primary aldosteronism could maximize the detection of functionally active aldosterone-producing adenomas (16). The costs and benefits of extending a similar practice have to be carefully considered in the future.

Secondly, it appears clear from our results that the prevalence of primary aldosteronism in the general population is similar to or higher than that observed in patients referred to hypertension units. Although indirect, this evidence is difficult to refute. A wide range of severity seems to characterize the disease, from very mild to more severe forms, but all characterized by raised AARR. This is consistent with the view that an increased AARR constitutes a specific marker for a subgroup of patients with similar genetic backgrounds, but different phenotype expressions or penetrances (34, 35).

The final consideration stems from Lim’s concept that an elevated AARR may serve as a guide for targeting drug therapy in hypertensive patients independently of the established diagnosis of aldosteronism (18, 19). Although this option was recommended for patients with resistant hypertension or those requiring more than two agents for BP control (17, 26), our results suggest that a much larger population could take advantage of such a therapeutic option. The hypothesis is surely worthy of future investigation. Once validated by controlled trials and adequately extended to all sensitive patients, this approach should prove highly cost-effective in terms of cardiovascular prevention and public health, taking into consideration the low cost of spironolactone treatment (0.4 Euros/100 mg/d in Italy). Future controlled trials capable of demonstrating (or refuting) the hypothesis are therefore mandatory, so that a substantial proportion of individuals affected by hypertension can finally receive adequate treatment based on their pathogenetic features.

	Acknowledgments

 
We are grateful to the following GPs for their important contributions to data collection and patient recruitment: Paolo Adami, Carlo Ballarini, Anna Barbera, Gaetano Benati, Bruno Benedetti, Claudio Bertaiola, Tiziano Bonaldi, Annarosa Bovo, Umberto Cacchi, Marco Cherubini, Damiano Chiesa, Massimo Chincarini, Giorgio Ciampalini, Roberto Ciresa, Giuseppe Coccia, Giuliana Dal Pozzo, Roberto Esposti, Francesco Faraci, Marina Ferrarini, Guido Filippini, Anna Fioretta, Adelheid Fischer, Carlo Andrea Franchini, Guglielmo Frapporti, Federica Galvani, Beatrice Gargiulo, Angelo Garofalo, Walter Idolazzi, Giorgio Laciniati, Moreno Leoncini, Livio Libardi, Serena Losi, Italo Lovato, Silvio Mantovani, Raffaella Marrocchella, Innocenzo Maurelli, Marco Pietro Mazzi, Silvia Menegazzi, Ernesto Menini, Mauro Montana, Osvaldo Morbioli, Franco Motta, Antonio Panzino, Adriano Ramanzini, Giandomenico Righetti, Arianna Rizzi, Rudi Santini, Gustavo Sartori, Paolo Scarpolini, Francesco Schiera, Maurizio Sciortino, Alessandro Severi, Lionello Signorati, Cesare Testi, Mariella Varaschin, and Matteo Venturi. We are also thankful to G. Parise for his valuable help in collecting blood samples.

	Footnotes

 
This work was supported by grants from the Italian Ministry for Scientific Research and Technology and Regione Veneto Ricerca Finalizzata, Venice, Italy.

Abbreviations: AARR, Aldosterone to active renin ratio; ARR, aldosterone to renin activity ratio; BP, blood pressure; DAR, direct active renin; GP, general practitioner; PRA, plasma renin activity.

Received December 18, 2003.

Accepted May 17, 2004.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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