Gaetana Palumbo

Renal Damage in Primary Aldosteronism: Results of the PAPY Study

Primary aldosteronism (PA) has been associated with cardiovascular hypertrophy and fibrosis, in part independent of the blood pressure level, but deleterious effects on the kidneys are less clear. Likewise, it remains unknown if the kidney can be diversely involved in PA caused by aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Hence, in the Primary Aldosteronism Prevalence in Italy (PAPY) Study, a prospective survey of newly diagnosed consecutive patients referred to hypertension centers nationwide, we sought signs of renal damage in patients with PA and in comparable patients with primary hypertension (PH). Patients (n=1180) underwent a predefined screening protocol followed by tests for confirming PA and identifying the underlying adrenocortical pathology. Renal damage was assessed by 24-hour urine albumin excretion (UAE) rate and glomerular filtration rate (GFR). UAE rate was measured in 490 patients; all had a normal GFR. Of them, 31 (6.4%) had APA, 33 (6.7%) had IHA, and the rest (86.9%) had PH. UAE rate was predicted (P<0.001) by body mass index, age, urinary Na+ excretion, serum K+, and mean blood pressure. Covariate-adjusted UAE rate was significantly higher in APA and IHA than in PH patients; there were more patients with microalbuminuria in the APA and IHA than in the PH group (P=0.007). Among the hypertensive patients with a preserved GFR, those with APA or IHA have a higher UAE rate than comparable PH patients. Thus, hypertension because of excess autonomous aldosterone secretion features an early and more prominent renal damage than PH.

Body Mass Index Predicts Plasma Aldosterone Concentrations in Overweight-Obese Primary Hypertensive Patients

CONTEXTnBody mass index (BMI) shows a direct correlation with plasma aldosterone concentration (PAC) and urinary aldosterone excretion in normotensive individuals; whether the same applies to hypertensive patients is unknown.nnnOBJECTIVEnOur objective was to determine if BMI predicts PAC and the PAC/plasma renin activity ratio [aldosterone renin ratio (ARR)] in hypertensive patients, and if this affects the identification of primary aldosteronism (PA).nnnDESIGNnThis was a prospective evaluation of consecutive hypertensive patients referred nationwide to specialized hypertension centers.nnnMAIN OUTCOME MEASURESnSitting PAC, plasma renin activity, and the ARR, baseline and after 50 mg captopril orally with concomitant assessment of parameters, including BMI and daily sodium intake, were calculated.nnnRESULTSnComplete biochemical data and a definite diagnosis were obtained in 1125 consecutive patients. Of them 999 had primary (essential) hypertension (PH) and 126 (11.2%) PA caused by an aldosterone-producing adenoma in 54 (4.8%). BMI independently predicted PAC (beta = 0.153; P < 0.0001) in PH, particularly in the overweight-obese, but not in the PA group. Covariance analysis and formal comparison of the raw, and the BMI-, sex-, and sodium intake-adjusted ARR with receiver operator characteristic curves, showed no significant improvement for the discrimination of aldosterone-producing adenoma from PH patients with covariate-adjusted ARR.nnnCONCLUSIONSnBMI correlated with PAC independent of age, sex, and sodium intake in PH, but not in PA patients. This association of BMI is particularly evident in overweight-obese PH patients, and suggests a pathophysiological link between visceral adiposity and aldosterone secretion. However, it does not impact on the diagnostic accuracy of the ARR for discriminating PA from PH patients.

Comparison of the Captopril and the Saline Infusion Test for Excluding Aldosterone-Producing Adenoma

We performed a prospective head-to-head comparison of the accuracy of the captopril test (CAPT) and the saline infusion test (SAL) for confirming primary aldosteronism due to an aldosterone-producing adenoma (APA) in patients with different sodium intake. A total of 317 (26.9%) of the 1125 patients screened in the Primary Aldosteronism Prevalence in Italy Study underwent both CAPT and SAL. They were composed of the patients with a high aldosterone/renin ratio baseline and 1 every 4 patients without such criterion. The accuracy of post-CAPT or post-SAL plasma aldosterone values for diagnosing APA was estimated with the area under the receiver operator characteristics curves. Primary aldosteronism was found in 120 patients, of which 46 had an APA. No untoward effect occurred with either test. The area under the receiver operator characteristics curve of plasma aldosterone for both tests was higher (P<0.0001) than that under the diagonal, but the between-test difference was borderline significant (P=0.054). The optimal aldosterone cutoff value for identifying APA was 13.9 and 6.75 ng/dL for the CAPT and SAL, respectively. Even at these cutoffs, sensitivity and specificity were moderate because of overlap of values between patients with and without APA. When examined in relation to sodium intake, the accuracy of the SAL surpassed that of the CAPT in the patients with a sodium intake ≤130 mEq per day; this difference waned at a higher Na+ intake. Thus, both the CAPT and the SAL are safe and moderately accurate for excluding APA; at a sodium intake >7.6 g per day, the SAL offers no advantage over the easier-to-perform CAPT.

Prospective evaluation of the saline infusion test for excluding primary aldosteronism due to aldosterone-producing adenoma

Background Data on the performance of the tests used to confirm the diagnosis of primary aldosteronism (PA) are limited. Objective To prospectively investigate the accuracy of the saline infusion test (SIT). Methods Three hundred and seventeen (26.9%) out of 1125 patients screened in the PAPY study underwent measurement of plasma aldosterone, cortisol and renin activity after infusion of 2 l of isotonic saline intravenously over 4 h. They comprised patients with a baseline aldosterone/renin ratio (ARR) > 40 and one every four patients not fulfilling such criterion. The area under the receiver-operator characteristic curves (AUC) of aldosterone values after SIT was used as a measure of accuracy for diagnosing PA, aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA). Results One hundred and twenty (37.9%) patients had PA that was due to an APA in 46 (38.3%) and to IHA in 74 (61.7%). No untoward effect occurred with the SIT. The AUC (0.811 ± 0.026, 0.878 ± 0.040 and 0.784 ± 0.034 for identification of PA, APA and IHA, respectively) was higher (P < 0.0001) than that under the diagonal. By sensitivity/specificity versus criterion values plot, the best aldosterone cut-off values for identifying APA and IHA were 6.75 and 6.91 ng/dl, respectively. However, even at these optimal cut-offs, sensitivity and specificity were moderate because of values overlapping between patients with and without the disease. Moreover, there were no differences of AUC and aldosterone cut-offs between APA and IHA. Conclusion In a multicenter study the SIT was safe and specific for excluding PA, but had no place for discriminating between an APA and IHA.

Within-Patient Reproducibility of the Aldosterone:Renin Ratio in Primary Aldosteronism

The plasma aldosterone concentration:renin ratio (ARR) is widely used for the screening of primary aldosteronism, but its reproducibility is unknown. We, therefore, investigated the within-patient reproducibility of the ARR in a prospective multicenter study of consecutive hypertensive patients referred to specialized centers for hypertension in Italy. After the patients were carefully prepared from the pharmacological standpoint, the ARR was determined at baseline in 1136 patients and repeated after, on average, 4 weeks in the patients who had initially an ARR ≥40 and in 1 of every 4 of those with an ARR <40. The reproducibility of the ARR was assessed with Passing and Bablok and Deming regression, coefficient of reproducibility, and Bland-Altman and Mountain plots. Within-patient ARR comparison was available in 268 patients, of whom 49 had an aldosterone-producing adenoma, on the basis of the “4-corner criteria.” The ARR showed a highly significant within-patient correlation (r=0.69; P<0.0001) and reproducibility. Bland-Altman plot showed no proportional, magnitude-related, or absolute systematic error between the ARR; moreover, only 7% of the values, for example, slightly more than what could be expected by chance, fell out of the 95% CI for the between-test difference. The accuracy of each ARR for pinpointing aldosterone-producing adenoma patients was ≈80%. Thus, although it was performed under different conditions in a multicenter study, the ARR showed a good within-patient reproducibility. Hence, contrary to previously claimed poor reproducibility of the ARR, these data support its use for the screening of primary aldosteronism.

The Hyper-Pract Study : a multicentre survey on the accuracy of the echocardiographic assessment of hypertensive left ventricular hypertrophy in clinical practice.

Left ventricular hypertrophy (LVH) assessed by echocardiography has a relevant impact in clinical decision making in hypertensive patients. We investigated the precision and accuracy of hypertensive LVH determination in current clinical practice by a regional‐based survey. The study included 211 patients with essential hypertension consecutively attending six hospital outpatient hypertension clinics in the northern Italian region of Lombardy; all subjects had undergone an echocardiographic examination for hypertension‐related problems in a non‐academic or research ultrasound laboratory within 2 years. The original echocardiographic report was examined to ascertain whether the diagnosis of LVH was based on calculation of left ventricular (LV) mass according to validated formulae and indexed to body size (primary outcome) and whether LV geometrical patterns and indices of diastolic function were provided (secondary outcome). A total of 211 echocardiograms performed by 120 physicians operating in 73 different hospital and out‐of‐hospital ultrasound laboratories were collected. Absolute LV mass, LV mass index and relative wall thickness were calculated in 45.5%, 24.6% and 12.3% of the cases, respectively. Parameters of LV diastolic filling were measured in two‐thirds of the cases and estimation of E/A ratio was provided by less than 20% of the examinations. This study shows that a large majority of echocardiographic examinations, routinely performed in hypertensive subjects in order to detect cardiac damage, do not report qualifying data on LV mass, LV geometry and diastolic function. These results indicate that a quantitative assessment of LVH and LV function is rarely provided in clinical practice.

Quantitative value of aldosterone-renin ratio for detection of aldosterone-producing adenoma: The Aldosterone-Renin Ratio for Primary Aldosteronism (AQUARR) study

Background Current guidelines recommend use of the aldosterone‐renin ratio (ARR) for the case detection of primary aldosteronism followed by confirmatory tests to exclude false‐positive results from further diagnostic workup. We investigated the hypothesis that this could be unnecessary in patients with a high ARR value if the quantitative information carried by the ARR is taken into due consideration. Methods and Results We interrogated 2 large data sets of prospectively collected patients studied with the same predefined protocol, which included the captopril challenge test. We used an unambiguous diagnosis of aldosterone‐producing adenoma as reference index. We also assessed whether the post‐captopril ARR and plasma aldosterone concentration fall furnished a diagnostic gain over baseline ARR values. We found that the false‐positive rate fell exponentially, and, conversely, the specificity increased with rising ARR values. At receiver operating characteristics curves and diagnostic odds ratio analysis, the high baseline ARR values implied very high positive likelihood ratio and diagnostic odds ratio values. The baseline and post‐captopril ARR showed similar diagnostic accuracy (area under the receiver operating characteristics curve) in both the exploratory and validation cohorts, indicating lack of diagnostic gain with this confirmatory test (between‐area under the curve difference, 0.005; 95% CI, −0.031 to 0.040; P=0.7 for comparison, and 0.05; 95% CI, −0.061 to 0.064; P=0.051 for comparison, respectively). Conclusions These results indicate that the ARR conveys key quantitative information that, if properly used, can simplify the diagnostic workup, resulting in saving of money and resources. This can offer the chance of diagnosis and ensuing adrenalectomy to a larger number of hypertensive patients, ultimately resulting in better control of blood pressure.