Confirmatory testing in normokalaemic primary aldosteronism: the value of the saline infusion test and urinary aldosterone metabolites.

OBJECTIVE: Primary aldosteronism has recently been recognized as the most frequent cause of secondary hypertension. Since most patients are normokalaemic, differentiation to essential hypertension is challenging. As differentiation by baseline aldosterone/renin ratio may be insufficient, diagnosis should be confirmed by additional tests. However, as most confirmatory tests have been evaluated in hypokalaemic primary aldosteronism only, we reassessed the value of the saline infusion test and 24 h urinary aldosterone metabolites as confirmatory tests for both normo- and hypokalaemic primary aldosteronism under current antihypertensive medication. PATIENTS AND METHODS: 25 patients with primary aldosteronism (11 hypokalaemic, 14 normokalaemic), 29 patients with essential hypertension and 47 normotensive subjects were studied. The hypertensives received their usual medication with the exception of spironolactone. All subjects underwent a standard saline infusion test (determination of plasma aldosterone before and after 2.0 liters of isotonic saline for 4 hours i.v.) and collected a 24 h urine sample for examination of urinary tetrahydroaldosterone and aldosterone-18-glucuronide. RESULTS: In hypokalaemic primary aldosteronism the saline infusion test showed a reasonable sensitivity (91%) and specificity (90%). However, the test failed to differentiate sufficiently between essential hypertension and normokalaemic primary aldosteronism (sensitivity 57%, specificity 90%). Similarly, urinary tetrahydroaldosterone had higher sensitivity in hypokalaemic than in normokalaemic primary aldosteronism (sensitivity 64% vs 36%, specificity 100%), whereas for aldosterone-18-glucuronide, no differences in hypo- and normokalaemic primary aldosteronism were found (sensitivity 45% and 43%, specificity 100%). CONCLUSIONS: These data show that the saline infusion test as an established test in classical hypokalaemic primary aldosteronism is not a reliable test in the normokalaemic variant of the disease. Due to its low accuracy, determination of urinary aldosterone metabolites did not prove useful in confirming either normo- or hypokalaemic patients. We conclude from our data that these tests should not be used as confirmatory testing in the normokalaemic variant of primary aldosteronism.

Diagnosis of primary aldosteronism: value of different screening parameters and influence of antihypertensive medication.

OBJECTIVE: The aim of this study was to investigate the utility of different screening techniques for primary aldosteronism (PA), including serum aldosterone (SA), plasma renin activity (PRA) and the SA/PRA ratio in hypertensive patients of a tertiary-care centre. Furthermore, the influence of antihypertensive medication on SA and the SA/PRA ratio were studied. DESIGN: Clinical records of 425 hypertensive patients who had SA and PRA measurements over a 27-month period were analysed retrospectively. Eighty patients were excluded from further analysis because of incomplete data. The remaining 345 patients were classified into the following groups: patients with essential hypertension (EH) (n=260, 75.4%), patients with PA (n=49, 14.2%) and patients with secondary hypertension other than PA (n=36, 10.4%). Diagnosis of PA was made in accordance with established laboratory criteria (including measurements of SA, PRA, urinary excretion of aldosterone and metabolites, imaging techniques and response to treatment). RESULTS: Although mean serum potassium values were significantly lower (P<0.001) in the PA group compared with the EH group, 61% of PA subjects were normokalaemic (3.4-5.2 mmol/l). The SA/PRA ratio alone identified 94% of the patients with PA, but was false positive in 30% of the patients with EH. The SA/PRA ratio together with SA>150 g/ml increased the diagnostic accuracy, led to the correct identification of 84% of the patients with PA, and decreased the false-positive rate to 3%. A multivariate binary logistic regression analysis based on SA and PRA was performed, which identified PA with 90% sensitivity and 91% accuracy. The SA(2)/PRA or the SA(3)/PRA ratio was found useful for simplification of the regression analysis. Antihypertensive medication influenced SA, PRA and the SA/PRA ratio only in EH patients. In EH patients taking beta-adrenoceptor antagonists PRA tended to be lower, leading to a significantly higher SA/PRA ratio and therefore increasing the false-negative rate. CONCLUSION: To reduce false-positive results in screening for PA, and thereby avoid unnecessary and cost-intensive diagnostic procedures, SA should be taken into account in addition to the SA/PRA ratio as a second screening criterion. Alternatively, the SA(2)/PRA or the SA(3)/PRA ratio is more accurate screening tests than the SA/PRA ratio. Beta-blockers should be avoided whilst screening for PA.

Adrenal venous sampling: evaluation of the German Conn's registry.

In patients with primary aldosteronism, adrenal venous sampling is helpful to distinguish between unilateral and bilateral adrenal diseases. However, the procedure is technically challenging, and selective bilateral catheterization often fails. The aim of this analysis was to evaluate success rate in a retrospective analysis and compare data with procedures done prospectively after introduction of measures designed to improve rates of successful cannulation. Patients were derived from a cross-sectional study involving 5 German centers (German Conn's registry). In the retrospective phase, 569 patients with primary aldosteronism were registered between 1990 and 2007, of whom 230 received adrenal venous sampling. In 200 patients there were sufficient data to evaluate the procedure. In 2008 and 2009, primary aldosteronism was diagnosed in 156 patients, and adrenal venous sampling was done in 106 and evaluated prospectively. Retrospective evaluation revealed that 31% were bilaterally selective when a selectivity index (cortisol adrenal vein/cortisol inferior vena cava) of ≥2.0 was applied. Centers completing <20 procedures had success rates between 8% and 10%. Overall success rate increased in the prospective phase from 31% to 61%. Retrospective data demonstrated the pitfalls of performing adrenal venous sampling. Even in specialized centers, success rates were poor. Marked improvements could be observed in the prospective phase. Selected centers that implemented specific measures to increase accuracy, such as rapid-cortisol-assay and introduction of standard operating procedures, reached success rates of >70%. These data demonstrate the importance of throughput, expertise, and various potentially beneficial measures to improve adrenal vein sampling.

Automated chemiluminescence-immunoassay for aldosterone during dynamic testing: comparison to radioimmunoassays with and without extraction steps.

BACKGROUND: Measurements of aldosterone have become more common since the recognition that primary aldosteronism is a more frequent cause of hypertension than previously believed. Our aim was to compare concentrations reported by 4 assays for samples obtained after saline infusion during dynamic testing. METHODS: We tested 104 participants (27 with primary aldosteronism, 30 with essential hypertension, and 47 healthy controls) with the intravenous saline infusion test (2.0 L isotonic saline over 4 h), with repetitive sampling. In all blood samples, aldosterone concentration was measured by an in-house RIA after extraction and chromatography, by 2 commercially available RIAs without extraction (Aldosterone Maia, Adaltis; Active Aldosterone, Diagnostics Systems Laboratories) and by an automated CLIA (Advantage, Nichols Institute Diagnostics). RESULTS: Correlation coefficients for results of pairs of assays ranged from 0.74 to 0.98. Agreement between commercial assays and in-house RIA was best at the low to intermediate concentrations after saline infusion. Mean (SD) Adaltis and DSL RIA results were 2- to 3-times higher [healthy participants: 78 (25) ng/L and 56 (18) ng/L, respectively] than those obtained by Nichols CLIA [17 (8) ng/L] and in-house RIA [23 (18) ng/L]. Aldosterone concentrations measured by the Nichols CLIA were below the limit of detection (limit of the blank) in 27 of 47 healthy participants. CONCLUSIONS: Aldosterone concentrations reported by the Adaltis and DSL nonextraction RIAs were consistently higher than those produced by the Nichols CLIA and the in-house RIA. The convenient Nichols CLIA showed better agreement with the in-house RIA, but the concentrations in healthy participants were frequently undetectable by this method. Uncritical application of cutoff values from the literature must be avoided.

[The aldosterone to Renin ratio in secondary hypertension]. / Der Aldosteron-Renin-Quotient bei sekundärer Hypertonie.

CLASSICAL FEATURES AND SCREENING: The classical features of primary aldosteronism-hypertension, hypokalemia and metabolic alkalosis-were first described by J. Conn in the midfifties of the last century. The classical form of primary aldosteronism is a rare disease with prevalence rates of 0.1-0.5% within the hypertensive population. The normokalemic variant of primary aldosteronism seems to be much more frequent (5-13%). Although a validated and standardized diagnostic protocol for this entity is still missing recent studies established the aldosterone to renin ratio as a useful screening test. To increase diagnostic sensitivity and specificity of the ratio aldosterone should be added as second screening criterion (sensitivity and specificity about 90%). Dynamic confirmatory testing proving autonomous aldosterone secretion is required to verify the diagnosis in case of a positive screening test. A simple confirmatory test is the salt loading test. Alternatively, the fludrocortisone-suppression-test, the Captopril-challenge- test or the daily exretion rate of aldosterone-18-glucuronide and tetrahydroaldosterone in urine can be used. In case of proven primary aldosteronism further diagnostic evaluation (e. g. CT scanning, postural-test and in case of discrepancy adrenal vein catheterization) is mandatory to differentiate the most common forms of primary aldosteronism, aldosterone producing adenoma and idiopathic hyperaldosteronism. Since many patients with primary aldosteronism can be cured by surgery and missing the diagnosis often leads to significant end-organ damage it is important to evaluate hypertensive patients with therapy-resistant hypertension for primary aldosteronism.

Rapid screening test for primary hyperaldosteronism: ratio of plasma aldosterone to renin concentration determined by fully automated chemiluminescence immunoassays.

BACKGROUND: The ratio of plasma aldosterone concentration to plasma renin activity (PAC/PRA) is the most common screening test for primary hyperaldosteronism (PHA), but it is not standardized among laboratories. We evaluated new automated assays for the simultaneous measurement of PAC and plasma renin concentration (PRC). METHODS: We studied 76 healthy normotensive volunteers and 28 patients with confirmed PHA. PAC and PRC were measured immunochemically in EDTA plasma on the Nichols Advantage chemiluminescence analyzer, and PRA was determined by an activity assay. RESULTS: In volunteers, PAC varied from 33.3 to 1930 pmol/L, PRA from 1.13 to 19.7 ng.mL(-1).h(-1) (0.215 ng.mL(-1).h(-1) = 1 pmol.L(-1).s(-1)), and PRC from 5.70 to 116 mU/L. PAC/PRA ratios ranged from 4.35 to 494 (pmol/L)/(ng.mL(-1).h(-1)) and PAC/PRC ratios from 0.69 to 71.0 pmol/mU. In PHA patients, PAC ranged from 158 to 5012 pmol/L, PRA from 0.40 to 1.70 ng.mL(-1).h(-1), and PRC from 0.80 to 11.7 mU/L. PAC/PRA ratios were between 298 and 6756 (pmol/L)/(ng.mL(-1).h(-1)) and PAC/PRC ratios between 105 and 2328 pmol/mU. Whereas PAC or PRC showed broad overlap between PHA patients and volunteers, the PAC/PRC ratio indicated distinct discrimination of these two groups at a cutoff of 71 pmol/mU. CONCLUSION: The PAC/PRC ratio offers several practical advantages compared with the PAC/PRA screening method. The present study offers preliminary evidence that it may be a useful screening test for PHA. Further studies are required to validate these results, especially in hypertensive cohorts.