TABLE 4. Factors that may affect the aldosterone-renin ratio and thus lead to false positive or falsenegative resultsEffect onaldosterone Effect on Effect onFactor levels renin levels ARRMedicationsBeta-adrenergic blockers↑ ↑ ↑↑(FP)Central alpha-2 agonists(e.g., clonidine, alpha-methyldopa↑ ↑ ↑↑(FP)NSAIDs↑ ↑ ↑↑(FP)K+-wasting diuretics↑↑↑↑↑(FN)K+-sparing diuretics↑↑↑↑(FN)ACE inhibitors↑↑↑↑(FN)ARBs↑↑↑↑(FN)Ca2+ blockers (DHPs)↑↑↑↑(FN)Renin inhibitors ↑ * ↑ (FP)*↑ ↑↑(FN)*Potassium statusHypokalemia↑↑↑↑(FN)Potassium loading↑↑↑↑(FP)Dietary sodiumSodium restricted↑↑↑↑(FN)Sodium loaded↑ ↑ ↑↑(FP)Advancing age↑ ↑ ↑↑(FP)Other conditionsRenal impairment↑↑↑(FP)PHA-2↑↑↑(FP)Pregnancy↑↑↑↑(FN)THE ENDOCRINE SOCIETY’S CLINICAL <strong>GUIDELINES</strong>Renovascular HTMalignant HTARR, aldosterone-renin ratio; NSAIDs, non-steroidal anti-inflammatory drugs; K+, potassium; ACE, angiotensin converting enzyme; ARBs, angiotensin II type 1receptor blockers; DHPs, dihydropyridines; PHA-2, pseudohypoaldosteronism type 2 (familial hypertension and hyperkalemia with normal glomerular filtrationrate); HT, hypertension; FP, false positive; FN, false negative.*Renin inhibitors lower plasma renin activity (PRA), but raise direct active renin concentrations (DRC). This would be expected to result in false positive ARRlevels for renin measured as PRA and false negatives for renin measured as DRC.DRC of approximately 12 mU/L (7.6 ng/L) whenmeasured by the recently introduced and alreadywidely used Diasorin automated chemiluminescenceimmunoassay. Here, we express aldosterone andPRA levels in conventional units (aldosterone innanograms per deciliter; plasma renin activity in↑↑↑↑↑↑(FN)(FN)nanograms per milliliter per hour) with SI units foraldosterone and DRC (using the 8.2 conversionfactor) given in parentheses. Lack of uniformity indiagnostic protocols and assay methods for ARRmeasurement has been associated with substantialvariability in cut-off values used by different groups↑↑10
anging from 20 to 100 (68 to 338) (11, 14, 15, 19, 29,53, 54). Most groups, however, use cut-offs of 20 to 40(68 to 135) when testing is performed in the morningon a seated ambulatory patient. Table 5 lists ARR cutoffvalues using some commonly expressed assay unitsfor plasma aldosterone concentration, plasma reninactivity, and direct measurement of plasma reninconcentration.Some investigators require elevated aldosterone levelsin addition to elevated ARR for a positive screeningtest for PA (usually aldosterone >15 ng/dL [416pmol/L]) (55). An alternative approach is to avoid aformal cut-off level for plasma aldosterone, but torecognize that the likelihood of a false positive ARRbecomes greater when renin levels are very low (11).Against a formal cut-off level for aldosterone are thefindings of several studies. In one study, seatedplasma aldosterone levels were 100) and showing failure of aldosterone to suppressduring fludrocortisone suppression testing (FST), andin four of 21 patients found by adrenal venoussampling (AVS) to have unilateral, surgicallycorrectable PA (56). Another study reported plasmaaldosterone levels of 9–16 ng/dL (250–440 pmol/L) in16 of 37 patients diagnosed with PA by FST (16).While it would clearly be desirable to provide firmrecommendations for ARR and plasma aldosteronecut-offs, the variability of assays between laboratoriesand the divided literature to date make it moreprudent to point out relative advantages anddisadvantages, leaving clinicians the flexibility tojudge for themselves.2.0. CASE CONFIRMATION2.1. Instead of proceeding directly to subtypeclassification, we recommend that patients with apositive ARR measurement undergo testing, by any offour confirmatory tests, to definitively confirm orexclude the diagnosis (Figure 1). (1| )2.1.EVIDENCE<strong>The</strong> current literature does not identify a gold standardconfirmatory test for PA. Test performance has beenevaluated only retrospectively, in relatively small seriesof patients selected with high prior (pre-test)probability of PA, commonly in comparison with othertests rather than towards a conclusive diagnosis of PA.Some of these limitations are illustrated in thefollowing example. <strong>The</strong>re is empirical evidence thatcase-control designs for establishing the accuracy ofdiagnostic tests overestimate their accuracy.Giacchetti et al. (57) used such a design including 61PA patients (26 with confirmed APA) and 157patients with essential hypertension. In this context,they found that a post-sodium infusion test with acut-off value for plasma aldosterone of 7 ng/dLTABLE 5. ARR cut-off values, depending on assay and based on whether PAC, PRA, and DRC aremeasured in conventional or SI unitsPRA PRA DRC a DRC a(measured in (measured in (measured in (measured inng/mL/h) pmol/L/min) mU/L) ng/L)PAC (as ng/dL) 20 1.6 2.4 3.830 b 2.5 3.7 5.740 3.1 4.9 7.7PAC (as pmol/L) 750 b 60 91 1441000 80 122 192ARR, Aldosterone-renin ratio; PAC, plasma aldosterone concentration; PRA, plasma renin activity; DRC, direct renin concentration; SI, Système International.a Values shown are on the basis of a conversion factor of PRA (ng/mL/h) to DRC (mU/L) of 8.2. DRC assays are still in evolution, and in a recently introducedand already commonly used automated DRC assay, the conversion factor is 12 (see text).b <strong>The</strong> most commonly adopted cut-off values are shown in bold: 30 for PAC and PRA in conventional units (equivalent to 830 when PAC is in SI units) and 750when PAC is expressed in SI units (equivalent to 27 in conventional units).CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PA TIENTS WITH PRIMARY ALDOSTERONISM11
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