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Journal of Human (2006) 20, 482–489 & 2006 Nature Publishing Group All rights reserved 0950-9240/06 $30.00 www.nature.com/jhh REVIEW Optimal use and interpretation of the renin ratio to detect aldosterone excess in hypertension

SAR Doi, S Abalkhail, MM Al-Qudhaiby, K Al-Humood, MF Hafez and KAS Al-Shoumer Divisions of Endocrinology & Medicine, Mubarak Al Kabeer Teaching Hospital, Jabriya, Kuwait

With the introduction of the aldosterone/renin ratio as a per lg/l/h or 800 pmol/l per lg/l/h or 130 pmol/ng or screening test, the detection rate of primary aldosteron- 80 pmol/mU. We explore enhancing measures such as ism has increased considerably. Nevertheless, no con- loading or use with a plasma aldosterone sensus has so far been reached regarding the cutoff cutoff as well as pitfalls with the test such as confound- points, operating characteristics or indeed even the ing medications or the need for confirmatory testing. reference values for reporting the aldosterone/renin For the latter, demonstration of autonomous aldosterone ratio using plasma active renin (ng/l or mU/l) measured production via salt loading is widely used, but may not by immunoradiometric assay. We review the character- be most advantageous and may even be contraindicated istics of this ratio in normal individuals, essential in patients with severe hypertension. The renin stimula- hypertension and primary in an tion test may be an alternative being safe, well tolerated, attempt to reach an agreement regarding its optimum and cost effective. use and interpretation – both using the renin activity or Journal of Human Hypertension (2006) 20, 482–489. concentration. It seems that the optimal cutoff for doi:10.1038/sj.jhh.1002024; published online 13 April 2006 patients with is above 30 ng/dl

Keywords: primary hyperaldosteronism; hypertension; aldosterone-renin ratio

Introduction potentially curable form of hypertension. It was

1–3 previously thought that it was only worthwhile to It has generally been recommended that screening perform diagnostic workup for primary hyperaldos- for hyperaldosteronism be considered for at least teronism in hypokalaemic patients in the belief that hypertensive patients with spontaneous hypokalae- the great majority of patients with normokalaemic mia (Ko3.5 mmol/l), hypertensive patients with primary hyperaldosteronism have bilateral adrenal marked diuretic-induced hypokalaemia (Ko3.0 hyperplasia rather than aldosterone-producing ade- mmol/l), patients with hypertension refractory to noma and are therefore rarely surgically curable.9 treatment with three or more drugs or hypertensive However, retrospective evaluation of the diagnosis patients found to have an incidental adrenal of primary hyperaldosteronism from clinical centers adenoma. Although primary hyperaldosteronism in five continents suggest that the application of a was previously believed to account for less than widespread screening strategy to a greater number of 1% of hypertensive patients and hypokalaemia was hypertensives will lead to a 5- to 15-fold increase in considered a prerequisite for pursuing diagnostic 3 the identification of patients affected by primary tests, recent studies pursuing screening of both hyperaldosteronism.10 Only a small proportion of hypokalaemic and normokalaemic hypertensives patients (between 9 and 37%) are hypokalaemic and have reported a much higher prevalence of this the annual detection rate of aldosterone-producing disease, with primary hyperaldosteronism account- adenoma (APA) increased in all centers by up to six ing for up to 12% of hypertensive patients and 4–8 times after the widespread application of screen- most patients being normokalaemic. Therefore, ing.10 Overall, it seems therefore that the widespread primary hyperaldosteronism could be the most screening of all hypertensive patients will lead to a common identifiable, specifically treatable and marked increase in the detection rate of primary hyperaldosteronism. Indeed, the decision taken by Correspondence: Dr SAR Doi, Division of Endocrinology, Mubar- the Brisbane group to screen all (and not just ak Al Kabeer Teaching Hospital, Department of Medicine, Kuwait hypokalemic or resistant) hypertensives led to a University, PO Box 24923 Safat, 13110 Kuwait. 10-fold increase in detection rate of primary hyper- E-mail: [email protected] Received 11 October 2005; revised 2 March 2006; accepted 2 aldosteronism and four-fold increase in removal rate 11 March 2006; published online 13 April 2006 of APAs. Optimal use and interpretation of the aldosterone renin ratio SAR Doi et al 483 Increased detection not only allows increased loss in sensitivity. We therefore decided to extract diagnosis of primary hyperaldosteronism but can relevant information from the literature on this topic help toward optimizing antihypertensive therapy in and make recommendations for clinical use. To individual patients with hypertension and thereby establish the most inclusionary literature set pos- potentially reduce costs by decreasing the number of sible, extensive systematic searches were conduc- drugs required. The prescription of antihypertensive ted of PubMed, starting with the MeSH term therapy based on the renin profile of the patient ‘Hyperaldosteronism/diagnosis’ followed by hand has resulted in a mean reduction of 0.6 drugs (from searches of selected journals, author searches, and 2.1 to 1.5) per patient, compared with a random searches of selected reference lists, especially of prescription,12 which is in turn associated with review articles. reductions in cost (À20%) and side effects. Further- more, such a strategy allows a diagnosis of second- ary hypertension in a fifth of such patients, half of Operating characteristics and threshold whom are indeed patients with primary hyperaldos- value teronism.12 Owing to poor sensitivity and specificity, (up to To compute this ratio, blood is drawn for PA & PRA 60% of patients with primary aldosteronism may after 2 h of ambulation, but preferably at 0800 h, have normal plasma aldosterone concentrations13), since at that time plasma aldosterone is normally at measures of renin and aldosterone by themselves its highest level. In healthy volunteers, the range of are considered to have limited value in screening the ARR (ng/dl per mg/l/h) is 2–17 with a mean of 5.5 for primary aldosteronism. Hiramatsu et al.14 first (50–470, mean 150 when aldosterone is expressed as proposed the computation of the plasma aldosterone pmol/l).20 Others report higher values in healthy concentration (PA) to (PRA) volunteers but usually ARR not exceeding 21–34 ratio (ARR) for evaluation of primary hyperaldoster- (amounting to a ratio of 580–940 when plasma onism in 1981. Today, calculation of this ratio, aldosterone is expressed as pmol/l).13,21 In essential which reduces these measures to a single number, is hypertensives too, the ARR is usually less than this widely advocated as a useful screening method15,16 and remains within this range during antihyperten- because it presents less day-to-day fluctuation than sive treatment.14,17 A recent study concluded that if either plasma aldosterone or plasma renin activity.17 the ARR value is less than 23.6 ng/dl per mg/l/h However, it is difficult to make out from the (o650 if PA in pmol/l), clinicians can be assured literature what are the operating characteristics or that the likelihood of primary hyperaldosteronism is optimum threshold levels for the ARR. A review extremely low17 so we can be confident that patients of the literature up to October 2001 that included with later proven APA or idiopathic hyperaldoster- 16 studies with 3136 participants demonstrated onism (IHA) usually will have an ARR above 25–34 ARR cutoff values that ranged widely from 200 to (690–940 if plasma aldosterone is expressed in 2774 pmol/l per mg/l/h.18 As the predictive value of pmol/l) (Table 1).13,17,21 the ARR is dependent on the threshold used with It has been shown that the ARR has greater than a higher ARR making the diagnosis of primary 90% sensitivity22 around a threshold of the ratio of 30 aldosteronism more likely,19 the higher the thresh- (830 if plasma aldosterone is expressed in pmol/l),15 old, the more specific the ARR with a concomitant and a negative predictive value of 93–99%.23

Table 1 Operating characteristics and threshold values of assays

Method Units Optimum value for Sensitivity (%) Estimated specificity (%) cutoff

PAC25,49 pmol/l 330–415 E90 Lower than the ARR with ng/dl (divide pmol/l by 27.7) 12–15 about 40% sampling variability41 PRA34,49 mg/l/h or ng/ml/h 0.5–1.7 E90 Lower than the ARR with pmol/l/min (multiply by 12.7) 6.4–21.6 about 50% sampling ng/l/s (divide by 3.6) 0.15–0.5 variability41 PRC34 mU/l 5–14 Probably similar to PRA Probably similar to PRA ng/l (multiply mU/l by 0.6) 3–8 (1 mg/l/hE8 mU/l) PAC/PRA ratio25,28,50–52 (pmol/l)/(mg/l/h) 800 (pmol/l)/(pmol/l/min) 63 E90% E70 with about 30% (ng/dl)/(mg/l/h) 30 sampling variability41 PAC/PRC ratio34,53 pmol/mU 80 No clear data but probably No clear data but probably pmol/ng 133 similar to above similar to above

Abbreviations: ARR: plasma aldosterone concenteration to plasma renin activity ratio; PRA: plasma renin ativity; PRC: plasma renin concenteration.

Journal of Human Hypertension Optimal use and interpretation of the aldosterone renin ratio SAR Doi et al 484 This makes it possible to confirm a definitive latter study was a retrospective analysis of data diagnosis of primary aldosteronism in a significant collected over a 15-year period. Although adenomas proportion of such normokalaemic hypertensive were confirmed by surgical excision, the absence of patients, leading to a remarkable increase in the an adenoma was presumed based on negative CT rate of diagnosis.24 Using this sensitive test thres- findings as opposed to adrenal sampling. More hold to screen unselected hypertensive patients, the recent studies indicate that CT imaging is not a very prevalence of primary aldosteronism in this group is reliable method of excluding APA and therefore over 10%.4 As the cutoff is increased to 50 (1380 if AVS is probably necessary to exclude APA. PA in pmol/l) for the ARR, there is a significantly lower negative predictive value (drops by a third from the cutoff of 30) but far less false-positive Captopril enhancement diagnoses are made.8,25 Above 66.9 ng/dl per ng/ml/ Measurement of the ARR 60–120 min after a single h(41850 if PA in pmol/l), the diagnosis of primary dose of 25–50 mg of captopril might enhance hyperaldosteronism can practically be considered diagnostic discrimination28 by increasing specificity established17 although now the negative predictive and decreasing the number of false positives.28–30 value is poor. The use of captopril therefore increases the utility of Quantitative studies using ROC analysis of the the ARR by increasing specificity and thus decreas- ARR suggest that combining this ratio with a PA ing the need for confirmatory testing. In 1983, Lyons threshold might improve diagnostic discrimination et al.30 compared the use of the ARR obtained 2 h of APA and IHA from low-renin essential hyperten- after a dose of captopril with results obtained using sion (LREH)25 and overcome renin dependency of the ‘gold standard’ saline infusion. They found that the ratio because when plasma renin levels are very the acute suppression of aldosterone and removal of low, plasma aldosterone levels as low as 114 pmol/l any negative feedback on circulating levels of renin might result in a positive ARR.26,27 Using the using the post captopril ARR were as efficacious as combined ROC-defined cutoff points of 27–30 the more cumbersome infusion of saline over a 4 h for the ARR (750 if PA in pmol/l) and 12 ng/dl period. They also found that the plasma aldosterone (330 pmol/l) for aldosterone, the reported discrimi- is usually less than 15 ng/dl (415 pmol/l) in all nation of patients with primary aldosteronism (APA normotensive subjects and in 9 of 10 essential and IHA) from those with low-renin essential hypertensives, while it remained above this thresh- hypertension was with greater than 90% sensitivity old in all 6 patients with APA and in 4 of 5 with and specificity.25 Weinberger, also has suggested that IHA. More recently, Agharazii et al.31 published a an ARR 430 (830 if PA is expressed in pmol/l) with detailed comparison of the captopril test and 3 days an absolute PA 4420 pmol/l (15 ng/dl) might not of high-salt loading in 49 patients with a presumed need a confirmatory study.15 Caution is advised diagnosis of primary aldosteronism. These investi- here, however, since although such a strategy gators demonstrated that the captopril test is as increases the specificity of the test (i.e., decreases efficacious in confirming the diagnosis as is the the number of false positives), it also markedly ‘gold standard’ test of 3 days of oral salt loading. decreases sensitivity (i.e., increases the number of Thus, the captopril-stimulated ARR seems to have false negatives). For example, it has been shown that now been confirmed using two different ‘gold- imposition of a threshold value of aldosterone of standard’ salt-loading tests.30,31 The simple addition 420 nmol/l (15 ng/dl), as suggested by the authors in of 25 mg oral captopril 2 h before obtaining a second the above-cited studies, to the optimum ARR set of blood samples for the ARR, therefore, not only threshold increased the specificity of the ARR from serves as a screening test but also might establish a 74 to 97% but markedly decreased the sensitivity definitive diagnosis of primary aldosteronism.32 The from 73 to 33%.22 Thus, based on this finding, such specificity of the ARR test is more dependent on a strategy may be ill advised in screening for demonstrating that the post-captopril ARR remains primary aldosteronism.22 above 12 (330 if PA in pmol/l), despite the loss of the It has been suggested that since patients with an inhibitory levels of II, and the PA fails to APA are the sole ones who will benefit from surgery, be suppressed to less than a definable level ( 240– they can be identified (positive predictive value of o 330 pmol/l).31,32 This test saves time and money and 90%) and separated from other causes (IHA and could lead directly to definitive studies localizing LREH) of the low-renin hypertension syndrome the lesion (Figure 1). using a higher combined cutoff values for the ARR 4100 (42760 if PA in pmol/l) and PAC (420 ng/dl; 4550 pmol/l) which has a positive predictive value Plasma renin concentration of 89.5% in discriminating APA from IHA (with 84% sensitivity and 82.6% specificity).25 It is The plasma renin concentration (PRC) is replacing unlikely, however, that APA can be distinguished the PRA as a measure of renin in clinical practice. It from IHA based solely on a high ARR. Although a seems that the lower limit of the PRC assay increases high ratio is likely very specific for APA, its negative in numerical value and this may necessitate a lower predictive value remains questionable. Also, the cutoff for the ARR. Although one study with a fully

Journal of Human Hypertension Optimal use and interpretation of the aldosterone renin ratio SAR Doi et al 485 Hypertension*

Three ARR requests

Any ARR > 180 pmol/mU All ARR < 80 pmol/mU

Any ARR > 80 AND < 180 pmol/mU

Confirmatory testing

PRA < 1.7µg/l/h (PRC < 14 mU/l or 8 ng/l) PRA ≥ 1.7µg/l/h (PRC ≥ 14 mU/l or 8 ng/l) Renin stimulation

µ ARR >12 ng/dl per g/L/h ARR < 12 ng/dl per µg/L/h µ or (330 pmol per g/L/h or 33 pmol/mU) (330 pmol per µg/L/h or 33 pmol/mU) Secondary Primary and PA > 330 pmol/L and PA < 330 pmol/L aldosteronism aldosteronism ARR after captopril (APA or IHA) Essential or hypertension

PA after infusion ≥ 236 pmol/L / (≥ 8.5 ng/dl) PA after infusion < 236 pmol/L / (< 8.5 ng/dl) Salt Loading

PRA-Plasma renin activity; PRC-Plasma active renin concentration; ARR-Plasma aldosterone to plasma renin ativity ratio; APA-aldosterone-producing adenomia; IHA-idiopathic hyperaid osteronism -Or selected hypertension with either: a) Spontaneuous hypokalemia; b) Diuretic induced hypokalemia; c) Three or more drugs; d) Adrenal incidentaloma Figure 1 Summary of the diagnostic pathway for primary hyperaldosteronism. automated system and two studies with manual PRC However, the ratio is more sensitive than screening assays for screening for primary hyperaldosteronism by either determination considered singly and have been published,33–35 the comparison with data appears to be less affected by drug administration, from the literature is limited. Trenkel et al.33 sug- day-to-day and diurnal variation and by the position gested a cutoff value of 50 (aldosterone measured in of the subjects, thus allowing its use under random serum by RIA, expressed in ng/l; PRC measured by conditions.13 IRMA, expressed in ng/l), which corresponds to Caution should be exercised in recognizing falsely 83 pmol/mU (for PRC, 1 mU/l ¼ 0.6 ng/l34). Ferrari elevated values in patients with renal failure (5 of 17 et al.35 and Racine et al.36 recommended a cutoff of patients with renal failure presented with a ratio 140–150 (PA in pmol/l and PRC in ng/l) correspond- above the limit of 34);13 furthermore, there is the ing to 84–90 pmol/mU. Perschel et al.34 produced a possibility of false-positive values under treatment tentatively proposed cutoff value of 71 pmol/mU. with beta-blocking agents or diuretics or when Subsequent studies including essential hypertensive aldosterone is abruptly stimulated by potassium cohorts may necessitate readjustment, although there administration resulting in a stimulation of aldos- is good concordance with the recommendations terone biosynthesis and a lowering of PRA,38 and made by Trenkel et al.33, Ferrari et al.34 and Perschel false-negative values under treatment with ACEI et al.35 The equivalent cutoff for the ratio using PRC and perhaps calcium antagonists, although in the in mU/l (480) is therefore approximately one-tenth long term, in contrast to their acute effect, these of the ratio derived using PRA in mg/l/h (4800). agents appear to affect neither renin nor aldoster- one.39 Workers have investigated the effects of therapy with atenolol, , doxazosin, fosi- Pitfalls nopril, and on the aldosterone renin ratio in a group of 230 patients with suspected primary Subjects ingesting large amounts of , patients aldosteronism.8 The percent change from control of with renal impairment or those taking beta-adreno- ARR in patients taking amlodipine was À17%732; ceptor blockers can have false-positive results.37 Salt atenolol, 62%782; doxazosin, À5%726; , restriction, ingestion of spironolactone and other À30%724; and irbesartan, À43%727. The ARR diuretics, especially potassium-wasting diuretics change induced by atenolol was significantly higher can lead to false-negative results. Optimal perfor- compared with that induced by all other drugs, and mance of this test consists of eliminating other the ARR change induced by irbesartan was signifi- factors that can affect renin and aldosterone such as cantly lower than that induced by doxazosin. One of correction of hypokalaemia with potassium chloride 55 patients from the group taking amlodipine (1.8%) supplements, cessation of diuretics and beta block- and 4/17 of the patients taking irbesartan (23.5%) ers. It was initially recommended to avoid or stop all gave a false-negative ARR (o50). None of the antihypertensive treatments for at least 2 weeks, patients of the groups taking fosinopril, doxazosin, especially beta-blockers and ACEI which could give and atenolol displayed a false-negative ARR. It false-positive or false-negative values, respectively. seems that alpha-blockers (doxazosin) and calcium

Journal of Human Hypertension Optimal use and interpretation of the aldosterone renin ratio SAR Doi et al 486 Table 2 Reported effect of drugs on the ARR

Drug Renin Aldosterone Effect

No-effect Non-Dihydropyridine calcium channel blocker – Minimal Minimal No effect Nifedipine/Verapamil17,40,57,58 Dihydropyridine calcium channel blocker- Amlodipine8,59 Minimal Decreased-minimal Nil – False negative a-blockers8,17,40,60 Nil Nil No effect Hydralazine17 Minimal Minimal No effect

False-negative effect ACE inhibitors8,40,61,62 Increased Decreased False negative Diuretics40 Increased markedly Increased False negative Minoxidil17 Increased Minimal False negative Angiotensin receptor blockers8,40,63 Increased Decreased False negative probably similar to ACEI

False-positive effect b-blockers8,40,61,64 Decreased Minimal False positive a-methyl dopa17 Decreased Minimal False positive

Abbreviations: ACEI: Angiotensin converting inhibitor; ARR: plasma aldosterone concenteration to plasma renin activity ratio.

Table 3 Confirmatory tests

Type of test Strategy Confirmation of PA

Fludrocortisone suppression test10,53,54 Fludrocortisone acetate (0.1 mg every 6 h), Upright PAC 4166 pmol/l and PRA o1.0 mg/l/h sodium chloride (30 mmol every 8 h) and at 10 am on day 4, coupled with normal potassium supplementation for 4 days plasma potassium levels, at 1000 hours no greater than at 0700 hours on day 4, and urinary sodium 43 mmol/kg/day on day 3 Intravenous saline load6,10,53,55,56 Intravenous infusion of 2 l of 0.9% sodium Plasma aldosterone after infusion 4236 pmol/l chloride solution over 4 h (500 ml/h) (140–235 pmol/l grey zone) Oral sodium load10,20,22 Oral sodium chloride supplementation Urinary aldosterone on the third day (300 mmol of sodium per day for 3 days) and 439 nmol (412 mg) in 24 h, and urinary potassium supplementation (if required) sodium 4200 mmol in 24 h ARR after captopril31,32 A second determination of the ARR 2 h after Post-captopril ARR 412 (ng/dl)/(mg/l/h) AND oral 25 mg captopril PA 4 330 pmol/l Renin stimulation test44,47,48 Furosemide 40 mg orally every 8 h the PRA remains below 1.7 mg/l/h (PRC below proceeding day and 0800 hours the next day 14 mU/l or 8 ng/l) followed by 2 h ambulation and sampling of renin. OR i.v. furosemide 40 mg and ambulation for 2 h followed by sampling of renin

Abbreviations: ARR: plasma aldosterone concenteration to plasma renin activity ratio; PA: plasma aldosterone concenteration; PRA: plasma renin ativity.

channel blockers (amlodipine) can be used in (pmol/l)/(mg/l/h) or PA/PRC480 pmol/mU or PA/ hypertensive patients who need to undergo aldos- PRC4130 pmol/ng) this is followed by a confirma- terone and PRA measurement for the diagnosis of tory suppression or stimulation test.3,42 This is primary aldosteronism. Beta-Blockers can be re- because with the ARR up to a quarter of subjects sponsible for an increased rate of false-positive may have false-positive results22 with a correspond- aldosterone renin ratio’s and ACEI/ARB for in- ing positive predictive value of 33–56% (but a creased false negative ratios. Beta-blockers and negative predictive value of 93–99%).22,23 Even aldosterone antagonists have the strongest impact among African-American subjects, where the ARR on the renin–angiotensin system (Table 2).40 is less sensitive than in white subjects (75 vs 80%), it still had a high negative predictive value (92 vs 94%)23 suggesting that while the ARR is valid as a Confirmatory testing screening test for primary hyperaldosteronism in African American and white patients on stable Usually the ARR ratio is repeated at least thrice41 as antihypertensive treatments, there will be signifi- primary hyperaldosteronism may occur in hyper- cant false-positivity and a high ratio while sugges- tensive patients despite a normal renin/aldosterone tive of primary hyperaldosteronism, must be profile on limited occasions. If positive (ARR4800 confirmed (Table 3).43

Journal of Human Hypertension Optimal use and interpretation of the aldosterone renin ratio SAR Doi et al 487 The suppression type of confirmatory testing is ratio is repeated at least once and if positive aimed at demonstrating autonomy of aldosterone (ARR4800 (pmol/l)/(mg/l/h) or 480 pmol/mU or secretion and is commonly utilized and comprise 4130 pmol/ng) is followed by a confirmatory sup- basically of sodium loading (and measurement of pression or stimulation test. Above 66.9 ng/dl per serum or urinary aldosterone) or fludrocortisone mg/l/h (41850 if PA in pmol/l), the diagnosis of suppression of PA. However, false-negative results primary hyperaldosteronism can practically be are likely to occur in cases of overproduction of considered established17 and no confirmatory test- aldosterone which is responsive to angiotensin II ing is required (Figure 1). (IHA and angiotensin II-responsive APA). Further- more, in elderly patients and patients with severe hypertension, sodium loading is not without risk. An alternative therefore, is the use of captopril loading as previously discussed and demonstrating What is known about this topic K Hyperaldosteronism is fairly common in hypertensives and failure to decrease the ARR ratio below 12 ng/dl/mg/ should be looked for l/h (330 pmol/l per mg/l/h or 33 pmol/mU) in K The aldosterone renin ratio (ARR) is a useful screening test combination with a failure to decrease PA below for hyperaldosteronism in such patients but cutoffs vary 240–330 pmol/l. widely in the literature K A saline-loading test is required to confirm a suggestive Another alternative is the stimulation of PRA or ARR PRC.44–48 This is done using furosemide 40 mg given orally eight hourly the preceding day and in the What this review adds morning followed after 2 h of upright ambulation K The ARR cutoff using either the plama renin activity or by blood sampling for PRA at 0800 hours. After active renin concentration may be placed at 800 pmol/l per mg/l/h or 80 pmol/mU, respectively such a hypovolaemic stimulation, PRA remains K A plasma aldosterone cutoff with the ARR should not be suppressed. It is easily performed with the subject used for screening ambulatory, requires only one blood sample, and it K Confirmatory tests other than saline loading may be just as is not necessary to stop antihypertensive treatment effective and simpler K Use of the ARR after captopril loading confirms except for beta-blocking agents. It offers the advan- hyperaldosteronism tage of a simple and safe confirmatory test, not just for primary aldosteronism, but also for the syndrome of apparent mineralocorticoid excess, DOC-produ- cing adenoma, and even in Liddle’s syndrome. More References recently,44 renin stimulation has been assessed by measurement of PRA after patients have been supine 1 Hemmelgarn BR, McAllister FA, Myers MG, McKay for 30 min, and again after an i.v. bolus of 40 mg DW, Bolli P, Abbott C et al. The 2005 Canadian furosemide followed by 1 h or 2 h in an upright Hypertension Education Program recommendations posture. These authors found that renin stimulation for the management of hypertension: Part 1 – measurement, diagnosis and assessment of by the frusemide and upright posture may not be as risk. Can J Cardiol 2005; 21: 645–656. accurate or effective as the ARR in distinguishing 2 Mulatero P, Dluhy RG, Giacchetti G, Boscaro M, Veglio 44 APA vs non-APA in low-renin hypertensives F, Stewart PM. Diagnosis of primary aldosteronism: although it is not clear from the study whether the from screening to subtype differentiation. Trends non-APA group included only IHA or some low- Endocrinol Metab 2005; 16: 114–119. renin essential hypertensives. It is likely, based on 3 Ganguly A. Primary aldosteronism. N Engl J Med 1998; the data they presented, that these were all mainly 339: 1828–1834. patients with primary hyperaldosteronism and their 4 Gordon RD, Ziesak MD, Tunny TJ, Stowasser M, data44 suggests a post stimulation cutoff for low- Klemm SA. Evidence that primary aldosteronism may renin hypertension be placed at 0.5 ng/l/s which is not be uncommon: 12% incidence among antihyper- tensive drug trial volunteers. Clin Exp Pharmacol 1.7 ng/ml/h and equivalent to a PRC of 14 mU/l or Physiol 1993; 20: 296–298. 8 ng/l. 5 Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Rutherford JC. High incidence of primary aldosteron- ism in 199 patients referred with hypertension. Clin Conclusion Exp Pharmacol Physiol 1994; 21: 315–318. 6 Loh KC, Koay ES, Khaw MC, Emmanuel SC, Young Jr Altogether the computation of the ARR, particularly WF. Prevalence of primary aldosteronism among Asian when correlated to the PA value,30 appears the most hypertensive patients in Singapore. J Clin Endocrinol robust screening test for primary aldosteronism.24 Metab 2000; 85: 2854–2859. Now that plasma aldosterone and renin assessments 7 Fardella CE, Mosso L, Gomez-Sanchez C, Cortes P, Soto J, Gomez L et al. Primary hyperaldosteronism are readily available in most commercial labora- in essential hypertensives: prevalence, biochemical tories and major hospitals at a reasonable cost, profile, and molecular biology. J Clin Endocrinol Metab measurement of these parameters in simultaneously 2000; 85: 1863–1867. drawn blood samples is recommended, followed by 8 Mulatero P, Rabbia F, Milan A, Paglieri C, Morello F, computation of the ARR (Figure 1). Usually the ARR Chiandussi L et al. Drug effects on aldosterone/plasma

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