Factors Affecting the Aldosterone/Renin Ratio

M. Stowasser; A. H. Ahmed; E. Pimenta; P. J. Taylor; R. D. Gordon

doi:10.1055/s-0031-1295460

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2012; 44(03): 170-176
DOI: 10.1055/s-0031-1295460

Review

Factors Affecting the Aldosterone/Renin Ratio

M. Stowasser

¹Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia

,

A. H. Ahmed

¹Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia

,

E. Pimenta

¹Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia

,

P. J. Taylor

¹Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia

,

R. D. Gordon

¹Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia

› Author Affiliations

Abstract

Although the aldosterone/renin ratio (ARR) is the most reliable screening test for primary aldosteronism, false positives and negatives occur. Dietary salt restriction, concomitant malignant or renovascular hypertension, pregnancy and treatment with diuretics (including spironolactone), dihydropyridine calcium blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor antagonists can produce false negatives by stimulating renin. We recently reported selective serotonin reuptake inhibitors lower the ratio. Because potassium regulates aldosterone, uncorrected hypokalemia can lead to false negatives. Beta-blockers, alpha-methyldopa, clonidine, and nonsteroidal anti-inflammatory drugs suppress renin, raising the ARR with potential for false positives. False positives may occur in patients with renal dysfunction or advancing age. We recently showed that (1) females have higher ratios than males, and (2) false positive ratios can occur during the luteal menstrual phase and while taking an oral ethynylestradiol/drospirenone (but not implanted subdermal etonogestrel) contraceptive, but only if calculated using direct renin concentration and not plasma renin activity. Where feasible, diuretics should be ceased at least 6 weeks and other interfering medications at least 2 before ARR measurement, substituting noninterfering agents (e. g., verapamil slow-release±hydralazine and prazosin or doxazosin) were required. Hypokalemia should be corrected and a liberal salt diet encouraged. Collecting blood midmorning from seated patients following 2–4 h upright posture improves sensitivity. The ARR is a screening test only and should be repeated once or more before deciding whether to proceed to confirmatory suppression testing. Liquid chromatography-tandem mass spectrometry aldosterone assays represent a major advance towards addressing inaccuracies inherent in other available methods.

Key words

primary aldosteronism - screening - aldosterone - renin - aldosterone/renin ratio - assay

Full Text

References

References
1 Hiramatsu K, Yamada T, Yukimura Y, Komiya I, Ichikawa K, Ishihara M, Nagata H, Izumiyama T. A screening test to identify aldosterone-producing adenoma by measuring plasma renin activity. Results in hypertensive patients. Arch Intern Med 1981; 141: 1589-1593
2 Gordon RD, Klemm SA, Tunny TJ, Stowasser M. Primary aldosteronism: Hypertension with a genetic basis. Lancet 1992; 340: 159-161
3 Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Rutherford JC. High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol 1994; 21: 315-318
4 Loh KC, Koay ES, Khaw MC, Emmanuel SC, Young Jr WF. Prevalence of primary aldosteronism among asian hypertensive patients in singapore. J Clin Endocrinol Metab 2000; 85: 2854-2859
5 Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, Ganzaroli C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Mannelli M, Mattarello MJ, Moretti A, Palumbo G, Parenti G, Porteri E, Semplicini A, Rizzoni D, Rossi E, Boscaro M, Pessina AC, Mantero F. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 2006; 48: 2293-2300
6 Stowasser M, Gordon RD. Primary aldosteronism – careful investigation is essential and rewarding. Mol Cell Endocrinol 2004; 217: 33-39
7 Young Jr WF. Primary aldosteronism: A common and curable form of hypertension. Cardiol Rev 1999; 7: 207-214
8 Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young Jr WF. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004; 89: 1045-1050
9 Conn JW. The evolution of primary aldosteronism: 1954-1967. Harvey Lect 1966; 62: 257-291
10 Stowasser M, Gordon RD. The aldosterone-renin ratio for screening for primary aldosteronism. Endocrinologist 2004; 14: 267-276
11 Tuck ML, Dluhy RG, Williams GH. Sequential responses of the renin-angiotensin-aldosterone axis to acute postural change: Effect of dietary sodium. J Lab Clin Med 1975; 86: 754-763
12 Gordon RD. Primary aldosteronism. J Endocrinol Invest 1995; 18: 495-511
13 Nowaczynski W, Genest J, Kuchel O, Messerli FH, Guthrie Jr GP, Richardson K, Grose J. Age- and posture-related changes in plasma protein binding and metabolism of aldosterone in essential and secondary hypertension. J Lab Clin Med 1977; 90: 475-489
14 Balikian HM, Brodie AH, Dale SL, Melby JC, Tait JF. Effect of posture on the metabolic clearance rate, plasma concentration and blood production rate of aldosterone in man. J Clin Endocrinol Metab 1968; 28: 1630-1640
15 Gordon RD, Gomez-Sanchez CE, Hamlet SM, Tunny TJ, Klemm SA. Angiotensin-responsive aldosterone-producing adenoma masquerades as idiopathic hyperaldosteronism (iha: Adrenal hyperplasia) or low-renin essential hypertension. J Hypertens Suppl 1987; 5: S103-S106
16 Stowasser M, Gordon RD, Gunasekera TG, Cowley DC, Ward G, Archibald C, Smithers BM. High rate of detection of primary aldosteronism, including surgically treatable forms, after ‘non-selective’ screening of hypertensive patients. J Hypertens 2003; 21: 2149-2157
17 Espiner EA, Ross DG, Yandle TG, Richards AM, Hunt PJ. Predicting surgically remedial primary aldosteronism: Role of adrenal scanning, posture testing, and adrenal vein sampling. J Clin Endocrinol Metab 2003; 88: 3637-3644
18 Mulatero P, Bertello C, Rossato D, Mengozzi G, Milan A, Garrone C, Giraudo G, Passarino G, Garabello D, Verhovez A, Rabbia F, Veglio F. Roles of clinical criteria, computed tomography scan, and adrenal vein sampling in differential diagnosis of primary aldosteronism subtypes. J Clin Endocrinol Metab 2008; 93: 1366-1371
19 Gordon RD, Wolfe LK, Island DP, Liddle GW. A diurnal rhythm in plasma renin activity in man. J Clin Invest 1966; 45: 1587-1592
20 Gordon RD. The challenge of more robust and reproducible methodology in screening for primary aldosteronism. J Hypertens 2004; 22: 251-255
21 Vagnucci AH, McDonald Jr RH, Drash AL, Wong AK. Intradiem changes of plasma aldosterone, cortisol, corticosterone and growth hormone in sodium restriction. J Clin Endocrinol Metab 1974; 38: 761-776
22 Kem DC, Weinberger MH, Gomez-Sanchez C, Kramer NJ, Lerman R, Furuyama S, Nugent CA. Circadian rhythm of plasma aldosterone concentration in patients with primary aldosteronism. J Clin Invest 1973; 52: 2272-2277
23 Ney RL, Shimizu N, Nicholson WE, Island DP, Liddle GW. Correlation of plasma acth concentration with adrenocortical response in normal human subjects, surgical patients, and patients with cushing’s disease. J Clin Invest 1963; 42: 1669-1677
24 Crane MG, Harris JJ. Effect of aging on renin activity and aldosterone excretion. J Lab Clin Med 1976; 87: 947-959
25 Derkx FH, Steunkel C, Schalekamp MP, Visser W, Huisveld IH, Schalekamp MA. Immunoreactive renin, prorenin, and enzymatically active renin in plasma during pregnancy and in women taking oral contraceptives. J Clin Endocrinol Metab 1986; 63: 1008-1015
26 Goldhaber SZ, Hennekens CH, Spark RF, Evans DA, Rosner B, Taylor JO, Kass EH. Plasma renin substrate, renin activity, and aldosterone levels in a sample of oral contraceptive users from a community survey. Am Heart J 1984; 107: 119-122
27 Fischer M, Baessler A, Schunkert H. Renin angiotensin system and gender differences in the cardiovascular system. Cardiovasc Res 2002; 53: 672-677
28 Oelkers WK. Effects of estrogens and progestogens on the renin-aldosterone system and blood pressure. Steroids 1996; 61: 166-171
29 Fommei E, Ghione S, Ripoli A, Maffei S, Di Cecco P, Iervasi A, Turchi S. The ovarian cycle as a factor of variability in the laboratory screening for primary aldosteronism in women. J Hum Hypert 2009; 23: 130-135
30 Young WF. Primary aldosteronism: Renaissance of a syndrome. Clin Endocrinol 2007; 66: 607-618
31 Pizzolo F, Raffaelli R, Memmo A, Chiecchi L, Pavan C, Guarini P, Guidi GC, Franchi M, Corrocher R, Olivieri O. Effects of female sex hormones and contraceptive pill on the diagnostic work-up for primary aldosteronism. J Hypertens 2010; 28: 135-142
32 Ahmed AH, Gordon RD, Taylor PJ, Ward G, Pimenta E, Stowasser M. Are women more at risk of false-positive primary aldosteronism screening and unnecessary suppression testing than men?. J Clin Endocrinol Metab 2011; 96: E340-E346
33 Montori VM, Schwartz GL, Chapman AB, Boerwinkle E, Turner ST. Validity of the aldosterone-renin ratio used to screen for primary aldosteronism. Mayo Clin Proc 2001; 76: 877-882
34 Stowasser M, Gordon RD, Rutherford JC, Nikwan NZ, Daunt N, Slater GJ. Diagnosis and management of primary aldosteronism. J Renin Angiotensin Aldosterone Syst 2001; 2: 156-169
35 Kerstens MN, Muller KAC, Volmer M, Koerts J, Sluiter WJ, Dullaart RP. Reference values for aldosterone-renin ratios in normotensive individuals and effect of changes in dietary sodium consumption. Clin Chem 2011; 57: 1607-1611
36 Cain JP, Tuck ML, Williams GH, Dluhy RG, Rosenoff SH. The regulation of aldosterone secretion in primary aldosteronism. Am J Med 1972; 53: 627-637
37 Brown JJ, Chinn RH, Davies DL, Fraser R, Lever AF, Rae RJ, Robertson JI. Falsely high plasma potassium values in patients with hyperaldosteronism. Br Med J 1970; 2: 18-20
38 Don BR, Sebastian A, Cheitlin M, Christiansen M, Schambelan M. Pseudohyperkalemia caused by fist clenching during phlebotomy. N Engl J Med 1990; 322: 1290-1292
39 Ahmed AH, Gordon RD, Taylor P, Ward G, Pimenta E, Stowasser M. Effect of atenolol on aldosterone/renin ratio calculated by both plasma renin activity and direct renin concentration in healthy male volunteers. J Clin Endocrinol Metab 2010; 95: 3201-3206
40 Gordon MS, Williams GH, Hollenberg NK. Renal and adrenal responsiveness to angiotensin ii: Influence of beta adrenergic blockade. Endocr Res 1992; 18: 115-131
41 Oparil S. Review of therapeutic modalities acting directly via central pathways. Clin Exp Hypertens A 1982; 4: 579-593
42 Manhem P, Paalzow L, Hokfelt B. Plasma clonidine in relation to blood pressure, catecholamines, and renin activity during long-term treatment of hypertension. Clin Pharmacol Ther 1982; 31: 445-451
43 Mitnick PD, Greenberg A, DeOreo PB, Weiner BM, Coffman TM, Walker BR, Agus ZS, Goldfarb S. Effects of two nonsteroidal anti-inflammatory drugs, indomethacin and oxaprozin, on the kidney. Clin Pharmacol Ther 1980; 28: 680-689
44 Seifarth C, Trenkel S, Schobel H, Hahn EG, Hensen J. Influence of antihypertensive medication on aldosterone and renin concentration in the differential diagnosis of essential hypertension and primary aldosteronism. Clin Endocrinol (Oxf) 2002; 57: 457-465
45 Young WF. Primary aldosteronism: Renaissance of a syndrome. Clin Endocrinol (Oxf) 2007; 66: 607-618
46 Steingold KA, Matt DW, DeZiegler D, Sealey JE, Fratkin M, Reznikov S. Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. J Clin Endocrinol Metab 1991; 73: 275-280
47 Ahmed AH, Gordon RD, Taylor PJ, Ward G, Pimenta E, Stowasser M. Effect of contraceptives on aldosterone/renin ratio may vary according to the components of contraceptive, renin assay method, and possibly route of administration. J Clin Endocrinol Metab 2011; 96: 1797-1804
48 Young WFJ. Primary aldosteronism: Update on diagnosis and treatment. Endocrinologist 1997; 7: 213-221
49 Brown MJ, Hopper RV. Calcium-channel blockade can mask the diagnosis of conn’s syndrome. Postgrad Med J 1999; 75: 235-236
50 Mulatero P, Rabbia F, Milan A, Paglieri C, Morello F, Chiandussi L, Veglio F. Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism. Hypertension 2002; 40: 897-902
51 Anderson Jr GH, Howland T, Domschek R, Streeten DH. Effect of sodium balance and calcium channel-blocking drugs on plasma aldosterone responses to infusion of angiotensin ii in normal subjects and patients with essential hypertension. J Clin Endocrinol Metab 1986; 63: 1126-1135
52 Atkinson AB, Morton JJ, Brown JJ, Davies DL, Fraser R, Kelly P, Leckie B, Lever AF, Robertson JI. Captopril in clinical hypertension. Changes in components of renin-angiotensin system and in body composition in relation to fall in blood pressure with a note on measurement of angiotensin ii during converting enzyme inhibition. Br Heart J 1980; 44: 290-296
53 Ahmed AH, Calvird M, Gordon RD, Taylor PJ, Ward G, Pimenta E, Young R, Stowasser M. Effects of two selective serotonin reuptake inhibitor antidepressants, sertraline and escitalopram, on aldosterone/renin ratio in normotensive depressed male patients. J Clin Endocrinol Metab 2011; 96: 1039-1045
54 Campbell DJ, Nussberger J, Stowasser M, Danser AH, Morganti A, Frandsen E, Ménard J. Activity assays and immunoassays for plasma renin and prorenin: Information provided and precautions necessary for accurate measurement. Clin Chem 2009; 55: 867-877
55 McKenna TJ, Sequeira SJ, Heffernan A, Chambers J, Cunningham S. Diagnosis under random conditions of all disorders of the renin-angiotensin-aldosterone axis, including primary hyperaldosteronism. J Clin Endocrinol Metab 1991; 73: 952-957
56 Gordon RD, Tunny TJ. Aldosterone-producing-adenoma (a-p-a): Effect of pregnancy. Clin Exp Hypertens A 1982; 4: 1685-1693
57 Stowasser M, Gordon RD, Klemm SA, Tunny TJ. Renin-aldosterone response to dexamethasone in glucocorticoid-suppressible hyperaldosteronism is altered by coexistent renal artery stenosis. J Clin Endocrinol Metab 1993; 77: 800-804
58 Beevers DG, Brown JJ, Ferriss JB, Fraser R, Lever AF, Robertson JI, Tree M. Renal abnormalities and vascular complications in primary hyperaldosteronism. Evidence on tertiary hyperaldosteronism. Q J Med 1976; 45: 401-410
59 Kaplan NM. Primary aldosteronism with malignant hypertension. N Engl J Med 1963; 269: 1282-1286
60 Murphy BF, Whitworth JA, Kincaid-Smith P. Malignant hypertension due to an aldosterone producing adrenal adenoma. Clin Exp Hypertens A 1985; 7: 939-950
61 Gordon RD, Geddes RA, Pawsey CG, O’Halloran MW. Hypertension and severe hyperkalaemia associated with suppression of renin and aldosterone and completely reversed by dietary sodium restriction. Australas Ann Med 1970; 19: 287-294
62 Warnock DG. Liddle syndrome: Genetics and mechanisms of na+ channel defects. Am J Med Sci 2001; 322: 302-307
63 Palermo M, Quinkler M, Stewart PM. Apparent mineralocorticoid excess syndrome: An overview. Arq Bras Endocrinol Metabol 2004; 48: 687-696
64 Schirpenbach C, Seiler L, Maser-Gluth C, Beuschlein F, Reincke M, Bidlingmaier M. Automated chemiluminescence-immunoassay for aldosterone during dynamic testing: Comparison to radioimmunoassays with and without extraction steps. Clin Chem 2006; 52: 1749-1755
65 Stowasser M, Gordon RD. Aldosterone assays: An urgent need for improvement. Clin Chem 2006; 52: 1640-1642
66 Taylor PJ, Cooper DP, Gordon RD, Stowasser M. Measurement of aldosterone in human plasma by semiautomated hplc-tandem mass spectrometry. Clin Chem 2009; 55: 1155-1162
67 Guo T, Taylor RL, Singh RJ, Soldin SJ. Simultaneous determination of 12 steroids by isotope dilution liquid chromatography-photospray ionization tandem mass spectrometry. Clin Chim Acta 2006; 372: 76-82
68 Taylor PJ, van RSP, Coombes JS, Gordon RD, Stowasser M. Simultaneous measurement of aldosterone and cortisol by high-performance liquid chromatography-tandem mass spectrometry: Application to dehydration-rehydration studies. J Chromat B 2010; 878: 1195-1198
69 Ferrari P, Shaw SG, Nicod J, Saner E, Nussberger J. Active renin versus plasma renin activity to define aldosterone-to-renin ratio for primary aldosteronism. J Hypertens 2004; 22: 377-381
70 Rutherford JC, Taylor WL, Stowasser M, Gordon RD. Success of surgery for primary aldosteronism judged by residual autonomous aldosterone production. World J Surg 1998; 22: 1243-1245
71 Sukor N, Kogovsek C, Gordon RD, Robson D, Stowasser M. Improved quality of life, blood pressure, and biochemical status following laparoscopic adrenalectomy for unilateral primary aldosteronism. J Clin Endocrinol Metab 2010; 95: 1360-1364
72 Ahmed AH, Gordon RD, Pimenta E, Stowasser M. Quality of life in patients with bilateral primary aldosteronism before and during treatment with spironolactone and/or amiloride, including a comparison with our previously published results in those with unilateral disease treated surgically. J Clin Endocrinol Metab 2011; 96: 2904-2911