Assay Characteristics Influence the Aldosterone to Renin Ratio as a Screening Tool for Primary Aldosteronism: Results of the German Conn’s Registry

Abstract

Primary aldosteronism (PA) is the most frequent cause of secondary arterial hypertension. The aldosterone to renin ratio (ARR) is the gold standard for screening, but variability between biochemical methods used remains of concern. The aim of the study was to analyze center-specific features of biochemical diagnostic strategies prior to the 2008 consensus within the German Conn’s Registry. The study was designed as a retrospective study in 5 tertiary care hospitals. Patients analyzed for PA between 1990 and 2006 were studied. Characteristics of the assays used to determine ARR during establishing the diagnosis of PA were analyzed in the retrospective part of the German Conn’s Registry. Eighty-six out of 484 documented ARR values had to be excluded from further evaluations because the laboratory or the assays were unknown. In the remaining 398 patients ARR was determined using 10 different assay combinations in the centers (aldosterone plus plasma renin activity or concentration). Considerable differences were seen between the mean concentrations for aldosterone (p<0.0001), renin concentration (p<0.001), and renin activity (p=0.009) for the different assays. The differences between the absolute concentrations measured by the different assays also had significant impact upon the resulting mean ratios. If published cutoff values are applied, the use of different commercial assays to determine the ARR in clinical routine results in major differences in positive screening rates. This heterogeneity affects sensitivity and specificity of screening for PA. Our data emphasize the importance of standardized screening procedures, which must include standardization of biochemical methods.

Key words

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

• References

• 1 Conn JW, Louis LH. Primary aldosteronism: a new clinical entity. Trans Assoc Am Physicians 1955; 68: 215-231 discussion, 231–213
• 2 Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young Jr WF, Montori VM. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 3266-3281
• 3 Hannemann A, Wallaschofski H. Prevalence of Primary Aldosteronism in Patient’s Cohorts and in Population-based Studies – A Review of the Current Literature. Horm Metab Res 2012; 44: 157-162
• 4 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
• 5 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
• 6 Monticone S, Viola A, Tizzani D, Crudo V, Burrello J, Galmozzi M, Veglio F, Mulatero P. Primary aldosteronism: who should be screened?. Horm Metab Res 2012; 44: 163-169
• 7 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
• 8 Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 2005; 45: 1243-1248
• 9 Fallo F, Federspil G, Veglio F, Mulatero P. The metabolic syndrome in primary aldosteronism. Curr Diab Rep 2008; 8: 42-47
• 10 Catena C, Colussi G, Nadalini E, Chiuch A, Baroselli S, Lapenna R, Sechi LA. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med 2008; 168: 80-85
• 11 Born-Frontsberg E, Reincke M, Rump LC, Hahner S, Diederich S, Lorenz R, Allolio B, Seufert J, Schirpenbach C, Beuschlein F, Bidlingmaier M, Endres S, Quinkler M. Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn’s Registry. J Clin Endocrinol Metab 2009; 94: 1125-1130
• 12 Quinkler M, Born-Frontsberg E, Fourkiotis VG. Comorbidities in primary aldosteronism. Horm Metab Res 2010; 42: 429-434
• 13 Reincke M, Fischer E, Gerum S, Merkle K, Schulz S, Pallauf A, Quinkler M, Hanslik G, Lang K, Hahner S, Allolio B, Meisinger C, Holle R, Beuschlein F, Bidlingmaier M, Endres S. Observational study mortality in treated primary aldosteronism: the German Conn’s registry. Hypertension 2012; 60: 618-624
• 14 Padfield PL. Prevalence and role of a raised aldosterone to renin ratio in the diagnosis of primary aldosteronism: a debate on the scientific logic of the use of the ratio in practice. Clin Endocrinol (Oxf) 2003; 59: 422-426
• 15 Tiu SC, Choi CH, Shek CC, Ng YW, Chan FK, Ng CM, Kong AP. The use of aldosterone-renin ratio as a diagnostic test for primary hyperaldosteronism and its test characteristics under different conditions of blood sampling. J Clin Endocrinol Metab 2005; 90: 72-78
• 16 Gordon RD. The challenge of more robust and reproducible methodology in screening for primary aldosteronism. J Hypertens 2004; 22: 251-255
• 17 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
• 18 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
• 19 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
• 20 Montori VM, Young Jr WF. Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism. A systematic review of the literature. Endocrinol Metab Clin North Am 2002; 31: 619-632 xi
• 21 Lim PO, MacDonald TM. Primary aldosteronism, diagnosed by the aldosterone to renin ratio, is a common cause of hypertension. Clin Endocrinol (Oxf) 2003; 59: 427-430
• 22 Schwartz GL, Turner ST. Screening for primary aldosteronism in essential hypertension: diagnostic accuracy of the ratio of plasma aldosterone concentration to plasma renin activity. Clin Chem 2005; 51: 386-394
• 23 Fischer E, Beuschlein F, Reincke M. Diagnosis of endocrinological hypertension: when to screen, and by which method?. Dtsch Med Wochenschr 2011; 136: 537-540
• 24 Jansen PM, Boomsma F, van den Meiracker AH. Aldosterone-to-renin ratio as a screening test for primary aldosteronism – the Dutch ARRAT Study. Neth J Med 2008; 66: 220-228
• 25 Tomaschitz A, Pilz S. Aldosterone to renin ratio – a reliable screening tool for primary aldosteronism?. Horm Metab Res 2010; 42: 382-391
• 26 Cartledge S, Lawson N. Aldosterone and renin measurements. Ann Clin Biochem 2000; 37 (Pt 3) 262-278
• 27 Stowasser M, Ahmed AH, Pimenta E, Taylor PJ, Gordon RD. Factors affecting the aldosterone/renin ratio. Horm Metab Res 2012; 44: 170-176
• 28 Fischer E, Beuschlein F, Bidlingmaier M, Reincke M. Commentary on the Endocrine Society Practice Guidelines: Consequences of adjustment of antihypertensive medication in screening of primary aldosteronism. Rev Endocr Metab Disord 2011; 12: 43-48
• 29 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
• 30 Hannemann A, Bidlingmaier M, Friedrich N, Manolopoulou J, Spyroglou A, Volzke H, Beuschlein F, Seissler J, Rettig R, Felix SB, Biffar R, Doring A, Meisinger C, Peters A, Wichmann HE, Nauck M, Wallaschofski H, Reincke M. Screening for primary aldosteronism in hypertensive subjects: results from two German epidemiological studies. Eur J Endocrinol 2012; 167: 7-15
• 31 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
• 32 Hartman D, Sagnella GA, Chesters CA, Macgregor GA. Direct renin assay and plasma renin activity assay compared. Clin Chem 2004; 50: 2159-2161
• 33 Unger N, Lopez Schmidt I, Pitt C, Walz MK, Philipp T, Mann K, Petersenn S. Comparison of active renin concentration and plasma renin activity for the diagnosis of primary hyperaldosteronism in patients with an adrenal mass. Eur J Endocrinol 2004; 150: 517-523
• 34 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
• 35 Schirpenbach C, Segmiller F, Diederich S, Hahner S, Lorenz R, Rump LC, Seufert J, Quinkler M, Bidlingmaier M, Beuschlein F, Endres S, Reincke M. The diagnosis and treatment of primary hyperaldosteronism in Germany: results on 555 patients from the German Conn Registry. Dtsch Arztebl Int 2009; 106: 305-311
• 36 Vonend O, Ockenfels N, Gao X, Allolio B, Lang K, Mai K, Quack I, Saleh A, Degenhart C, Seufert J, Seiler L, Beuschlein F, Quinkler M, Podrabsky P, Bidlingmaier M, Lorenz R, Reincke M, Rump LC. Adrenal Venous Sampling: Evaluation of the German Conn’s Registry. Hypertension 2011; 57: 990-995
• 37 Reincke M, Rump LC, Quinkler M, Hahner S, Diederich S, Lorenz R, Seufert J, Schirpenbach C, Beuschlein F, Bidlingmaier M, Meisinger C, Holle R, Endres S. Risk factors associated with a low glomerular filtration rate in primary aldosteronism. J Clin Endocrinol Metab 2009; 94: 869-875
• 38 Fogari R, Preti P, Zoppi A, Rinaldi A, Fogari E, Mugellini A. Prevalence of primary aldosteronism among unselected hypertensive patients: a prospective study based on the use of an aldosterone/renin ratio above 25 as a screening test. Hypertens Res 2007; 30: 111-117
• 39 Benchetrit S, Bernheim J, Podjarny E. Normokalemic hyperaldosteronism in patients with resistant hypertension. Isr Med Assoc J 2002; 4: 17-20
• 40 Olivieri O, Ciacciarelli A, Signorelli D, Pizzolo F, Guarini P, Pavan C, Corgnati A, Falcone S, Corrocher R, Micchi A, Cressoni C, Blengio G. Aldosterone to Renin ratio in a primary care setting: the Bussolengo study. J Clin Endocrinol Metab 2004; 89: 4221-4226
• 41 Perschel FH, Schemer R, Seiler L, Reincke M, Deinum J, Maser-Gluth C, Mechelhoff D, Tauber R, Diederich S. Rapid screening test for primary hyperaldosteronism: ratio of plasma aldosterone to renin concentration determined by fully automated chemiluminescence immunoassays. Clin Chem 2004; 50: 1650-1655
• 42 Trenkel S, Seifarth C, Schobel H, Hahn EG, Hensen J. Ratio of serum aldosterone to plasma renin concentration in essential hypertension and primary aldosteronism. Exp Clin Endocrinol Diabetes 2002; 110: 80-85
• 43 Seiler L, Rump LC, Schulte-Monting J, Slawik M, Borm K, Pavenstadt H, Beuschlein F, Reincke M. Diagnosis of primary aldosteronism: value of different screening parameters and influence of antihypertensive medication. Eur J Endocrinol 2004; 150: 329-337
• 44 Seiler L, Reincke M. The aldosterone to Renin ratio in secondary hypertension. Herz 2003; 28: 686-691
• 45 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
• 46 Fischer E, Hanslik G, Pallauf A, Degenhart C, Linsenmaier U, Beuschlein F, Bidlingmaier M, Mussack T, Ladurner R, Hallfeldt K, Quinkler M, Reincke M. Prolonged Zona Glomerulosa Insufficiency Causing Hyperkalemia in Primary Aldosteronism after Adrenalectomy. J Clin Endocrinol Metab 2012; 97: 3695-3673
• 47 Van Der Gugten JG, Dubland J, Liu HF, Wang A, Joseph C, Holmes DT. Determination of serum aldosterone by liquid chromatography and tandem mass spectrometry: a liquid-liquid extraction method for the ABSCIEX API-5000 mass spectrometry system. J Clin Pathol 2012; 65: 457-462
• 48 Stowasser M, Gordon RD. Aldosterone assays: an urgent need for improvement. Clin Chem 2006; 52: 1640-1642
• 49 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