Reference Intervals for Aldosterone, Renin, and the Aldosterone-to-Renin Ratio in the Population-based Study of Health in Pomerania (SHIP-1)

Abstract

The renin-angiotensin-aldosterone system plays a key role in the regulation of human blood pressure. The aldosterone-to-renin ratio (ARR) is widely accepted for screening the primary hyperaldosteronism (PAL). Various cutoffs for positive PAL screening have been defined in patient cohorts from endocrinological referral centers and primary care. However, the distribution of the ARR in the general population is largely unknown. We aim to provide reference ranges for plasma aldosterone concentration (PAC), plasma renin concentration (PRC), and the ARR for the general population of north-east Germany. A cohort of 3 300 subjects participated in the first follow-up of the longitudinal, population-based Study of Health in Pomerania (SHIP). PAC and PRC were measured by radioimmunometric procedures. The reference interval was defined as the central 95% range between the 2.5^th and 97.5^th percentiles. A reference population comprising 1 347 healthy subjects was selected. Sex and age-specific (25–54 and 55–74 years) reference ranges are presented. The upper reference limit for the ARR was 14.2 and 20.3 in younger, and 22.4 and 25.5 in older men and women, respectively. Time of blood sampling had no influence on the ARR, while beta blockers, and agents acting on the renin-angiotensin system were associated with higher and lower ARR, respectively. Our upper reference limit for the ARR is clearly lower than previously reported values from studies of hypertensive patients in primary care or hypertension referral centers. We confirm that PAC and PRC are associated with various factors, including sex, age, intake of estrogen, and various antihypertensive medications.

primary aldosteronism - active renin concentration - plasma aldosterone concentration - endocrine hypertension

References

• 1 Crowley SD, Gurley SB, Coffman TM. AT(1) receptors and control of blood pressure: the kidney and more.  Trends Cardiovasc Med. 2007;  17 30-34
• 2 Beuschlein F. Renin-angiotensin-aldosterone-system (RAAS) und hypertonie.  Thieme-Refresher Innere Medizin. 2008;  R1-R14
• 3 Fardella CE, Mosso L, Gomez-Sanchez C, Cortes P, Soto J, Gomez L, Pinto M, Huete A, Oestreicher E, Foradori A, Montero J. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology.  J Clin Endocrinol Metab. 2000;  85 1863-1867
• 4 Weidmann P. Hyporeninemic hypoaldosteronism and the differential diagnosis of hyperkalemia.  Schweiz Med Wochenschr. 1982;  112 1764-1774
• 5 Torpy DJ, Stratakis CA, Chrousos GP. Hyper- and hypoaldosteronism.  Vitam Horm. 1999;  57 177-216
• 6 Connell JM, MacKenzie SM, Freel EM, Fraser R, Davies E. A lifetime of aldosterone excess: long-term consequences of altered regulation of aldosterone production for cardiovascular function.  Endocr Rev. 2008;  29 133-154
• 7 Brown NJ. Aldosterone and end-organ damage.  Curr Opin Nephrol Hypertens. 2005;  14 235-241
• 8 Krug AW, Ehrhart-Bornstein M. Adrenocortical dysfunction in obesity and the metabolic syndrome.  Horm Metab Res. 2008;  40 515-517
• 9 Young WF. Primary aldosteronism: renaissance of a syndrome.  Clin Endocrinol (Oxf). 2007;  66 607-618
• 10 Stewart PM. Mineralocorticoid hypertension.  Lancet. 1999;  353 1341-1347
• 11 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
• 12 Douma S, Petidis K, Doumas M, Papaefthimiou P, Triantafyllou A, Kartali N, Papadopoulos N, Vogiatzis K, Zamboulis C. Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study.  Lancet. 2008;  371 1921-1926
• 13 Schirpenbach C, Reincke M. Screening for primary aldosteronism.  Best Pract Res Clin Endocrinol Metab. 2006;  20 369-384
• 14 Young Jr WF. Minireview: primary aldosteronism – changing concepts in diagnosis and treatment.  Endocrinology. 2003;  144 2208-2213
• 15 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
• 16 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
• 17 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
• 18 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
• 19 Schirpenbach C, Seiler L, Maser-Gluth C, Rudiger F, Nickel C, Beuschlein F, Reincke M. Confirmatory testing in normokalaemic primary aldosteronism: the value of the saline infusion test and urinary aldosterone metabolites.  Eur J Endocrinol. 2006;  154 865-873
• 20 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
• 21 Bauer JH. Age-related changes in the renin-aldosterone system. Physiological effects and clinical implications.  Drugs Aging. 1993;  3 238-245
• 22 John U, Greiner B, Hensel E, Ludemann J, Piek M, Sauer S, Adam C, Born G, Alte D, Greiser E, Haertel U, Hense HW, Haerting J, Willich S, Kessler C. Study of Health In Pomerania (SHIP): a health examination survey in an east German region: objectives and design.  Soz Praventivmed. 2001;  46 186-194
• 23 Tanabe A, Naruse M, Takagi S, Tsuchiya K, Imaki T, Takano K. Variability in the renin/aldosterone profile under random and standardized sampling conditions in primary aldosteronism.  J Clin Endocrinol Metab. 2003;  88 2489-2494
• 24 Hurwitz S, Cohen RJ, Williams GH. Diurnal variation of aldosterone and plasma renin activity: timing relation to melatonin and cortisol and consistency after prolonged bed rest.  J Appl Physiol. 2004;  96 1406-1414
• 25 Brandenberger G, Follenius M, Muzet A, Ehrhart J, Schieber JP. Ultradian oscillations in plasma renin activity: their relationships to meals and sleep stages.  J Clin Endocrinol Metab. 1985;  61 280-284
• 26 White WB. Importance of blood pressure control over a 24-hour period.  J Manag Care Pharm. 2007;  13 34-39
• 27 Gallay BJ, Ahmad S, Xu L, Toivola B, Davidson RC. Screening for primary aldosteronism without discontinuing hypertensive medications: plasma aldosterone-renin ratio.  Am J Kidney Dis. 2001;  37 699-705
• 28 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
• 29 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
• 30 Danser AH, Derkx FH, Schalekamp MA, Hense HW, Riegger GA, Schunkert H. Determinants of interindividual variation of renin and prorenin concentrations: evidence for a sexual dimorphism of (pro)renin levels in humans.  J Hypertens. 1998;  16 853-862
• 31 Fischer M, Baessler A, Schunkert H. Renin angiotensin system and gender differences in the cardiovascular system.  Cardiovasc Res. 2002;  53 672-677
• 32 Newton-Cheh C, Guo CY, Gona P, Larson MG, Benjamin EJ, Wang TJ, Kathiresan S, O’Donnell CJ, Musone SL, Camargo AL, Drake JA, Levy D, Hirschhorn JN, Vasan RS. Clinical and genetic correlates of aldosterone-to-renin ratio and relations to blood pressure in a community sample.  Hypertension. 2007;  49 846-856
• 33 Baas SJ, Endert E, Fliers E, Prummel MF, Wiersinga WM. Establishment of reference values for endocrine tests. III: Primary aldosteronism.  Neth J Med. 2003;  61 37-43
• 34 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
• 35 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
• 36 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
• 37 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
• 38 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
• 39 Westerdahl C, Bergenfelz A, Isaksson A, Wihl A, Nerbrand C, Valdemarsson S. High frequency of primary hyperaldosteronism among hypertensive patients from a primary care area in Sweden.  Scand J Prim Health Care. 2006;  24 154-159
• 40 Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.  Hypertension. 2008;  51 1403-1419
• 41 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr, JL, Jones DW, Materson BJ, Oparil S, Wright Jr JT, Roccella EJ. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.  Hypertension. 2003;  42 1206-1252
• 42 Koch CA, Wofford MR, Ayala AR, Pacak K. Overview of Endocrine Hypertension. In: DeGroot (ed) http://www.endotext.com S. Darthmouth: MDTEXT.COM, INC, version of December 11, 2009
• 43 Willenberg HS, Schinner S, Ansurudeen I. New mechanisms to control aldosterone synthesis.  Horm Metab Res. 2008;  40 435-441
• 44 Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N, Benjamin EJ, Levy D. Serum aldosterone and the incidence of hypertension in nonhypertensive persons.  N Engl J Med. 2004;  351 33-41

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