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1.
Plouin PF, Amar L, Chatellier G.COMETE-Conn Study Group.  Trends in the prevalence of primary aldosteronism, aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension.  Nephrol Dial Transplant. 2004;19:774-77715031328Google ScholarCrossref
2.
Mulatero P, Stowasser M, Loh KC.  et al.  Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents.  J Clin Endocrinol Metab. 2004;89:1045-105015001583Google ScholarCrossref
3.
Gordon RD. The challenge of more robust and reproducible methodology in screening for primary aldosteronism.  J Hypertens. 2004;22:251-25515076180Google ScholarCrossref
4.
Sawka AM, Young WF Jr, Thompson GB.  et al.  Primary aldosteronism: factors associated with normalization of blood pressure after surgery.  Ann Intern Med. 2001;135:258-26111511140Google ScholarCrossref
5.
Conn JW, Knopf RF, Nesbit RM. Clinical characteristics of primary aldosteronism from an analysis of 145 cases.  Am J Surg. 1964;107:159-17214099489Google ScholarCrossref
6.
Laragh JH. Vasoconstriction-volume analysis for understanding and treating hypertension: the use of renin and aldosterone profiles.  Am J Med. 1973;55:261-2744355699Google ScholarCrossref
7.
Rocha R, Funder JW. The pathophysiology of aldosterone in the cardiovascular system.  Ann N Y Acad Sci. 2002;970:89-10012381544Google ScholarCrossref
8.
Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat.  J Clin Invest. 1996;98:1063-10688770880Google ScholarCrossref
9.
Hollenberg NK. Aldosterone in the development and progression of renal injury.  Kidney Int. 2004;66:1-915200407Google ScholarCrossref
10.
Rossi G, Boscaro M, Ronconi V, Funder JW. Aldosterone as a cardiovascular risk factor.  Trends Endocrinol Metab. 2005;16:104-10715808807Google ScholarCrossref
11.
Pitt B, Zannad F, Remme WJ.  et al. Randomized Aldactone Evaluation Study Investigators.  The effect of spironolactone on morbidity and mortality in patients with severe heart failure.  N Engl J Med. 1999;341:709-71710471456Google ScholarCrossref
12.
Pitt B, Remme W, Zannad F.  et al.  Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.  N Engl J Med. 2003;348:1309-132112668699Google ScholarCrossref
13.
Ibrahim HN, Hostetter TH. Aldosterone in progressive renal disease.  Semin Nephrol. 2001;21:573-57911709805Google ScholarCrossref
14.
Epstein M. Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications.  Am J Kidney Dis. 2001;37:677-68811273866Google ScholarCrossref
15.
Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy.  Hypertension. 2003;41:64-6812511531Google ScholarCrossref
16.
Schjoedt KJ, Rossing K, Juhl TR.  et al.  Beneficial impact of spironolactone in diabetic nephropathy.  Kidney Int. 2005;68:2829-283616316360Google ScholarCrossref
17.
Epstein M, Buckalew V, Altamirano J, Roniker B, Krause S, Kleiman J. Eplerenone reduces proteinuria in type II diabetes mellitus: implications for aldosterone involvement in the pathogenesis of renal dysfunction.  J Am Coll Cardiol. 2002;39:249AGoogle ScholarCrossref
18.
Epstein M. Aldosterone receptor blockade and the role of eplerenone: evolving perspectives.  Nephrol Dial Transplant. 2003;18:1984-199213679471Google ScholarCrossref
19.
Bianchi S, Bigazzi R, Campese VM. Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study.  Am J Kidney Dis. 2005;46:45-5115983956Google ScholarCrossref
20.
Ribstein J, Du Cailar G, Fesler P, Mimran A. Relative glomerular hyperfiltration in primary aldosteronism.  J Am Soc Nephrol. 2005;16:1320-132515800124Google ScholarCrossref
21.
Sechi LA, Kronenberg F, De Carli S.  et al.  Association of serum lipoprotein(a) levels and apolipoprotein(a) size polymorphism with target-organ damage in arterial hypertension.  JAMA. 1997;277:1689-16959169895Google ScholarCrossref
22.
Sechi LA, Zingaro L, Catena C, Casaccio D, De Marchi S. Relationship of fibrinogen levels and hemostatic abnormalities with organ damage in hypertension.  Hypertension. 2000;36:978-98511116111Google ScholarCrossref
23.
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;22:377-38115076197Google ScholarCrossref
24.
Seelig HP. The Jaffe reaction with creatinine: reaction product and general reaction conditions.  Z Klin Chem Klin Biochem. 1969;7:581-5855365462Google Scholar
25.
Hofman W, Guder W. Preanalytical and analytical factors involved in the determination of urinary immunoglobulin G, albumin, alpha 1-microglobin and retinol binding protein using the Behring nephelometer system.  Lab Med. 1989;13:470-478Google Scholar
26.
Sechi LA, Zingaro L, Catena C, Perin A, De Marchi S, Bartoli E. Lipoprotein(a) and apolipoprotein(a) isoforms and proteinuria in patients with moderate renal failure.  Kidney Int. 1999;56:1049-105710469373Google ScholarCrossref
27.
Kimura G, Saito F, Kojima S.  et al.  Renal function curve in patients with secondary forms of hypertension.  Hypertension. 1987;10:11-153298041Google ScholarCrossref
28.
Laird NM, Ware JH. Random-effects models for longitudinal data.  Biometrics. 1982;38:963-9747168798Google ScholarCrossref
29.
Uhrenholt TR, Schjerning J, Hansen PB.  et al.  Rapid inhibition of vasoconstriction in renal afferent arterioles by aldosterone.  Circ Res. 2003;93:1258-126614615288Google ScholarCrossref
30.
Arima S, Kohagura K, Xu HL.  et al.  Endothelium-derived nitric oxide modulates vascular action of aldosterone in renal arteriole.  Hypertension. 2004;43:352-35714691200Google ScholarCrossref
31.
Rowe JW, Andres R, Tobin JD, Norris AH, Shock NW. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study.  J Gerontol. 1976;31:155-1631249404Google ScholarCrossref
32.
Berl T, Katz FH, Henrich WL, de Torrente A, Schrier RW. Role of aldosterone in the control of sodium excretion in patients with advanced chronic renal failure.  Kidney Int. 1978;14:228-235723150Google ScholarCrossref
33.
Hene RJ, Boer P, Koomans HA, Dorhout Mees EJ. Plasma aldosterone concentrations in chronic renal disease.  Kidney Int. 1982;21:98-1017043053Google ScholarCrossref
34.
Beevers DG, Brown JJ, Ferriss JB.  et al.  Renal abnormalities and vascular complications in primary aldosteronism: evidence of tertiary hyperaldosteronism.  Q J Med. 1976;45:401-410948542Google Scholar
35.
Nishimura M, Uzu T, Fujii T.  et al.  Cardiovascular complications in patients with primary aldosteronism.  Am J Kidney Dis. 1999;33:261-26610023636Google ScholarCrossref
36.
Oelkers W, Diederich S, Bahr V. Primary hyperaldosteronism without suppressed renin due to secondary hypertensive kidney damage.  J Clin Endocrinol Metab. 2000;85:3266-327010999820Google ScholarCrossref
37.
ACE Inhibitors in Diabetic Nephropathy Trialist Group.  Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? a meta-analysis of individual patient data.  Ann Intern Med. 2001;134:370-37911242497Google ScholarCrossref
38.
Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.  N Engl J Med. 2001;345:870-87811565519Google ScholarCrossref
39.
Epstein M, Campese VM. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on renal function.  Am J Kidney Dis. 2005;45:2-1415696439Google ScholarCrossref
Original Contribution
June 14, 2006

Long-term Renal Outcomes in Patients With Primary Aldosteronism

Author Affiliations
 

Author Affiliations: Hypertension Unit, Division of Internal Medicine, Department of Experimental and Clinical Pathology and Medicine, University of Udine, Udine, Italy.

JAMA. 2006;295(22):2638-2645. doi:10.1001/jama.295.22.2638
Abstract

Context Experimental animal studies indicate that exposure to increased aldosterone levels might result in renal damage, but the clinical evidence supporting this role of aldosterone is preliminary.

Objective To determine the long-term outcome of renal function in patients with primary aldosteronism after surgical or medical treatment.

Design, Setting, and Participants Prospective study conducted at an Italian university medical center among a consecutive sample of 50 patients who were diagnosed as having primary aldosteronism between January 1994 and December 2001 and who were followed up for a mean of 6.4 years after treatment with adrenalectomy or spironolactone. Patients with primary aldosteronism were compared with 100 patients with essential hypertension, matched for severity and duration of hypertension. All patients were treated with antihypertensive drugs to reach a target blood pressure of less than 140/90 mm Hg.

Main Outcome Measures Primary outcome measures were rates of change of glomerular filtration rate and albuminuria during follow-up. Detection of new-onset microalbuminuria and restoration of normal albumin excretion during follow-up were considered as secondary outcomes.

Results At baseline, glomerular filtration rate and albuminuria were higher in patients with primary aldosteronism than those with essential hypertension. The mean blood pressure during the study was 136/81 mm Hg in the primary aldosteronism group and 137/81 mm Hg in the essential hypertension group. Glomerular filtration rate and albuminuria declined during the initial 6-month period in both groups, with a change that was significantly greater (P<.001 for both variables) in patients with primary aldosteronism. Subsequent rate of decline of glomerular filtration was comparable in the 2 groups, whereas albuminuria did not progress in the remainder of the follow-up. Restoration of normal albumin excretion from microalbuminuria was significantly more frequent in primary aldosteronism than in essential hypertension (P = .02).

Conclusion In the majority of patients in this study, primary aldosteronism was characterized by partially reversible renal dysfunction in which elevated albuminuria is a marker of a dynamic rather than structural renal defect.

Primary aldosteronism is a form of endocrine hypertension characterized by high blood pressure, hypokalemia, suppressed plasma renin activity, and inappropriate aldosterone secretion. Recent studies have reported a greater frequency of primary aldosteronism among patients with hypertension than the previously accepted prevalence of approximately 1%.1,2 Such increased frequency may be the result of more effective identification of this condition due to widespread use of the aldosterone-renin ratio as a screening test.3 Although primary aldosteronism is considered correctable with either removal of an adrenal adenoma or administration of mineralocorticoid receptor antagonists, in many cases, hypertension may persist after treatment.4

Primary aldosteronism has long been considered a relatively benign form of hypertension associated with low incidence of organ complications.5 This has been generally ascribed to the suppression of the renin-angiotensin axis that occurs as a result of an aldosterone-generated volume expansion.6 Recent experimental studies, however, suggest that long-term exposure to increased aldosterone levels might result in cardiovascular7 and renal8,9 structural damage, independent of the blood pressure level. Cardiovascular surrogate end points, including endothelial dysfunction, structural changes in resistance vessels, left ventricular hypertrophy, and impaired diastolic function, have been demonstrated in patients with primary aldosteronism,10 and indirect evidence of aldosterone-related damage has been obtained from clinical trials conducted in patients with heart failure who were treated with mineralocorticoid receptor antagonists, with significant decrease in the mortality rate.11,12 The clinical evidence of a role of aldosterone as a potential contributor to renal dysfunction is weaker than that which has emerged for the cardiovascular system and has been summarized in thorough reviews.9,13,14 Studies performed in patients with diabetic nephropathy15-17 and chronic kidney disease18,19 suggest a beneficial effect of aldosterone antagonists on urinary protein excretion, and a recent study has demonstrated increased albuminuria in patients with primary aldosteronism compared with patients with essential hypertension.20 This study was designed to test the hypothesis that the excess renal damage found in primary aldosteronism is mainly related to a functional and reversible hemodynamic adaptation of the kidney and that treatment of primary aldosteronism can improve renal dysfunction, reflecting correction of this functional abnormality. We investigated the short-term and long-term outcomes of renal function in patients with primary aldosteronism who were followed up after either surgical or medical treatment.

Methods
Results
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Article Information

Corresponding Author: Leonardo A. Sechi, MD, Clinica Medica, Università di Udine, Piazzale S. Maria della Misericordia 1, 33100 Udine, Italy (sechi@uniud.it).

Author Contributions: Dr Sechi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Sechi and Catena contributed equally to this work.

Study concept and design: Sechi, Catena.

Acquisition of data: Sechi, Novello, Lapenna, Baroselli, Nadalini, Colussi, Catena.

Analysis and interpretation of data: Sechi, Novello, Lapenna, Baroselli, Nadalini, Colussi, Catena.

Drafting of the manuscript: Sechi, Catena.

Critical revision of the manuscript for important intellectual content: Sechi, Novello, Lapenna, Baroselli, Nadalini, Colussi, Catena.

Statistical analysis: Sechi, Catena.

Obtained funding: Sechi, Novello, Colussi, Catena.

Administrative, technical, or material support: Sechi, Novello, Lapenna, Baroselli, Nadalini, Colussi, Catena.

Study supervision: Sechi, Novello, Lapenna, Baroselli, Nadalini, Colussi, Catena.

Financial Disclosures: None reported.

Funding/Support: This work was supported by research grants from the Italian Ministry of the University and Scientific and Technologic Research to Drs Sechi and Catena and by research grants from the Italian Society of Hypertension to Drs Novello and Colussi.

Role of the Sponsors: The research sponsors had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, and in the preparation, review, or approval of the manuscript.

References
1.
Plouin PF, Amar L, Chatellier G.COMETE-Conn Study Group.  Trends in the prevalence of primary aldosteronism, aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension.  Nephrol Dial Transplant. 2004;19:774-77715031328Google ScholarCrossref
2.
Mulatero P, Stowasser M, Loh KC.  et al.  Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents.  J Clin Endocrinol Metab. 2004;89:1045-105015001583Google ScholarCrossref
3.
Gordon RD. The challenge of more robust and reproducible methodology in screening for primary aldosteronism.  J Hypertens. 2004;22:251-25515076180Google ScholarCrossref
4.
Sawka AM, Young WF Jr, Thompson GB.  et al.  Primary aldosteronism: factors associated with normalization of blood pressure after surgery.  Ann Intern Med. 2001;135:258-26111511140Google ScholarCrossref
5.
Conn JW, Knopf RF, Nesbit RM. Clinical characteristics of primary aldosteronism from an analysis of 145 cases.  Am J Surg. 1964;107:159-17214099489Google ScholarCrossref
6.
Laragh JH. Vasoconstriction-volume analysis for understanding and treating hypertension: the use of renin and aldosterone profiles.  Am J Med. 1973;55:261-2744355699Google ScholarCrossref
7.
Rocha R, Funder JW. The pathophysiology of aldosterone in the cardiovascular system.  Ann N Y Acad Sci. 2002;970:89-10012381544Google ScholarCrossref
8.
Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat.  J Clin Invest. 1996;98:1063-10688770880Google ScholarCrossref
9.
Hollenberg NK. Aldosterone in the development and progression of renal injury.  Kidney Int. 2004;66:1-915200407Google ScholarCrossref
10.
Rossi G, Boscaro M, Ronconi V, Funder JW. Aldosterone as a cardiovascular risk factor.  Trends Endocrinol Metab. 2005;16:104-10715808807Google ScholarCrossref
11.
Pitt B, Zannad F, Remme WJ.  et al. Randomized Aldactone Evaluation Study Investigators.  The effect of spironolactone on morbidity and mortality in patients with severe heart failure.  N Engl J Med. 1999;341:709-71710471456Google ScholarCrossref
12.
Pitt B, Remme W, Zannad F.  et al.  Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.  N Engl J Med. 2003;348:1309-132112668699Google ScholarCrossref
13.
Ibrahim HN, Hostetter TH. Aldosterone in progressive renal disease.  Semin Nephrol. 2001;21:573-57911709805Google ScholarCrossref
14.
Epstein M. Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications.  Am J Kidney Dis. 2001;37:677-68811273866Google ScholarCrossref
15.
Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy.  Hypertension. 2003;41:64-6812511531Google ScholarCrossref
16.
Schjoedt KJ, Rossing K, Juhl TR.  et al.  Beneficial impact of spironolactone in diabetic nephropathy.  Kidney Int. 2005;68:2829-283616316360Google ScholarCrossref
17.
Epstein M, Buckalew V, Altamirano J, Roniker B, Krause S, Kleiman J. Eplerenone reduces proteinuria in type II diabetes mellitus: implications for aldosterone involvement in the pathogenesis of renal dysfunction.  J Am Coll Cardiol. 2002;39:249AGoogle ScholarCrossref
18.
Epstein M. Aldosterone receptor blockade and the role of eplerenone: evolving perspectives.  Nephrol Dial Transplant. 2003;18:1984-199213679471Google ScholarCrossref
19.
Bianchi S, Bigazzi R, Campese VM. Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study.  Am J Kidney Dis. 2005;46:45-5115983956Google ScholarCrossref
20.
Ribstein J, Du Cailar G, Fesler P, Mimran A. Relative glomerular hyperfiltration in primary aldosteronism.  J Am Soc Nephrol. 2005;16:1320-132515800124Google ScholarCrossref
21.
Sechi LA, Kronenberg F, De Carli S.  et al.  Association of serum lipoprotein(a) levels and apolipoprotein(a) size polymorphism with target-organ damage in arterial hypertension.  JAMA. 1997;277:1689-16959169895Google ScholarCrossref
22.
Sechi LA, Zingaro L, Catena C, Casaccio D, De Marchi S. Relationship of fibrinogen levels and hemostatic abnormalities with organ damage in hypertension.  Hypertension. 2000;36:978-98511116111Google ScholarCrossref
23.
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;22:377-38115076197Google ScholarCrossref
24.
Seelig HP. The Jaffe reaction with creatinine: reaction product and general reaction conditions.  Z Klin Chem Klin Biochem. 1969;7:581-5855365462Google Scholar
25.
Hofman W, Guder W. Preanalytical and analytical factors involved in the determination of urinary immunoglobulin G, albumin, alpha 1-microglobin and retinol binding protein using the Behring nephelometer system.  Lab Med. 1989;13:470-478Google Scholar
26.
Sechi LA, Zingaro L, Catena C, Perin A, De Marchi S, Bartoli E. Lipoprotein(a) and apolipoprotein(a) isoforms and proteinuria in patients with moderate renal failure.  Kidney Int. 1999;56:1049-105710469373Google ScholarCrossref
27.
Kimura G, Saito F, Kojima S.  et al.  Renal function curve in patients with secondary forms of hypertension.  Hypertension. 1987;10:11-153298041Google ScholarCrossref
28.
Laird NM, Ware JH. Random-effects models for longitudinal data.  Biometrics. 1982;38:963-9747168798Google ScholarCrossref
29.
Uhrenholt TR, Schjerning J, Hansen PB.  et al.  Rapid inhibition of vasoconstriction in renal afferent arterioles by aldosterone.  Circ Res. 2003;93:1258-126614615288Google ScholarCrossref
30.
Arima S, Kohagura K, Xu HL.  et al.  Endothelium-derived nitric oxide modulates vascular action of aldosterone in renal arteriole.  Hypertension. 2004;43:352-35714691200Google ScholarCrossref
31.
Rowe JW, Andres R, Tobin JD, Norris AH, Shock NW. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study.  J Gerontol. 1976;31:155-1631249404Google ScholarCrossref
32.
Berl T, Katz FH, Henrich WL, de Torrente A, Schrier RW. Role of aldosterone in the control of sodium excretion in patients with advanced chronic renal failure.  Kidney Int. 1978;14:228-235723150Google ScholarCrossref
33.
Hene RJ, Boer P, Koomans HA, Dorhout Mees EJ. Plasma aldosterone concentrations in chronic renal disease.  Kidney Int. 1982;21:98-1017043053Google ScholarCrossref
34.
Beevers DG, Brown JJ, Ferriss JB.  et al.  Renal abnormalities and vascular complications in primary aldosteronism: evidence of tertiary hyperaldosteronism.  Q J Med. 1976;45:401-410948542Google Scholar
35.
Nishimura M, Uzu T, Fujii T.  et al.  Cardiovascular complications in patients with primary aldosteronism.  Am J Kidney Dis. 1999;33:261-26610023636Google ScholarCrossref
36.
Oelkers W, Diederich S, Bahr V. Primary hyperaldosteronism without suppressed renin due to secondary hypertensive kidney damage.  J Clin Endocrinol Metab. 2000;85:3266-327010999820Google ScholarCrossref
37.
ACE Inhibitors in Diabetic Nephropathy Trialist Group.  Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? a meta-analysis of individual patient data.  Ann Intern Med. 2001;134:370-37911242497Google ScholarCrossref
38.
Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.  N Engl J Med. 2001;345:870-87811565519Google ScholarCrossref
39.
Epstein M, Campese VM. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on renal function.  Am J Kidney Dis. 2005;45:2-1415696439Google ScholarCrossref
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