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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;19:774-777PubMedArticle
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;89:1045-1050PubMedArticle
3.
Gordon RD. The challenge of more robust and reproducible methodology in screening for primary aldosteronism.  J Hypertens. 2004;22:251-255PubMedArticle
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;135:258-261PubMedArticle
5.
Conn JW, Knopf RF, Nesbit RM. Clinical characteristics of primary aldosteronism from an analysis of 145 cases.  Am J Surg. 1964;107:159-172PubMedArticle
6.
Laragh JH. Vasoconstriction-volume analysis for understanding and treating hypertension: the use of renin and aldosterone profiles.  Am J Med. 1973;55:261-274PubMedArticle
7.
Rocha R, Funder JW. The pathophysiology of aldosterone in the cardiovascular system.  Ann N Y Acad Sci. 2002;970:89-100PubMedArticle
8.
Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat.  J Clin Invest. 1996;98:1063-1068PubMedArticle
9.
Hollenberg NK. Aldosterone in the development and progression of renal injury.  Kidney Int. 2004;66:1-9PubMedArticle
10.
Rossi G, Boscaro M, Ronconi V, Funder JW. Aldosterone as a cardiovascular risk factor.  Trends Endocrinol Metab. 2005;16:104-107PubMedArticle
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;341:709-717PubMedArticle
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;348:1309-1321PubMedArticle
13.
Ibrahim HN, Hostetter TH. Aldosterone in progressive renal disease.  Semin Nephrol. 2001;21:573-579PubMedArticle
14.
Epstein M. Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications.  Am J Kidney Dis. 2001;37:677-688PubMedArticle
15.
Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy.  Hypertension. 2003;41:64-68PubMedArticle
16.
Schjoedt KJ, Rossing K, Juhl TR.  et al.  Beneficial impact of spironolactone in diabetic nephropathy.  Kidney Int. 2005;68:2829-2836PubMedArticle
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;39:249AArticle
18.
Epstein M. Aldosterone receptor blockade and the role of eplerenone: evolving perspectives.  Nephrol Dial Transplant. 2003;18:1984-1992PubMedArticle
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;46:45-51PubMedArticle
20.
Ribstein J, Du Cailar G, Fesler P, Mimran A. Relative glomerular hyperfiltration in primary aldosteronism.  J Am Soc Nephrol. 2005;16:1320-1325PubMedArticle
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;277:1689-1695PubMedArticle
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;36:978-985PubMedArticle
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;22:377-381PubMedArticle
24.
Seelig HP. The Jaffe reaction with creatinine: reaction product and general reaction conditions.  Z Klin Chem Klin Biochem. 1969;7:581-585PubMed
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;13:470-478
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;56:1049-1057PubMedArticle
27.
Kimura G, Saito F, Kojima S.  et al.  Renal function curve in patients with secondary forms of hypertension.  Hypertension. 1987;10:11-15PubMedArticle
28.
Laird NM, Ware JH. Random-effects models for longitudinal data.  Biometrics. 1982;38:963-974PubMedArticle
29.
Uhrenholt TR, Schjerning J, Hansen PB.  et al.  Rapid inhibition of vasoconstriction in renal afferent arterioles by aldosterone.  Circ Res. 2003;93:1258-1266PubMedArticle
30.
Arima S, Kohagura K, Xu HL.  et al.  Endothelium-derived nitric oxide modulates vascular action of aldosterone in renal arteriole.  Hypertension. 2004;43:352-357PubMedArticle
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;31:155-163PubMedArticle
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;14:228-235PubMedArticle
33.
Hene RJ, Boer P, Koomans HA, Dorhout Mees EJ. Plasma aldosterone concentrations in chronic renal disease.  Kidney Int. 1982;21:98-101PubMedArticle
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;45:401-410PubMed
35.
Nishimura M, Uzu T, Fujii T.  et al.  Cardiovascular complications in patients with primary aldosteronism.  Am J Kidney Dis. 1999;33:261-266PubMedArticle
36.
Oelkers W, Diederich S, Bahr V. Primary hyperaldosteronism without suppressed renin due to secondary hypertensive kidney damage.  J Clin Endocrinol Metab. 2000;85:3266-3270PubMedArticle
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;134:370-379PubMedArticle
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;345:870-878PubMedArticle
39.
Epstein M, Campese VM. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on renal function.  Am J Kidney Dis. 2005;45:2-14PubMedArticle
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
Context

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 nephropathy1517 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
COMMENT
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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;19:774-777PubMedArticle
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;89:1045-1050PubMedArticle
3.
Gordon RD. The challenge of more robust and reproducible methodology in screening for primary aldosteronism.  J Hypertens. 2004;22:251-255PubMedArticle
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;135:258-261PubMedArticle
5.
Conn JW, Knopf RF, Nesbit RM. Clinical characteristics of primary aldosteronism from an analysis of 145 cases.  Am J Surg. 1964;107:159-172PubMedArticle
6.
Laragh JH. Vasoconstriction-volume analysis for understanding and treating hypertension: the use of renin and aldosterone profiles.  Am J Med. 1973;55:261-274PubMedArticle
7.
Rocha R, Funder JW. The pathophysiology of aldosterone in the cardiovascular system.  Ann N Y Acad Sci. 2002;970:89-100PubMedArticle
8.
Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat.  J Clin Invest. 1996;98:1063-1068PubMedArticle
9.
Hollenberg NK. Aldosterone in the development and progression of renal injury.  Kidney Int. 2004;66:1-9PubMedArticle
10.
Rossi G, Boscaro M, Ronconi V, Funder JW. Aldosterone as a cardiovascular risk factor.  Trends Endocrinol Metab. 2005;16:104-107PubMedArticle
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;341:709-717PubMedArticle
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;348:1309-1321PubMedArticle
13.
Ibrahim HN, Hostetter TH. Aldosterone in progressive renal disease.  Semin Nephrol. 2001;21:573-579PubMedArticle
14.
Epstein M. Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications.  Am J Kidney Dis. 2001;37:677-688PubMedArticle
15.
Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy.  Hypertension. 2003;41:64-68PubMedArticle
16.
Schjoedt KJ, Rossing K, Juhl TR.  et al.  Beneficial impact of spironolactone in diabetic nephropathy.  Kidney Int. 2005;68:2829-2836PubMedArticle
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;39:249AArticle
18.
Epstein M. Aldosterone receptor blockade and the role of eplerenone: evolving perspectives.  Nephrol Dial Transplant. 2003;18:1984-1992PubMedArticle
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;46:45-51PubMedArticle
20.
Ribstein J, Du Cailar G, Fesler P, Mimran A. Relative glomerular hyperfiltration in primary aldosteronism.  J Am Soc Nephrol. 2005;16:1320-1325PubMedArticle
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;277:1689-1695PubMedArticle
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;36:978-985PubMedArticle
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;22:377-381PubMedArticle
24.
Seelig HP. The Jaffe reaction with creatinine: reaction product and general reaction conditions.  Z Klin Chem Klin Biochem. 1969;7:581-585PubMed
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;13:470-478
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;56:1049-1057PubMedArticle
27.
Kimura G, Saito F, Kojima S.  et al.  Renal function curve in patients with secondary forms of hypertension.  Hypertension. 1987;10:11-15PubMedArticle
28.
Laird NM, Ware JH. Random-effects models for longitudinal data.  Biometrics. 1982;38:963-974PubMedArticle
29.
Uhrenholt TR, Schjerning J, Hansen PB.  et al.  Rapid inhibition of vasoconstriction in renal afferent arterioles by aldosterone.  Circ Res. 2003;93:1258-1266PubMedArticle
30.
Arima S, Kohagura K, Xu HL.  et al.  Endothelium-derived nitric oxide modulates vascular action of aldosterone in renal arteriole.  Hypertension. 2004;43:352-357PubMedArticle
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;31:155-163PubMedArticle
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;14:228-235PubMedArticle
33.
Hene RJ, Boer P, Koomans HA, Dorhout Mees EJ. Plasma aldosterone concentrations in chronic renal disease.  Kidney Int. 1982;21:98-101PubMedArticle
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;45:401-410PubMed
35.
Nishimura M, Uzu T, Fujii T.  et al.  Cardiovascular complications in patients with primary aldosteronism.  Am J Kidney Dis. 1999;33:261-266PubMedArticle
36.
Oelkers W, Diederich S, Bahr V. Primary hyperaldosteronism without suppressed renin due to secondary hypertensive kidney damage.  J Clin Endocrinol Metab. 2000;85:3266-3270PubMedArticle
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;134:370-379PubMedArticle
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;345:870-878PubMedArticle
39.
Epstein M, Campese VM. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on renal function.  Am J Kidney Dis. 2005;45:2-14PubMedArticle
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