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In the Literature: Prevalence and Conn-sequences of Primary Aldosteronism
In the Literature: Prevalence and Conn-sequences of Primary Aldosteronism Commentary on Rossi GP, Bernini G, Caliumi C, et al, for the PAPY Study Investigators: A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 48:2293-2300, 2006.
A
n expanded role of aldosterone in the pathogenesis of cardiovascular disease has been proposed. First, the low prevalence of primary aldosteronism among patients with hypertension has been challenged. Estimates of prevalence showed a wide range (2%-30%), but most studies have reported that 5% to 15% of hypertensives fulfill the biochemical criteria for primary aldosteronism.1 If these estimates are correct, primary aldosteronism would be one of the most frequent causes of secondary hypertension. The criteria for diagnosing primary aldosteronism are heterogeneous, although most agree that the aldosterone (in ng/dL) to renin (in ng/mL/h) ratio (ARR) is the preferred screening test. An elevated ratio above a given cutoff reflects the pathophysiology of primary aldosteronism; that is, hyperaldosteronism and suppressed plasma renin activity. Some centers prefer the measurement of the ARR before and 60 minutes after the administration of captopril (50 mg orally). A positive screening test is usually followed by a salt suppression study (either intravenous or oral salt loading) to confirm the autonomous production of aldosterone. Clinicians traditionally search for aldosterone-producing adenomas, since surgical resection results in cure or substantial amelioration of hypertension in most patients. However, most patients with primary aldosteronism exhibit mild hyperaldosteronism, usually idiopathic bilateral hyperplasia; most subjects are normokalemic. Others argue that hyperaldosteronism is a spectrum of disorders including low renin essential hypertension. What is common to all etiologies of primary aldosteronism is that the aldosterone production is inappropriate for the Support: None. Potential conflicts of interest: None. Address reprint requests to Robert G. Dluhy, MD, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, RFB-2, Boston, MA. E-mail: [email protected] © 2007 by the National Kidney Foundation, Inc. 0272-6386/07/4905-0002$32.00/0 doi:10.1053/j.ajkd.2007.03.014 566
level of sodium intake. In this setting hypertension ensues, but recent evidence also indicates that chronic exposure to excess aldosterone results in cardiovascular damage. Recent studies suggest that aldosterone may have deleterious consequences in addition to its hypertensive effects. Animal models have confirmed aldosterone-mediated renal and cardiac damage in nonepithelial target tissues (Table 1). These actions are independent of blood pressure and, more importantly, damage can be prevented by mineralocorticoid receptor blockade. Such aldosterone-induced tissue injury is not observed in animals on a low-salt diet; analogous to the hyperaldosteronism state described above, cardiovascular damage results when the level of aldosterone is inappropriate for the level of sodium intake. Two clinical trials (the Randomized Aldactone Evaluation Study (RALES)2 and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)3 have demonstrated a beneficial effect on survival when mineralocorticoid-antagonism is added to usual standard-of-care treatments. Other studies in humans have reported excess remodeling of the left ventricle as well as diastolic dysfunction in primary aldosteronism. What have been missing from the literature are prospective studies examining the prevalence of primary aldosteronism in large populations of newly diagnosed hypertensives. There is also a paucity of information on possible excess renal damage in primary aldosteronism compared to patients with essential hypertension. WHAT DID THIS STUDY SHOW?
The Rossi et al PAPY (Primary Aldosteronism Prevalence in Hypertensives) study is a prospective survey conducted by the Working Group of the Italian Society of Arterial Hypertension.4 The study was aimed at determining the prevalence of aldosterone-producing adenomas in over 1,000 newly diagnosed consecutive patients referred to 14 hypertension centers. Variable prevalence es-
American Journal of Kidney Diseases, Vol 49, No 5 (May), 2007: pp 566-568
Editorial
567
Table 1. Pathophysiologic Consequences of Primary Aldosteronism in Animals on a Normal to High Sodium Diet Tissue
Organ
Action
End Result
Epithelial
Kidney
Non-epithelial
Kidney Heart
Sodium reabsorption Potassium Secretion Vascular inflammation Endothelial dysfunction
Hypertension Hypokalemia Albuminuria Cardiac fibrosis
timates of primary aldosteronism in prior retrospective studies have been attributed to the hypertensive populations studied and the heterogeneous criteria for diagnosing primary aldosteronism. A major criticism has been that estimates in hypertension centers reflect referral bias of patients more likely to have primary aldosteronism, such as those with hypokalemia or resistant hypertension. The Rossi study was designed to minimize selection bias by enrolling consecutive patients referred by their family doctor to hypertension centers for diagnosis and treatment of hypertension nationwide in Italy. Before biochemical and hormonal screening tests were performed, there were strict criteria for withdrawing certain medications for 2-6 weeks; only long-acting calcium channel blocker and/or doxazosin were allowed as treatment to minimize the risk of uncontrolled hypertension. Nevertheless, the study population was not in a primary care setting5 and could have been biased by referring physicians not wishing to withdraw their patients from hypertensive treatments (such as those with severe or wellcontrolled hypertension which might become difficult to manage). The investigators also found heterogeneity of primary aldosteronism prevalence across centers, which also suggested referral bias. A strength of this study is the rigor of the diagnostic criteria for primary aldosteronism by the investigators. A baseline ARR greater than or equal to 40 at baseline had to be corroborated by a captopril test or a logistic multivariate discriminant function greater than or equal to 0.5, previously developed by the same authors.6 Although confirmatory saline suppression testing was performed, these data unfortunately were not reported. This study underscores the value of the ARR as a screening test and prospectively confirms a prevalence of primary aldosteronism of 11% in a large hypertensive population. Of these, 4.8% had aldosterone-producing adenomas and 6.4% had idiopathic hyperaldosteronism. The importance of adrenal vein sampling was also
confirmed in this multicenter trial, since in those centers where adrenal vein sampling was available there were more aldosterone-producing adenomas and fewer idiopathic bilateral hyperplasia cases; the opposite occurred where adrenal vein sampling was unavailable. Finally, in a subset of the PAPY cohort, 490 patients had measurements of glomerular filtration (GFR) and urine albumin excretion (UAE) rates.7 In this group, 6.4% of patients had aldosterone-producing adenomas, 6.7% had idiopathic bilateral hyperplasia, and the rest (87%) had primary hypertension. Compared to those with primary hypertension, patients with primary aldosteronism had preserved GFR but had significantly higher covariate-adjusted UAE rates; there were also significantly more patients with aldosterone-producing adenomas and idiopathic bilateral hyperplasia who had microalbuminuria. The authors concluded that the results confirm those seen in animal models and several small studies in human hypertension: primary aldosteronism seen in a setting of a normal-sodium diet is associated with early and more prominent renal damage than primary hypertension. The Rossi study reporting early renal damage in primary aldosteronism confirms pleiotropic cardiovascular toxicity of hyperaldosteronism in the setting of a normal-sodium diet. There are also reports of a higher prevalence of metabolic syndrome and insulin resistance in primary aldosteronism with amelioration in insulin sensitivity following treatment.8 WHAT SHOULD CLINICIANS AND RESEARCHERS DO?
The 10% prevalence of primary aldosteronism in the setting of a high prevalence of arterial hypertension in the general population raises important questions. Should all hypertensives be screened for primary aldosteronism? Is this costeffective? What is the best screening test? Should testing be done by the primary care physician or
568
the hypertensive specialist? Although guidelines are still being developed, the Rossi studies provide clues that can inform practice. First, primary care physicians should be encouraged to initiate screening appropriate patients for primary aldosteronism using the ARR; withdrawing medications is not needed except for those taking aldosterone antagonists. If the ratio is abnormal it is recommended that the patient be referred to a hypertensive specialist; costly imaging studies should be avoided at this point until the biochemical diagnosis of primary aldosteronism is confirmed. Who should be screened? Certainly all patients who present with spontaneous hypokalemia; that is, with a low potassium in the absence of potassium-wasting diuretic therapy. In the Rossi study, 10% of patients had spontaneous hypokalemia (about 50% of patients with aldosterone-producing adenomas, but only 17% of those with idiopathic bilateral hyperplasia), compared to 7% of patients with primary hypertension. However, overall the mean potassium levels in subjects diagnosed with primary aldosteronism (3.6mEq/L [mmol/L]) were significantly less than the levels seen in primary hypertension (4.0 mEq/L [mmol/L]). Frank hypokalemia (⬍3.5 mEq/L [mmol/L]) is typically rare in idiopathic bilateral hyperplasia patients who have mild hyperaldosteronism; most of these subjects have potassium levels that range between 3.5-4.0 mEq/L (mmol/L). It is suggested that potassium levels consistently less than 4.0 mEq/L (mmol/L) should be viewed with suspicion in hypertensives and could be a clue to an underlying diagnosis of primary aldosteronism. Importantly, patients with primary aldosteronism typically have higher blood pressures than those with primary hypertension; for example, the mean systolic blood pressure levels were 10 mm Hg higher in primary aldosteronism versus primary hypertension patients in the Rossi study.4 Moreover, primary aldosteronism is being increasingly recognized in subjects with resistant or refractory hypertension (blood pressure greater than 140/90 mm Hg in compliant individuals who take 3 or more different classes of antihyper-
Robert G. Dluhy
tensive drugs).9 In such patients, some have also reported therapeutic benefits of treatment with aldosterone antagonists.10 As a result, identifying patients with primary aldosteronism may lead to gratifying therapeutic responses. Future studies should be directed at understanding the mechanism(s) underlying the toxicity of excess aldosterone, such as markers of oxidant stress and endothelial dysfunction. Finally, prospective studies are needed in primary aldosteronism to investigate the role of mineralocorticoid receptor antagonists in preventing or reversing aldosterone-mediated target organ injury. Robert G. Dluhy, MD Brigham and Women’s Hospital Boston, Massachusetts REFERENCES 1. 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 89:1045-1050, 2004 2. Pitt B, Zannad F, Remme W, et al: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 341:709-717, 1999 3. 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 348:1309-1321, 2003 4. Rossi GP, Bernini G, Caliumi C, et al: A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Cardiol 48:2293-2300, 2006 5. Olivieri O, Ciacciarelli A, Signorelli D, et al: Aldosterone to renin ratio in a primary care setting: The Bussolengo study. J Clin Endocrinol Metab 89:2421-2426, 2004 6. Rossi GP, Ross E, Pavan E, et al: Screening for primary aldosteronism with a logistic multivariate discriminant analysis. Clin Endocrinol 49:713-723, 1999 7. Rossi GP, Bernini G, Caliumi C, et al: Renal damage in primary aldosteronism: results of the PAPY study. Hypertension 48:232-238, 2006 8. Giacchetti G, Ronconi V, Turchi F, et al: Aldosterone as a key mediator of the cardiometabolic syndrome in primary aldosteronism: an observational study. J Hypertens 25:177-786, 2007 9. Sartori M, Calo LA, Mascagna V, et al: Aldosterone and refractory hypertension: a prospective cohort study. Am J Hypertens 19:373-379, 2006 10. Calhoun DA: Use of aldosterone antagonists in resistant hypertension. Prog Cardiovasc Dis 48:387-396, 2006
A
n expanded role of aldosterone in the pathogenesis of cardiovascular disease has been proposed. First, the low prevalence of primary aldosteronism among patients with hypertension has been challenged. Estimates of prevalence showed a wide range (2%-30%), but most studies have reported that 5% to 15% of hypertensives fulfill the biochemical criteria for primary aldosteronism.1 If these estimates are correct, primary aldosteronism would be one of the most frequent causes of secondary hypertension. The criteria for diagnosing primary aldosteronism are heterogeneous, although most agree that the aldosterone (in ng/dL) to renin (in ng/mL/h) ratio (ARR) is the preferred screening test. An elevated ratio above a given cutoff reflects the pathophysiology of primary aldosteronism; that is, hyperaldosteronism and suppressed plasma renin activity. Some centers prefer the measurement of the ARR before and 60 minutes after the administration of captopril (50 mg orally). A positive screening test is usually followed by a salt suppression study (either intravenous or oral salt loading) to confirm the autonomous production of aldosterone. Clinicians traditionally search for aldosterone-producing adenomas, since surgical resection results in cure or substantial amelioration of hypertension in most patients. However, most patients with primary aldosteronism exhibit mild hyperaldosteronism, usually idiopathic bilateral hyperplasia; most subjects are normokalemic. Others argue that hyperaldosteronism is a spectrum of disorders including low renin essential hypertension. What is common to all etiologies of primary aldosteronism is that the aldosterone production is inappropriate for the Support: None. Potential conflicts of interest: None. Address reprint requests to Robert G. Dluhy, MD, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, RFB-2, Boston, MA. E-mail: [email protected] © 2007 by the National Kidney Foundation, Inc. 0272-6386/07/4905-0002$32.00/0 doi:10.1053/j.ajkd.2007.03.014 566
level of sodium intake. In this setting hypertension ensues, but recent evidence also indicates that chronic exposure to excess aldosterone results in cardiovascular damage. Recent studies suggest that aldosterone may have deleterious consequences in addition to its hypertensive effects. Animal models have confirmed aldosterone-mediated renal and cardiac damage in nonepithelial target tissues (Table 1). These actions are independent of blood pressure and, more importantly, damage can be prevented by mineralocorticoid receptor blockade. Such aldosterone-induced tissue injury is not observed in animals on a low-salt diet; analogous to the hyperaldosteronism state described above, cardiovascular damage results when the level of aldosterone is inappropriate for the level of sodium intake. Two clinical trials (the Randomized Aldactone Evaluation Study (RALES)2 and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)3 have demonstrated a beneficial effect on survival when mineralocorticoid-antagonism is added to usual standard-of-care treatments. Other studies in humans have reported excess remodeling of the left ventricle as well as diastolic dysfunction in primary aldosteronism. What have been missing from the literature are prospective studies examining the prevalence of primary aldosteronism in large populations of newly diagnosed hypertensives. There is also a paucity of information on possible excess renal damage in primary aldosteronism compared to patients with essential hypertension. WHAT DID THIS STUDY SHOW?
The Rossi et al PAPY (Primary Aldosteronism Prevalence in Hypertensives) study is a prospective survey conducted by the Working Group of the Italian Society of Arterial Hypertension.4 The study was aimed at determining the prevalence of aldosterone-producing adenomas in over 1,000 newly diagnosed consecutive patients referred to 14 hypertension centers. Variable prevalence es-
American Journal of Kidney Diseases, Vol 49, No 5 (May), 2007: pp 566-568
Editorial
567
Table 1. Pathophysiologic Consequences of Primary Aldosteronism in Animals on a Normal to High Sodium Diet Tissue
Organ
Action
End Result
Epithelial
Kidney
Non-epithelial
Kidney Heart
Sodium reabsorption Potassium Secretion Vascular inflammation Endothelial dysfunction
Hypertension Hypokalemia Albuminuria Cardiac fibrosis
timates of primary aldosteronism in prior retrospective studies have been attributed to the hypertensive populations studied and the heterogeneous criteria for diagnosing primary aldosteronism. A major criticism has been that estimates in hypertension centers reflect referral bias of patients more likely to have primary aldosteronism, such as those with hypokalemia or resistant hypertension. The Rossi study was designed to minimize selection bias by enrolling consecutive patients referred by their family doctor to hypertension centers for diagnosis and treatment of hypertension nationwide in Italy. Before biochemical and hormonal screening tests were performed, there were strict criteria for withdrawing certain medications for 2-6 weeks; only long-acting calcium channel blocker and/or doxazosin were allowed as treatment to minimize the risk of uncontrolled hypertension. Nevertheless, the study population was not in a primary care setting5 and could have been biased by referring physicians not wishing to withdraw their patients from hypertensive treatments (such as those with severe or wellcontrolled hypertension which might become difficult to manage). The investigators also found heterogeneity of primary aldosteronism prevalence across centers, which also suggested referral bias. A strength of this study is the rigor of the diagnostic criteria for primary aldosteronism by the investigators. A baseline ARR greater than or equal to 40 at baseline had to be corroborated by a captopril test or a logistic multivariate discriminant function greater than or equal to 0.5, previously developed by the same authors.6 Although confirmatory saline suppression testing was performed, these data unfortunately were not reported. This study underscores the value of the ARR as a screening test and prospectively confirms a prevalence of primary aldosteronism of 11% in a large hypertensive population. Of these, 4.8% had aldosterone-producing adenomas and 6.4% had idiopathic hyperaldosteronism. The importance of adrenal vein sampling was also
confirmed in this multicenter trial, since in those centers where adrenal vein sampling was available there were more aldosterone-producing adenomas and fewer idiopathic bilateral hyperplasia cases; the opposite occurred where adrenal vein sampling was unavailable. Finally, in a subset of the PAPY cohort, 490 patients had measurements of glomerular filtration (GFR) and urine albumin excretion (UAE) rates.7 In this group, 6.4% of patients had aldosterone-producing adenomas, 6.7% had idiopathic bilateral hyperplasia, and the rest (87%) had primary hypertension. Compared to those with primary hypertension, patients with primary aldosteronism had preserved GFR but had significantly higher covariate-adjusted UAE rates; there were also significantly more patients with aldosterone-producing adenomas and idiopathic bilateral hyperplasia who had microalbuminuria. The authors concluded that the results confirm those seen in animal models and several small studies in human hypertension: primary aldosteronism seen in a setting of a normal-sodium diet is associated with early and more prominent renal damage than primary hypertension. The Rossi study reporting early renal damage in primary aldosteronism confirms pleiotropic cardiovascular toxicity of hyperaldosteronism in the setting of a normal-sodium diet. There are also reports of a higher prevalence of metabolic syndrome and insulin resistance in primary aldosteronism with amelioration in insulin sensitivity following treatment.8 WHAT SHOULD CLINICIANS AND RESEARCHERS DO?
The 10% prevalence of primary aldosteronism in the setting of a high prevalence of arterial hypertension in the general population raises important questions. Should all hypertensives be screened for primary aldosteronism? Is this costeffective? What is the best screening test? Should testing be done by the primary care physician or
568
the hypertensive specialist? Although guidelines are still being developed, the Rossi studies provide clues that can inform practice. First, primary care physicians should be encouraged to initiate screening appropriate patients for primary aldosteronism using the ARR; withdrawing medications is not needed except for those taking aldosterone antagonists. If the ratio is abnormal it is recommended that the patient be referred to a hypertensive specialist; costly imaging studies should be avoided at this point until the biochemical diagnosis of primary aldosteronism is confirmed. Who should be screened? Certainly all patients who present with spontaneous hypokalemia; that is, with a low potassium in the absence of potassium-wasting diuretic therapy. In the Rossi study, 10% of patients had spontaneous hypokalemia (about 50% of patients with aldosterone-producing adenomas, but only 17% of those with idiopathic bilateral hyperplasia), compared to 7% of patients with primary hypertension. However, overall the mean potassium levels in subjects diagnosed with primary aldosteronism (3.6mEq/L [mmol/L]) were significantly less than the levels seen in primary hypertension (4.0 mEq/L [mmol/L]). Frank hypokalemia (⬍3.5 mEq/L [mmol/L]) is typically rare in idiopathic bilateral hyperplasia patients who have mild hyperaldosteronism; most of these subjects have potassium levels that range between 3.5-4.0 mEq/L (mmol/L). It is suggested that potassium levels consistently less than 4.0 mEq/L (mmol/L) should be viewed with suspicion in hypertensives and could be a clue to an underlying diagnosis of primary aldosteronism. Importantly, patients with primary aldosteronism typically have higher blood pressures than those with primary hypertension; for example, the mean systolic blood pressure levels were 10 mm Hg higher in primary aldosteronism versus primary hypertension patients in the Rossi study.4 Moreover, primary aldosteronism is being increasingly recognized in subjects with resistant or refractory hypertension (blood pressure greater than 140/90 mm Hg in compliant individuals who take 3 or more different classes of antihyper-
Robert G. Dluhy
tensive drugs).9 In such patients, some have also reported therapeutic benefits of treatment with aldosterone antagonists.10 As a result, identifying patients with primary aldosteronism may lead to gratifying therapeutic responses. Future studies should be directed at understanding the mechanism(s) underlying the toxicity of excess aldosterone, such as markers of oxidant stress and endothelial dysfunction. Finally, prospective studies are needed in primary aldosteronism to investigate the role of mineralocorticoid receptor antagonists in preventing or reversing aldosterone-mediated target organ injury. Robert G. Dluhy, MD Brigham and Women’s Hospital Boston, Massachusetts REFERENCES 1. 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 89:1045-1050, 2004 2. Pitt B, Zannad F, Remme W, et al: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 341:709-717, 1999 3. 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 348:1309-1321, 2003 4. Rossi GP, Bernini G, Caliumi C, et al: A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Cardiol 48:2293-2300, 2006 5. Olivieri O, Ciacciarelli A, Signorelli D, et al: Aldosterone to renin ratio in a primary care setting: The Bussolengo study. J Clin Endocrinol Metab 89:2421-2426, 2004 6. Rossi GP, Ross E, Pavan E, et al: Screening for primary aldosteronism with a logistic multivariate discriminant analysis. Clin Endocrinol 49:713-723, 1999 7. Rossi GP, Bernini G, Caliumi C, et al: Renal damage in primary aldosteronism: results of the PAPY study. Hypertension 48:232-238, 2006 8. Giacchetti G, Ronconi V, Turchi F, et al: Aldosterone as a key mediator of the cardiometabolic syndrome in primary aldosteronism: an observational study. J Hypertens 25:177-786, 2007 9. Sartori M, Calo LA, Mascagna V, et al: Aldosterone and refractory hypertension: a prospective cohort study. Am J Hypertens 19:373-379, 2006 10. Calhoun DA: Use of aldosterone antagonists in resistant hypertension. Prog Cardiovasc Dis 48:387-396, 2006