Background: Aldosterone antagonists have proven efficacy for management of resistant hypertension and proteinuria reduction; however, they are not widely used due to risk of hyperkalemia. This study assesses the risk factors for hyperkalemia in patients with chronic kidney disease (CKD) and resistant hypertension whose blood pressure (BP) is reduced to a guideline goal. Methods: This is a two-center study conducted in university-based hypertension clinics directed by clinical hypertension specialists. Forty-six patients with resistant hypertension and stages 2 or 3 CKD (mean estimated glomerular filtration rate (eGFR) 56.5 ± 16.2 ml/min/1.73 m2) were evaluated for safety and efficacy of aldosterone blockade added to preexisting BP-lowering regimens. All patients were on three mechanistically complementary antihypertensive agents including a diuretic and a renin-angiotensin system blocker. Patients were evaluated after a median of 45 treatment days. The primary endpoint was change in systolic BP. Secondary endpoints included change in serum potassium, creatinine, eGFR, diastolic BP and tolerability. Results: The mean age of the patients studied was 64.9 ± 10.7 years, all were obese and 86% had type 2 diabetes, with 82% being African-American. Addition of aldosterone antagonism yielded a further mean reduction in systolic BP of 14.7 ± 5.1 mm Hg (p = 0.001). Females with BMI >30 and those with a baseline systolic BP >160 mm Hg were more likely to have a greater BP reduction to aldosterone antagonism. In total, 39% of the patients had a >30% decrease in eGFR when the BP goal was achieved. The mean increase in serum potassium was 0.4 mEq/l above baseline (p = 0.001), with 17.3% manifesting hyperkalemia, i.e. serum potassium >5.5 mEq/l. Predictors of hyperkalemia included a baseline eGFR of ≤45 ml/min/1.73 m2 in whom serum potassium was >4.5 mEq/l on appropriately dosed diuretics. Contributing risks in this subgroup included a systolic BP reduction of >15 mm Hg associated with an eGFR fall of >30%. Conclusion: Aldosterone antagonism is effective and safe for achieving a BP goal among people with diabetic nephropathy when added to a triple antihypertensive regimen that includes a blocker of the renin-angiotensin system and an appropriately selected and dosed diuretic. Caution is advised when using aldosterone blockade for BP control in people with advanced stage 3 nephropathy with a serum potassium of >4.5 mEq/l for safety reasons.

1.
Pimenta E, Calhoun DA: Resistant hypertension and aldosteronism. Curr Hypertens Rep 2007;9:353–359.
2.
Sarafidis PA, Bakris GL: Resistant hypertension: an overview of evaluation and treatment. J Am Coll Cardiol 2008;52:1749–1757.
3.
Brown NJ: Aldosterone and end-organ damage. Curr Opin Nephrol Hypertens 2005;14:235–241.
4.
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–717.
5.
Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JF, Sever PS, Thom SM: British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ 2004;328:634–640.
6.
Chapman N, Dobson J, Wilson S, Dahlof B, Sever PS, Wedel H, Poulter NR: Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007;49:839–845.
7.
Epstein M, Williams GH, Weinberger M, Lewin A, Krause S, Mukherjee R, Patni R, Beckerman B: Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol 2006;1:940–951.
8.
Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Tarnow L, Rossing P, Parving HH: Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int 2006;70:536–542.
9.
Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ: Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis 2008;51:199–211.
10.
Pimenta E, Gaddam KK, Pratt-Ubunama MN, Nishizaka MK, Cofield SS, Oparil S, Calhoun DA: Aldosterone excess and resistance to 24-hour blood pressure control. J Hypertens 2007;25:2131–2137.
11.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–2572.
12.
Pitt B, Bakris G, Ruilope LM, DiCarlo L, Mukherjee R: Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation 2008;118:1643–1650.
13.
Bakris GL, Weir MR: Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med 2000;160:685–693.
14.
Kidney Disease Outcomes Quality Initiative (K/DOQI): K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004;43(suppl 1):S1–S290.
15.
Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, Wang X, Maggioni A, Budaj A, Chaithiraphan S, Dickstein K, Keltai M, Metsarinne K, Oto A, Parkhomenko A, Piegas LS, Svendsen TL, Teo KK, Yusuf S: Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547–553.
16.
Ahuja TS, Freeman D Jr, Mahnken JD, Agraharkar M, Siddiqui M, Memon A: Predictors of the development of hyperkalemia in patients using angiotensin-converting enzyme inhibitors. Am J Nephrol 2000;20:268–272.
17.
Bianchi S, Bigazzi R, Campese VM: Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study. Am J Kidney Dis 2005;46:45–51.
18.
Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ: Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker. Clin J Am Soc Nephrol 2006;1:256–262.
19.
Gonzaga CC, Calhoun DA: Resistant hypertension and hyperaldosteronism. Curr Hypertens Rep 2008;10:496–503.
20.
Fisher ND, Hurwitz S, Ferri C, Jeunemaitre X, Hollenberg NK, Williams GH: Altered adrenal sensitivity to angiotensin II in low-renin essential hypertension. Hypertension 1999;34:388–394.
21.
Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P: Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 2002;40:892–896.
22.
Shankar RR, Ferrari P, Dick B, Ambrosius WT, Eckert GJ, Pratt JH: Activity of 11β-hydroxysteroid dehydrogenase type 2 in normotensive blacks and whites. Ethn Dis 2005;15:407–410.
23.
MacGregor GA, Markandu ND, Rotellar C, Smith SJ, Sagnella GA: Different effect of nifedipine in normotensive and hypertensive individuals: a functional anomaly of vascular smooth muscle in essential hypertension (in Spanish)? Rev Esp Cardiol 1983;36:473–477.
24.
Krug AW, Vleugels K, Schinner S, Lamounier-Zepter V, Ziegler CG, Bornstein SR, Ehrhart-Bornstein M: Human adipocytes induce an ERK1/2 MAP kinases-mediated upregulation of steroidogenic acute regulatory protein (StAR) and an angiotensin II-sensitization in human adrenocortical cells. Int J Obes (Lond) 2007;31:1605–1616.
25.
Arima S: Aldosterone and the kidney: rapid regulation of renal microcirculation. Steroids 2006;71:281–285.
26.
Loutzenhiser R, Griffin KA, Bidani AK: Systolic blood pressure as the trigger for the renal myogenic response: protective or autoregulatory? Curr Opin Nephrol Hypertens 2006;15:41–49.
27.
Bomback AS, Klemmer PJ: Interaction of aldosterone and extracellular volume in the pathogenesis of obesity-associated kidney disease: a narrative review. Am J Nephrol 2009;30:140–146.
28.
Epstein M: Hyperkalemia as a constraint to therapy with combination renin-angiotensin system blockade: the elephant in the room. J Clin Hypertens (Greenwich) 2009;11:55–60.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.