Hyperkalemia Associated with Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers

Cardiovascular Therapeutics

Volumn 30, Issue 3, 2012, Pages

  Raebel, Marsha A ^a,b  

^a KAISER PERMANENTE   (United States)

^b UNIVERSITY OF COLORADO   (United States)

Author keywords

Angiotensin receptor blocker (ARB); Angiotensin converting enzyme inhibitor (ACEi); Hyperkalemia; Hyperpotassemia

Indexed keywords

ANGIOTENSIN RECEPTOR ANTAGONIST; BICARBONATE; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; FUROSEMIDE; GLUCONATE CALCIUM; GLUCOSE; INSULIN; POTASSIUM; SALBUTAMOL; SPIRONOLACTONE;

CHRONIC KIDNEY FAILURE; CLINICAL FEATURE; CLINICAL TRIAL; DRUG INDUCED DISEASE; GLOMERULUS FILTRATION RATE; HEART ARRHYTHMIA; HUMAN; HYPERKALEMIA; KIDNEY; PATHOPHYSIOLOGY; POTASSIUM BLOOD LEVEL; PRIORITY JOURNAL; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; RISK FACTOR;

ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKERS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; ANIMALS; BIOLOGICAL MARKERS; HUMANS; HYPERKALEMIA; KIDNEY; POTASSIUM; RENIN-ANGIOTENSIN SYSTEM; RISK ASSESSMENT; RISK FACTORS; UP-REGULATION;

EID: 84860617929     PISSN: 17555914     EISSN: 17555922     Source Type: Journal    
DOI: 10.1111/j.1755-5922.2010.00258.x     Document Type: Review

References (107)

1. Ambrosioni E, Borghi C, Magnani B. The effect of the angio-tensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995;332:80-85.
2. 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;348:1309-1321.
3. Brenner BM, Cooper ME, deZeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869.
4. Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomized trial against atenolol. Lancet 2002;359:1004-1010.
5. HOPE (Heart Outcomes Prevention Evaluation) Study Investigators. Effects of an antiogensin converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-153.
6. Chobanian AV, Bakris GI, Black HR, Cushman WC, Green LA, Izzo JL. The Seventh Report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA 2003;39(Suppl 1):S94-S98.
7. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised trial-the losartan heart failure survival study ELITE II. Lancet 2000;355:1582-1587.
8. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675.
9. McMurray JJV, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: The CHARM-Added trial. Lancet 2003;362:767-771.
10. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet 1995;345:669-685.
11. Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-1906.
12. Swedberg K, Held P, Kjekshus J, Rasmussen K, Ryden L, Wedel H. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 1992;327:678-684.
13. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-828.
14. Kober L, Torp-Pedersen C, Carlsen JE. A clinical trial of the angiotensin-converting enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333:1670-1676.
15. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-860.
16. Pfeffer MA, Braunwald E, Moye LA. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the Survival and Ventricular Enlargement trial. N Engl J Med 1992;327:669-677.
17. Gruppo Italiano per lo Studio della Sopravvivenza nell'infart Miocardico. GISSI-3: Effects of lisinopril and transfermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after myocardial infarction. Lancet 1994;343:1115-1122.
18. Desai AS, Swedberg K, McMurray JJV, et al. Incidence and predictors of hyperkalemia in patients with heart failure: An analysis of the CHARM program. J Am Coll Cardiol 2007;50:1959-1966.
19. Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: Pathophysiology and indications. Kidney Int 2005;67:799-812.
20. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997;349:1857-1863.
21. Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: A meta-analysis of patient-level data. Ann Intern Med 2001;135:73-87.
22. Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G. Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial: Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN): Ramipril Efficacy in Nephropathy. Lancet 1998;352:1252-1256.
23. Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med 2006;354:131-140.
24. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline update for the diagnosis and management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association task force on practice guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation 2005;112:e154-e235.
25. Baker WL, Coleman CI, Kluger J, et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers for ischemic heart disease. Ann Intern Med 2009;151:861-871.
26. Kostis JB, Shelton B, Gosselin G, et al. Adverse effects of enalapril in the studies of left ventricular dysfunction (SOLVD). Am Heart J 1996;131:350-355.
27. 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.
28. Palmer BF. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: What to do if the serum creatinine and/or serum potassium concentration rises. Nephrol Dial Transplant 2003;18:1973-1975.
29. Ramadan FH, Masoodi N, El-Solh AA. Clinical factors associate with hyperkalemia in patients with congestive heart failure. J Clin Pharm Therapeutics 2005;30:233-239.
30. Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med 2009;169:1156-1162.
31. Antrobus JH, Doolan LA, Bethune DW. Hyperkalemia and myocardial atonia following cardioselective beta-blockade. J Cardiothorac Vasc Anesth 1993;7:76-78.
32. Mahoney BA, Smith WAD, Lo DS, Tsoi K, Tonelli M, Clase C. Emergency interventions for hyperkalaemia. Cochrane Database of Systematic Reviews 1, 2006 2005, Issue 2, Article no. CD003235. doi:
33. Schaefer TJ, Wolford RW. Disorders of potassium. Emerg Med Clin N Am 2005;23:723-747.
34. HCUPNet: Healthcare Cost and Utilization Project. Rockville, MD : Agency for Healthcare Research and Quality, 2010.
35. Maddirala S, Khan A, Vincent A, Lau K. Effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on serum potassium levels and renal function in ambulatory outpatients: Risk factors analysis. Am J Med Sci 2008;336:330-335.
36. Schepkens H, Vanholder R, Billiouw JM, Lameire N. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: An analysis of 25 cases. Am J Med 2001;110:438-441.
37. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004;351:585-592.
38. Bakris G, Williams M, Dworkin L. Preserving renal function in adults with hypertension and diabetes: A consensus approach. Am J Kidney Dis 2000;36:646-661.
39. 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.
40. Ramadan FH, Masoodi N, El-Solh AA. Clinical factors associate with hyperkalemia in patients with congestive heart failure. J Clin Pharm Therapeutics 2005;30:233-239.
41. Weinberg JM, Appel LJ, Bakris G, et al. Risk of hyperkalemia in nondiabetic patients with chronic kidney disease receiving antihypertensive therapy. Arch Intern Med 2009;169:1587-1594.
42. Saseen JJ, Maclaughlin EJ. Hypertension. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy. A pathophysiologic approach, 7th ed. New York : McGraw Hill Medical, 2008;139-171.
43. George AL Jr., Neilson EG. Cellular and molecular biology of the kidney (chapter). In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison's principles of internal medicine, 17th ed. New York : McGraw Hill Medical, 2008. Available from: [Assessed 6 January 2011.
44. Young DB, Smith MJ Jr., Jackson TE, Scott RE. Multiplicative interaction between angiotensin II and K concentration in stimulation of aldosterone. Am J Physiol 1984;247:E328-E335.
45. Pratt JH, Rothrock JK, Dominguez JH. Evidence that angiotensin-II and potassium collaborate to increase cytosolic calcium and stimulate the secretion of aldosterone. Endocrinology 1989;125:2463-2439.
46. Shier DN, Kusano E, Stoner GD, Franco-Saenz R, Mulrow PJ. Production of renin, angiotensin II, and aldosterone by adrenal explant cultures: Response to potassium and converting enzyme inhibition. Endocrinology 1989;125:486-491.
47. Bakris GL, Siomos M, Richardson D, et al. ACE inhibition or angiotensin receptor blockade: Impact on potassium in renal failure VAL-K Study Group. Kidney Int 2000;58:2084-2092.
48. Johnson ES, Weinstein JR, Thorp ML, et al. Predicting the risk of hyperkalemia in patients with chronic kidney disease starting lisinopril. Pharmacoepidemiol Drug Saf 2010;19:266-272.
49. Palmer BF. Renal dysfunction complicating the treatment of hypertension. N Engl J Med 2002;347:1256-1261.
50. Sevastos N, Theodossiades G, Archimandritis AJ. Pseudohyperkalemia in serum: A new insight into an old phenomenon. Clin Med Res 2008;6:30-32.
51. Williams ME. Endocrine crises. Hyperkalemia. Crit. Care Clin 1991;7:155-174.
52. Antrobus JH, Doolan LA, Bethune DW. Hyperkalemia and myocardial atonia following cardioselective beta-blockade. J Cardiothorac Vasc Anesth 1993;7:76-78.
53. Mount DB, Zandi-Nejad K. Disorders of potassium balance. In: Brenner BM, Levine SA, editors. Brenner and Rector's The Kidney, 8th ed. Philadelphia : Saunders Elsevier, 2007;547-587.
54. Freeman K, Feldman JA, Mitchell P, et al. Effects of presentation and electrocardiogram on time to treatment of hyperkalemia. Acad Emerg Med 2008;15:239-249.
55. Rastegar A, Soleimani M, Rastergar A. Hypokalaemia and hyperkalaemia. Postgrad Med J 2001;77:759-764.
56. Charytan D, Goldfarb DS. Indications for hospitalization of patients with hyperkalemia. Arch Intern Med 2000;160:1605-1611.
57. Acker CG, Johnson JP, Palevsky PM, Greenberg A. Hyperkalemia in hospitalized patients: Causes, adequacy of treatment, and results of an attempt to improve physician compliance with published therapy guidelines. Arch Intern Med 1998;158:917-924.
58. Raebel MA, Ross C, Xu S, et al. Diabetes and drug-associated hyperkalemia: Effect of serum potassium monitoring. J Gen Intern Med 2010;25:326-333 DOI:
59. Perazella MA. Drug-induced hyperkalemia: Old culprits and new offenders. Am J Med 2000;109:307-314.
60. Rimmer JM, Horn JF, Gennari FJ. Hyperkalemia as a complication of drug therapy. Arch Intern Med 1987;147:867-869.
61. Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. Arch Intern Med 1998;158:26-32.
62. Massie BM, Armstrong PW, Cleland JGF, et al. Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: Results from the ATLAS trial. Arch Intern Med 2001;161:165-171.
63. de Denus S, Tardif J-C, White M, Bourassa MG, Racine N, Levesque S, et al. Quantification of the risk and predictors of hyperkalemia in patients with left ventricular dysfunction: A retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) trials. Am Heart J 2006;152:705-712.
64. Raebel MA, Ross C, Cheetham C, et al. Increasingly restrictive definitions of hyperkalemia outcomes in a database study: Effect on incidence estimates. Pharmacoepidemiol Drug Saf 2010;19:19-25. PMID 19937982.
65. Jarman PR, Mather HM. Diabetes may be independent risk factor for hyperkalemia. BMJ 2003;327:812.
66. Jarman PR, Kehely AM, Mather HM. Hyperkalemia in diabetes: Prevalence and associations. Postgrad Med J 1995;71:551-552.
67. Vanpee D, Swine CH. Elderly heart failure patients with drug-induced serious hyperkalemia. Aging (Milano) 2000;12:315-319.
68. Berry C, McMurray J. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone. Am J Med 2001;111:587.
69. Hurley JS, Roberts M, Solberg LI, et al. Laboratory safety monitoring of chronic medications in ambulatory care settings. J Gen Intern Med 2005;20:331-333.
70. Raebel MA, Lyons EE, Andrade SE, et al. Laboratory monitoring of drugs at initiation of therapy in ambulatory care. J Gen Intern Med 2005;20:1120-1126.
71. Raebel MA, McClure DL, Simon SR, et al. Laboratory monitoring of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in ambulatory patients. Pharmacoepidemiol Drug Saf 2007;16:55-64.
72. Raebel MA, Lyons EE, Bodily MA, et al. Improving laboratory monitoring at initiation of drug therapy: A randomized trial. Arch Intern Med 2005;165:2395-2401.
73. Raebel MA, Chester EA, Newsom EE, et al. Randomized trial to improve laboratory safety monitoring of drug therapy in ambulatory patients. Pharmacotherapy 2006;26:619-626.
74. Feldstein AC, Smith DH, Perrin N, et al. Improved therapeutic monitoring with several interventions: A randomized trial. Arch Intern Med 2006;166:1848-1854.
75. Palen TE, Raebel MA, Lyons E, Magid DJ. Evaluation of laboratory monitoring alerts within a computerized physician order entry system for medications orders. Am J Manag Care 2006;12:389-395.
76. Knight EL, Avorn J. Quality indicators for appropriate medication use in vulnerable elders. Ann Intern Med 2001;135:703-710.
77. NCQA. Annual monitoring for patients on persistent medications: New measure for HEDIS 2006. In: 2006. Available from: [Assessed 6 January 2011.
78. The RALES Investigators. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the randomized aldactone evaluation study [RALES]). Am J Cardiol 1996;78:902-907.
79. Hunt SA, Baker DW, Chin MH, Cinquergrani MP, Feldman AM, Francis GS, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: Executive summary. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001;38:2101-2113.
80. Moore CR, Lin JJ, O'Connor N, Halm EA. Follow-up of markedly elevated serum potassium results in the ambulatory setting: Implications for patient safety. Am J Med Qual 2006;21:115-124.
81. Brophy DF, Gehr TWB. Disorders of potassium and magnesium homeostasis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy a pathophysiologic approach, 7th ed. New York : McGraw Hill Medical, 2008;877-888.
82. Palmer BF, Levi M. Effect of aging on renal function and disease. In: Brenner BM, editor Brenner & Rector's The Kidney. Vol. 2, 5th ed. Philadelphia : W.B. Saunders, 1996;2274- 2296.
83. DeFronzo RA. Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int 1980;17:118-134.
84. Arruda J, Batlle D, Sehy J, Roseman M, Baronowski R, Kurtzman NA. Hyperkalemia and renal insufficiency: Role of selective aldosterone deficiency and tubular unresponsiveness to aldosterone. Am J Nephrol 1981;1:160-167.
85. Singer GG, Brenner BM. Fluid and electrolyte disturbances (chapter). In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison's principles of internal medicine. New York : McGraw Hill Medical, 2008. Available from: [Assessed 6 January 2011.
86. Kokko JP. Fluids and electrolytes. In: Goldman L, Ausiello D, editors. Cecil textbook of medicine, 22nd ed. Philadelphia : Saunders, 2004;685-687.
87. Institute of Medicine. Dietary reference intakes: Water, potassium, sodium, chloride, and sulfate. Available from: [Assessed 6 January 2011.
88. Cheng TO. Herbal interactions with cardiac drugs. Arch Intern Med 2000;160:870-871.
89. Mueller BA, Scott MK, Sowinski KM, Prag KA. Noni juice (Morinda citrifolia): Hidden potential for hyperkalemia? Am J Kidney Dis 2000;35:310-312.
90. Pantanowitz L. Drug-induced hyperkalemia. Am J Med 2002;112:334-335.
91. Williams CA, Goldstone F, Greenham J. Flavonoids, cinnamic acids and coumarins from the different tissues and medicinal preparations of taraxacum officinale. Phytochemistry 1996;42:121-127.
92. Perazella MA. Trimethoprim is a potassium-sparing diuretic like amiloride and causes hyperkalemia in high-risk patients. Am J Ther 1997;343-348.
93. Antoniou T, Gomes T, Juurlink DN, Loutfy MR, Glazier RH, Mamdani MM. Trimethoprim-sulfamethoxazole-induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system: A population-based study. Arch Intern Med 2010;170:1045-1049.
94. Kleyman TR, Roberts C, Ling BN. A mechanism for pentamidine-induced hyperkalemia: Inhibition of distal nephron sodium transport. Ann Intern Med 1995;122:103-106.
95. Product information: tekturna(R) oral tablets, aliskiren oral tablets. East Hanover, NJ : Novartis Pharmaceuticals Corporation, 2007.
96. Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003;289:1652-1658.
97. Chiu TF, Bullard MJ, Chen JC, Liaw SJ, Ng CJ. Rapid life-threatening hyperkalemia after addition of amiloride HCl/hydrochlorothiazide to angiotensin-converting enzyme inhibitor therapy. Ann Emerg Med 1997;30:612-615.
98. McCauley J, Murray J, Jordan M, Scantlebury V, Vivas C, Shapiro R. Labetalol-induced hyperkalemia in renal transplant recipients. Am J Nephrol 2002;22:347-351.
99. Castellino P, Simonson DC, DeFronzo RA. Adrenergic modulation of potassium metabolism during exercise in normal and diabetic humans. Am J Physiol 1987;252:E68-E76.
100. Kaplan B, Wang Z, Abecassis MM, Fryer JP, Stuart FP, Kaufman DB. Frequency of hyperkalemia in recipients of simultaneous pancreas and kidney transplants with bladder drainage. Transplantation 1996;62:1174-1175.
101. Kamel KS, Ethier JH, Quaggin S, et al. Studies to determine the basis for hyperkalemia in recipients of a renal transplant who are treated with cyclosporine. J Am Soc Nephrol 1992;2:1279-1284.
102. Zimran A, Kramer M, Plaskin M, Hershko C. Incidence of hyperkalaemia induced by indomethacin in a hospital population. BMJ (Clin Res Ed) 1985;291:107-108.
103. Palmer BF. Renal complications associated with use of nonsteroidal anti-inflammatory agents. J Investig Med 1995;43:516-533.
104. Campbell WB, Gomez-Sanchez CE, Adams BV, Schmitz JM, Itskovitz HD. Attenuation of angiotensin II- and III-induced aldosterone release by prostaglandin synthesis inhibitors. J Clin Invest 1979;64:1552-1557.
105. Kurata C, Uehara A, Sugi T, Yamazaki K. Syncope caused by nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors. Jap Circ J 1999;63:1002-1003.
106. Oster JR, Singer I, Fishman LM. Heparin-induced aldosterone suppression and hyperkalemia. Am J Med 1995;98:575-586.
107. Gheno G, Cinetto L, Savarino C, Vellar S, Carraro M, Randon M. Variations of serum potassium level and risk of hyperkalemia in inpatients receiving low-molecular-weight heparin. Eur J Clin Pharmacol 2003;59:373-377.