Abstract
Background: Hyperkalemia is an important clinical problem that is associated with significant lifethreatening complications. Several conditions are associated with increased risk for hyperkalemia such as chronic kidney disease, diabetes mellitus, heart failure, and the use of renin-angiotensin-aldosterone system (RAAS) inhibitors.
Objective: The purpose of this review is to present and critically discuss treatment options for the management of hyperkalemia.
Method: A comprehensive review of the literature was performed to identify studies assessing the drug-induced management of hyperkalemia.
Results: The management of chronic hyperkalemia seems to be challenging and includes a variety of traditional interventions, such as restriction in the intake of the dietary potassium, loop diuretics or sodium polystyrene sulfonate. In the last few years, several new agents have emerged as promising options to reduce potassium levels in hyperkalemic patients. Patiromer and sodium zirconium cyclosilicate 9 (ZS-9) have been examined in hyperkalemic patients and were found to be efficient and safe. Importantly, the efficacy of these novel drugs might allow the continuation of the use of RAAS inhibitors, morbidity- and mortality-wise beneficial class of drugs in the setting of chronic kidney disease and heart failure.
Conclusion: Data support that the recently emerged patiromer and ZS-9 offer significant hyperkalemia-related benefits. Larger trials are needed to unveil the impact of these drugs in other patients’ subpopulations, as well.
Keywords: Hyperkalemia, MRAs, sodium polystyrene sulfonate, patiromer, zirconium cyclosilicate 9, RAAS.
[1]
Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004; 351(6): 585-92.
[2]
Palmer BF. A physiologic-based approach to the evaluation of a patient with hyperkalemia. Am J Kidney Dis 2010; 56(2): 387-93.
[3]
Fleet JL, Shariff SZ, Gandhi S, Weir MA, Jain AK, Garg AX. Validity of the International Classification of Diseases 10th revision code for hyperkalaemia in elderly patients at presentation to an emergency department and at hospital admission. BMJ Open 2012; 2(6): e002011.
[4]
Drawz PE, Babineau DC, Rahman M. Metabolic complications in elderly adults with chronic kidney disease. J Am Geriatr Soc 2012; 60(2): 310-5.
[5]
Sarafidis PA, Blacklock R, Wood E, et al. Prevalence and factors associated with hyperkalemia in predialysis patients followed in a low-clearance clinic. Clin J Am Soc Nephrol 2012; 7(8): 1234-41.
[6]
Drion I, Joosten H, Dikkeschei LD, Groenier KH, Bilo HJ. eGFR and creatinine clearance in relation to metabolic changes in an unselected patient population. Eur J Intern Med 2009; 20(7): 722-7.
[7]
Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med 2009; 169(12): 1156-62.
[8]
Hayes J, Kalantar-Zadeh K, Lu JL, Turban S, Anderson JE, Kovesdy CP. Association of hypo- and hyperkalemia with disease progression and mortality in males with chronic kidney disease: the role of race. Nephron Clin Pract 2012; 120(1): c8-c16.
[9]
Korgaonkar S, Tilea A, Gillespie BW, et al. Serum potassium and outcomes in CKD: insights from the RRI-CKD cohort study. Clin J Am Soc Nephrol 2010; 5(5): 762-9.
[10]
Susantitaphong P, Sewaralthahab K, Balk EM, Eiam-ong S, Madias NE, Jaber BL. Efficacy and safety of combined vs. single renin-angiotensin-aldosterone system blockade in chronic kidney disease: a meta-analysis. Am J Hypertens 2013; 26(3): 424-41.
[11]
Kovesdy CP. Management of hyperkalaemia in chronic kidney disease. Nat Rev Nephrol 2014; 10(11): 653-62.
[13]
KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney inter 2013. 3: 1-150.
[14]
James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311(5): 507-20.
[15]
McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33(14): 1787-847.
[16]
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62(16): e147-239.
[17]
Raebel MA. Hyperkalemia associated with use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Cardiovasc Ther 2012; 30(3): e156-66.
[18]
K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004; 43(5)(Suppl. 1): S1-S290.
[19]
Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Huang IZ. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J 2011; 32(7): 820-8.
[20]
Faselis C, Boutari C, Doumas M, Imprialos K, Stavropoulos K, Kokkinos P. Novel drugs for hypertension and heart failure: struggling for a place under the sun. Curr Pharm Des 2017; 23(10): 1540-50.
[21]
Weir MR, Rolfe M. Potassium homeostasis and renin-angiotensin-aldosterone system inhibitors. Clin J Am Soc Nephrol 2010; 5(3): 531-48.
[22]
Lazich I, Bakris GL. Prediction and management of hyperkalemia across the spectrum of chronic kidney disease. Semin Nephrol 2014; 34(3): 333-9.
[23]
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341(10): 709-17.
[24]
Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015; 386(10008): 2059-68.
[25]
Oxlund CS, Henriksen JE, Tarnow L, Schousboe K, Gram J, Jacobsen IA. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J Hypertens 2013; 31(10): 2094-102.
[26]
Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351(6): 543-51.
[28]
Toto RD. Aldosterone blockade in chronic kidney disease: can it improve outcome? Curr Opin Nephrol Hypertens 2010; 19(5): 444-9.
[29]
Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 2009; 20(12): 2641-50.
[30]
Nielsen SE, Persson F, Frandsen E, et al. Spironolactone diminishes urinary albumin excretion in patients with type 1 diabetes and microalbuminuria: a randomized placebo-controlled crossover study. Diabet Med 2012; 29(8): e184-90.
[31]
Ogawa S, Takeuchi K, Mori T, Nako K, Ito S. Spironolactone further reduces urinary albumin excretion and plasma B-type natriuretic peptide levels in hypertensive type II diabetes treated with angiotensin-converting enzyme inhibitor. Clin Exp Pharmacol Physiol 2006; 33(5-6): 477-9.
[32]
Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care 2005; 28(9): 2106-12.
[33]
Saklayen MG, Gyebi LK, Tasosa J, Yap J. Effects of additive therapy with spironolactone on proteinuria in diabetic patients already on ACE inhibitor or ARB therapy: results of a randomized, placebo-controlled, double-blind, crossover trial. J Investig Med 2008; 56(4): 714-9.
[34]
Schjoedt KJ, Rossing K, Juhl TR, et al. Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int 2005; 68(6): 2829-36.
[35]
Schjoedt KJ, Rossing K, Juhl TR, et al. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int 2006; 70(3): 536-42.
[36]
van den Meiracker AH, Baggen RG, Pauli S, et al. Spironolactone in type 2 diabetic nephropathy: Effects on proteinuria, blood pressure and renal function. J Hypertens 2006; 24(11): 2285-92.
[37]
Esteghamati A, Noshad S, Jarrah S, Mousavizadeh M, Khoee SH, Nakhjavani M. Long-term effects of addition of mineralocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: a randomized clinical trial. Nephrol Dial Transplant 2013; 28(11): 2823-33.
[38]
Momeni A, Behradmanesh MS, Kheiri S, Karami Horestani M. Evaluation of spironolactone plus hydrochlorothiazide in reducing proteinuria in type 2 diabetic nephropathy. J Renin Angiotensin Aldosterone Syst 2015; 16(1): 113-8.
[39]
Ziaee A, Abbas Vaezi A, Oveisi S, Javadi A, Hashemipour S, Kazemifar AM. Effects of additive therapy with spironolactone on albuminuria in diabetes mellitus: A pilot randomized clinical trial. Caspian J Intern Med 2013; 4(2): 648-53.
[40]
Van Buren PN, Adams-Huet B, Nguyen M, Molina C, Toto RD. Potassium handling with dual renin-angiotensin system inhibition in diabetic nephropathy. Clin J Am Soc Nephrol 2014; 9(2): 295-301.
[41]
Kato S, Maruyama S, Makino H, et al. Anti-albuminuric effects of spironolactone in patients with type 2 diabetic nephropathy: a multicenter, randomized clinical trial. Clin Exp Nephrol 2015; 19(6): 1098-106.
[42]
Epstein M, Buckalew V, Martinez F, et al. Antiproteinuric efficacy of eplerenone, enalapril, and eplerenone/enalapril combination in diabetic hypertensives with microalbuminuria. Am J Hypertens 2005; 15: 24A. [Abstract].
[43]
Bakris GL, Agarwal R, Chan JC, et al. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial. JAMA 2015; 314(9): 884-94.
[44]
Sun LJ, Sun YN, Shan JP, Jiang GR. Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy. J Diabetes Investig 2017; 8(4): 609-18.
[45]
Pitt B, Bakris GL. New potassium binders for the treatment of hyperkalemia: current data and opportunities for the future. Hypertension 2015; 66(4): 731-8.
[47]
Alfonzo AV, Isles C, Geddes C, Deighan C. Potassium disorders--clinical spectrum and emergency management. Resuscitation 2006; 70(1): 10-25.
[48]
Sterns RH, Grieff M, Bernstein PL. Treatment of hyperkalemia: something old, something new. Kidney Int 2016; 89(3): 546-54.
[49]
Schafers S, Naunheim R, Vijayan A, Tobin G. Incidence of hypoglycemia following insulin-based acute stabilization of hyperkalemia treatment. J Hosp Med 2012; 7(3): 239-42.
[50]
Elliott MJ, Ronksley PE, Clase CM, Ahmed SB, Hemmelgarn BR. Management of patients with acute hyperkalemia. CMAJ 2010; 182(15): 1631-5.
[51]
Mahoney BA, Smith WA, Lo DS, Tsoi K, Tonelli M, Clase CM. Emergency interventions for hyperkalaemia. Cochrane Database Syst Rev 2005; (2): CD003235.
[52]
Blumberg A, Weidmann P, Ferrari P. Effect of prolonged bicarbonate administration on plasma potassium in terminal renal failure. Kidney Int 1992; 41(2): 369-74.
[53]
Gutierrez R, Schlessinger F, Oster JR, Rietberg B, Perez GO. Effect of hypertonic versus isotonic sodium bicarbonate on plasma potassium concentration in patients with end-stage renal disease. Miner Electrolyte Metab 1991; 17(5): 297-302.
[54]
Sterns RH, Rojas M, Bernstein P, Chennupati S. Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective? J Am Soc Nephrol 2010; 21(5): 733-5.
[55]
Pitt B, Rossignol P. Potassium lowering agents: Recommendations for physician and patient education, treatment reappraisal, and serial monitoring of potassium in patients with chronic hyperkalemia. Pharmacol Res 2017; 118: 2-4.
[56]
Scherr L, Ogden DA, Mead AW, Spritz N, Rubin AL. Management of hyperkalemia with a cation-exchange resin. N Engl J Med 1961; 264: 115-9.
[57]
Evans BM, Jones NC, Milne MD, Yellowlees H. Ion-exchange resins in the treatment of anuria. Lancet 1953; 265(6790): 791-5.
[59]
Harel Z, Harel S, Shah PS, Wald R, Perl J, Bell CM. Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review. Am J Med 2013; 126(3): 264.e9-264.e24.
[60]
Chernin G, Gal-Oz A, Ben-Assa E, et al. Secondary prevention of hyperkalemia with sodium polystyrene sulfonate in cardiac and kidney patients on renin-angiotensin-aldosterone system inhibition therapy. Clin Cardiol 2012; 35(1): 32-6.
[61]
Lepage L, Dufour AC, Doiron J, et al. Randomized Clinical Trial of Sodium Polystyrene Sulfonate for the Treatment of Mild Hyperkalemia in CKD. Clin J Am Soc Nephrol 2015; 10(12): 2136-42.
[62]
Thompson CA. FDA approves patiromer for nonemergent hyperkalemia. Am J Health Syst Pharm 2015; 72(23): 2006.
[63]
Li L, Harrison SD, Cope MJ, et al. Mechanism of action and pharmacology of patiromer, a nonabsorbed cross-linked polymer that lowers serum potassium concentration in patients with hyperkalemia. J Cardiovasc Pharmacol Ther 2016; 21(5): 456-65.
[64]
Sterns RH, Rojas M, Bernstein P, Chennupati S. Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective? J Am Soc Nephrol 2010; 21(5): 733-5.
[65]
Fordtran JS, Locklear TW. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating. Am J Dig Dis 1966; 11(7): 503-21.
[66]
Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 2015; 372(3): 211-21.
[67]
Bakris GL, Pitt B, Weir MR, et al. Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: the AMETHYST-DN randomized clinical trial. JAMA 2015; 314(2): 151-61.
[68]
Fulton TB. Diffusion and transport across cell membranes [lecture].Available at http://biochemistry2.ucsf.edu/programs/ptf/prologue %20links/Diff%20&%20Trans%20Membranes.pdf Accessed July 21, 2018.
[69]
Stavros F, Yang A, Leon A, Nuttall M, Rasmussen HS. Characterization of structure and function of ZS-9, a K+ selective ion trap. PLoS One 2014; 9(12): e114686.
[70]
Bakris GL, Pitt B, Weir MR, et al. Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial. JAMA 2015; 314(2): 151-61.
[71]
Bushinsky DA, Williams GH, Pitt B, et al. Patiromer induces rapid and sustained potassium lowering in patients with chronic kidney disease and hyperkalemia. Kidney Int 2015; 88(6): 1427-33.
[72]
Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 2015; 372(3): 211-21.
[73]
Pitt B, Bakris GL, Bushinsky DA, et al. Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors. Eur J Heart Fail 2015; 17(10): 1057-65.
[74]
Weir MR, Mayo MR, Garza D, et al. Effectiveness of patiromer in the treatment of hyperkalemia in chronic kidney disease patients with hypertension on diuretics. J Hypertens 2017; 35(Suppl. 1): S57-63.
[75]
Weir MR, Bakris GL, Gross C, et al. Treatment with patiromer decreases aldosterone in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors. Kidney Int 2016; 90(3): 696-704.
[76]
Bushinsky DA, Spiegel DM, Gross C, et al. Effect of Patiromer on Urinary Ion Excretion in Healthy Adults. Clin J Am Soc Nephrol 2016; 11(10): 1769-76.
[77]
Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Huang IZ. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J 2011; 32(7): 820-8.
[78]
Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med 2015; 372(3): 222-31.
[79]
Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA 2014; 312(21): 2223-33.
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