Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Management of hyperkalaemia consequent to mineralocorticoid-receptor antagonist therapy

Nature Reviews Nephrology volume 8, pages 691–699 (2012)Cite this article

Abstract

Mineralocorticoid-receptor antagonists (MRAs) reduce blood pressure and albuminuria in patients treated with angiotensin-converting-enzyme inhibitors or angiotensin-II-receptor blockers. The use of MRAs, however, is limited by the occurrence of hyperkalaemia, which frequently occurs in patients older than 65 years with impaired kidney function, and/or diabetes. Patients with these characteristics might still benefit from MRA therapy, however, and should not be excluded from this treatment option. This limitation raises the question of how to optimize the therapeutic use of MRAs in this population of patients. Understanding the individual variability in patients' responses to MRAs, in terms of albuminuria, blood pressure and serum potassium levels, might lead to targeted intervention. MRA use might be restricted to patients with high levels of mineralocorticoid activity, evaluated by circulating renin and aldosterone levels or renal excretion of potassium. In addition, reviewing the patient's diet and concomitant medications might prove useful in reducing the risk of developing subsequent hyperkalaemia. If hyperkalaemia does develop, treatment options exist to decrease potassium levels, including administration of calcium gluconate, insulin, β2-agonists, diuretics and cation-exchange resins. In combination with novel aldosterone blockers, these strategies might offer a rationale with which to optimize therapeutic intervention and extend the population of patients who can benefit from use of MRAs.

Key Points

  • Hyperkalaemia is a well-known adverse effect of mineralocorticoid-receptor antagonist (MRA) therapy that can cause cardiac dysfunction and even lead to premature death

  • Understanding intraindividual variability in responses to MRA therapy—in terms of albuminuria, blood pressure and serum K+ levels—might help to dissociate beneficial effects of MRAs from harmful ones

  • Identification of risk factors that predispose patients to develop hyperkalaemia and monitoring of mineralocorticoid activity might help to improve personalization of MRA therapy

  • Serum levels of K+ should be closely monitored in the first 2 weeks of MRA therapy, for example by trans-tubular potassium gradient measurement

  • Use of loop and osmotic diuretics, treatment with Na+ bicarbonate, reducing K+ intake and avoiding medications that affect K+ homeostasis might reduce the risk of hyperkalaemia during MRA therapy

  • Several pharmacological options are currently available (and others are in development) to prevent and control hyperkalaemia in patients with chronic kidney disease receiving MRAs

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Serum K+ levels increase after short-term treatment with spironolactone in patients with chronic kidney disease.

Similar content being viewed by others

References

  1. MacKinnon, M. et al. Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data. Am. J. Kidney Dis. 48, 8–20 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Werner, C. et al. RAS blockade with ARB and ACE inhibitors: current perspective on rationale and patient selection. Clin. Res. Cardiol. 97, 418–431 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. de Zeeuw, D. et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 65, 2309–2320 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. de Zeeuw, D. et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 110, 921–927 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Holtkamp, F. A. et al. Albuminuria and blood pressure, independent targets for cardioprotective therapy in patients with diabetes and nephropathy: a post hoc analysis of the combined RENAAL and IDNT trials. Eur. Heart J. 32, 1493–1499 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Ong, K. L., Cheung, B. M., Man, Y. B., Lau, C. P. & Lam, K. S. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999–2004. Hypertension 49, 69–75 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Coresh, J., Astor, B. C., Greene, T., Eknoyan, G. & Levey, A. S. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am. J. Kidney Dis. 41, 1–12 (2003).

    Article  PubMed  Google Scholar 

  8. Bomback, A. S. & Klemmer, P. J. The incidence and implications of aldosterone breakthrough. Nat. Clin. Pract. Nephrol. 3, 486–492 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Gilbert, K. C. & Brown, N. J. Aldosterone and inflammation. Curr. Opin. Endocrinol. Diabetes Obes. 17, 199–204 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Epstein, M. Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications. Am. J. Kidney Dis. 37, 677–688 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Waanders, F. et al. Aldosterone, from (patho)physiology to treatment in cardiovascular and renal damage. Curr. Vasc. Pharmacol. 9, 594–605 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Bianchi, S., Bigazzi, R. & Campese, V. M. Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study. Am. J. Kidney Dis. 46, 45–51 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Bianchi, S., Bigazzi, R. & Campese, V. M. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int. 70, 2116–2123 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Boesby, L., Elung-Jensen, T., Klausen, T. W., Strandgaard, S. & Kamper, A. L. Moderate antiproteinuric effect of add-on aldosterone blockade with eplerenone in non-diabetic chronic kidney disease. A randomized cross-over study. PLoS ONE 6, e26904 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chrysostomou, A. & Becker, G. Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease. N. Engl. J. Med. 345, 925–926 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Chrysostomou, A., Pedagogos, E., MacGregor, L. & Becker, G. J. 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. 1, 256–262 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Furumatsu, Y. et al. Effect of renin-angiotensin-aldosterone system triple blockade on non-diabetic renal disease: addition of an aldosterone blocker, spironolactone, to combination treatment with an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker. Hypertens. Res. 31, 59–67 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Epstein, M. et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin. J. Am. Soc. Nephrol. 1, 940–951 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. González, M. E. et al. Addition of spironolactone to dual blockade of renin angiotensin system dramatically reduces severe proteinuria in renal transplant patients: an uncontrolled pilot study at 6 months. Transplant. Proc. 42, 2899–2901 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Mehdi, U. F., Adams-Huet, B., Raskin, P., Vega, G. L. & Toto, R. D. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J. Am. Soc. Nephrol. 20, 2641–2650 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rachmani, R. et al. The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: a randomized controlled study. Diabet. Med. 21, 471–475 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Rossing, K., Schjoedt, K. J., Smidt, U. M., Boomsma, F. & Parving, H. H. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care 28, 2106–2112 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Sato, A., Hayashi, K. & Saruta, T. Antiproteinuric effects of mineralocorticoid receptor blockade in patients with chronic renal disease. Am. J. Hypertens. 18, 44–49 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Schjoedt, K. J. et al. Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int. 68, 2829–2836 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Schjoedt, K. J. et al. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int. 70, 536–542 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Sengul, E., Sahin, T., Sevin, E. & Yilmaz, A. Effect of spironolactone on urinary protein excretion in patients with chronic kidney disease. Ren. Fail. 31, 928–932 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Tylicki, L. et al. Triple pharmacological blockade of the renin-angiotensin-aldosterone system in nondiabetic CKD: an open-label crossover randomized controlled trial. Am. J. Kidney Dis. 52, 486–493 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. van den Meiracker, A. H. et al. Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function. J. Hypertens. 24, 2285–2292 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Sato, A., Hayashi, K., Naruse, M. & Saruta, T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 41, 64–68 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Volk, M. J., Bomback, A. S. & Klemmer, P. J. Mineralocorticoid receptor blockade in chronic kidney disease. Curr. Hypertens. Rep. 13, 282–288 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Levy, D. G., Rocha, R. & Funder, J. W. Distinguishing the antihypertensive and electrolyte effects of eplerenone. J. Clin. Endocrinol. Metab. 89, 2736–2740 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Mattu, A., Brady, W. J. & Robinson, D. A. Electrocardiographic manifestations of hyperkalemia. Am. J. Emerg. Med. 18, 721–729 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Desai, A. S. et al. Incidence and predictors of hyperkalemia in patients with heart failure: an analysis of the CHARM Program. J. Am. Coll. Cardiol. 50, 1959–1966 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Einhorn, L. M. et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch. Intern. Med. 169, 1156–1162 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Shah, K. B., Rao, K., Sawyer, R. & Gottlieb, S. S. The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure. J. Am. Coll. Cardiol. 46, 845–849 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Takaichi, K., Takemoto, F., Ubara, Y. & Mori, Y. Analysis of factors causing hyperkalemia. Intern. Med. 46, 823–829 (2007).

    Article  PubMed  Google Scholar 

  37. Meneton, P., Loffing, J. & Warnock, D. G. Sodium and potassium handling by the aldosterone-sensitive distal nephron: the pivotal role of the distal and connecting tubule. Am. J. Physiol. Renal Physiol. 287, F593–F601 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Oh, M. S. et al. A mechanism for hyporeninemic hypoaldosteronism in chronic renal disease. Metabolism 23, 1157–1166 (1974).

    Article  CAS  PubMed  Google Scholar 

  39. Schambelan, M., Stockigt, J. R. & Biglieri, E. G. Isolated hypoaldosteronism in adults. A renin-deficiency syndrome. N. Engl. J. Med. 287, 573–578 (1972).

    Article  CAS  PubMed  Google Scholar 

  40. DeFronzo, R. A. Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int. 17, 118–134 (1980).

    Article  CAS  PubMed  Google Scholar 

  41. Bakris, G. L. et al. ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. VAL-K Study Group. Kidney Int. 58, 2084–2092 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Csukas, S., Hanke, C. J., Rewolinski, D. & Campbell, W. B. Prostaglandin E2-induced aldosterone release is mediated by an EP2 receptor. Hypertension 31, 575–581 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Aull, L., Chao, H. & Coy, K. Heparin-induced hyperkalemia. DICP 24, 244–246 (1990).

    Article  CAS  PubMed  Google Scholar 

  44. Mount, D. B. & Zandi-Nejad, K. in Brenner and Rector's The Kidney (ed. Brenner, B. M.) 997–1040 (WB Saunders, Philadelphia, 2004).

    Google Scholar 

  45. Salem, M. M., Rosa, R. M. & Batlle, D. C. Extrarenal potassium tolerance in chronic renal failure: implications for the treatment of acute hyperkalemia. Am. J. Kidney Dis. 18, 421–440 (1991).

    Article  CAS  PubMed  Google Scholar 

  46. Blumberg, A., Weidmann, P., Shaw, S. & Gnädinger, M. Effect of various therapeutic approaches on plasma potassium and major regulating factors in terminal renal failure. Am. J. Med. 85, 507–512 (1988).

    Article  CAS  PubMed  Google Scholar 

  47. Rosa, R. M. et al. Adrenergic modulation of extrarenal potassium disposal. N. Engl. J. Med. 302, 431–434 (1980).

    Article  CAS  PubMed  Google Scholar 

  48. Berl, T., Katz, F. H., Henrich, W. L., de Torrente, A. & Schrier, R. W. Role of aldosterone in the control of sodium excretion in patients with advanced chronic renal failure. Kidney Int. 14, 228–235 (1978).

    Article  CAS  PubMed  Google Scholar 

  49. Schrier, R. W. & Regal, E. M. Influence of aldosterone on sodium, water and potassium metabolism in chronic renal disease. Kidney Int. 1, 156–168 (1972).

    Article  CAS  PubMed  Google Scholar 

  50. Sica, D. A. Diuretic use in renal disease. Nat. Rev. Nephrol. 8, 100–109 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Perez, G. O., Pelleya, R., Oster, J. R., Kem, D. C. & Vaamonde, C. A. Blunted kaliuresis after an acute potassium load in patients with chronic renal failure. Kidney Int. 24, 656–662 (1983).

    Article  CAS  PubMed  Google Scholar 

  52. Preston, R. A. et al. Mechanisms of impaired potassium handling with dual renin-angiotensin-aldosterone blockade in chronic kidney disease. Hypertension 53, 754–760 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Musso, C. G. Potassium metabolism in patients with chronic kidney disease (CKD), Part I: patients not on dialysis (stages 3–4). Int. Urol. Nephrol. 36, 465–468 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Miao, Y. et al. Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. Diabetologia 54, 44–50 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. 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. 43, S1–290 (2004).

  56. Gennari, F. J. Hypokalemia. N. Engl. J. Med. 339, 451–458 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Raymond, C. B., Sood, A. R. & Wazny, L. D. Treatment of hyperkalemia in patients with chronic kidney disease–a focus on medications. CANNT J. 20, 49–53; quiz 54–55 (2010).

    PubMed  Google Scholar 

  58. Pitt, B. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N. Engl. J. Med. 341, 709–717 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Pitt, B., Bakris, G., Ruilope, L. M., DiCarlo, L. & Mukherjee, R., EPHESUS Investigators. Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation 118, 1643–1650 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Zannad, F. et al. Eplerenone in patients with systolic heart failure and mild symptoms. N. Engl. J. Med. 364, 11–21 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Take, C., Ikeda, K., Kurasawa, T. & Kurokawa, K. Increased chloride reabsorption as an inherited renal tubular defect in familial type II pseudohypoaldosteronism. N. Engl. J. Med. 324, 472–476 (1991).

    Article  CAS  PubMed  Google Scholar 

  62. Chacko, M., Fordtran, J. S. & Emmett, M. Effect of mineralocorticoid activity on transtubular potassium gradient, urinary [K]/[Na] ratio, and fractional excretion of potassium. Am. J. Kidney Dis. 32, 47–51 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Choi, M. J. & Ziyadeh, F. N. The utility of the transtubular potassium gradient in the evaluation of hyperkalemia. J. Am. Soc. Nephrol. 19, 424–426 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Armanini, D. et al. Aldosterone-receptor deficiency in pseudohypoaldosteronism. N. Engl. J. Med. 313, 1178–1181 (1985).

    Article  CAS  PubMed  Google Scholar 

  65. Kater, C. E. & Biglieri, E. G. Disorders of steroid 17 α-hydroxylase deficiency. Endocrinol. Metab. Clin. North Am. 23, 341–357 (1994).

    Article  CAS  PubMed  Google Scholar 

  66. Clark, B. A., Brown, R. S. & Epstein, F. H. Effect of atrial natriuretic peptide on potassium-stimulated aldosterone secretion: potential relevance to hypoaldosteronism in man. J. Clin. Endocrinol. Metab. 75, 399–403 (1992).

    CAS  PubMed  Google Scholar 

  67. Eudy, R. J. et al. The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism. J. Transl. Med. 9, 180 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ramsay, L., Harrison, I., Shelton, J. & Tidd, M. Relative potency of prorenoate and spironolactone in normal man. Clin. Pharmacol. Ther. 18, 391–400 (1975).

    Article  CAS  PubMed  Google Scholar 

  69. Ramsay, L. E., Shelton, J. R. & Tidd, M. J. The pharmacodynamics of single doses of prorenoate potasssium and spironolactone in fludrocortisone treated normal subjects. Br. J. Clin. Pharmacol. 3, 475–482 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Edmonds, C. J. & Wilson, G. M. The action of hydroflumethiazide in relation to adrenal steroids and potassium loss. Lancet 1, 505–509 (1960).

    Article  CAS  PubMed  Google Scholar 

  71. Eggert, R. C. Spironolactone diuresis in patients with cirrhosis and ascites. Br. Med. J. 4, 401–403 (1970).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kamel, K. S., Ethier, J. H., Richardson, R. M., Bear, R. A. & Halperin, M. L. Urine electrolytes and osmolality: when and how to use them. Am. J. Nephrol. 10, 89–102 (1990).

    Article  CAS  PubMed  Google Scholar 

  73. Levine, D., Ramsay, L., Auty, R., Branch, R. & Tidd, M. Antagonism of endogenous mineralocorticoids in normal subjects by prorenoate potassium and spironolactone. Eur. J. Clin. Pharmacol. 09, 381–386 (1976).

    Article  CAS  PubMed  Google Scholar 

  74. McInnes, G. T., Perkins, R. M., Shelton, J. R. & Harrison, I. R. Spironolactone dose-response relationships in healthy subjects. Br. J. Clin. Pharmacol. 13, 513–518 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ethier, J. H., Kamel, K. S., Magner, P. O., Lemann, J. Jr & Halperin, M. L. The transtubular potassium concentration in patients with hypokalemia and hyperkalemia. Am. J. Kidney Dis. 15, 309–315 (1990).

    Article  CAS  PubMed  Google Scholar 

  76. Rodríguez-Soriano, J., Ubetagoyena, M. & Vallo, A. Transtubular potassium concentration gradient: a useful test to estimate renal aldosterone bio-activity in infants and children. Pediatr. Nephrol. 4, 105–110 (1990).

    Article  PubMed  Google Scholar 

  77. Mayan, H., Kantor, R. & Farfel, Z. Trans-tubular potassium gradient in patients with drug-induced hyperkalemia. Nephron 89, 56–61 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Musso, C. et al. Correlation between creatinine clearance and transtubular potassium concentration gradient in old people and chronic renal disease patients. Saudi J. Kidney Dis. Transpl. 18, 551–555 (2007).

    PubMed  Google Scholar 

  79. Zettle, R. M. et al. Renal potassium handling during states of low aldosterone bio-activity: a method to differentiate renal and non-renal causes. Am. J. Nephrol. 7, 360–366 (1987).

    Article  CAS  PubMed  Google Scholar 

  80. Fujii, H. et al. Life-threatening hyperkalemia during a combined therapy with the angiotensin receptor blocker candesartan and spironolactone. Kobe J. Med. Sci. 51, 1–6 (2005).

    PubMed  Google Scholar 

  81. Lim, Y. S. et al. Monitoring of transtubular potassium gradient in the diuretic management of patients with cirrhosis and ascites. Liver 22, 426–432 (2002).

    Article  PubMed  Google Scholar 

  82. Gennari, F. J. & Segal, A. S. Hyperkalemia: an adaptive response in chronic renal insufficiency. Kidney Int. 62, 1–9 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Raebel, M. A. et al. Diabetes and drug-associated hyperkalemia: effect of potassium monitoring. J. Gen. Intern. Med. 25, 326–333 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Weir, M. R. & Rolfe, M. Potassium homeostasis and renin-angiotensin-aldosterone system inhibitors. Clin. J. Am. Soc. Nephrol. 5, 531–548 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Lambers Heerspink, H. J., Laverman, G. D., Lewis, J., Parving, H.-H. & de Zeeuw, D. Both hypokalemia and hyperkalemia predict cardiovascular risk during blood pressure lowering therapy in patients with diabetes and nephropathy [abstract # SA-PO2407, 663A]. J. Am. Soc. Nephrol. 21, (2010).

  86. Juurlink, D. N. et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N. Engl. J. Med. 351, 543–551 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Saudan, P. et al. Safety of low-dose spironolactone administration in chronic haemodialysis patients. Nephrol. Dial. Transplant. 18, 2359–2363 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. 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. 78, 902–907 (1996).

  89. Schjoedt, K. J., Andersen, S., Rossing, P., Tarnow, L. & Parving, H. H. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 47, 1936–1939 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Fagart, J. et al. A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule. J. Biol. Chem. 285, 29932–29940 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Nariai, T. et al. SM-368229, a novel selective and potent non-steroidal mineralocorticoid receptor antagonist with strong urinary Na+ excretion activity. J. Pharmacol. Sci. 115, 346–353 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Nariai, T. et al. Antihypertensive and cardiorenal protective effects of SM-368229, a novel mineralocorticoid receptor antagonist, in aldosterone/salt-treated rats. Pharmacology 89, 44–52 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Nariai, T. et al. SM-368229, a novel promising mineralocorticoid receptor antagonist, shows anti-hypertensive efficacy with minimal effect on serum potassium level in rats. J. Cardiovasc. Pharmacol. 59, 458–464 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. Lea, W. B. et al. Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt. Kidney Int. 75, 936–944 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Rigel, D. F. et al. Pharmacodynamic and pharmacokinetic characterization of the aldosterone synthase inhibitor FAD286 in two rodent models of hyperaldosteronism: comparison with the 11beta-hydroxylase inhibitor metyrapone. J. Pharmacol. Exp. Ther. 334, 232–243 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Amar, L. et al. Aldosterone synthase inhibition with LCI699: a proof-of-concept study in patients with primary aldosteronism. Hypertension 56, 831–838 (2010).

    Article  CAS  PubMed  Google Scholar 

  97. Calhoun, D. A. et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation 124, 1945–1955 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Davey, M. & Caldicott, D. Calcium salts in management of hyperkalaemia. Emerg. Med. J. 19, 92–93 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sherman, R. A., Hwang, E. R., Bernholc, A. S. & Eisinger, R. P. Variability in potassium removal by hemodialysis. Am. J. Nephrol. 6, 284–288 (1986).

    Article  CAS  PubMed  Google Scholar 

  100. Rastegar, A. & Soleimani, M. Hypokalaemia and hyperkalaemia. Postgrad. Med. J. 77, 759–764 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Sterns, R. H., Rojas, M., Bernstein, P. & Chennupati, S. Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective? J. Am. Soc. Nephrol. 21, 733–735 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Pitt, B. et al. 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. 32, 820–828 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Pitt, B. et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. 348, 1309–1321 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan, Groningen, 9713 AV, The Netherlands

    Sara S. Roscioni, Dick de Zeeuw & Hiddo J. Lambers Heerspink

  2. Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan, Groningen, 9713 AV, The Netherlands

    Stephan J. L. Bakker

Authors
  1. Sara S. Roscioni
    View author publications

    Search author on:PubMed Google Scholar

  2. Dick de Zeeuw
    View author publications

    Search author on:PubMed Google Scholar

  3. Stephan J. L. Bakker
    View author publications

    Search author on:PubMed Google Scholar

  4. Hiddo J. Lambers Heerspink
    View author publications

    Search author on:PubMed Google Scholar

Contributions

S. S. Roscioni researched the data for the article, S. S. Roscioni, S. J. L. Bakker and H. J. Lambers Heerspink wrote the manuscript, S. S. Roscioni, D. de Zeeuw, S. J. L. Bakker and H. J. Lambers Heerspink provided substantial contributions to review or editing of the manuscript and discussions of its content before submission.

Corresponding author

Correspondence to Sara S. Roscioni.

Ethics declarations

Competing interests

D. de Zeeuw has consulted for Abbott, Astellas, Bristol–Myers Squibb, Hemocue, Johnson & Johnson, Merck Sharpe & Dohme, Novartis, Reata Pharmaceuticals, and Vitae. H. J. Lambers Heerspink has consulted for Abbott, Johnson & Johnson, Reata Pharmaceuticals and Vitae. The other authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roscioni, S., de Zeeuw, D., Bakker, S. et al. Management of hyperkalaemia consequent to mineralocorticoid-receptor antagonist therapy. Nat Rev Nephrol 8, 691–699 (2012). https://doi.org/10.1038/nrneph.2012.217

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nrneph.2012.217

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing