Potassium has several physiological roles including maintenance of the resting membrane action potential, particularly of the myocardium. Because 98% of potassium is stored intracellularly, homeostasis of the extracellular 2% is essential, and leads to a narrow normal range of 3.5-5 mmol/l. An upset in this balance resulting in hyperkalemia can have life threatening consequences.
Hyperkalemia is most commonly caused by a reduction in the effective elimination of potassium by the kidneys as a result of kidney disease. However, renal potassium excretion can also be reduced by medications such as renin-angiotensin aldosterone system (RAAS) inhibitors, often used in patients already at risk due to their comorbidity.2
RAAS inhibitors include drugs such as:
- angiotensin-converting enzyme inhibitors (ACEIs)
- angiotensinreceptor blockers (ARBs)
- aldosterone receptor antagonists(ARAs), and
- direct renin inhibitors (DRIs)
RAAS inhibition forms a key part of the treatment strategy for diseases such as hypertension, chronic kidney disease (CKD), heart failure (HF), and diabetes. They have been shown to provide antihypertensive, renoprotective and cardioprotective5 benefits. However, they are associated with an increased risk of hyperkalemia, particularly when different classes are administered in combination.
‘The incidence of hyperkalemia is increased in patients with HF or CKD by 5% to 10%’
(Weir 2010 )
A study by David Juurlink et al7 analysed the rate of prescription of spironolactone (an ARA, marketed as Aldactone), hospitalization for hyperkalemia and associated mortality before and after the publication of spionolactone’s key efficacy trial, RALES. Patients over 66 yrs treated with ACEIs and recently hospitalized for HF saw a significant increase in spironolactone prescription, from 34 per 1000 in 1994, 30 per 1000 in 1999 to 149 per 1000 at the end of 2001 (p<0.001). In the same time period hospitalizations for hyperkalemia and hyperkalemia-related mortality significantly increased, resulting in 560 additional hospitalizations and at least 73 additional in-hospital deaths in the Ontario area during 2001.
Although a low-potassium diet may be recommended in these patients, several factors make this difficult to achieve. Potassium is present in healthy foods, including many fruits and vegetables. It is also sometimes a hidden ingredient in items such as salt substitutes, which can have as much as 200 mmol of potassium per tablespoon.
The multitude of variables affecting hyperkalemia risk mean that a number of factors need to be taken into consideration when assessing patients for additional therapy. Concurrent prescriptions for other medications that contribute to hyperkalemia should be minimized, and renal function and potassium levels need to be closely monitored.[7,9]
Fortunately, novel potassium-binders are currently under development which may provide an alternative. These evolving treatment options will be discussed in subsequent articles on COMPACT.
Figure 1: The hyperkalemia / RAAS conundrum
- Kraft MD, Btaiche IF, Sacks GS, Kudsk K a. Treatment of electrolyte disorders in adult patients in the intensive care unit. Am J Heal Pharm. 2005;62:1663-1682. doi:10.2146/ajhp040300.
- Weir MR. Are Drugs That Block the Renin-Angiotensin System Effective and Safe in Patients With Renal Insufficiency? Am J Hypertens. 1999;7061(99):195-203.
- Weir M, Bush C, Anderson D, Zhang J, Keefe D, Satlin A. Antihypertensive efficacy, safety, and tolerability of the oral direct renin inhibitor aliskiren in patients with hypertension: a pooled analysis. J Am Assoc Hypertens. 2007;1(4):264-277.
- BRENNER B, COOPER M, DE ZEEUW 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(12):861-869.
- Pitt P, ZANNAD F, REMME W, et al. The Effect of Spironolactone on Morbidity and Mortality in Patients With Severe Heart Failure. N Engl J Med. 1999;341(10):709-717. doi:10.1056/NEJM199909023411001.
- Weir MR, Rolfe M. Potassium homeostasis and renin-angiotensin-aldosterone system inhibitors. Clin J Am Soc Nephrol. 2010;5(3):531-548. doi:10.2215/CJN.07821109.
- Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351:543-551. doi:10.1056/NEJMoa040135.
- Rastegar A, Soleimani M. Hypokalaemia and Hyperkalaemia. Postgrad Med J. 2001;77:759-764. doi:10.1136/pmj.77.914.759.
- 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. doi:10.1001/archinternmed.2009.132.