Insulin for the treatment of hyperkalemia: a double-edged sword?

Potassium plays a critical role in cellular metabolism and normal neuromuscular function. Tightly regulated homeostatic mechanisms have developed in the process of evolution to provide primary defense against the threats of hyperand hypokalemia. The kidney plays a primary role in potassium balance, by increasing or decreasing the rate of potassium excretion. Distribution of potassium between the intracellular and the extracellular fluid compartments is regulated by physiologic factors such as insulin and catecholamines which stimulate the activity of the Na-K ATPase. Only about 10% of the ingested potassium is excreted via the gut under normal physiologic conditions [1]. End stage renal disease (ESRD) patients rely largely on extra-renal mechanisms and dialysis to maintain potassium homeostasis. Despite the availability of dialysis and the adaptive increase in colonic excretion of potassium in renal insufficiency, severe hyperkalemia (defined as serum potassium level > 6 mEq/L [6 mmol/L]) is observed in 5-10% of maintenance dialysis patients and is responsible for 0.7% of deaths in the dialysis population in the United States [2–4]. Several factors can explain the high incidence of hyperkalemia in this population. Tolerance for a rapid potassium load is impaired in ESRD, not only because of lack of renal excretion, but also as a result of impaired cellular distribution of potassium [5]. The latter may result from defect in the Na-K ATPase and possibly elevated glucagon levels in uremia [5, 6]. High dietary potassium intake and missed dialysis treatments are common contributors to hyperkalemia in ESRD patients. Other factors such as constipation (decreased colonic excretion) and fasting state (relative lack of insulin) may also predispose ESRD patients to hyperkalemia [7]. Patients who are new to dialysis may still have some residual renal function and remain sensitive to several classes of medications that impair potassium excretion. These include inhibitors of the renin-angiotensinaldosterone system (RAAS), potassium sparing diuretics, heparin, trimethoprim, pentamidine and non-steroidal anti-inflammatory medications (NSAIDS). Use of spironolactone in prevalent ESRD patients has also been implicated as a cause for hyperkalemia due to its effect on colonic handling of potassium. Non-selective beta blockers can also lead to hyperkalemia by preventing intracellular shifts of potassium [8]. The treatment of acute hyperkalemia in ESRD patients is emergent dialysis. When dialysis is not immediately available, temporizing measures are employed. Intravenous calcium is used to counter the adverse myocardial effects of hyperkalemia but does not affect the serum concentration of potassium. Cation exchange resins are frequently used to increase colonic secretion of potassium. However, due to their late onset of action (at least two hours), questionable efficacy, and possible toxicities such as colonic necrosis, cation exchange resins are not the recommended first-line therapy in acute hyperkalemia [9]. The use of intravenous bicarbonate therapy has also been discouraged due to the lack of benefit [10, 11]. Other measures that result in the shift of potassium from the extracellular to intracellular space, such as albuterol and insulin, have been proven to be effective in patients with chronic kidney disease (CKD) and are more rapid in onset, usually over 30–60 minutes [2, 12–14]. However, for unclear reasons, a subset of ESRD patients is resistant to the actions of albuterol [8]. Intravenous (IV) insulin is therefore often the first-line therapy for acute hyperkalemia in hospitalized ESRD patients. It is typically used in conjunction with dextrose to prevent hypoglycemia, and is often combined with other therapies such as nebulized albuterol. Even though insulin-mediated glucose uptake is impaired in uremia, the potassium-lowering effect of insulin is unaffected [7]. This is thought to be due to the independent pathways for potassium and glucose transport across cell membrane [15]. Insulin shifts potassium into cells by stimulating the activity of Na-H antiporter on cell membrane, promoting the entry of sodium into cells, which leads to activation of the Na-K ATPase, causing an electrogenic influx of potassium. IV insulin leads to a dose-dependent decline in serum potassium levels [16]. A combination of IV insulin dose of 10 units plus 25 g of dextrose reliably lowers the serum potassium level by 1 mEq/L (mmol/L) within 10–20 minutes and the effect lasts about 4-6 hours [17, 18]. However, this therapy may be associated with significant hypoglycemia [14, 18–21]. In one study of hospitalized patients treated with IV insulin for hyperkalemia, 8.7% of the patients developed hypoglycemia (defined as blood glucose of <70 mg/dL [3.9 mmol/L]) [20]. In a study of hemodialysis patients, 75% of patients treated with insulin and glucose to lower serum potassium level developed hypoglycemia [14]. The definition of hypoglycemia has been a topic of debate. The workgroup of the American Diabetes Association and the Endocrine Society defines iatrogenic hypoglycemia in patients with diabetes mellitus (DM) as “all episodes of an abnormally low plasma glucose concentration that expose the individual to potential harm.”