Hyperkalemia 

Potassium homeostasis

Hyperkalemia is defined as a condition in which serum potassium greater than 5.3 mEq/L.

Potassium, the most abundant intracellular cation, is essential for the life of the organism. Potassium is obtained through the diet. Common potassium-rich foods include meats, beans, fruits, and potatoes. Gastrointestinal absorption is complete, resulting in daily excess intake of about 1 mEq/kg/d (60-100 mEq). This excess is excreted through the kidneys (90%) and the gut (10%). Potassium homeostasis is maintained predominantly through the regulation of renal excretion. The most important site of regulation is the distal nephron, including the distal convoluted tubule, the connecting tubule, and the cortical collecting tubule, where aldosterone receptors are present.

The regulation of potassium excretion at the cortical collecting tubule has been extensively studied. Sodium reabsorption through epithelial sodium channels (ENaC) located on the apical membrane of cortical collecting tubule cells, is driven by aldosterone and generates a tubular lumen negative electrical potential, driving the secretion of potassium at this site through specific potassium channels called the renal outer medullary K channels (ROMK). Studies have demonstrated, however that aldosterone also regulates sodium transport in the thick ascending limb of the loop of Henle, the distal convoluted tubule, and the connecting tubule.

A family of signaling molecules, the WNK (with no K [lysine]) kinases, play a critical role in the regulation of sodium and potassium transport in the distal nephron^[1] The WNK kinases are suspected to play a role in the pathogenesis of several forms of hypertension.^{[2, 3]}

Excretion is increased by the following:

• Aldosterone
• High sodium delivery to the distal tubule (eg, diuretics)
• High urine flow (eg, osmotic diuresis)
• High serum potassium level
• Delivery of negatively charged ions to the distal tubule (eg, bicarbonate)

Excretion is decreased by the following:

• Absence of aldosterone
• Low sodium delivery to the distal tubule
• Low urine flow
• Low serum potassium level
• Renal failure

Kidneys adapt to acute and chronic alterations in potassium intake. When potassium intake is chronically high, potassium excretion also is increased. In the absence of potassium intake, obligatory renal losses are 10-15 mEq/d. Thus, chronic losses occur in the absence of any ingested potassium. The kidney maintains a central role in the maintenance of potassium homeostasis, even in the setting of chronic renal failure. Renal adaptive mechanisms allow the kidneys to maintain potassium homeostasis until the glomerular filtration rate drops to less than 15-20 mL/min. Additionally, in the presence of renal failure, the proportion of potassium excreted through the gut increases.

The colon is the major site of gut regulation of potassium excretion. Therefore, potassium levels can remain relatively normal under stable conditions, even with advanced renal insufficiency. However, as renal function worsens, the kidneys may not be capable of handling an acute potassium load. An excess of only 100-200 mEq will increase the serum potassium concentration by about 1 mEq/L.^[4]

Serum potassium level

Potassium is predominantly an intracellular cation; thus, serum potassium levels can be a very poor indicator of total body stores. Potassium moves easily across cell membranes; therefore, serum potassium levels reflect the movement of potassium between intracellular and extracellular fluid compartments as well as total-body potassium homeostasis. Several factors regulate the distribution of potassium between the intracellular and extracellular space.

• Glucoregulatory hormones

  • Insulin enhances potassium entry into cells.
  • Glucagon impairs potassium entry into cells.
• Adrenergic stimuli

  • Beta-adrenergic stimuli enhance potassium entry into cells, whereas beta-blocking drugs inhibit potassium entry into cells.
  • Alpha-adrenergic stimuli impair potassium entry into cells.
• pH

  • Alkalosis enhances potassium entry into cells.
  • Acidosis causes shift of potassium from intracellular space into extracellular space. Inorganic or mineral acid acidoses are more likely to cause a shift of potassium out of the cells than organic acidoses.
• Shift from intracellular pool

  • Acute increase in osmolality, such as hyperglycemia, causes potassium to exit from cells.
  • Acute cell-tissue breakdown releases potassium into extracellular space.

The 2 sets of regulatory factors, those that regulate total-body homeostasis and those that regulate the distribution of potassium between intracellular and extracellular space, meld to create smooth control of potassium levels throughout the day. For example, a high-protein meal, such as a steak, may contain enough potassium to raise the serum potassium acutely to lethal levels if the potassium remained in the extracellular space. Although renal potassium excretion can increase fairly rapidly, this mechanism easily is overwhelmed by such an acute potassium load.

The acute hyperkalemic effect of an extremely potassium-rich meal is blunted substantially by the release of insulin, which causes potassium to be taken up into cells. The excessive potassium then can be excreted by the kidneys, allowing serum potassium levels to return to normal. This integrated regulatory process is manifested in the diurnal rhythm for renal potassium excretion. The highest excretion occurs at midday, approximately 18 hours after peak potassium ingestion at the evening meal.

Recent studies

In a retrospective observational study of 27,355 patients with diabetes, Raebel et al investigated whether potassium monitoring could lower the rate of hyperkalemic adverse events in such patients after the initiation of renin-angiotensin-aldosterone system (RAAS) inhibitor therapy. (RAAS inhibitor treatment has been associated with the development of hyperkalemia.) Potassium levels were monitored in 19,391 of the study's patients, with the authors determining relative risks by comparing the incidence of serious hyperkalemia-associated adverse events in these patients (calculated in person-years) with those in unmonitored patients, during the first year of RAAS inhibitor treatment.

The investigators found the adjusted relative risk for the monitored patients to be 0.50. Monitored patients who also had chronic kidney disease had an adjusted relative risk of 0.29. According to Raebel et al, their data supported the efficacy of potassium monitoring in reducing the incidence of serious hyperkalemia-associated adverse events in patients with a combination of diabetes and chronic kidney disease who are undergoing RAAS inhibitor therapy.^[5]

Any of the following 3 pathogenetic mechanisms can cause hyperkalemia:

• Excessive intake - Excessive potassium intake alone is an uncommon cause of hyperkalemia. The mechanisms for shifting potassium intracellularly and for renal excretion allow a person with normal potassium homeostatic mechanisms to ingest virtually unlimited quantities of potassium. Even parenteral administration of as much as 60 mEq/h for several hours creates only a minimal increase in serum potassium concentration in healthy individuals. Most often, hyperkalemia is caused by a relatively high potassium intake in a patient with impaired mechanisms for the intracellular shift of potassium or for renal potassium excretion.
• Decreased excretion - Decreased excretion of potassium, especially coupled with excessive intake, is the most common cause of hyperkalemia. The most common causes of decreased renal potassium excretion include renal failure, ingestion of drugs that interfere with potassium excretion (eg, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors,^{[5, 6, 7, 8]} nonsteroidal anti-inflammatory drugs), or impaired responsiveness of the distal tubule to aldosterone (eg, type IV renal tubular acidosis observed with diabetes mellitus, sickle cell disease, or chronic partial urinary tract obstruction).^{[9, 10]}
• Shift from intracellular to extracellular space - This pathogenetic mechanism alone is a relatively uncommon cause of hyperkalemia but can exacerbate hyperkalemia produced by a high intake or impaired renal excretion of potassium. Clinical situations in which this mechanism is the major cause of hyperkalemia include hyperosmolality, rhabdomyolysis, tumor lysis, and succinylcholine administration, which depolarizes the cell membrane and thus permits potassium to leave the cells.^[11] However, more often, mild to moderate impairment of intracellular shifting of potassium occurs with insulin deficiency or acute acidosis.

Hyperkalemia may also be caused by IV administration of epsilon amino caproic acid (EACA), a synthetic amino acid. EACA has been found to cause hyperkalemia in studies conducted in dogs. The mechanism of action is presumed to be a similarity in structure of EACA to arginine and lysine. These latter amino acids enter the muscle cell in exchange for potassium, thereby leading to an increase in extracellular potassium.^{[12, 13]}

Regardless of the cause, hyperkalemia produces similar signs and symptoms. Because potassium overwhelmingly is an intracellular cation and various factors can regulate the actual serum potassium concentration, an individual can ingest a substantial potassium load without exhibiting frank hyperkalemia. Conversely, hyperkalemia does not always reflect a true increase in total body potassium stores.

Frequency

United States

Hyperkalemia, defined as serum potassium greater than 5.3 mEq/L, is rare in a general population of healthy individuals. However, certain groups definitely exhibit a higher incidence of hyperkalemia. In patients who are hospitalized, the incidence of hyperkalemia has ranged from 1-10%, depending on the definition of hyperkalemia. Patients at the extremes of life, either premature or elderly, are at high risk. The presence of decreased renal function, genitourinary disease, cancer, severe diabetes, or polypharmacy also predisposes patients to hyperkalemia. Generally, in patients who are hospitalized, drugs are implicated in the development of hyperkalemia in as many as 75% of cases.

Military recruits, individuals with sickle cell traits, and people who abuse drugs are at risk for hyperkalemia due to acute rhabdomyolysis. These cases disproportionately occur in males, probably reflecting the higher muscle mass of males, although an underlying hormonal predisposition cannot be excluded absolutely.

Patients with diabetes constitute a unique high-risk group. They develop defects in all aspects of potassium metabolism. The typical healthy diabetic diet often is high in potassium and low in sodium. Diabetic persons frequently have underlying renal disease and often develop hyporeninemic hypoaldosteronism (ie, decreased aldosterone secondary to suppressed renin levels), impairing renal excretion of potassium.^{[9, 10]} They frequently are placed on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for treatment of diabetic nephropathy, exacerbating the defect in potassium excretion. Finally, persons with diabetes have insulin deficiency and/or resistance to insulin action, limiting their ability to shift potassium intracellularly. All of these factors combine to render people with diabetes particularly prone to hyperkalemia.^{[5, 6]}

One review of the incidence of hyperkalemia in people with diabetes found that, in an unselected group of diabetic persons treated in a clinic, hyperkalemia (defined as a serum potassium level >5 mEq/L) was found in 15% (270 out of 1764 patients).^[14] However, fewer than 4% had potassium levels that were higher than 5.4 mEq/L. Clinical risk factors significant in predicting the occurrence of hyperkalemia included renal insufficiency, duration of diabetes mellitus, age, glycosylated hemoglobin levels, and retinopathy. Interestingly, neither the serum glucose level nor the agent for diabetes treatment was significantly correlated.

Significant concern also has been raised about the potential for hyperkalemia in patients taking angiotensin-converting enzyme inhibitors, particularly because the indications for their use in high-risk populations, such as diabetic persons, are broadening rapidly. In one series, the incidence of hyperkalemia in an outpatient clinic was 11%.^[15] Hyperkalemia occurred in less than 6% of patients with normal renal function. Risk factors for hyperkalemia in patients using angiotensin-converting enzyme inhibitors included elevated blood urea nitrogen (BUN) and serum creatinine, severe diabetes mellitus, congestive heart failure, peripheral vascular disease, and the use of a long-acting drug.

As cardiovascular therapy has evolved, the growing population of patients with congestive heart failure also has come to constitute a high-risk group. The factors promoting the development of hyperkalemia in these patients include underlying renal insufficiency due to poor cardiac output and reduced renal blood flow, as well as the high prevalence of diabetes mellitus in patients with heart failure and the growing use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone inhibitors, such as spironolactone.^{[9, 10]} Initial studies examining the risk of hyperkalemia in patients with heart failure who were treated with aldosterone inhibitors revealed only a minor increase in hyperkalemia, but later studies showed that as the treatment became more widespread, the morbidity and mortality from hyperkalemia had increased.^[16]

International

As in the United States, the incidence of hyperkalemia in the general population has been reported in less than 5% of people. Patients who are hospitalized in countries as diverse as England, Australia, and Israel experience hyperkalemia approximately 10% of the time. Similar to those reported in the United States, risk factors include advanced age, significant prematurity, and the presence of renal failure, diabetes mellitus, and heart failure. Additionally, one series documented an increased incidence of hyperkalemia with cancer and gastrointestinal disease.^[17] Polypharmacy, particularly the use of potassium supplements and potassium-sparing diuretics, in patients with underlying renal insufficiency contributed to hyperkalemia in almost one half of the cases.

Mortality/Morbidity

Hyperkalemia in a patient who is hospitalized is an independent risk factor for death. In one series, 1.4% of patients who were hospitalized (406 out of 29,063 patients) developed hyperkalemia.^[17]

• The overall mortality rate in patients with hyperkalemia was 14.3% (58 out of 406 patients), with the risk increasing as the potassium level increases.
• Twenty-eight percent of patients with a serum potassium level greater than 7 mEq/L died, as opposed to 9% of those with a potassium level below 6.5 mEq/L. In 7 out of 58 deaths, the cause of death was directly attributable to hyperkalemia. Most cases resulting in death were complicated by renal failure.
• Interestingly, all patients who died of hyperkalemia had normal potassium levels within the 36 hours prior to death.

Race

No racial predisposition to hyperkalemia appears to exist.

Sex

Men are significantly more prone to hyperkalemia than are women. This difference has been noted in several series and stands in contrast to the increased incidence of hypokalemia in women. The reasons for this discrepancy are unknown.

Age

Several series document the increasing tendency for hyperkalemia in patients at the extremes of life, that is, small, premature infants and elderly people, with renal insufficiency playing a significant role in both groups.

• Premature infants are a high-risk group. Relative renal immaturity is likely to be a contributory factor; studies comparing small, premature infants who developed hyperkalemia to those who did not indicate that incidence is increased in infants with a lower glomerular filtration rate as estimated by endogenous creatinine clearance. In these small infants, hyperkalemia often occurs within the first 48 hours of life.
• Elderly patients are another high-risk group. In several series, an age older than 60 years was an independent risk factor for the development of hyperkalemia in the hospital. Several factors contribute to the increased propensity for elderly people to become hyperkalemic. Renal function tends to deteriorate with age, even in relatively healthy individuals. The glomerular filtration rate decreases by 1 mL/min/y in people older than 30 years. Renal blood flow also decreases. Oral intake declines, resulting in decreased urine flow rates. Plasma renin activity and aldosterone levels also tend to decrease with age, reducing the ability of the distal nephron to secrete potassium.
• Elderly patients are more likely to be taking medications that could interfere with potassium secretion, such as nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, and potassium-sparing diuretics. Elderly individuals who are bedridden often are placed on subcutaneous heparin, which can decrease aldosterone production.