eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders

Hyperkalemia

Author: Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine, Director of Nephrology Training Program, Kidney Disease Program, University of Louisville School of Medicine; Director, Metabolic Stone Clinic
Coauthor(s): Rosemary Ouseph, MD, Professor of Medicine, Director of Kidney Transplant, University of Louisville School of Medicine; Vibha Nayak, MD, Fellow in Nephrology, Department of Internal Medicine, University of Louisville School of Medicine; Son Dinh, MD, Nephrologist, Southland Renal Medical Group, Inc
Contributor Information and Disclosures

Updated: Apr 7, 2009

Introduction

Background

Potassium homeostasis

Hyperkalemia is defined as a condition in which serum potassium greater than 5.3 mEq/L. (See image below and Image 1.)

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.

Pathophysiology

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-convening enzyme inhibitors, 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).^5,6
• 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.⁷ 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.^8,9

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.^5,6 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.

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).¹⁰ 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%.¹¹ 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.^5,6 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.¹²

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.¹³ 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.¹³

• 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.

Clinical

History

Symptoms are nonspecific and predominantly related to muscular or cardiac function. The most common complaints are weakness and fatigue. Occasionally, a patient may complain of frank muscle paralysis or shortness of breath. Patients also may complain of palpitations or chest pain.

When hyperkalemia is discovered, investigate potential pathophysiologic mechanisms.

• For excessive potassium intake, query patients about the following:
  • Eating disorders - Very unusual diets consisting almost exclusively of high-potassium foods, such as fruits, dried fruits, juices, and vegetables with little to no sodium
  • Heart healthy diets - Very low–sodium and high-potassium diets recommended for patients with cardiac disease, hypertension, and diabetes mellitus
  • Use of potassium supplements in over-the-counter herbal supplements, salt substitutes, or prescribed pharmacologic agents - Many patients with renal insufficiency and hypertension have heard the advice to eat a banana a day because the potassium reduces blood pressure. They may not realize that in the case of renal insufficiency and hypertension, this is potentially a life-threatening therapy.
• For decreased potassium excretion, query patients about the following:
  • Ingestion of medications that impair renal potassium excretion
    • Potassium-sparing diuretics, especially popular in the treatment of cirrhosis and congestive heart failure
    • Nonsteroidal anti-inflammatory drugs
    • Angiotensin-converting enzyme inhibitors
    • Angiotensin receptor blockers
    • Cyclosporine or tacrolimus
    • Antibiotics, such as pentamidine or trimethoprim/sulfamethoxazole¹⁴
    • EACA⁸
  • History of renal insufficiency or renal failure
  • History of diabetes mellitus, sickle cell disease or trait, or symptoms of lower urinary tract obstruction - These diseases predispose people to type IV renal tubular acidosis, also called hyperkalemic renal tubular acidosis. Type IV renal tubular acidosis also may accompany other tubulointerstitial disorders, such as polycystic kidney disease or amyloidosis. Often, patients with type IV renal tubular acidosis have hyporeninemic hypoaldosteronism.^5,6 One example is diabetes mellitus, where the relative volume overload leads to low renin.
• For a shift of potassium into the extracellular space, query patients about the following:
  • Recurrent episodes of flaccid paralysis
  • Presence of diabetes mellitus
  • Use of beta-adrenergic antagonist therapy (eg, for hypertension or angina)
  • Risk factors for rhabdomyolysis, such as heat stroke, chronic alcoholism, seizures, sudden excessive exertion (eg, in military recruits undergoing basic training), or use of medications that interfere with heat dissipation (eg, tricyclic antidepressants or anesthesia)
  • Risk factors for tumor lysis syndrome, such as ongoing treatment for widespread lymphoma, leukemia, or other large tumors
  • Risk factors for hemolysis, such as blood transfusion and sickle cell disease
• Other mechanisms
  • Drugs, such as cyclooxygenase-2 (COX-2) inhibitors¹⁵
  • Ingestion of toad venom (Bufo bufo gargarizans) in southeastern Asian countries
    • In Southeast Asia, toads are a common folk remedy for strengthening the heart. Bufadienolides, which are forms of cardiac glycoside that are present in toad venom, have a similar structure and biochemical activity to digitalis and cardenolides, the major plant-derived cardiac glycosides. Bufadienolides cause hyperkalemia by binding to the alpha subunit of Na⁺ –K⁺ –ATPase, thus inhibiting the reuptake of potassium from the extracellular space.¹⁶
    • This compound has also turned up in some aphrodisiacs and Chinese medications (eg, chan su).
    • With regard to Western countries, at least 2 cases of poisoning by toad and eggs have been reported in the United States.¹⁷

Physical

• In patients with hyperkalemia, vital signs generally are normal, except occasionally in bradycardia due to heart block or tachypnea due to respiratory muscle weakness.
• Muscle weakness and flaccid paralysis
• Depressed or absent deep tendon reflexes
• In general, the results of the physical examination alone do not alert the physician to the diagnosis, except when severe bradycardia is present or muscle tenderness accompanies muscle weakness, suggesting rhabdomyolysis.

Causes

Listed by pathophysiologic mechanisms, causes of hyperkalemia include increased potassium intake, decreased potassium excretion, or a shift of potassium from the intracellular to the extracellular space. The most common causes are due to decreased excretion. Alone, excessive intake or an extracellular shift is distinctly uncommon. Often, several disorders are present simultaneously.

• Increased intake - Alone, this is a rare cause of hyperkalemia, because the mechanisms for renal excretion and intracellular disposition are very efficient. In general, a relatively high potassium intake contributes to hyperkalemia in individuals who have impaired renal excretion and/or impaired intracellular shift.
  • High-potassium, low-sodium diets
  • Ingestion of potassium supplements - Ingested amounts would have to be massive to be the sole cause of hyperkalemia, but even relatively small amounts can produce hyperkalemia in a patient with impaired renal excretion.
  • High concentrations of potassium in intravenous fluid preparations, such as total parenteral nutrition
  • Dietary salt substitutes, penicillin potassium therapy
• Decreased excretion - Impaired renal excretion almost always is present when a patient presents with persistent hyperkalemia. Mild degrees of renal failure generally do not result in resting hyperkalemia, due to adaptive mechanisms in the kidneys and gastrointestinal tract. However, once the glomerular filtration rate falls below 15-20 mL/min, significant hyperkalemia can occur, even in the absence of an abnormally large potassium load. The simple lack of nephron mass prevents normal potassium homeostasis. Hyperkalemia due to decreased renal excretion can occur when a patient has normal or only mildly decreased renal function as a result of other mechanisms, such as drugs or renal tubular acidosis. Two other causes of decreased excretion of potassium include reduced distal sodium delivery and reduced tubular fluid flow rate.
  • Drugs
    • Potassium-sparing diuretics, spironolactone, triamterene, amiloride
    • Nonsteroidal anti-inflammatory drugs
    • Angiotensin-converting enzyme inhibitors
    • Angiotensin receptor blockers
    • Cyclosporine or tacrolimus
    • Pentamidine
    • Trimethoprim/sulfamethoxazole
    • Heparin
    • Ketoconazole
    • Metyrapone
    • Herbs
  • Type IV renal tubular acidosis
    • Diabetes mellitus
    • Sickle cell disease or trait
    • Lower urinary tract obstruction
    • Adrenal insufficiency
    • Primary Addison syndrome due to autoimmune disease, tuberculosis, or infarct
    • Enzyme deficiencies
  • Disorders of steroid metabolism and mineralocorticoid receptors^18,19
    • 21-hydroxylase deficiency in classical form and aldosterone synthase deficiency result in hyperkalemia due to low aldosterone levels.
    • 11-beta hydroxylase deficiency, 3-beta hydroxysteroid dehydrogenase deficiency, and 17 alpha-hydroxylase/17,20-lyase deficiency are generally not characterized by the development of hyperkalemia.
    • Type 1 pseudohypoaldosteronism is caused by an inactivating mutation of the mineralocorticoid receptor, resulting in impaired potassium secretion due to impaired sodium reabsorption in the distal tubule.²⁰
  • Gordon syndrome, or pseudohypoaldosteronism Type II, characterized by hyperkalemia and hypertension, is caused by mutations in either WNK1 or WNK4, protein kinases that are localized to the distal tubule and that regulate ion transport in this nephron segment. WNK4 appears to have several roles in regulating sodium, potassium, and chloride transport through transcellular and paracellular pathways.²¹
• Shift of potassium into the extracellular space - Like increased intake, this rarely is the sole cause of hyperkalemia, because the mechanisms for renal excretion are very efficient. However, the inability to transport potassium intracellularly exacerbates hyperkalemia in individuals who have impaired renal excretion.
  • Hyperkalemic periodic paralysis
  • Insulin deficiency or insulin resistance (ie, type I or type II diabetes mellitus)
  • Use of beta-adrenergic antagonist therapy (eg, for hypertension or angina)
  • Tissue breakdown
    • Rhabdomyolysis
    • Tumor lysis syndrome
    • Massive hemolysis
  • Drugs
    • Nonselective beta blockers (inhibits Na-K-ATPase pump)
    • Digitalis toxicity (inhibits Na-K-ATPase pump)
    • Succinylcholine (membrane leak)
    • Inhibition of the sodium pump will impair K entry into the cells and facilitate K exit from the cells.
  • Hypertonicity - This may lead to hyperkalemia by 2 mechanisms: (1) loss of intracellular water, resulting in an increased intracellular potassium concentration, favoring a gradient for potassium to move out of the cells, and (2) as water exits the cells, "solvent drag," which sweeps potassium along. The most common cause of hyperosmolality is hyperglycemia in uncontrolled diabetes mellitus. Other conditions with hypertonicity are hypernatremia and hypertonic mannitol.
  • Aldosterone deficiency - This is somewhat controversial. Some evidence that long-term aldosterone deficiency impairs cell potassium uptake exists.

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