What causes hyperkalemia?

Causes of Hyperkalemia

Hyperkalemia results from three fundamental mechanisms: decreased renal potassium excretion (the dominant cause), transcellular shift of potassium out of cells, or excessive potassium intake. 1

Decreased Renal Potassium Excretion (Most Common)

This represents the primary mechanism in clinical practice and includes:

Chronic Kidney Disease

• The incidence of hyperkalemia increases dramatically with severity of renal impairment, occurring in up to 73% of patients with advanced CKD. 1
• Risk progressively increases as eGFR decreases, particularly when eGFR falls below 60 mL/min per 1.73 m², and is generally increased once eGFR is less than 15 mL/min per 1.73 m². 2

Acute Kidney Injury

• AKI is often accompanied by acute pancreatitis or hepatic failure, and was present in all cases of hyperkalemia-induced cardiac arrest in one retrospective analysis. 1

Hypoaldosteronism

• Reduced mineralocorticoid level or activity impairs renal potassium excretion. 3
• Heparin and derivatives can suppress aldosterone synthesis, contributing to hyperkalemia. 2

Drug-Induced Hyperkalemia (Most Important Iatrogenic Cause)

Medications represent the most important iatrogenic cause of hyperkalemia in everyday clinical practice, with up to 40% of heart failure patients and 5-10% of combination therapy patients developing hyperkalemia. 1

RAAS Inhibitors (Primary Culprits)

• ACE inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs) are the leading medication causes. 1, 2
• Combination RAAS therapy increases hyperkalemia risk to 5-10% in patients with heart failure or CKD. 4
• Up to one-third of heart failure patients requiring MRAs develop hyperkalemia >5.0 mEq/L. 4

Potassium-Sparing Diuretics

• Spironolactone, triamterene, and amiloride directly reduce renal potassium excretion. 1, 2

NSAIDs

• Impair renal potassium excretion by reducing prostaglandin synthesis. 1, 2

Other Medications

• Trimethoprim and pentamidine block epithelial sodium channels in the collecting duct. 2
• Beta-blockers reduce renin release. 2
• Calcineurin inhibitors (cyclosporine, tacrolimus) impair renal excretion. 2
• Digitalis can cause hyperkalemia. 2

Transcellular Potassium Shift

Metabolic Acidosis

• Causes potassium to shift out of cells in exchange for hydrogen ions. 1

Massive Tissue Breakdown

• Rhabdomyolysis, tumor lysis syndrome, and severe burns release large amounts of intracellular potassium. 1, 5

Insulin Deficiency

• Impairs cellular potassium uptake via Na/K-ATPase. 2

Hyperglycemia

• Alters transcellular potassium distribution. 6

Excessive Potassium Intake

While rarely the sole cause, excessive intake can contribute, especially with impaired renal function:

Direct Sources

• Potassium supplements are a direct exogenous source. 1
• Salt substitutes often contain potassium chloride (e.g., DASH diet products). 1, 2
• High-potassium foods include bananas, melons, orange juice, potatoes, and tomatoes. 1

Iatrogenic Sources

• Stored blood products can release significant potassium during transfusion. 4, 2
• Certain herbal supplements (alfalfa, dandelion, horsetail). 2

Pseudohyperkalemia (False Elevation)

Pseudohyperkalemia represents falsely elevated potassium in the test tube without true elevation in the body. 1

Causes

• Hemolysis during blood draw (most common). 1, 2
• Prolonged tourniquet application or fist clenching during phlebotomy. 1, 2
• Thrombocytosis or leukocytosis causing in vitro potassium release. 1
• Delayed specimen processing. 2

Diagnostic Approach

• If pseudohyperkalemia is suspected, repeat measurement with proper blood sampling technique or obtain an arterial sample for confirmation. 1, 2
• Plasma potassium concentrations are usually 0.1-0.4 mEq/L lower than serum levels due to platelet potassium release during coagulation. 2

High-Risk Patient Populations

Patients with advanced CKD, heart failure, diabetes mellitus, resistant hypertension, myocardial infarction, and advanced age have dramatically elevated risk of developing hyperkalemia. 1, 2

Prevalence by Setting

• 2-4% in the general population. 1
• 10-55% in hospitalized patients. 1
• Up to 73% in advanced CKD. 1

Multiple Coexisting Mechanisms

Multiple mechanisms of hyperkalemia often coexist, such as CKD + RAAS inhibitor + NSAID, which compounds the risk. 2 Both the absolute potassium level and the rate of rise determine clinical significance, with rapid increases more likely to cause cardiac abnormalities than gradual elevations over months. 1