What are the causes of hyperkalemia?

Causes of Hyperkalemia

Primary Mechanisms

Hyperkalemia results from three fundamental mechanisms: decreased renal potassium excretion (most common), transcellular shift of potassium out of cells, or excessive potassium intake—with impaired renal excretion being the dominant cause in clinical practice. 1, 2

Decreased Renal Potassium Excretion

This is the most clinically significant mechanism and includes:

• Chronic kidney disease: The incidence increases dramatically with severity of renal impairment, occurring in up to 73% of patients with advanced CKD 1
• Acute kidney injury: Often accompanied by acute pancreatitis or hepatic failure, and was present in all cases of hyperkalemia-induced cardiac arrest in one retrospective analysis 3
• Reduced sodium delivery to the distal nephron: Impairs the kidney's ability to excrete potassium 2
• Decreased mineralocorticoid level or activity (hypoaldosteronism): Disrupts the hormonal regulation of potassium excretion 2, 4
• Abnormalities in the cortical collecting duct: Direct tubular dysfunction prevents normal potassium secretion 2

Transcellular Potassium Shift

Potassium moves from intracellular to extracellular space due to:

• 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 3, 4
• Hemolysis: Can occur in the body (true hyperkalemia) or in the test tube (pseudohyperkalemia) 1
• Stored blood products: Release significant potassium during transfusion 3

Excessive Potassium Intake

Rarely causes hyperkalemia alone but contributes significantly when combined with impaired renal function:

• Potassium supplements: Direct exogenous source 1
• Salt substitutes: Often contain potassium chloride (e.g., DASH diet products) 1
• High-potassium foods: Bananas, melons, orange juice, potatoes, tomatoes 1, 3
• Herbal supplements: Alfalfa, dandelion, hawthorne berry, horsetail, nettle, noni juice, Siberian ginseng 1

Drug-Induced Hyperkalemia

Medications represent the most important iatrogenic cause of hyperkalemia in everyday clinical practice, with RAAS inhibitors being the most common culprits. 1, 5

Drugs That Decrease Potassium Excretion

• RAAS inhibitors: ACE inhibitors, ARBs, direct renin inhibitors (aliskiren), and mineralocorticoid receptor antagonists cause hyperkalemia in up to 40% of heart failure patients and 5-10% when used in combination therapy 1, 3
• Potassium-sparing diuretics: Spironolactone, triamterene, amiloride 1
• NSAIDs: Impair renal potassium excretion by reducing prostaglandin synthesis 1, 3, 5
• Calcineurin inhibitors: Cyclosporine, tacrolimus 1, 5
• Antimicrobials: Trimethoprim-sulfamethoxazole, pentamidine 1, 5
• Heparin and derivatives: Suppress aldosterone synthesis 1, 5
• Other agents: Beta-blockers, sacubitril/valsartan, digitalis, penicillin G 1

Drugs That Promote Transcellular Shift

• Beta-blockers: Impair cellular potassium uptake 1, 5
• Suxamethonium: Causes rapid potassium release from muscle cells 5
• Mannitol: Increases serum osmolality, drawing potassium out of cells 1, 5
• Amino acids: Aminocaproic acid, arginine, lysine 1

High-Risk Comorbidities

Certain patient populations have dramatically elevated risk, with up to 73% of advanced CKD patients and 40% of chronic heart failure patients developing hyperkalemia. 1, 6

• Chronic kidney disease: Risk increases proportionally with declining eGFR 1
• Heart failure: Particularly heart failure with reduced ejection fraction (HFrEF) 1
• Diabetes mellitus: Associated with hyporeninemic hypoaldosteronism 1, 7
• Advanced age: Reduced renal function and polypharmacy increase risk 1
• Arterial hypertension: Especially when treated with multiple RAAS inhibitors 1
• Coronary artery disease: Often requires RAAS inhibitor therapy 1

Pseudohyperkalemia

Always rule out pseudohyperkalemia before initiating treatment, as this represents falsely elevated potassium in the test tube without true elevation in the body. 1, 3

• Hemolysis during blood draw: Poor phlebotomy technique or delayed sample processing 1, 3
• Prolonged tourniquet application: Causes local tissue ischemia and potassium release 1
• Fist clenching during phlebotomy: Muscle activity releases potassium 1
• Thrombocytosis or leukocytosis: Cells release potassium after collection 1

If pseudohyperkalemia is suspected, repeat measurement with proper blood sampling technique or obtain an arterial sample for confirmation. 1, 3

Critical Clinical Context

The prevalence varies dramatically by setting: 2-4% in the general population, 10-55% in hospitalized patients depending on severity thresholds used, and up to 73% in advanced CKD 1. Both the absolute potassium level and the rate of rise determine clinical significance—rapid increases are more likely to cause cardiac abnormalities than gradual elevations over months. 1