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

1. Decreased Renal Potassium Excretion

This represents the most clinically significant mechanism and is predominantly iatrogenic in nature:

Medications Blocking the Renin-Angiotensin-Aldosterone System (RAAS)

• RAAS inhibitors are the most important drug-related cause of hyperkalemia, including ACE inhibitors, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and direct renin inhibitors like aliskiren 2, 3
• These medications are paradoxically the cornerstone of cardiovascular disease treatment (Class IA recommendation for heart failure with reduced ejection fraction), creating a clinical dilemma where life-saving drugs cause hyperkalemia 2
• RAASi-induced hyperkalemia occurs in up to 40% of patients with chronic heart failure and up to 73% of patients with advanced chronic kidney disease 2

Other Medications Impairing Renal Excretion

• Potassium-sparing diuretics (spironolactone, triamterene, amiloride) 2, 3
• NSAIDs (reduce renal potassium excretion) 2, 3
• Calcineurin inhibitors (cyclosporine, tacrolimus) 2, 3
• Trimethoprim-sulfamethoxazole (blocks epithelial sodium channels) 2, 3
• Heparin (suppresses aldosterone production) 2, 3
• Beta-blockers (reduce renin release) 2, 3
• Pentamidine, digitalis, and penicillin G 2

Underlying Medical Conditions

• Chronic kidney disease is the most significant non-drug risk factor, with prevalence increasing as renal impairment worsens 3, 4
• Diabetes mellitus (hyporeninemic hypoaldosteronism) 3, 4
• Adrenal insufficiency (reduced aldosterone production) 5
• Heart failure (reduced renal perfusion and concurrent RAAS inhibitor use) 2, 4

2. Transcellular Potassium Shift

Potassium moves from intracellular to extracellular space, causing transient hyperkalemia:

Medications Causing Cell Shift

• Beta-blockers (impair cellular potassium uptake) 2, 6
• Mannitol (hyperosmolarity drives potassium out of cells) 2, 6
• Suxamethonium (depolarizing muscle relaxant) 6
• Digitalis (inhibits Na-K-ATPase pump) 2
• Amino acids (aminocaproic acid, arginine, lysine) 2

Metabolic and Tissue Conditions

• Tumor lysis syndrome (massive intracellular potassium release, high risk for acute kidney injury) 4
• Metabolic acidosis (hydrogen ions enter cells in exchange for potassium) 1
• Tissue breakdown from rhabdomyolysis, hemolysis, or burns 1
• Severe hyperglycemia (hyperosmolarity) 1

3. Excessive Potassium Intake

Rarely causes hyperkalemia alone unless renal function is impaired, but contributes significantly when combined with other mechanisms:

Dietary Sources

• High-potassium foods: bananas, melons, orange juice, potatoes, tomatoes 2, 5
• Salt substitutes (often contain potassium chloride, particularly DASH diet products) 2, 3

Supplementation and Medical Products

• Potassium supplements (prescribed or over-the-counter) 2, 3
• Stored blood products (potassium leaks from aging red blood cells) 2, 3

Herbal and Alternative Products

• Alfalfa, dandelion, horsetail, nettle 2, 3
• Noni juice, Siberian ginseng, hawthorne berry 2
• Dried toad skin, lily of the valley, milkweed 2

High-Risk Patient Populations

Hyperkalemia prevalence increases dramatically with comorbidity burden:

• General population: 2-4% 2, 3
• Hospitalized patients: 10-55% (depending on definition) 2, 3
• Advanced chronic kidney disease: up to 73% 2, 3
• Chronic heart failure: up to 40% 2

Risk factors compound exponentially when patients have cardiovascular disease combined with renal impairment, diabetes, and advanced age 2, 3

Critical Pitfall: Pseudo-Hyperkalemia

Always rule out pseudo-hyperkalemia before initiating treatment, as this represents falsely elevated potassium in the test tube without true hyperkalemia in the body 2, 3, 5

Causes include:

• Hemolysis during blood draw or delayed specimen processing 3, 5
• Excessive fist clenching during phlebotomy 3
• Potassium release from blood cells in the collection tube 2

If suspected, repeat measurement with proper technique or obtain arterial sample 2