What causes hyperkalemia (elevated potassium levels)?

What Causes Elevated Potassium (Hyperkalemia)?

Hyperkalemia (serum potassium >5.0 mEq/L) is most commonly caused by impaired renal potassium excretion, particularly from medications that block the renin-angiotensin-aldosterone system (RAAS), with up to 50% of patients on RAAS inhibitors developing hyperkalemia in real-world settings. 1

Primary Mechanisms

Hyperkalemia develops through three main pathways 2, 3:

• Impaired renal excretion (most common mechanism) - The kidney's inability to eliminate potassium adequately, especially when eGFR falls below 15 mL/min/1.73 m², affecting up to 73% of patients with advanced chronic kidney disease 1, 4

• Transcellular shifts - Movement of potassium from inside cells to the bloodstream 2, 3

• Increased potassium intake or supply - Excessive dietary potassium or exogenous sources 2, 3

Medication-Induced Hyperkalemia (Most Important in Clinical Practice)

RAAS inhibitors represent the most critical drug-related cause 3:

• ACE inhibitors and ARBs cause hyperkalemia in 15-30% of severe heart failure patients and 5-15% of those with mild-moderate symptoms, with real-world incidence reaching 50% compared to only 6-12% in controlled trials 1, 4

• Mineralocorticoid receptor antagonists (spironolactone, eplerenone) cause hyperkalemia in up to one-third of heart failure patients over 2 years, with particularly high risk when combined with ACE inhibitors or ARBs 1, 4, 3

• Potassium-sparing diuretics (amiloride, triamterene) impair renal potassium excretion 5, 3

• NSAIDs impair renal potassium excretion through prostaglandin inhibition 5, 1, 3

• Direct renin inhibitors (aliskiren) increase hyperkalemia risk 4, 3

Other medications that cause hyperkalemia include 3:

• Calcineurin inhibitors (tacrolimus, cyclosporine)
• Heparin and derivatives
• Trimethoprim and pentamidine
• Beta-blockers (cause transcellular shift)
• Calcium channel blockers
• Succinylcholine

Renal Insufficiency

Chronic kidney disease is the second most important cause, with hyperkalemia incidence increasing dramatically as kidney function declines 4, 2:

• Up to 73% of patients with eGFR <15 mL/min/1.73 m² develop hyperkalemia 1, 4
• The risk escalates particularly when eGFR falls below 45 mL/min/1.73 m² 1

Dietary and Exogenous Sources

High potassium intake from 5, 4, 2:

• Fruits: bananas, melons, oranges and orange juice
• Vegetables: potatoes, tomato products, legumes and lentils
• Dairy: yogurt
• Other: chocolate, salt substitutes containing potassium chloride
• Stored blood products during transfusions 4

Critical caveat: Breast milk has the lowest potassium content (546 mg/L) compared to standard infant formulas (700-740 mg/L), and volumes exceeding 165 mL/kg may aggravate hyperkalemia in infants 5

Tumor Lysis Syndrome

Rapid tumor cell destruction releases massive intracellular potassium into the bloodstream 5:

• Occurs within 12-72 hours after initiating chemotherapy, radiation, or cytolytic antibody therapy
• Most common in malignancies with high proliferative rate, large tumor burden, and high chemotherapy sensitivity
• Can cause life-threatening cardiac arrhythmias, ventricular tachycardia, fibrillation, or cardiac arrest 5

Non-Dietary Causes to Investigate When Hyperkalemia Persists

When dietary restriction fails, evaluate 5:

• Spurious/pseudohyperkalemia from hemolysis during blood draw
• Metabolic acidosis (causes transcellular potassium shift)
• Constipation (impairs colonic potassium excretion)
• Inadequate dialysis in dialysis-dependent patients
• Tissue destruction from catabolism, infection, surgery, or chemotherapy
• Exogenous potassium sources including IV fluids and medications

High-Risk Populations

Patients at greatest risk include 1, 4:

• Advanced chronic kidney disease patients (up to 73% affected)
• Chronic heart failure patients (up to 40% affected)
• Diabetic patients
• Elderly patients
• Those on multiple RAAS inhibitors simultaneously

Predictors of recurrent hyperkalemia 1, 4:

• Initial moderate to severe hyperkalemia (>5.6 mEq/L)
• Low eGFR (<45 mL/min/1.73 m²)
• Diabetes mellitus
• Concurrent spironolactone use
• 50% of cardiovascular disease patients with chronic kidney disease experience two or more recurrences within 1 year 1

Critical Clinical Pitfalls

Do not discontinue or reduce RAAS inhibitors after a single elevated potassium measurement, as this offsets the survival benefits of these medications 1, 4. Hyperkalemia is frequently under-monitored in patients on RAAS inhibitors despite guideline recommendations 1, 4. Less than one-third of patients achieve guideline-recommended target doses of RAAS inhibitors due to hyperkalemia concerns 1, 4.