What are the causes of hyperkalemia?

Causes of Hyperkalemia

Hyperkalemia is primarily caused by decreased renal potassium excretion, increased potassium intake, and transcellular potassium shifts, with chronic kidney disease and medication use being the most common etiologies in clinical practice. 1

Pathophysiological Mechanisms

Hyperkalemia occurs through three main mechanisms:

1. Decreased Renal Potassium Excretion

   • Most common cause (accounts for ~90% of potassium elimination)
   • Occurs in:
     • Chronic kidney disease (especially eGFR <50 ml/min) 2
     • Acute kidney injury
     • Hypoaldosteronism or aldosterone resistance

2. Increased Potassium Intake/Administration

   • Dietary sources (high-potassium foods)
   • Potassium supplements
   • Stored blood products

3. Transcellular Potassium Shift (from intracellular to extracellular space)

   • Acidosis
   • Insulin deficiency
   • Tissue damage (rhabdomyolysis, tumor lysis syndrome)
   • Beta-blocker effects

Medication-Induced Hyperkalemia

Medications are the most common cause of hyperkalemia in clinical practice 1, 3:

1. Drugs Decreasing Potassium Excretion:

   • RAAS Inhibitors:
     • ACE inhibitors
     • Angiotensin receptor blockers (ARBs)
     • Direct renin inhibitors (aliskiren)
     • Mineralocorticoid receptor antagonists (spironolactone, eplerenone)
   • Potassium-Sparing Diuretics:
     • Triamterene
     • Amiloride
   • Other Medications:
     • NSAIDs
     • Beta-blockers
     • Calcineurin inhibitors (cyclosporine, tacrolimus)
     • Heparin and derivatives
     • Trimethoprim-sulfamethoxazole
     • Pentamidine
     • Mannitol
     • Digitalis
     • Penicillin G

2. Drugs Causing Transcellular Potassium Shift:

   • Succinylcholine
   • Beta-blockers
   • Digoxin toxicity
   • Amino acids (arginine, lysine)

High-Risk Patient Populations

Certain populations are at increased risk for hyperkalemia 1, 4:

• Advanced chronic kidney disease (especially eGFR <50 ml/min)
• Heart failure
• Diabetes mellitus
• Advanced age
• Resistant hypertension
• Myocardial infarction
• Combined comorbidities (e.g., CKD + heart failure + diabetes)
• Male gender (slightly higher risk)

Dietary and Supplement Sources

Excessive intake from these sources can contribute to hyperkalemia 1:

• Potassium supplements
• Salt substitutes (e.g., DASH diet components)
• High-potassium fruits (bananas, melons, orange juice)
• Herbal products (alfalfa, dandelion, hawthorne berry, horsetail, lily of the valley, milkweed, nettle, noni juice, Siberian ginseng)

Pseudo-hyperkalemia

Important to recognize false elevations of potassium 1:

• Hemolysis during blood collection
• Prolonged tourniquet use
• Fist clenching during venipuncture
• Thrombocytosis (>1,000/μL)
• Leukocytosis (>100,000/μL)

Clinical Pearls and Pitfalls

• Critical Threshold: Hyperkalemia is particularly dangerous when serum K+ exceeds 6.0 mEq/L or when ECG changes are present 4
• Monitoring Frequency: Patients on RAAS inhibitors with eGFR <60 ml/min require more frequent potassium monitoring 1
• Drug Combinations: The risk of hyperkalemia increases significantly with concurrent use of multiple potassium-affecting medications (e.g., ACE inhibitor + spironolactone) 2
• Renal Function: eGFR <50 ml/min represents a critical threshold for hyperkalemia risk in patients on potassium-influencing medications 2
• Avoid Triple Therapy: Combination of ACE inhibitor, ARB, and aldosterone antagonist significantly increases hyperkalemia risk 4

Understanding these causes allows for appropriate prevention, monitoring, and management strategies to reduce morbidity and mortality associated with hyperkalemia.