Causes of Hyperkalemia
Hyperkalemia is primarily caused by impaired renal excretion of potassium, medication effects, transcellular shifts, and increased potassium intake, with renal dysfunction being the most significant risk factor. 1
Major Causes of Hyperkalemia
1. Impaired Renal Excretion
- Renal dysfunction: The most significant risk factor, with patients having eGFR <50 ml/min showing a fivefold increased risk for hyperkalemia when using potassium-influencing medications 2
- Acute kidney injury (AKI) and chronic kidney disease (CKD): Decreased tubular flow rate in AKI and limitations in adaptive responses in CKD 3
- Hyporeninemic hypoaldosteronism: Results in diminished circulating aldosterone concentrations 3
2. Medication-Induced Hyperkalemia
Medications can cause hyperkalemia through several mechanisms:
Medications that Inhibit Renin-Angiotensin-Aldosterone System
- Angiotensin-converting enzyme inhibitors (ACEIs)
- Angiotensin-II receptor blockers (ARBs)
- Direct renin inhibitors
- Aldosterone antagonists (spironolactone, eplerenone)
- Potassium-sparing diuretics (amiloride, triamterene) 4
Medications that Alter Transmembrane Potassium Movement
- Beta-blockers
- Calcium channel blockers
- Suxamethonium (depolarizing muscle relaxant)
- Mannitol
- Amino acids 4
Other Medications
- NSAIDs (inhibit prostaglandin synthesis and reduce renal blood flow)
- Calcineurin inhibitors (cyclosporine, tacrolimus)
- Heparin and derivatives (suppress aldosterone production)
- Trimethoprim and pentamidine (block distal tubule sodium channels) 4
3. Transcellular Shifts
- Acidosis: Hydrogen ions move into cells, forcing potassium out
- Insulin deficiency/hyperglycemia: Reduces cellular potassium uptake
- Beta-blocker therapy: Blocks cellular potassium uptake
- Cell lysis conditions: Tumor lysis syndrome, rhabdomyolysis, hemolysis, severe burns 1, 5
4. Increased Potassium Intake
- Excessive dietary intake (especially in patients with impaired renal function)
- Potassium supplements
- Potassium-containing salt substitutes
- Blood transfusions (particularly stored blood) 1, 4
Risk Factors for Developing Hyperkalemia
- Decreased renal function: eGFR <50 ml/min is the most significant risk factor 2
- Heart failure: Up to 40% of patients with chronic heart failure develop hyperkalemia 6
- Diabetes mellitus: Often associated with hyporeninemic hypoaldosteronism
- Concomitant use of multiple potassium-influencing medications: Particularly RAAS inhibitors with potassium-sparing diuretics or potassium supplements 2
- Advanced age: Associated with decreased renal function
- Volume depletion: Can worsen renal function and paradoxically increase hyperkalemia risk 6
Clinical Implications
- Hyperkalemia follows a U-shaped mortality curve, with both high and low potassium levels increasing risk 6
- Potassium levels >5 mmol/L are associated with higher mortality in heart failure patients 6
- Even upper normal range potassium levels (4.8-5.0 mmol/L) are associated with increased 90-day mortality in heart failure patients 6
- ECG changes correlate with increasing potassium levels, from peaked T waves at 5.5-6.5 mmol/L to potentially fatal arrhythmias at >10 mmol/L 6
Common Pitfalls and Caveats
- Laboratory errors: Pseudohyperkalemia can occur due to hemolysis during blood collection, thrombocytosis, or leukocytosis
- Overlooking medication interactions: Failing to recognize combinations of medications that synergistically increase potassium levels
- Inadequate monitoring: Not monitoring potassium levels in high-risk patients, especially when starting or adjusting doses of RAAS inhibitors
- Transcellular shifts: Not considering conditions that cause potassium to shift from intracellular to extracellular space
- Rebound hyperkalemia: Can occur after treatment if the underlying cause is not addressed
Understanding these causes and risk factors is essential for preventing, identifying, and appropriately managing hyperkalemia in clinical practice.