Main Causes of Hyperkalemia
The primary causes of hyperkalemia are impaired renal potassium excretion (particularly in chronic kidney disease), medications that interfere with the renin-angiotensin-aldosterone system, and transcellular potassium shifts from cells into the extracellular space. 1, 2
Mechanisms of Hyperkalemia
Hyperkalemia develops through three fundamental pathways that often overlap in clinical practice:
1. Impaired Renal Potassium Excretion
Renal insufficiency is the most critical cause, with incidence increasing dramatically as kidney function declines, particularly when eGFR falls below 15 mL/min/1.73 m² 1. Patients with chronic kidney disease lose their adaptive capacity to excrete potassium loads, despite compensatory mechanisms that increase potassium excretion per remaining nephron 3.
- Up to 73% of patients with advanced chronic kidney disease develop hyperkalemia 1
- Decreased tubular fluid flow rate in acute renal failure directly impairs distal tubule potassium secretion 3
- Hyporeninemic hypoaldosteronism reduces circulating aldosterone, further limiting renal potassium excretion 3
2. Drug-Induced Hyperkalemia
Medications represent the most important cause of hyperkalemia in everyday clinical practice, primarily through inhibition of the renin-angiotensin-aldosterone system 2. This mechanism is particularly problematic because these medications are guideline-recommended therapies for cardiovascular disease.
Key medication classes include:
- RAAS inhibitors (ACE inhibitors, ARBs, direct renin inhibitors like aliskiren): Block aldosterone-mediated potassium excretion 1, 2
- Mineralocorticoid receptor antagonists (spironolactone, eplerenone): Up to one-third of heart failure patients starting an MRA develop hyperkalemia (>5.0 mEq/L) over 2 years 4
- Potassium-sparing diuretics: Directly inhibit renal potassium excretion 2
- NSAIDs: Impair renal potassium handling 1, 2
- Other agents: Trimethoprim, pentamidine, calcineurin inhibitors, heparin 2
In real-world settings, the incidence of hyperkalemia can reach 50% in unselected populations receiving RAAS inhibitors, far exceeding the 6-12% seen in controlled clinical trials 4.
3. Transcellular Potassium Shifts
Drugs and conditions that promote potassium movement from intracellular to extracellular compartments 2:
- Beta-blockers: Impair cellular potassium uptake 2
- Hyperglycemia: Common in diabetic patients 5
- Amino acids, calcium channel blockers, suxamethonium, mannitol: Alter transmembrane potassium movement 2
4. Increased Potassium Supply
- Dietary sources: Potassium-rich foods including bananas, melons, orange juice, and vegetables 1
- Stored blood products: Particularly relevant in transfusion settings 1
- Potassium-containing medications: Direct exogenous potassium load 2
High-Risk Populations
Certain patient groups face substantially elevated risk:
- Chronic heart failure patients: Up to 40% develop hyperkalemia 1
- Diabetic patients: Multiple mechanisms including hyporeninemic hypoaldosteronism and medication use 1, 5
- Elderly patients: Age-related decline in renal function and polypharmacy 1
Critical Clinical Context
Hyperkalaemia is frequently under-monitored in patients treated with RAAS inhibitors despite guideline recommendations 4. This represents a major quality gap, as 50% of cardiovascular disease patients with chronic kidney disease experience two or more recurrences within 1 year 4.
A common pitfall: Clinicians often discontinue or reduce RAAS inhibitors after a single elevated potassium measurement, offsetting the survival benefits of these medications 4. In the ESC Heart Failure Long-Term Registry, hyperkalemia was the reason for non-use of ACE inhibitors/ARBs in 8.5% and MRAs in 35.1% of patients, yet less than one-third achieved guideline-recommended target doses 4.