Causes of Hyperkalemia
Primary Mechanisms
Hyperkalemia develops through three fundamental pathways: impaired renal potassium excretion (the dominant cause in clinical practice), transcellular shift of potassium from cells into the bloodstream, or excessive potassium intake—though intake alone rarely causes hyperkalemia without concurrent renal dysfunction. 1, 2
Decreased Renal Potassium Excretion
This represents the most common mechanism for sustained hyperkalemia in clinical practice.
Chronic Kidney Disease
- The incidence of hyperkalemia increases dramatically as kidney function declines, occurring in up to 73% of patients with advanced CKD 1
- Risk escalates progressively when eGFR falls below 60 mL/min per 1.73 m², with particularly high risk when eGFR drops below 15 mL/min per 1.73 m² 1
Acute Kidney Injury
- AKI is frequently accompanied by acute pancreatitis or hepatic failure, and was present in all cases of hyperkalemia-induced cardiac arrest in one retrospective analysis 1
Hypoaldosteronism
- Diabetes mellitus increases hyperkalemia risk through hyporeninemic hypoaldosteronism and insulin deficiency, even with normal kidney function 1
- Heparin and derivatives suppress aldosterone synthesis 1
Reduced Distal Sodium Delivery
- Impaired sodium delivery to the distal nephron reduces the driving force for potassium secretion 2, 3
Drug-Induced Hyperkalemia
Medications represent the most important iatrogenic cause of hyperkalemia in everyday clinical practice, with RAAS inhibitors being the primary culprits. 1, 4
RAAS Inhibitors
- ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists cause hyperkalemia in up to 40% of heart failure patients and 5-10% of those on combination therapy 1
- The triple combination of ACE inhibitor + ARB + MRA carries excessive hyperkalemia risk and is not recommended 5
Potassium-Sparing Diuretics
- Spironolactone, triamterene, and amiloride directly impair renal potassium excretion 1
- Amiloride and triamterene must be avoided when using MRAs due to compounded hyperkalemia risk 5
NSAIDs
- NSAIDs impair renal potassium excretion by reducing prostaglandin synthesis and attenuating diuretic effects 1, 5
Other Medications
- Trimethoprim and pentamidine block epithelial sodium channels in the collecting duct 1, 4
- Beta-blockers impair cellular potassium uptake via Na/K-ATPase inhibition 1, 4
- Calcineurin inhibitors (tacrolimus, cyclosporine) reduce renal potassium excretion 4
Transcellular Potassium Shift
These mechanisms cause transient hyperkalemia by releasing intracellular potassium into the bloodstream.
Metabolic Acidosis
Insulin Deficiency
- Insulin deficiency impairs cellular potassium uptake via Na/K-ATPase 1
Massive Tissue Breakdown
- Rhabdomyolysis, tumor lysis syndrome, and severe burns release large amounts of intracellular potassium 1, 6
- Hemolysis can occur in vivo (true hyperkalemia) or in vitro (pseudohyperkalemia) 1
Hyperglycemia
- Elevated glucose levels can promote transcellular potassium shifts 7
Excessive Potassium Intake
Excessive intake alone rarely causes sustained hyperkalemia unless renal excretion is impaired, but it significantly worsens hyperkalemia when kidney function is compromised. 1, 3
Exogenous Sources
- Potassium supplements provide direct potassium loading 1
- Salt substitutes often contain potassium chloride (common in DASH diet products) 1
- High-potassium foods include bananas, melons, orange juice, potatoes, and tomatoes 1
- Stored blood products release significant potassium during transfusion 8
Pseudohyperkalemia
Before concluding true hyperkalemia exists, pseudohyperkalemia must be excluded—this represents falsely elevated potassium in the test tube without true elevation in the body. 1, 3
Causes
- Hemolysis during blood draw 1, 3
- Prolonged tourniquet application or fist clenching during phlebotomy 1
- Thrombocytosis or leukocytosis (platelets and white blood cells release potassium during clotting) 1
- Delayed specimen processing 1
Diagnostic Approach
- Plasma potassium concentrations are typically 0.1-0.4 mEq/L lower than serum levels due to platelet potassium release during coagulation 1
- If suspected, repeat measurement with proper blood sampling technique or obtain an arterial sample for confirmation 1, 3
High-Risk Patient Populations
Comorbidities
- Advanced CKD, heart failure, diabetes mellitus, resistant hypertension, myocardial infarction, and advanced age dramatically elevate hyperkalemia risk 1
- Men have slightly higher risk than women after RAAS inhibitor initiation 1
Multiple Concurrent Mechanisms
- Multiple mechanisms frequently coexist (e.g., CKD + RAAS inhibitor + NSAID), compounding hyperkalemia risk 1, 5
Clinical Context and Prevalence
- Prevalence varies dramatically by setting: 2-4% in the general population, 10-55% in hospitalized patients, and up to 73% in advanced CKD 1
- Both the absolute potassium level and the rate of rise determine clinical significance—rapid increases are more likely to cause cardiac abnormalities than gradual elevations over months 1, 8