Causes of Hyperkalemia
Primary Mechanisms
Hyperkalemia results from three fundamental mechanisms: decreased renal potassium excretion (the dominant cause in clinical practice), transcellular shift of potassium out of cells, or excessive potassium intake 1.
Decreased Renal Potassium Excretion
This is the most clinically important mechanism in everyday practice.
Chronic Kidney Disease
- The incidence of hyperkalemia increases dramatically with declining kidney function, occurring in up to 73% of patients with advanced chronic kidney disease (eGFR <15 mL/min/1.73 m²) 2, 3.
- Hyperkalemia risk progressively increases as eGFR decreases, particularly when eGFR falls below 60 mL/min/1.73 m² in patients on RAAS inhibitors 4.
- Even moderate renal impairment (eGFR 30-60 mL/min/1.73 m²) significantly increases risk, especially when combined with medications affecting potassium homeostasis 2.
Acute Kidney Injury
- Acute kidney injury is often accompanied by acute pancreatitis or hepatic failure, and was present in all cases of hyperkalemia-induced cardiac arrest in one retrospective analysis 4.
- AKI dramatically impairs the kidney's ability to excrete potassium, leading to rapid accumulation 2.
Medication-Induced Hyperkalemia (Most Important Iatrogenic Cause)
Medications, particularly RAAS inhibitors, represent the most important iatrogenic cause of hyperkalemia in everyday clinical practice 2, 4.
RAAS Inhibitors (ACE Inhibitors, ARBs, Direct Renin Inhibitors)
- Up to 50% of patients on RAAS inhibitors develop hyperkalemia in real-world settings, far exceeding the 6-12% seen in controlled trials 3.
- ACE inhibitors cause hyperkalemia in 15-30% of severe heart failure patients and 5-15% of those with mild-moderate symptoms 3.
- In hypertensive patients without risk factors, the incidence is <2% with monotherapy, increasing to 5% with dual RAAS inhibition and 5-10% when administered in patients with heart failure or chronic kidney disease 2.
- These medications reduce renal potassium excretion by interfering with aldosterone production and secretion 5, 6.
Mineralocorticoid Receptor Antagonists (MRAs)
- Up to one-third of heart failure patients starting MRAs develop hyperkalemia (>5.0 mEq/L) over 2 years 3.
- Spironolactone, eplerenone, and other aldosterone antagonists block the kaliuretic effects of aldosterone 2, 5.
- The combination of ACE inhibitors/ARBs with MRAs dramatically increases hyperkalemia risk 2.
Potassium-Sparing Diuretics
- Spironolactone, triamterene, and amiloride may cause severe hyperkalemia, especially when combined with ACE inhibitors or ARBs 2, 3, 4.
- These agents block aldosterone's effects on the cortical collecting duct 5, 6.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
- NSAIDs impair renal potassium excretion by reducing prostaglandin synthesis, causing sodium retention, peripheral vasoconstriction, and worsening renal function 2, 3, 4.
- NSAIDs are particularly dangerous when combined with RAAS inhibitors, dramatically increasing hyperkalemia risk 2.
Other Medications Impairing Renal Excretion
- Beta-blockers decrease potassium excretion and can impair cellular potassium uptake 2, 4, 6.
- Trimethoprim and pentamidine block epithelial sodium channels in the collecting duct 2, 4, 5.
- Heparin and derivatives suppress aldosterone synthesis 2, 4, 5.
- Calcineurin inhibitors (cyclosporine, tacrolimus) interfere with aldosterone production 2, 5, 6.
- Sacubitril/valsartan can cause hyperkalemia through RAAS inhibition 2.
- Digitalis (in overdose) causes hyperkalemia through Na-K-ATPase inhibition 2, 5.
Transcellular Potassium Shift
These causes lead to transient increases in plasma potassium concentration 1.
Metabolic Acidosis
- Metabolic acidosis causes potassium to shift out of cells in exchange for hydrogen ions 4, 1.
- This mechanism is particularly important in diabetic ketoacidosis 4.
Insulin Deficiency
- Insulin deficiency impairs cellular potassium uptake via Na/K-ATPase 4, 6.
- This is a key mechanism in diabetic patients with hyperkalemia 4.
Massive Tissue Breakdown
- Rhabdomyolysis, tumor lysis syndrome, and severe burns release large amounts of intracellular potassium 4, 1.
- Significant tissue trauma is a predisposing condition for hyperkalemia 7.
Hemolysis
Medications Causing Transcellular Shift
- Succinylcholine causes potassium release from muscle cells 2, 5, 6.
- Hypertonic mannitol causes transcellular shift 2, 5.
- Amino acids (aminocaproic acid, arginine, lysine) can cause potassium shift 2, 6.
Excessive Potassium Intake
Excessive intake of potassium can cause hyperkalemia but usually only in the setting of impaired renal function 4, 1.
Potassium Supplements
- Potassium supplements are a direct exogenous source of potassium 2, 4.
- This is particularly problematic in patients with renal impairment or on RAAS inhibitors 2.
Salt Substitutes
- Salt substitutes often contain potassium chloride (e.g., DASH diet products) 2, 4.
- These are frequently overlooked sources of potassium intake 2.
High-Potassium Foods
- Bananas, melons, orange juice, potatoes, tomatoes, and legumes can contribute to hyperkalemia 2, 4.
- Fruits and vegetables high in potassium become problematic in patients with impaired renal function 2.
Nutritional Supplements and Herbal Products
- Alfalfa, dandelion, dried toad skin, hawthorne berry, horsetail, lily of the valley, milkweed, nettle, noni juice, and Siberian ginseng 2.
- These are often "hidden" sources of potassium that patients may not report 2.
Stored Blood Products
- Stored blood products contain significant amounts of potassium 2.
- This is particularly relevant in massive transfusion scenarios 2.
High-Risk Patient Populations
Certain patient populations have dramatically elevated risk of developing hyperkalemia 2, 3, 4.
Comorbid Conditions
- Advanced chronic kidney disease (up to 73% affected) 2, 3.
- Chronic heart failure (up to 40% affected) 2, 3.
- Diabetes mellitus increases risk through hyporeninemic hypoaldosteronism and insulin deficiency 3, 4.
- Advanced age is associated with altered potassium homeostasis 3, 4.
- Resistant hypertension requiring multiple medications 3.
- Myocardial infarction patients, especially on RAAS inhibitors 3.
Multiple Risk Factors
- 50% of cardiovascular disease patients with chronic kidney disease experience two or more recurrences of hyperkalemia within 1 year 3.
- Multiple mechanisms of hyperkalemia often coexist (e.g., CKD + RAAS inhibitor + NSAID) 4.
- Initial moderate to severe hyperkalemia (>5.6 mEq/L), low eGFR (<45 mL/min/1.73 m²), diabetes mellitus, and concurrent spironolactone use predict recurrent episodes 3.
Pseudohyperkalemia
Pseudohyperkalemia represents falsely elevated potassium in the test tube without true elevation in the body 2, 4.
Causes of Pseudohyperkalemia
- Hemolysis during blood draw 2, 4.
- Prolonged tourniquet application 4.
- Fist clenching during phlebotomy 4.
- Thrombocytosis or leukocytosis causing potassium release during clotting 4.
- Delayed specimen processing 4.
Diagnostic Approach
- If pseudohyperkalemia is suspected, repeat measurement with proper blood sampling technique or obtain an arterial sample for confirmation 2, 4.
- Plasma potassium concentrations are usually 0.1-0.4 mEq/L lower than serum levels due to platelet potassium release during coagulation 4.
Critical Clinical Context
Prevalence by Setting
- The prevalence of hyperkalemia varies dramatically by setting: 2-4% in the general population, 10-55% in hospitalized patients, and up to 73% in advanced CKD 2, 4.
- Hyperkalemia is present in 10-55% of patients hospitalized for any cause, depending on the potassium level used to define hyperkalemia 2.
Rate of Rise Matters
- Both the absolute potassium level and the rate of rise determine clinical significance, with rapid increases more likely to cause cardiac abnormalities than gradual elevations over months 4.
- This is why acute hyperkalemia from medications or AKI is more dangerous than chronic hyperkalemia in CKD 7.
Common Clinical Pitfall
- Hyperkalemia is frequently under-monitored in patients on RAAS inhibitors despite guideline recommendations 3.
- Less than one-third of patients achieve guideline-recommended target doses of RAAS inhibitors due to hyperkalemia concerns 3.
- Clinicians should not discontinue or reduce RAAS inhibitors after a single elevated potassium measurement without proper evaluation 3.