What causes hyperkalemia in patients, especially those with a history of kidney disease or heart failure?

Hyperkalemia Causes

Hyperkalemia results from three fundamental mechanisms: impaired renal potassium excretion (the dominant cause), transcellular shift of potassium out of cells, or excessive potassium intake—with decreased renal excretion being by far the most important in clinical practice. 1

Primary Mechanisms

Impaired Renal Potassium Excretion (Most Common)

• The kidneys are the primary regulators of potassium homeostasis, and impaired renal excretion is the dominant cause of sustained hyperkalemia in clinical practice. 1
• The incidence of hyperkalemia increases dramatically with severity of renal impairment, occurring in up to 73% of patients with advanced chronic kidney disease (CKD). 1
• Risk increases progressively as eGFR decreases, particularly when eGFR falls below 60 mL/min per 1.73 m², and is generally increased once eGFR is less than 15 mL/min per 1.73 m². 1
• 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. 1

Transcellular Potassium Shift

• Metabolic acidosis causes potassium to shift out of cells in exchange for hydrogen ions, raising serum potassium without total body potassium excess. 1
• Massive tissue breakdown releases large amounts of intracellular potassium into the bloodstream, including rhabdomyolysis, tumor lysis syndrome (within 12-72 hours after initiating chemotherapy), and severe burns. 1, 2
• Insulin deficiency impairs cellular potassium uptake via Na/K-ATPase, leading to extracellular potassium accumulation. 1
• Hemolysis can occur in the body (true hyperkalemia) or in the test tube (pseudohyperkalemia). 1

Excessive Potassium Intake

• Potassium supplements are a direct exogenous source that can precipitate hyperkalemia, particularly in patients with impaired renal function. 1
• Salt substitutes often contain potassium chloride (commonly used in DASH diet products) and can contribute significantly to potassium load. 1
• High-potassium foods include bananas, melons, orange juice, potatoes, tomatoes, chocolate, yogurt, and other dairy products. 1, 2
• Stored blood products can increase potassium levels, especially with massive transfusion. 2

Drug-Induced Hyperkalemia (Most Important Iatrogenic Cause)

RAAS Inhibitors

• Medications, particularly RAAS inhibitors, represent the most important iatrogenic cause of hyperkalemia in everyday clinical practice, with up to 40% of heart failure patients and 5-10% of combination therapy patients developing hyperkalemia. 1
• ACE inhibitors cause hyperkalemia in CHF or uremia patients, though increases are generally modest (1 mEq/L), with only 6.4% of patients in SOLVD trials developing serum potassium levels ≥5.5 mEq/L. 3
• 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. 2
• Up to one-third of heart failure patients starting a mineralocorticoid receptor antagonist (MRA) develop hyperkalemia (>5.0 mEq/L) over 2 years. 2

Other Medications

• Potassium-sparing diuretics (spironolactone, triamterene, amiloride) directly impair renal potassium excretion. 1, 2
• NSAIDs impair renal potassium excretion by reducing prostaglandin synthesis and attenuating diuretic effects. 1, 2
• Trimethoprim and pentamidine block epithelial sodium channels in the collecting duct, leading to hyperkalemia. 1
• Heparin and derivatives suppress aldosterone synthesis, contributing to hyperkalemia. 1, 2
• Beta-blockers can impair cellular potassium uptake and contribute to hyperkalemia. 2
• Calcium channel blockers can cause hyperkalemia in certain patients. 2

High-Risk Patient Populations

• Patients with advanced CKD, heart failure, diabetes mellitus, resistant hypertension, myocardial infarction, and advanced age have dramatically elevated risk of developing hyperkalemia. 1
• Men have slightly higher risk than women after RAAS inhibitor initiation. 1
• 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. 1
• Diabetic patients are at increased risk due to hyporeninemic hypoaldosteronism and frequent use of RAAS inhibitors. 1, 2

Pseudohyperkalemia (False Elevation)

• Pseudohyperkalemia represents falsely elevated potassium in the test tube without true elevation in the body, caused by hemolysis during blood draw, prolonged tourniquet application, fist clenching during phlebotomy, or thrombocytosis/leukocytosis. 1
• Plasma potassium concentrations are usually 0.1-0.4 mEq/L lower than serum levels due to platelet potassium release during coagulation. 1
• If pseudohyperkalemia is suspected, repeat measurement with proper blood sampling technique or obtain an arterial sample for confirmation. 1

Critical Clinical Context

• 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. 1
• Multiple mechanisms of hyperkalemia often coexist, such as CKD + RAAS inhibitor + NSAID, amplifying the risk. 1
• Hyperkalemia is a potential complication particularly in patients with diabetes or chronic renal failure, requiring monitoring of serum potassium early after initiation of therapy, appropriate reduction in dietary potassium intake, and avoidance of agents that can aggravate hyperkalemia (potassium-sparing diuretics and NSAIDs). 3