What are the causes of hyperkalemia in patients, particularly those with chronic kidney disease or adrenal insufficiency?

Causes of Hyperkalemia

Primary Mechanisms

Hyperkalemia results from three fundamental mechanisms: impaired renal potassium excretion (the dominant cause), transcellular shift of potassium out of cells, or excessive potassium intake. 1

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Impaired Renal Potassium Excretion

This is the most common pathway leading to sustained hyperkalemia in clinical practice:

Chronic Kidney Disease

• The incidence of hyperkalemia increases dramatically with severity of renal impairment, occurring in up to 73% of patients with advanced CKD. 1, 2
• Risk progressively increases as eGFR decreases, particularly when eGFR falls below 60 mL/min per 1.73 m². 1
• Renal potassium excretion typically is maintained until GFR decreases to less than 10 to 15 mL/min/1.73 m². 3

Acute Kidney Injury

• AKI 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

Hypoaldosteronism

• Diabetes mellitus increases the risk of hyperkalemia through hyporeninemic hypoaldosteronism and insulin deficiency, even in patients with normal kidney function. 1
• Heparin and derivatives can suppress aldosterone synthesis, contributing to hyperkalemia. 1

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Medication-Induced Hyperkalemia

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, 2

RAAS Inhibitors

• ACE inhibitors, ARBs, and direct renin inhibitors (aliskiren) impair aldosterone-mediated potassium excretion. 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. 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. 2

Potassium-Sparing Diuretics

• Amiloride and triamterene impair renal potassium excretion. 2
• Trimethoprim and pentamidine can block epithelial sodium channels in the collecting duct, leading to hyperkalemia. 1

NSAIDs

• NSAIDs impair renal potassium excretion by reducing prostaglandin synthesis. 1, 2

Beta-Blockers

• Beta-blockers can impair cellular potassium uptake, increasing the risk of hyperkalemia. 1

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Transcellular Potassium Shift

Potassium moves from the intracellular to extracellular compartment, causing acute elevations:

Metabolic Acidosis

• Metabolic acidosis causes potassium to shift out of cells in exchange for hydrogen ions. 1

Insulin Deficiency

• Insulin deficiency can impair 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
• Tumor lysis syndrome can occur within 12-72 hours after initiating chemotherapy, radiation, or cytolytic antibody therapy, and is most common in malignancies with high proliferative rates. 2

Hemolysis

• Hemolysis can occur in the body (true hyperkalemia) or in the test tube (pseudohyperkalemia). 1

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Excessive Potassium Intake

Excessive intake alone rarely causes hyperkalemia in patients with normal renal function, but significantly worsens hyperkalemia when renal excretion is impaired:

Dietary Sources

• High-potassium foods: bananas, oranges, melons, potatoes, tomato products, legumes, lentils, yogurt, and chocolate. 3, 1, 2
• Breast milk (mature) has the lowest potassium content (546 mg/L) compared with standard commercial cow's milk-based infant formulas (700 to 740 mg/L). 3

Salt Substitutes

• Salt substitutes often contain potassium chloride and may cause hyperkalemia with life-threatening consequences in individuals with hyperkalemia or a tendency toward it. 3, 1

Potassium Supplements

• Potassium supplements are a direct exogenous source of potassium. 1

Blood Products

• Stored blood products can release significant potassium during transfusion. 2, 4

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High-Risk Populations

Certain patient populations have dramatically elevated risk of developing hyperkalemia: 1

• Advanced CKD (up to 73% prevalence) 1, 2
• Chronic heart failure (up to 40% prevalence) 1, 2
• Diabetes mellitus (through hyporeninemic hypoaldosteronism) 1, 2
• Advanced age (altered potassium homeostasis) 1, 2
• Resistant hypertension and myocardial infarction 1

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Pseudohyperkalemia

Pseudohyperkalemia represents falsely elevated potassium in the test tube without true elevation in the body. 1

Causes

• Hemolysis during blood draw 1, 2
• Prolonged tourniquet application 1
• Fist clenching during phlebotomy 1
• Thrombocytosis or leukocytosis 1
• Delayed specimen processing 1

Diagnostic Approach

• If pseudohyperkalemia is suspected, repeat measurement with proper blood sampling technique or obtain an arterial sample for confirmation. 1
• Plasma potassium concentrations are usually 0.1-0.4 mEq/L lower than serum levels due to platelet potassium release during coagulation. 1

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Critical Clinical Context

• 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
• 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. 1