Differential Diagnosis of Hyperkalemia
Primary Mechanisms
Hyperkalemia results from three fundamental mechanisms: decreased renal potassium excretion (the dominant cause), transcellular shift of potassium out of cells, or excessive potassium intake. 1
1. Decreased Renal Potassium Excretion (Most Common)
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
- Risk progressively increases as eGFR decreases, particularly when eGFR falls below 60 mL/min per 1.73 m² in patients on RAAS inhibitors. 2
- Hyperkalemia risk is generally increased once eGFR is less than 15 mL/min per 1.73 m². 2
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 study. 1
- Represents a critical cause requiring immediate recognition and treatment. 3
Medication-Induced Impaired Renal Excretion
- RAAS inhibitors (ACE inhibitors, ARBs, direct renin inhibitors) represent the most important iatrogenic cause in everyday clinical practice, with up to 40% of heart failure patients developing hyperkalemia. 1, 4
- Combination RAAS therapy increases hyperkalemia risk to 5-10% in patients with heart failure or CKD. 1
- Mineralocorticoid receptor antagonists (spironolactone, eplerenone) cause hyperkalemia in up to one-third of heart failure patients. 5
- Potassium-sparing diuretics (triamterene, amiloride) directly impair renal potassium excretion. 1
- NSAIDs impair renal potassium excretion by reducing prostaglandin synthesis. 1, 4
- Calcineurin inhibitors (tacrolimus, cyclosporine) impair renal potassium handling. 4
- Trimethoprim and pentamidine block epithelial sodium channels in the collecting duct. 2, 4
- Heparin and derivatives suppress aldosterone synthesis. 2, 4
Hyporeninemic Hypoaldosteronism
- Common in diabetic nephropathy patients, representing a syndrome of aldosterone deficiency. 3
- Results in impaired distal nephron potassium secretion despite adequate GFR. 6
2. Transcellular Potassium Shift (Out of Cells)
Metabolic Acidosis
- Acidosis causes potassium to shift out of cells in exchange for hydrogen ions. 1
- Each 0.1 unit decrease in pH can increase serum potassium by approximately 0.6 mEq/L. 7
Tissue Breakdown/Cell Lysis
- Rhabdomyolysis releases massive amounts of intracellular potassium from damaged muscle cells. 1
- Tumor lysis syndrome causes rapid cell death with potassium release, particularly after chemotherapy. 1
- Severe burns result in extensive tissue destruction and potassium release. 1
- Hemolysis (intravascular) represents true hyperkalemia from red blood cell destruction. 1
Hyperglycemia and Insulin Deficiency
- Hyperglycemia is a common cause of transcellular potassium shift in diabetic patients. 7
- Insulin deficiency impairs cellular potassium uptake via Na/K-ATPase. 2
Medications Causing Transcellular Shift
- Beta-blockers impair cellular potassium uptake by blocking beta-2 receptors. 4
- Succinylcholine causes potassium release from muscle depolarization. 4
- Digoxin toxicity inhibits Na/K-ATPase, preventing potassium entry into cells. 4
3. Excessive Potassium Intake
Dietary Sources
- High-potassium foods: bananas, melons, orange juice, potatoes, tomatoes. 1, 5
- Salt substitutes often contain potassium chloride (e.g., DASH diet products). 1
- Usually requires concurrent impaired renal function to cause clinically significant hyperkalemia. 6
Exogenous Potassium Administration
- Potassium supplements (oral or intravenous) represent a direct source. 1
- Stored blood products can release significant potassium during transfusion. 5
- Potassium-containing medications and intravenous fluids. 4
4. Pseudohyperkalemia (Laboratory Artifact)
Pseudohyperkalemia represents falsely elevated potassium in the test tube without true elevation in the body. 1
Causes of Pseudohyperkalemia
- Hemolysis during blood draw from traumatic venipuncture or small-gauge needles. 1, 2
- Prolonged tourniquet application with repeated fist clenching. 2, 1
- Delayed specimen processing allowing potassium leakage from cells. 2
- Thrombocytosis (platelet count >400,000/μL) or leukocytosis (WBC >70,000/μL). 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. 2
High-Risk Comorbidities
Certain patient populations have dramatically elevated risk: advanced CKD, heart failure, diabetes mellitus, resistant hypertension, myocardial infarction, and advanced age. 2, 1
- Advanced CKD patients have up to 73% prevalence of hyperkalemia. 1
- Heart failure patients on RAAS inhibitors have 10-55% prevalence when hospitalized. 1
- Diabetes increases risk through multiple mechanisms including hyporeninemic hypoaldosteronism. 2
- Men have slightly higher risk than women after RAAS inhibitor initiation. 2
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
The prevalence varies dramatically: 2-4% in the general population, 10-55% in hospitalized patients, and up to 73% in advanced CKD. 1
Common Diagnostic Pitfalls
- Failing to rule out pseudohyperkalemia before initiating treatment can lead to unnecessary interventions. 5
- Overlooking medication review, particularly NSAIDs, which are often over-the-counter and not reported by patients. 5
- Missing hyporeninemic hypoaldosteronism in diabetic patients with "normal" creatinine. 3
- Not recognizing that multiple mechanisms often coexist (e.g., CKD + RAAS inhibitor + NSAID). 2