What is the differential diagnosis for hyperkalaemia?

Differential Diagnosis of Hyperkalemia

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

Primary Mechanisms and Causes

Decreased Renal Potassium Excretion

This is the most important mechanism causing sustained hyperkalemia in everyday practice. 2

• Chronic kidney disease: The incidence increases dramatically with severity of renal impairment, occurring in up to 73% of patients with advanced CKD 1
• Acute kidney injury: Often accompanied by acute pancreatitis or hepatic failure, and was present in all cases of hyperkalemia-induced cardiac arrest in one retrospective analysis 1
• Risk escalates progressively as eGFR decreases, particularly when eGFR falls below 60 mL/min per 1.73 m² in patients on RAAS inhibitors 1
• Hyperkalemia risk is generally increased once eGFR is less than 15 mL/min per 1.73 m² 3

Drug-Induced Hyperkalemia (Most Important Iatrogenic Cause)

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

RAAS Inhibitors

• ACE inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs) reduce aldosterone activity, impairing renal potassium excretion 3, 4
• Patients receiving RAAS inhibitors who have an eGFR of less than 60 mL/min per 1.73 m² have elevated hyperkalemia risk, which progressively increases as eGFR decreases 3

Potassium-Sparing Diuretics

• Spironolactone, triamterene, and amiloride block aldosterone or epithelial sodium channels in the collecting duct 1, 4

NSAIDs

• Impair renal potassium excretion by reducing prostaglandin synthesis 1, 4

Other Medications

• Trimethoprim and pentamidine block epithelial sodium channels in the collecting duct 3, 4
• Heparin and derivatives suppress aldosterone synthesis 3, 4
• Beta-blockers reduce renin release and impair cellular potassium uptake 3, 1
• Calcineurin inhibitors (cyclosporine, tacrolimus) impair renal potassium excretion 3, 4
• Digitalis in toxic doses causes hyperkalemia 4

Transcellular Potassium Shift

These causes lead to transient increases in plasma potassium concentration. 2

• Metabolic acidosis: Potassium shifts out of cells in exchange for hydrogen ions 1, 5
• Insulin deficiency: Impairs cellular potassium uptake via Na/K-ATPase 3
• Massive tissue breakdown: Rhabdomyolysis, tumor lysis syndrome, and severe burns release large amounts of intracellular potassium 1, 5
• Hemolysis: Can occur in the body (true hyperkalemia) or in the test tube (pseudohyperkalemia) 1
• Medications causing transcellular shift: Amino acids, beta-blockers, calcium channel blockers, suxamethonium, and mannitol 4

Excessive Potassium Intake

Excessive intake can cause hyperkalemia but usually only in the setting of impaired renal function. 2

• Potassium supplements are a direct exogenous source 1
• Salt substitutes often contain potassium chloride (e.g., DASH diet products) 1
• High-potassium foods: Bananas, melons, orange juice, potatoes, and tomatoes 1
• Stored blood products contain elevated potassium 6
• Herbal supplements: Alfalfa, dandelion, horsetail 6

Hypoaldosteronism

• Hyporeninemic hypoaldosteronism in diabetes mellitus increases hyperkalemia risk even in patients with normal kidney function 1
• Addison's disease (primary adrenal insufficiency) causes aldosterone deficiency 5

High-Risk Patient Populations

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

• Advanced stages of CKD 3, 1
• Heart failure 3, 1
• Diabetes mellitus 3, 1
• Resistant hypertension 3
• Myocardial infarction 3
• Advanced age (associated with altered potassium homeostasis) 3, 1
• Men have slightly higher risk than women after RAAS inhibitor initiation 1

Pseudohyperkalemia (Critical to Rule Out)

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

• Hemolysis during blood draw 1
• Prolonged tourniquet application 1
• Fist clenching during phlebotomy 1
• Thrombocytosis or leukocytosis (potassium release from cells during clotting) 1
• Delayed specimen processing 6
• If 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

Clinical Context and Multiple Mechanisms

Multiple mechanisms of hyperkalemia often coexist, such as CKD + RAAS inhibitor + NSAID. 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
• The prevalence varies dramatically by setting: 2-4% in the general population, 10-55% in hospitalized patients, and up to 73% in advanced CKD 1

Common Pitfalls to Avoid

• Always rule out pseudohyperkalemia before initiating aggressive treatment 1, 6
• Review the complete medication list systematically—drug-induced hyperkalemia is the most important cause in everyday practice 4
• Recognize that dietary restriction alone is unlikely to resolve hyperkalemia when renal function is impaired 2
• Remember that transcellular shifts cause transient hyperkalemia, while impaired renal excretion causes sustained elevation 2