Cited Evidence on Causes and Risk Factors of Hyperkalemia

Primary Pathophysiologic Mechanisms

Hyperkalemia arises through three main mechanisms: (1) increased potassium intake, (2) reduced renal potassium excretion (the most common mechanism), and (3) transcellular shift of potassium from the intracellular to the extracellular compartment. 1, 2

Renin‑angiotensin‑aldosterone system (RAAS) inhibitors—including ACE inhibitors, ARBs, mineralocorticoid‑receptor antagonists, and direct renin inhibitors—are associated with impaired potassium excretion and increased hyperkalemia risk. 3, 1
Potassium‑sparing diuretics (spironolactone, triamterene, amiloride) decrease renal potassium loss and predispose to hyperkalemia. 3, 1
Non‑steroidal anti‑inflammatory drugs (NSAIDs) reduce renal prostaglandin‑mediated flow, limiting potassium clearance. 3, 1
Sacubitril/valsartan (ARNI) can impair potassium excretion. 3
β‑blockers diminish cellular potassium uptake, contributing to retention. 3, 1
Calcineurin inhibitors (cyclosporine, tacrolimus) suppress aldosterone activity and reduce potassium excretion. 3, 1
Trimethoprim‑sulfamethoxazole interferes with distal tubular potassium handling. 3, 1
Heparin can cause hypoaldosteronism and potassium retention. 3, 1
Pentamidine, digitalis, penicillin G, and mannitol have all been linked to reduced potassium excretion. 3, 1

Chronic kidney disease (CKD) is a major driver of hyperkalemia; up to 73 % of patients with advanced CKD develop elevated serum potassium. 1, 2
Heart failure (HF) is associated with hyperkalemia in up to 40 % of patients with chronic HF. 1, 2
Diabetes mellitus, through hypoaldosteronism, increases the likelihood of hyperkalemia. 1

Oral potassium supplements can precipitate hyperkalemia, especially in the setting of reduced renal clearance. 3, 1
Salt substitutes (e.g., potassium‑based DASH diet products) have been implicated in hyperkalemia. 3, 4
High‑potassium foods (bananas, melons, orange juice, potatoes, tomato products, legumes, yogurt, chocolate) may contribute when renal excretion is compromised. 3, 4
Certain herbal supplements (alfalfa, dandelion, hawthorn berry, horsetail, lily of the valley, milkweed, noni juice, Siberian ginseng, dried toad skin) have been reported to raise serum potassium. 3, 1
Amino acids such as aminocaproic acid, arginine, and lysine can increase potassium load. 3
Stored blood products contain high potassium concentrations and may cause hyperkalemia after transfusion. 3, 1

Metabolic acidosis promotes potassium efflux from cells, leading to transient hyperkalemia. 4, 5
Tissue destruction (catabolism, infection, surgery, chemotherapy, tumor‑lysis syndrome) releases intracellular potassium. 4
In‑vivo hemolysis releases potassium into the circulation. 1, 2
β‑blocker therapy impairs cellular potassium uptake, contributing to a shift. 3

Pseudo‑hyperkalemia denotes a falsely elevated serum potassium due to potassium release from blood cells during or after sampling, not reflecting true extracellular potassium. 1, 2
Causes include:
- Hemolysis during blood draw (e.g., repeated fist clenching, poor phlebotomy technique). 1, 5
- Prolonged tourniquet application. 5
- Thrombocytosis or leukocytosis, where platelets or white cells release potassium during clotting. 1
Serum potassium concentrations are typically 0.1–0.4 mEq/L higher than plasma values because of platelet potassium release; repeat measurement with a properly obtained arterial or plasma sample is recommended when pseudo‑hyperkalemia is suspected. 1, 5

The presence of multiple risk factors (cardiovascular disease, renal impairment, diabetes, advanced age) markedly increases the likelihood of hyperkalemia. 1, 2

Patients receiving RAAS inhibitors who have CKD experience an incidence rise from < 2 % with monotherapy to 5–10 % when dual RAAS inhibition is used. 3
Advanced CKD patients show a prevalence of hyperkalemia of 2–4 % in the general population but 10–55 % among hospitalized individuals. 1, 2
Individuals on multiple potassium‑retaining medications are at heightened risk. 3

Evaluate for pseudo‑hyperkalemia, in‑vivo hemolysis, metabolic acidosis, exogenous potassium sources (medications, supplements, salt substitutes), constipation (reduced gastrointestinal potassium elimination), inadequate dialysis, and review of all potassium‑affecting drugs. All these considerations are supported by the literature. 4

Discontinuing life‑saving RAAS inhibitor therapy solely because of hyperkalemia is associated with higher mortality and major adverse cardiovascular events compared with continuation of therapy combined with appropriate hyperkalemia management. 3, 5