What is the mechanism by which Amphotericin B (antifungal medication) causes acute kidney injury and hypokalemia?

Mechanism of Amphotericin B-Induced Acute Kidney Injury and Hypokalemia

Amphotericin B causes acute kidney injury through two primary mechanisms: direct tubular toxicity by binding to cholesterol in renal tubular cell membranes, and renal vasoconstriction that reduces blood flow to the kidneys; hypokalemia occurs through selective distal tubular epithelial damage leading to urinary potassium wasting. 1, 2

Mechanism of Acute Kidney Injury

Direct Tubular Toxicity

• Amphotericin B binds to cholesterol in mammalian cell membranes, particularly affecting renal tubular cells with high cholesterol content, leading to cellular dysfunction and death 1, 3
• This direct tubular damage manifests as both glomerular injury (causing azotemia) and tubular injury (causing electrolyte wasting) 2
• The drug causes a significant decrease in the glomerular capillary ultrafiltration coefficient, reducing the kidney's filtering capacity 4

Renal Vasoconstriction

• Amphotericin B induces significant increases in both pre-glomerular (afferent arteriole) and post-glomerular (efferent arteriole) resistances, reducing renal blood flow by approximately 40% 4
• This vasoconstriction is a direct effect of amphotericin B on contractile vascular cells, not mediated by endothelin, angiotensin II, or nitric oxide systems 5
• The combined effect reduces glomerular filtration rate by approximately 35% acutely 4

Clinical Impact

• Conventional amphotericin B causes nephrotoxicity in the majority of patients, while lipid formulations still cause renal injury in 19-50% of patients 1
• The lipid formulation reduces direct exposure of renal tubular cells to free amphotericin B, explaining its improved safety profile 1, 6

Mechanism of Hypokalemia

Distal Tubular Damage

• Amphotericin B causes selective distal tubular epithelial toxicity, leading to potassium wasting through the distal tubules 2
• This tubular damage results in urinary potassium and magnesium wasting, independent of the glomerular effects 2

Clinical Manifestations

• Hypokalemia occurs in up to 80% of patients receiving conventional amphotericin B treatment 2
• The severity increases with higher doses (>1 mg/kg) 2
• Rapid intravenous infusion is associated with acute hypokalemia, arrhythmias, and hypotension 3

Clinical Consequences

• Amphotericin B-induced hypokalemia can potentiate digitalis toxicity, requiring close monitoring of serum potassium levels and cardiac function 3
• Hypokalemia may enhance the curariform effect of skeletal muscle relaxants 3
• Corticosteroids and ACTH may potentiate amphotericin B-induced hypokalemia, predisposing patients to cardiac dysfunction 3

Prevention Strategies

Mandatory Interventions

• Discontinue diuretics before each amphotericin B dose 1
• Administer 0.9% saline intravenously 30 minutes before infusion for sodium loading and volume repletion 1, 2, 3
• Provide potassium and magnesium supplementation, particularly with non-liposomal preparations 1

Monitoring Requirements

• Monitor serum creatinine and electrolytes at minimum once or twice weekly 1, 3
• Check magnesium and potassium levels regularly, as hypokalemia can potentiate cardiac dysfunction 1

Important Caveats

• Avoid concomitant nephrotoxic medications (aminoglycosides, vancomycin, cyclosporine, pentamidine, NSAIDs) which enhance nephrotoxicity risk 1, 3
• Dialysis does not remove amphotericin B, so dose adjustment for renal replacement therapy is not required 1
• Supplemental alkali medication may decrease renal tubular acidosis complications 3