How does Amphotericin B (Antifungal medication) cause Acute Kidney Injury (AKI) and what are the strategies to minimize this risk?

Amphotericin B-Induced Acute Kidney Injury

Avoid conventional amphotericin B deoxycholate entirely when treating systemic fungal infections—use azole antifungals, echinocandins, or liposomal amphotericin B instead, as conventional formulations cause nephrotoxicity in the majority of patients through direct tubular damage and renal vasoconstriction. 1

Mechanism of Nephrotoxicity

Amphotericin B causes AKI through two primary pathways:

• Direct tubular toxicity: Amphotericin B binds to cholesterol in mammalian cell membranes, particularly affecting renal tubular cells, leading to cellular dysfunction and death 2, 3
• Renal vasoconstriction: The drug induces afferent arteriolar constriction, reducing renal blood flow and glomerular filtration rate 3
• Pro-inflammatory response: Persistently elevated IL-6 and IL-8 levels during treatment increase the likelihood of AKI by 3.5 to 7-fold, suggesting an immunologically-mediated component 4

The FDA label confirms that decreased renal function occurs commonly, with some permanent impairment often developing, especially in patients receiving over 5 grams total dose 5.

Preferred Antifungal Strategy

The KDIGO guidelines provide a Grade 1A recommendation to use azole antifungals and/or echinocandins rather than conventional amphotericin B when equal therapeutic efficacy can be assumed. 1

When amphotericin B is absolutely necessary:

• Use liposomal formulations exclusively: Liposomal amphotericin B reduces nephrotoxicity risk by approximately 50% compared to conventional formulations (RR 0.49,95% CI 0.40-0.59) 6
• The lipid formulation reduces direct exposure of renal tubular cells to free amphotericin B, explaining the improved safety profile 2
• Despite being less nephrotoxic, 19-50% of patients still develop some degree of renal injury with liposomal preparations 2

Risk Mitigation Strategies

Mandatory Preventive Measures

Before each amphotericin B dose, implement these evidence-based interventions: 1, 5

• Discontinue diuretics prior to treatment initiation 1, 5
• Sodium loading and volume repletion: Administer 0.9% saline intravenously 30 minutes before infusion 2, 5
• Electrolyte supplementation: Provide potassium and magnesium supplementation, particularly with non-liposomal preparations 1, 5
• Avoid rapid infusion: Administer lipid formulations over at least 2 hours to prevent hypotension and arrhythmias 7, 5

Monitoring Requirements

Frequent renal function monitoring is mandatory: 5

• Monitor serum creatinine and electrolytes at minimum once or twice weekly 2
• Check magnesium and potassium levels regularly, as amphotericin B-induced hypokalemia can potentiate cardiac dysfunction and digitalis toxicity 5
• Baseline serum potassium <3.5 mEq/L before therapy is associated with severe AKI (stages 2-3) 8

High-Risk Situations to Avoid

These factors substantially increase AKI risk and should be avoided or carefully managed: 8

• Concomitant nephrotoxic medications: Aminoglycosides, vancomycin, cyclosporine, pentamidine, and NSAIDs enhance nephrotoxicity risk 1, 5
• High doses: Doses above 3.52 mg/kg/day significantly increase renal toxicity risk 8
• Catecholamines or immunosuppressants: Concomitant administration increases AKI likelihood 8
• ACE inhibitors/ARBs or carbapenems: Prior treatment with these agents is associated with higher AKI rates 8

Clinical Caveats

• Dialysis does not remove amphotericin B: Neither hemodialysis nor hemofiltration significantly reduces serum concentrations, so dose adjustment for renal replacement therapy is not required 2
• Cost-effectiveness of liposomal formulations: The decreased incidence of AKI and associated reduction in hospitalization costs makes lipid formulations cost-effective compared to conventional amphotericin B despite higher acquisition costs 1
• Treatment interruption: If therapy is interrupted for more than 7 days, resume with the lowest dosage (0.25 mg/kg) and increase gradually 5
• Even in patients with established AKI requiring urgent antifungal therapy, liposomal amphotericin B can be successfully used when the invasive fungal infection is life-threatening and no suitable alternatives exist 9