What is the nephrotoxic potential of liposomal (Liposomal) amphotericin B (Amphotericin B)?

Nephrotoxicity of Liposomal Amphotericin B

Liposomal amphotericin B is significantly less nephrotoxic than conventional amphotericin B deoxycholate, though approximately 19-50% of patients still experience some degree of renal injury during treatment. 1

Comparative Nephrotoxicity Profile

Liposomal amphotericin B demonstrates substantially reduced nephrotoxicity compared to conventional formulations:

• Nephrotoxicity occurs in approximately 19% of patients receiving liposomal amphotericin B versus 34% with conventional amphotericin B deoxycholate (defined as serum creatinine doubling from baseline). 2
• A systematic review confirmed liposomal amphotericin B is significantly safer, with a relative risk of 0.49 (95% CI 0.40-0.59) for serum creatinine increase compared to conventional formulation. 3
• In recent outpatient therapy studies, approximately 50% of patients experienced some renal injury during treatment, but adverse events were manageable with only 12% requiring readmission and treatment discontinuation in only one patient. 1

Mechanism of Nephrotoxicity

The nephrotoxic effects occur through multiple pathways:

• Liposomal amphotericin B binds to cholesterol in mammalian cell membranes, leading to end-organ dysfunction particularly affecting the kidneys. 4
• Nephrotoxicity manifests as both glomerular damage (causing azotemia) and tubular damage (causing electrolyte wasting including hypokalemia and renal tubular acidosis). 4, 5
• The lipid formulation reduces direct exposure of renal tubular cells to free amphotericin B, explaining the improved safety profile. 1

Risk Factors for Nephrotoxicity

Specific factors increase the risk and severity of renal injury:

• High doses are the primary risk factor for nephrotoxicity - doses above standard (particularly >5 mg/kg/day) significantly increase renal toxicity risk. 1
• Pre-existing renal impairment, diabetes mellitus, and underlying renal disease increase susceptibility. 4
• Concomitant use of other nephrotoxic medications (aminoglycosides, cyclosporine, pentamidine) substantially amplifies nephrotoxic risk. 4, 5
• Volume depletion and advanced age are additional patient-specific risk factors. 6

Time Course of Nephrotoxicity

Renal injury typically develops early in treatment:

• Patients who develop significant renal injury (≥0.5 mg/dL creatinine increase) typically do so within 4.5-9 days of starting therapy. 7
• Monitoring should be most intensive during the first 9 days of treatment. 7

Renal Function-Specific Considerations

Nephrotoxicity risk varies by baseline renal function:

• In patients with eGFR ≥60 mL/min, 27% experienced nephrotoxicity with significant creatinine increases observed. 7
• In patients with eGFR 30-60 mL/min, 30.8% experienced nephrotoxicity. 7
• In patients with eGFR <30 mL/min, 50% experienced nephrotoxicity. 7
• In hemodialysis patients, 40% experienced nephrotoxicity, though baseline renal function was already severely compromised. 7
• Liposomal amphotericin B is safer than conventional amphotericin B for patients with eGFR <60 and hemodialysis patients. 7

Prevention and Monitoring Strategies

Specific interventions reduce nephrotoxicity risk:

• Hydration with 0.9% saline intravenously 30 minutes before infusion ameliorates nephrotoxicity. 4
• Volume expansion with salt loading immediately prior to dosing is warranted. 4
• Monitor serum creatinine and electrolytes (particularly potassium, magnesium, and bicarbonate) frequently - at minimum once or twice weekly. 4, 5
• Supplemental alkali medication may decrease renal tubular acidosis complications. 4, 5
• Use the lowest effective dose and shortest duration of therapy. 6
• Discontinue or avoid concomitant nephrotoxic agents when possible. 5

Clinical Manifestations Beyond Creatinine Elevation

Nephrotoxicity extends beyond simple azotemia:

• Hypokalemia occurs in up to 80% of patients receiving conventional amphotericin B, though less frequently with liposomal formulation. 4, 8
• Renal tubular acidosis with bicarbonaturia develops through direct tubular epithelial toxicity. 4, 5
• Hypomagnesemia, hypocalcemia, and urinary potassium and magnesium wasting are common. 4, 5
• Nephrogenic diabetes insipidus has been reported. 5

Important Clinical Caveats

Several critical considerations affect clinical decision-making:

• Some permanent renal impairment often occurs, especially in patients receiving large cumulative amounts (>5 g total) or receiving other nephrotoxic agents. 5
• Neither dialysis nor hemofiltration significantly reduces amphotericin B serum concentrations, so dose adjustment for renal replacement therapy is not required. 1
• The standard dose of 3 mg/kg/day is better tolerated than higher doses (10 mg/kg/day) without sacrificing efficacy. 9
• Liposomal amphotericin B remains nephrotoxic enough that echinocandins (caspofungin, micafungin, anidulafungin) are better tolerated and preferred as first-line therapy when appropriate for the fungal pathogen. 1, 9