How does liposomal amphotericin B reduce nephrotoxicity?

How Liposomal Amphotericin B Reduces Nephrotoxicity

Liposomal amphotericin B dramatically reduces nephrotoxicity by encapsulating the drug within lipid vesicles that prevent direct exposure of renal tubular cells to free amphotericin B, while the liposomal carrier preferentially delivers the drug to target tissues rather than the kidneys. 1, 2

Mechanism of Reduced Nephrotoxicity

The fundamental mechanism involves the lipid formulation acting as a protective barrier:

• The liposomal encapsulation keeps amphotericin B sequestered within lipid vesicles in the circulation, preventing the free drug from directly contacting and damaging renal tubular epithelial cells 1, 3

• Conventional amphotericin B deoxycholate causes nephrotoxicity through two primary pathways: direct toxic effects on renal tubular cells and drug-induced renal vasoconstriction 4

• The lipid carrier alters the pharmacokinetic distribution, with liposomal amphotericin B being rapidly taken up by the reticuloendothelial system (liver and spleen) rather than accumulating in renal tissue 5

• Amphotericin B binds to cholesterol in mammalian cell membranes, but the liposomal formulation reduces this interaction at the level of renal tubules specifically 1

Comparative Nephrotoxicity Data

While not completely devoid of nephrotoxicity, the reduction is substantial:

• Conventional amphotericin B deoxycholate causes acute kidney injury in up to 50% of recipients, with electrolyte-wasting tubular acidosis occurring in the majority of patients 6

• Liposomal amphotericin B causes renal injury in approximately 19-50% of patients, but these adverse events are manageable with only 12% requiring readmission and treatment discontinuation in only one patient 1

• All three lipid formulations (liposomal amphotericin B, amphotericin B lipid complex, and amphotericin B colloidal dispersion) share considerable reduction of nephrotoxicity compared to conventional formulation 7

• The lipid formulations maintain equivalent antifungal efficacy to conventional amphotericin B when dosed appropriately (3-5 mg/kg/day for lipid formulations versus 0.5-0.7 mg/kg/day for conventional) 6, 2

Clinical Implications

The reduced nephrotoxicity profile has specific clinical applications:

• Liposomal amphotericin B is the mandatory choice for patients with pre-existing renal disease, where conventional amphotericin B would be contraindicated 6, 8

• Pre-existing renal impairment is not an absolute contraindication to liposomal amphotericin B, unlike conventional formulation 8

• In patients with varying degrees of renal function (eGFR ≥60,30-60, <30, and hemodialysis), the incidence of nephrotoxicity with liposomal amphotericin B did not differ significantly (27.0%, 30.8%, 50.0%, and 40.0% respectively, p=0.56) 9

• 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, due to high nephrotoxicity risk 2

Important Caveats

Despite the improved safety profile, nephrotoxicity remains a concern:

• Liposomal amphotericin B is NOT completely devoid of nephrotoxicity—approximately half of patients still experience some degree of renal injury 1

• High doses above 5 mg/kg/day significantly increase renal toxicity risk without improving efficacy, as demonstrated in the AmBiLoad trial comparing 10 mg/kg/day versus 3 mg/kg/day 8, 5

• Nephrotoxicity typically manifests within the first 9 days of treatment, requiring vigilant early monitoring 9

• Concomitant nephrotoxic medications substantially amplify the risk, and should be avoided or minimized 1, 2

• Volume depletion, diabetes mellitus, and advanced age are additional risk factors that increase susceptibility to nephrotoxicity 1

Prevention Strategies

To minimize the residual nephrotoxicity risk:

• Administer 0.9% saline intravenously 30 minutes before each infusion to maintain adequate hydration 1, 2, 8

• Monitor serum creatinine and electrolytes at minimum once or twice weekly throughout treatment 6, 1, 2

• Use the lowest effective dose (typically 3-5 mg/kg/day) and shortest duration of therapy necessary for clinical response 1, 2

• Avoid or minimize concomitant nephrotoxic agents including NSAIDs and other nephrotoxic drugs 6, 1

• Neither dialysis nor hemofiltration significantly reduces amphotericin B serum concentrations, so dose adjustment for renal replacement therapy is not required 1, 8