Amphotericin B and Renal Failure
Risk Profile and Incidence
Amphotericin B causes nephrotoxicity in up to 80% of treated patients, with conventional amphotericin B deoxycholate being significantly more nephrotoxic than lipid formulations. 1, 2
The renal complications manifest in multiple ways:
- Acute azotemia occurs in approximately 28% of patients receiving conventional amphotericin B, with 12% experiencing moderate-to-severe nephrotoxicity (defined as doubling of baseline creatinine) 3
- Electrolyte disturbances including hypokalemia (up to 80% of patients), hypomagnesemia, and hypocalcemia are extremely common 1, 2, 4
- Renal tubular acidosis develops through direct distal tubular epithelial toxicity 1, 2
- Nephrogenic diabetes insipidus with polyuria and impaired concentrating ability 1, 4
Mechanisms of Nephrotoxicity
The kidney damage occurs through two primary pathways 2, 5:
- Direct tubular toxicity: Amphotericin B binds to cholesterol in mammalian cell membranes, causing increased permeability and direct damage to renal tubular cells 2, 6
- Renal vasoconstriction: The drug activates intrarenal mechanisms (tubuloglomerular feedback) and releases mediators like thromboxane A2, causing acute decreases in renal blood flow and glomerular filtration rate 5, 7
Risk Factors for Severe Nephrotoxicity
Patients with ≥3 risk factors have a 29% incidence of moderate-to-severe nephrotoxicity, compared to only 4% in those with no risk factors. 3
The five key risk factors are 3:
- Mean daily amphotericin B dose ≥35 mg
- Male sex
- Body weight ≥90 kg
- Pre-existing chronic renal disease
- Concurrent use of nephrotoxic agents (amikacin, cyclosporine, aminoglycosides, tacrolimus) 1, 3
Additional risk factors include 1, 6:
- Cumulative doses exceeding 5 grams (associated with permanent renal damage) 4, 7
- Volume depletion or salt depletion 7
- Advanced age 6
Formulation-Specific Toxicity
Lipid formulations of amphotericin B are considerably less nephrotoxic than conventional amphotericin B deoxycholate and should be used preferentially in high-risk patients. 1, 6
- Liposomal amphotericin B at 3-6 mg/kg daily causes nephrotoxicity in approximately 19-50% of patients, but adverse events are generally manageable 1, 6
- Amphotericin B lipid complex (ABLC) at 5 mg/kg daily shows minimal nephrotoxicity even in patients with pre-existing renal insufficiency 8
- Conventional amphotericin B deoxycholate should be reserved for resource-limited settings where alternatives are unavailable 2
The indication for switching to lipid formulations is when serum creatinine rises above 2.5 mg/dL during conventional amphotericin B therapy 1
Prevention Strategies
Hydration with 0.9% saline intravenously 30 minutes before amphotericin B infusion significantly ameliorates nephrotoxicity and is the single most important preventive measure. 1, 2, 9
Additional protective strategies include 1, 2, 10:
- Volume expansion with salt loading immediately prior to dosing
- Use of the lowest effective dose and shortest duration necessary
- Monitoring and aggressive repletion of potassium and magnesium
- Supplemental alkali medication to decrease renal tubular acidosis 4
In low-risk patients (those not in ICU, not on vasoactive drugs, with normal baseline renal function), saline loading alone is sufficient to prevent significant renal dysfunction. 10
Monitoring Requirements
Monitor serum creatinine and electrolytes (particularly potassium, magnesium, and bicarbonate) at minimum once or twice weekly during therapy. 1, 6
Baseline and frequent monitoring should include 1, 9:
- Serum creatinine and BUN
- Electrolytes (potassium, magnesium, calcium, bicarbonate)
- Complete blood counts
- Liver function tests
Reversibility and Long-Term Outcomes
Most amphotericin B-induced nephrotoxicity is reversible upon drug discontinuation, but permanent renal impairment often occurs in patients receiving cumulative doses exceeding 5 grams. 4, 7
- At hospital discharge, 70% of patients with moderate-to-severe nephrotoxicity still have serum creatinine ≥0.5 mg/dL above baseline 3
- Renal function typically returns to baseline within 30 days after treatment completion in low-risk patients 10
- Chronic sequelae include persistent renal tubular acidosis and electrolyte abnormalities requiring ongoing supplementation 9
- Hemodialysis is rarely required (occurred in only 3 of 494 patients in one large series) 3
Critical Clinical Caveats
- Neither dialysis nor hemofiltration significantly reduces amphotericin B serum concentrations, so dose adjustment for renal replacement therapy is not required 6
- In patients with severe fungal infections and acute renal failure, continue liposomal amphotericin B rather than switching to azoles, as the poor prognosis justifies using the most effective therapy despite nephrotoxicity 1
- Patients receiving bone marrow transplantation, post-chemotherapy, or concurrent antibiotics have the highest risk of acute renal failure 10
- Longer infusion times (3-6 hours) are recommended for patients with azotemia to reduce toxicity 2