What type of renal lesion is caused by Amphotericin?

Amphotericin B-Induced Renal Lesions

Amphotericin B causes both tubular and glomerular renal damage, with the most clinically significant lesions being distal renal tubular acidosis, acute tubular necrosis, and a unique vascular lesion characterized by vacuolization of smooth muscle cells in renal arterioles. 1, 2, 3

Primary Renal Lesions

Tubular Damage

• Distal tubular epithelial toxicity is the hallmark lesion, leading to renal tubular acidosis with associated electrolyte wasting (hypokalemia, hypomagnesemia, bicarbonaturia) occurring in up to 80% of patients receiving conventional amphotericin B 1, 2
• Acute tubular necrosis develops as a dose-dependent complication, particularly when cumulative doses exceed 5g, and manifests as azotemia with elevated serum creatinine 4, 5
• Tubular calcification occurs in both the presence and absence of protective measures 3
• Impaired renal concentrating ability and polyuria develop secondary to tubular dysfunction 6, 4

Vascular Lesions

• A unique and previously unrecognized lesion consists of striking vacuolization of smooth muscle cells in the media of renal arterioles and arteries, observed in all renal biopsies from amphotericin-treated patients 3
• Renal vasoconstriction of the afferent arteriole contributes to decreased glomerular filtration rate and renal blood flow 6, 4

Glomerular Damage

• Azotemia develops from glomerular dysfunction, with decreased inulin and creatinine clearances occurring even with protective measures 3
• The glomerular damage is mediated through both direct membrane effects and indirect effects via tubuloglomerular feedback mechanisms and thromboxane A2 release 4

Pathophysiological Mechanisms

• Amphotericin B binds to cholesterol in mammalian cell membranes, increasing membrane permeability and causing direct cellular toxicity 2, 4
• Activation of intrarenal mechanisms (tubuloglomerular feedback) and release of vasoactive mediators (thromboxane A2) cause acute decreases in renal blood flow and filtration rate 4
• Changes in intracellular calcium levels contribute to the observed nephrotoxic effects 4

Clinical Manifestations and Severity

• Nephrotoxicity occurs in up to 80% of patients receiving conventional amphotericin B deoxycholate 1, 2
• The severity is dose-dependent, with permanent damage more likely when cumulative doses exceed 5g 4, 5
• Renal function typically returns to baseline gradually after drug withdrawal, though permanent damage can occur in some cases 6, 4

Prevention Strategies

Hydration and Electrolyte Management

• Vigorous hydration with 0.9% saline 30 minutes before infusion is essential, as salt depletion enhances nephrotoxicity 1, 2, 4
• Maintaining urine output >4000 mL/day with massive hydration prevents clinically significant renal damage 7
• Regular monitoring and aggressive replacement of urinary sodium, potassium (as 7.45% solution via central line), and magnesium losses is warranted 2, 7

Alternative Formulations

• Lipid formulations (liposomal amphotericin B, amphotericin B lipid complex) should be substituted when patients develop significant renal impairment (creatinine >2.5 mg/dL) or have pre-existing renal disease 1, 2
• These formulations are considerably less nephrotoxic than conventional amphotericin B deoxycholate while maintaining equivalent antifungal efficacy 1

Monitoring Requirements

• Baseline and frequent (once or twice weekly) monitoring of serum creatinine, electrolytes (particularly potassium, magnesium, bicarbonate), and renal function is essential 1, 2
• Fractional excretion of sodium and potassium should be monitored as early indicators of tubular damage 7
• In patients with azotemia, longer infusion times (3-6 hours) reduce toxicity 1

Common Pitfalls

• Mannitol (1 g/kg) does NOT protect against amphotericin B nephrotoxicity and should not be used for this purpose 3
• Concomitant use of other nephrotoxic medications (aminoglycosides, pentamidine, cyclosporine, NSAIDs) significantly increases risk and severity 1, 2, 8
• Inadequate hydration or salt depletion dramatically accelerates the development of nephrotoxicity 4, 7