Renal injury is a relatively common side effect of the chemotherapeutic agent ifosfamide. Unlike cyclophosphamide, its non-nephrotoxic isomeric relative, ifosfamide metabolism releases chloroacetaldehyde, which is the likely cause for kidney damage caused by this medication. Chloroacetaldehyde produces dose-dependent impairment in renal tubule cell function, depletion of cellular ATP and glutathione, and membrane lipid peroxidation in vitro. Clinically, this damage would cause the Fanconi syndrome, a common manifestation of ifosfamide toxicity, while complete loss of cell viability would produce acute tubular necrosis and renal insufficiency, another devastating ifosfamide side effect. Because the kidney is capable of absorbing and metabolizing ifosfamide, it appears that intrarenally rather than systemically generated chloroacetaldehyde or related metabolites are responsible for nephrotoxicity. For unknown reasons, currently available uroprotectant drugs, mesna and amifostine, are effective in vitro but not in vivo.
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