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Ifosfamide nephrotoxicity

Roderick Skinner, PhD, MBChB, FRCPCH
Section Editor
Richard H Sterns, MD
Deputy Editor
Albert Q Lam, MD


Ifosfamide is a synthetic structural isomer of cyclophosphamide that has been approved for concurrent use with other drugs (usually cisplatin, etoposide, or vinblastine) in the treatment of metastatic germ-cell testicular cancer and some (especially pediatric) sarcomas.

Nephrotoxicity due to direct tubular injury is a prominent complication of ifosfamide therapy; glomerular toxicity may also occur. Issues related to ifosfamide nephrotoxicity will be reviewed here.


Many in vitro studies suggest that the metabolite chloroacetaldehyde is directly toxic to the tubular cells, rather than the parent drug or another metabolite acrolein [1-3]. This relationship could explain why cyclophosphamide, although structurally similar to ifosfamide, has virtually no nephrotoxicity. At equivalent doses, the rate of chloroacetaldehyde generation with ifosfamide is much greater than with cyclophosphamide, although there is considerable variability from patient to patient in the amount of chloroacetaldehyde produced after ifosfamide administration [1]. Other toxic metabolites specific to ifosfamide but not cyclophosphamide may contribute to nephrotoxicity, such as isophosphoramide mustard, although in vitro studies have given conflicting results [4]. On the other hand, acrolein is believed to be the major cause of the bladder toxicity (hemorrhagic cystitis) seen with both ifosfamide and cyclophosphamide.

Cellular oxidative stress may be the mechanism of injury, leading to energy depletion via mitochondrial damage, a mechanism similar to that observed with the mitochondrial cytopathies [5]. Disruption of cell membrane function is another possible mechanism of toxicity.

Mesna, which is used concurrently with ifosfamide to prevent bladder toxicity, might also be expected to reduce renal damage due to chloroacetaldehyde or other nephrotoxic metabolites of ifosfamide. However, mesna has a complex intrarenal pharmacology and association with intratubular glutathione. Thus, it has not been possible to demonstrate a clear role for mesna in prevention of ifosfamide nephrotoxicity [1].


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Literature review current through: Sep 2016. | This topic last updated: Jul 24, 2015.
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