- Roderick Skinner, PhD, MBChB, FRCPCH
Roderick Skinner, PhD, MBChB, FRCPCH
- Consultant in Paediatric and Adolescent Oncology/Bone Marrow Transplantation
- Honorary Professor of Childhood Cancer
- Great North Children's Hospital
- Northern Institute of Cancer Research, Newcastle University
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. The nephrotoxicity of other chemotherapeutic agents is discussed separately. (See "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency" and "Cisplatin nephrotoxicity" and "Therapeutic use and toxicity of high-dose methotrexate", section on 'Renal toxicity'.)
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 . Other toxic metabolites specific to ifosfamide but not cyclophosphamide, such as isophosphoramide mustard, may contribute to nephrotoxicity, although in vitro studies have given conflicting results . 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 . 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 .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Skinner R, Sharkey IM, Pearson AD, Craft AW. Ifosfamide, mesna, and nephrotoxicity in children. J Clin Oncol 1993; 11:173.
- Zamlauski-Tucker MJ, Morris ME, Springate JE. Ifosfamide metabolite chloroacetaldehyde causes Fanconi syndrome in the perfused rat kidney. Toxicol Appl Pharmacol 1994; 129:170.
- Dubourg L, Michoudet C, Cochat P, Baverel G. Human kidney tubules detoxify chloroacetaldehyde, a presumed nephrotoxic metabolite of ifosfamide. J Am Soc Nephrol 2001; 12:1615.
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- Stöhr W, Paulides M, Bielack S, et al. Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System. Pediatr Blood Cancer 2007; 48:447.
- Skinner R, Cotterill SJ, Stevens MC. Risk factors for nephrotoxicity after ifosfamide treatment in children: a UKCCSG Late Effects Group study. United Kingdom Children's Cancer Study Group. Br J Cancer 2000; 82:1636.
- Oberlin O, Fawaz O, Rey A, et al. Long-term evaluation of Ifosfamide-related nephrotoxicity in children. J Clin Oncol 2009; 27:5350.
- Skinner R, Pearson AD, Price L, et al. Nephrotoxicity after ifosfamide. Arch Dis Child 1990; 65:732.
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- Skinner R, Parry A, Price L, et al. Glomerular toxicity persists 10 years after ifosfamide treatment in childhood and is not predictable by age or dose. Pediatr Blood Cancer 2010; 54:983.
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- Yaseen Z, Michoudet C, Baverel G, Dubourg L. In vivo mesna and amifostine do not prevent chloroacetaldehyde nephrotoxicity in vitro. Pediatr Nephrol 2008; 23:611.
- Chen N, Aleksa K, Woodland C, et al. N-Acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats. Br J Pharmacol 2008; 153:1364.
- Hanly L, Rieder MJ, Huang SH, et al. N-acetylcysteine rescue protocol for nephrotoxicity in children caused by ifosfamide. J Popul Ther Clin Pharmacol 2013; 20:e132.
- Dekkers IA, Blijdorp K, Cransberg K, et al. Long-term nephrotoxicity in adult survivors of childhood cancer. Clin J Am Soc Nephrol 2013; 8:922.
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- CLINICAL MANIFESTATIONS
- Etiology of polyuria
- RISK FACTORS
- Cumulative ifosfamide dose
- Young children
- Prior nephrectomy
- Prior or concomitant cisplatin therapy
- Limit ifosfamide dose
- Therapies of unproven efficacy
- - Mesna
- - N-acetylcysteine
- LONG-TERM PROGNOSIS
- SUMMARY AND RECOMMENDATIONS