- 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.
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 may contribute to nephrotoxicity, such as isophosphoramide mustard, 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 .
- 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.
- Zhang J, Tian Q, Zhou S-F. Clinical pharmacology of cyclophosphamide and ifosfamide. Curr Drug Ther 2006; 1:55.
- Rossi R. Nephrotoxicity of ifosfamide--moving towards understanding the molecular mechanisms. Nephrol Dial Transplant 1997; 12:1091.
- 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.
- Ho PT, Zimmerman K, Wexler LH, et al. A prospective evaluation of ifosfamide-related nephrotoxicity in children and young adults. Cancer 1995; 76:2557.
- Husband DJ, Watkin SW. Fatal hypokalaemia associated with ifosfamide/mesna chemotherapy. Lancet 1988; 1:1116.
- Skinner R, Pearson AD, English MW, et al. Risk factors for ifosfamide nephrotoxicity in children. Lancet 1996; 348:578.
- Rossi R, Gödde A, Kleinebrand A, et al. Concentrating capacity in ifosfamide-induced severe renal dysfunction. Ren Fail 1995; 17:551.
- Loebstein R, Koren G. Ifosfamide-induced nephrotoxicity in children: critical review of predictive risk factors. Pediatrics 1998; 101:E8.
- Aleksa K, Halachmi N, Ito S, Koren G. Renal ontogeny of ifosfamide nephrotoxicity. J Lab Clin Med 2004; 144:285.
- 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.
- Rossi R, Gödde A, Kleinebrand A, et al. Unilateral nephrectomy and cisplatin as risk factors of ifosfamide-induced nephrotoxicity: analysis of 120 patients. J Clin Oncol 1994; 12:159.
- Lee BS, Lee JH, Kang HG, et al. Ifosfamide nephrotoxicity in pediatric cancer patients. Pediatr Nephrol 2001; 16:796.
- Goren MP, Wright RK, Pratt CB, et al. Potentiation of ifosfamide neurotoxicity, hematotoxicity, and tubular nephrotoxicity by prior cis-diamminedichloroplatinum(II) therapy. Cancer Res 1987; 47:1457.
- 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.
- Farry JK, Flombaum CD, Latcha S. Long term renal toxicity of ifosfamide in adult patients--5 year data. Eur J Cancer 2012; 48:1326.
- 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