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Ifosfamide, mesna, and nephrotoxicity in children
R Skinner1, I M Sharkey, A D Pearson
1Department of Child Health, Medical School, Newcastle upon Tyne, United Kingdom.
Summary
Ifosfamide can cause serious kidney damage in children, particularly affecting the glomeruli and tubules. Chloroacetaldehyde, an ifosfamide metabolite, is a likely cause, and current protective measures may be insufficient.
Area of Science:
- Pediatric Oncology
- Clinical Pharmacology
- Toxicology
Background:
- Ifosfamide is a widely used chemotherapy agent in pediatric malignancies.
- Nephrotoxicity is a significant adverse effect of ifosfamide, potentially leading to dose limitation and chronic kidney damage.
- Understanding ifosfamide-induced nephrotoxicity is crucial for optimizing its use in children.
Purpose of the Study:
- To enhance the documentation of ifosfamide-induced nephrotoxicity in pediatric patients.
- To investigate the potential role of ifosfamide metabolites in causing renal damage.
- To evaluate patient and treatment-related risk factors for nephrotoxicity.
Main Methods:
- A grading system was developed to assess the severity and nature of reported ifosfamide nephrotoxicity.
- Published data were reviewed to analyze the relationship between ifosfamide/mesna pharmacology and nephrotoxicity.
- Metabolism of ifosfamide and its isomer cyclophosphamide was compared to identify toxic metabolites.
Main Results:
- Analysis of 16 reports (40 children) revealed that ifosfamide nephrotoxicity occurred across various ages and cumulative doses.
- Chloroacetaldehyde, a unique ifosfamide metabolite, is implicated as a primary cause of renal toxicity.
- Mesna's ability to detoxify metabolites may be limited by insufficient delivery to renal tubules, failing to prevent glutathione depletion and subsequent nephrotoxicity.
Conclusions:
- Interindividual variability in ifosfamide metabolism significantly influences susceptibility to renal damage.
- Further understanding of metabolic pathways can guide strategies to minimize ifosfamide-induced nephrotoxicity.
- Improved management may involve tailoring ifosfamide use based on individual metabolic profiles.