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- Title
Renal toxicity of ifosfamide in children with cancer: an exploratory study integrating aldehyde dehydrogenase enzymatic activity data and a wide-array urinary metabolomics approach.
- Authors
Febvey-Combes, Olivia; Guitton, Jérôme; Marec-Berard, Perrine; Faure-Conter, Cécile; Blanc, Ellen; Chabaud, Sylvie; Conjard-Duplany, Agnès; Schell, Matthias; Derain Dubourg, Laurence
- Abstract
Background: Ifosfamide is a major anti-cancer drug in children with well-known renal toxicity. Understanding the mechanisms underlying this toxicity could help identify children at increased risk of toxicity. Methods: The IFOS01 study included children undergoing ifosfamide-based chemotherapy for Ewing sarcoma or rhabdomyosarcoma. A fully evaluation of renal function was performed during and after chemotherapy. Proton nuclear magnetic resonance (NMR) and conventional biochemistry were used to detect early signs of ifosfamide-induced tubulopathy. The enzymatic activity of aldehyde dehydrogenase (ALDH) was measured in the peripheral blood lymphocytes as a marker of ifosfamide-derived chloroacetaldehyde detoxification capacity. Plasma and urine concentrations of ifosfamide and dechloroethylated metabolites were quantified. Results: The 15 participants received a median total ifosfamide dose of 59 g/m2 (range: 24–102), given over a median of 7 cycles (range: 4–14). All children had acute proximal tubular toxicity during chemotherapy that was reversible post-cycle, seen with both conventional assays and NMR. After a median follow-up of 31 months, 8/13 children presented overall chronic toxicity among which 7 had decreased glomerular filtration rate. ALDH enzymatic activity showed high inter- and intra-individual variations across cycles, though overall activity looked lower in children who subsequently developed chronic nephrotoxicity. Concentrations of ifosfamide and metabolites were similar in all children. Conclusions: Acute renal toxicity was frequent during chemotherapy and did not allow identification of children at risk for long-term toxicity. A role of ALDH in late renal dysfunction is possible so further exploration of its enzymatic activity and polymorphism should be encouraged to improve the understanding of ifosfamide-induced nephrotoxicity.
- Subjects
ALDEHYDE dehydrogenase; NEPHROTOXICOLOGY; IFOSFAMIDE; PROTON magnetic resonance; CHILDHOOD cancer; PROTON magnetic resonance spectroscopy
- Publication
BMC Pediatrics, 2024, Vol 24, Issue 1, p1
- ISSN
1471-2431
- Publication type
Article
- DOI
10.1186/s12887-024-04633-1