Renal Toxicity of Ifosfamide in Children with Cancer: an Exploratory Study Integrating Aldehyde Dehydrogenase Enzymatic Activity Data and a Wide-array Urinary Metabolomics Approach

Overview

Journal BMC Pediatr

Publisher Biomed Central

Specialty Pediatrics

Date 2024 Mar 20

PMID 38504218

Authors

Olivia Febvey-Combes

Jerome Guitton

Perrine Marec-Berard

Cecile Faure-Conter

Ellen Blanc

Sylvie Chabaud

Agnes Conjard-Duplany

Matthias Schell

Laurence Derain Dubourg

Affiliations

Soon will be listed here.

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/m (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.

References

Sottani C, Tranfo G, Faranda P, Minoia C . Highly sensitive high-performance liquid chromatography/selective reaction monitoring mass spectrometry method for the determination of cyclophosphamide and ifosfamide in urine of health care workers exposed to antineoplastic agents. Rapid Commun Mass Spectrom. 2005; 19(19):2794-800. DOI: 10.1002/rcm.2116. View

Pariyani R, Safinar Ismail I, Azam A, Khatib A, Abas F, Shaari K . Urinary metabolic profiling of cisplatin nephrotoxicity and nephroprotective effects of Orthosiphon stamineus leaves elucidated by H NMR spectroscopy. J Pharm Biomed Anal. 2016; 135:20-30. DOI: 10.1016/j.jpba.2016.12.010. View

Boddy A, Yule S, Wyllie R, Price L, Pearson A, Idle J . Comparison of continuous infusion and bolus administration of ifosfamide in children. Eur J Cancer. 1995; 31A(5):785-90. DOI: 10.1016/0959-8049(95)00090-6. View

Khwaja A . KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012; 120(4):c179-84. DOI: 10.1159/000339789. View

Lever M, Sizeland P, Bason L, Hayman C, Robson R, Chambers S . Abnormal glycine betaine content of the blood and urine of diabetic and renal patients. Clin Chim Acta. 1994; 230(1):69-79. DOI: 10.1016/0009-8981(94)90090-6. View

Dubourg L, Taniere P, Cochat P, Baverel G, Michoudet C . Toxicity of chloroacetaldehyde is similar in adult and pediatric kidney tubules. Pediatr Nephrol. 2002; 17(2):97-103. DOI: 10.1007/s00467-001-0765-2. View

Skinner R, Pearson A, Coulthard M, Skillen A, Hodson A, Goldfinch M . Assessment of chemotherapy-associated nephrotoxicity in children with cancer. Cancer Chemother Pharmacol. 1991; 28(2):81-92. DOI: 10.1007/BF00689694. View

Phillips R, Tyerman K, Al-Kassim M, Picton S . A systematic review of the accuracy and utility of early markers of Ifosfamide-induced proximal tubulopathy in survivors of childhood cancers. Pediatr Hematol Oncol. 2008; 25(2):107-13. DOI: 10.1080/08880010701885276. View

Rossi R, Ehrich J . Partial and complete de Toni-Debré-Fanconi syndrome after ifosfamide chemotherapy of childhood malignancy. Eur J Clin Pharmacol. 1993; 44 Suppl 1:S43-5. DOI: 10.1007/BF01428392. View

10.

Nicholson J, Lindon J, Holmes E . 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica. 1999; 29(11):1181-9. DOI: 10.1080/004982599238047. View

11.

Ehrhardt M, Skinner R, Castellino S . Renal and Hepatic Health After Childhood Cancer. Pediatr Clin North Am. 2020; 67(6):1203-1217. DOI: 10.1016/j.pcl.2020.07.011. View

12.

Skinner R, Sharkey I, Pearson A, Craft A . Ifosfamide, mesna, and nephrotoxicity in children. J Clin Oncol. 1993; 11(1):173-90. DOI: 10.1200/JCO.1993.11.1.173. View

13.

Caron H, Abeling N, van Gennip A, de Kraker J, VOUTE P . Hyperaminoaciduria identifies patients at risk of developing renal tubular toxicity associated with ifosfamide and platinate containing regimens. Med Pediatr Oncol. 1992; 20(1):42-7. DOI: 10.1002/mpo.2950200109. View

14.

Pierce C, Munoz A, Ng D, Warady B, Furth S, Schwartz G . Age- and sex-dependent clinical equations to estimate glomerular filtration rates in children and young adults with chronic kidney disease. Kidney Int. 2020; 99(4):948-956. PMC: 9083470. DOI: 10.1016/j.kint.2020.10.047. View

15.

Boddy A, Yule S, Wyllie R, Price L, Pearson A, Idle J . Pharmacokinetics and metabolism of ifosfamide administered as a continuous infusion in children. Cancer Res. 1993; 53(16):3758-64. View

16.

Boudonck K, Rose D, Karoly E, Lee D, Lawton K, Lapinskas P . Metabolomics for early detection of drug-induced kidney injury: review of the current status. Bioanalysis. 2010; 1(9):1645-63. DOI: 10.4155/bio.09.142. View

17.

Skinner R, Pearson A, English M, Price L, Wyllie R, Coulthard M . Risk factors for ifosfamide nephrotoxicity in children. Lancet. 1996; 348(9027):578-80. DOI: 10.1016/s0140-6736(96)03480-0. View

18.

Conjard A, Martin M, Guitton J, Baverel G, Ferrier B . Gluconeogenesis from glutamine and lactate in the isolated human renal proximal tubule: longitudinal heterogeneity and lack of response to adrenaline. Biochem J. 2001; 360(Pt 2):371-7. PMC: 1222237. DOI: 10.1042/0264-6021:3600371. View

19.

Skinner R, Parry A, Price L, Cole M, Craft A, Pearson A . Glomerular toxicity persists 10 years after ifosfamide treatment in childhood and is not predictable by age or dose. Pediatr Blood Cancer. 2010; 54(7):983-9. DOI: 10.1002/pbc.22364. View

20.

Skinner R . Late renal toxicity of treatment for childhood malignancy: risk factors, long-term outcomes, and surveillance. Pediatr Nephrol. 2017; 33(2):215-225. PMC: 5769827. DOI: 10.1007/s00467-017-3662-z. View