Skinner R, Sharkey I M, Pearson A D, Craft A W
Department of Child Health, Medical School, Newcastle upon Tyne, United Kingdom.
J Clin Oncol. 1993 Jan;11(1):173-90. doi: 10.1200/JCO.1993.11.1.173.
With the increasing use of ifosfamide in pediatric malignancies, nephrotoxicity has emerged as a potentially serious adverse effect, which may be dose-limiting or may cause severe chronic morbidity, including glomerular impairment and/or Fanconi's syndrome. The purpose of this review was (1) to improve the documentation of ifosfamide nephrotoxicity in children, and (2) to consider the possible causative role of ifosfamide metabolites.
(1) A grading system was developed that allowed documentation of the nature and severity of published reports of ifosfamide-induced nephrotoxicity, and evaluation of patient and treatment-related risk factors. (2) The relationship between the pharmacology of ifosfamide/mesna and nephrotoxicity was investigated by examination of published data, especially that concerning the quantitative differences in the metabolism of ifosfamide and its nonnephrotoxic structural isomer, cyclophosphamide.
(1) Examination of 16 published reports (with assessable data from 40 children) demonstrated that ifosfamide-induced nephrotoxicity was associated with a wide range of patient ages and ifosfamide cumulative doses given by different administration schedules. (2) Chloroacetaldehyde, a major metabolite of ifosfamide only, may be at least partly responsible for the renal toxicity of this drug. Although mesna may be capable of detoxifying the toxic metabolite(s), delivery to the renal tubule may not be sufficient to provide adequate protection of tubular glutathione from depletion by the metabolite(s), which results in a failure to prevent nephrotoxicity.
Increased understanding of the interindividual variability in the extent and nature of ifosfamide metabolism, which may be a major determinant of susceptibility to renal damage, may lead to improved use of the drug with less nephrotoxicity.
随着异环磷酰胺在儿童恶性肿瘤治疗中的应用日益增加，肾毒性已成为一种潜在的严重不良反应，可能限制剂量或导致严重的慢性发病，包括肾小球损害和/或范科尼综合征。本综述的目的是：（1）改进儿童异环磷酰胺肾毒性的记录；（2）探讨异环磷酰胺代谢产物可能的致病作用。
（1）制定了一个分级系统，用于记录已发表的异环磷酰胺诱导肾毒性报告的性质和严重程度，并评估患者及治疗相关的危险因素。（2）通过查阅已发表的数据，特别是关于异环磷酰胺及其非肾毒性结构异构体环磷酰胺代谢定量差异的数据，研究异环磷酰胺/美司钠的药理学与肾毒性之间的关系。
（1）对16篇已发表报告（来自40名儿童的可评估数据）的研究表明，异环磷酰胺诱导的肾毒性与广泛的患者年龄以及不同给药方案下的异环磷酰胺累积剂量有关。（2）氯乙醛是异环磷酰胺独有的主要代谢产物，可能至少部分导致该药物的肾毒性。尽管美司钠可能能够使有毒代谢产物解毒，但输送至肾小管的量可能不足以充分保护肾小管谷胱甘肽不被代谢产物耗尽，从而无法预防肾毒性。
对异环磷酰胺代谢程度和性质的个体间差异有了更多了解，这可能是易发生肾损害的主要决定因素，有望在使用该药物时减少肾毒性，实现更好的用药效果。
