URINARY PROTON MAGNETIC-RESONANCE STUDIES OF EARLY IFOSFAMIDE-INDUCEDNEPHROTOXICITY AND ENCEPHALOPATHY

Ifosfamide Is an oxazophosphorine widely used in the treatment of canc er in children and adults, Nephrotoxicity and neurotoxicity are major side effects, The aim of this study was to use high-resolution proton nuclear magnetic resonance (H-1 NMR) spectroscopy of urine to identify novel biochemical markers of ifosfamide-induced toxicity, Urine sampl es were collected from 10 nonencephalopathic patients (who had not pre viously received nephrotoxic chemotherapy) immediately prior to the fi rst ifosfamide dose and at timed intervals for up to four treatment cy cles, The findings were compared with those for urine samples collecte d from five patients during acute encephalopathic episodes. H-1 NMR ur inalysis identified a series of characteristic time related changes in the excretion profiles of low molecular weight endogenous metabolites during ifosfamide therapy, These changes included a decreased excreti on of hippurate and an increased excretion of glycine, histidine, gluc ose, lactate, and trimethylamine-N-oxide. Two nonencephalopathic patie nts had marked but transient glutaric or adipic aciduria during the se cond cycle of ifosfamide treatment, Urinary retinol-binding protein ro se acutely after each treatment cycle but usually returned to baseline levels. Maximum renal toxicity was observed by the fourth treatment c ycle, The ratio of the urinary excretion of the uroprotectant mesna (a ctive form) to dimesna (inactive form) correlated with the degree of r enal toxicity, For the encephalopathic patients, the ifosfamide-induce d changes in the urinary low molecular weight metabolite profile were similar to those for the nonencephalopathic group, In contrast to prev ious re ports, none of the encephalopathic group developed glutaric ac iduria, and i.v. methylene blue did not reverse neurotoxicity in the t wo patients who received it, The results suggest that ifosfamide nephr otoxicity involves both cortical and medullary regions of the nephron and that the urinary mesna:dimesna ratio may be important in assessing the degree of cytoprotection. This study demonstrates that H-1 NMR ca n provide novel biochemical information on ifosfamide-induced toxicity and will be of value in the optimization of ifosfamide therapy.