Risk factors for ifosfamide nephrotoxicity in children

Risk factors for long-term nephrotoxicity after ifosfamide for childhood cancers are not fully known. We have studied patient-related and treatment-related risk factors for chronic ifosfamide nephrotoxicity.

A group of 23 children who had received ifosfamide at age 2.1-16.2 years (median 6.9) for various cancers were assessed for nephrotoxicity, at 1-28 (2) months after the end of treatment, by renal function testing, laboratory values, and a grading score (none, mild, moderate, severe). No patient had received cisplatin or undergone nephrectomy. 13 children were reassessed at 10-26 (23) months; eight had died and two were not evaluable. The median total ifosfamide dose was 100.8 (9.0-160.4) g/m2 over a median of 15 courses every 3 weeks as a 48-72 h continuous intravenous infusion (in 22 cases), with mesna and hydration.

Glomerular filtration rate was below normal in ten (45%) of 22 evaluable children; their rate was 61-85 mL/min per 1.73 m2. Proximal tubular toxicity led to hypophosphataemic rickets and/or renal tubular acidosis in six children, and distal tubular toxicity caused nephrogenic diabetes insipidus in one. Of the risk factors analysed by multiple regression, only total ifosfamide dose was associated with proximal tubular toxicity. Only two of ten evaluable patients who received under 100 g/m2 developed moderate nephrotoxicity, whereas six of ten who received over this dose had moderate or severe nephrotoxicity.

High total ifosfamide dose was the only risk factor we identified. Although inter-patient variability was high, cumulative doses of 100 g/m2 or higher should be avoided in children with cancer.