Background: We sought to determine predicting risk factors for ifosphamide-induced nephrotoxicity in children and to examine the long-term outcome of this complication.

Patients and Methods: We retrospectively analyzed 174 children who had received ifosphamide for various cancers. Nephrotoxicity was assessed by laboratory markers of glomerular and tubular function and a grading score(none, mild, moderate, severe). Patients were assessed 4-12 weeks after each ifosphamide course, 3 months after completion of chemotherapy, and 5 years later.

Results: Seventy two out of 174 children (41.4%) developed tubular dysfunction: 40 (23%) demonstrated mild toxicity, 16 (9.2%) moderate and 16 (9.2%) developed generalized tubulopathy. These 4 groups received comparable doses/m2/cycle of ifosphamide and mesna. Children exhibiting severe toxicity were significantly younger compared to those with moderate, mild and no nephrotoxicity. (median age: 2.2, 7.0, 8.2 and 10.5 years respectively; p<0.001) and received significantly more cycles (8.3± 1.7, 7.5± 1.7, 6.1± 2.5 and 5.7± 2.5 respectively; p<0.001). Cumulative doses of cis/carbo platinum were higher among children with severe toxicity compared to those with moderate, mild or no toxicity although this difference did not reach statistical significance. Of all risk factors analysed by multiple regression age was the most significant predictor for the grade of nephrotoxicity (p<0.001) followed by the number of cycles(p=0.003) and the cumulative dose of platinums (p=0.04). Seven out of 16 children (43.7%) with severe nephrotoxicity demonstrated severe chronic tubular toxicity over a follow up period of 5 years. Four of the 7 developed hypophosphatemic rickets and 2 others, chronic renal failure.

Conclusions: As ifosphamide-induced renal toxicity tends to be chronic in a significant number of patients it should be balanced carefully against efficacy. Cumulative ifosphamide doses of 50 g/m2 should be avoided especially in children below 3 years of age.