Risk Factors for and Long-Term Outcome of Ifosphamide-Induced Nephrotoxicity in Children † 778

Abstract

Ifosfamide is widely used in the treatment of pediatric solid tumors. Its main adverse effects are various forms of renal tubular and glomerular damage. The authors sought to determine factors that predict the risk for the development and severity of ifosfamide‐induced nephrotoxicity in children and to examine the long‐term outcome of this complication. A total of 174 children who had received ifosfamide for various cancers were studied. Nephrotoxicity was assessed by laboratory markers of glomerular and tubular function and a grading score (none, mild, moderate, severe). Patients were assessed 4 to 12 weeks after each ifosfamide course, 3 months after completion of chemotherapy, and 5 years later. Of 174 children, 72 (41.4%) developed tubular dysfunction, whereas only 11 (6.3%) demonstrated glomerular dysfunction; 40 (23.0%) demonstrated mild toxicity, 16 (9.2%) demonstrated moderate toxicity, and 16 (9.2%) developed severe nephrotoxicity. The four severity subgroups (none, mild, moderate, severe) received comparable doses/m2/cycle of ifosfamide and mesna. Children exhibiting severe toxicity were significantly younger compared to those with moderate, mild, or no nephrotoxicity (median age: 2.2, 7.0, 8.2, and 10.5 years, respectively; p < 0.001) and received significantly higher cumulative doses of ifosfamide (49.6 ± 12.3, 46.0 ± 13.1, 36.2 ± 9.7, and 33.8 ± 7.6 g/m2, respectively; p < 0.001). Cumulative doses of cisplatin were higher among children with severe nephrotoxicity compared to those with moderate, mild, or no toxicity, although this difference did not reach statistical significance. Of all risk factors analyzed by multiple regression analysis, age was the most significant predictor for the grade of nephrotoxicity (p < 0.001), followed by the cumulative dose of ifosfamide (p = 0.005). Seven out of 16 children (44.0%) with severe nephrotoxicity and 4 out of 16 children (25.0%) with moderate nephrotoxicity demonstrated severe chronic tubular toxicity over a follow‐up period of 5 years. Since severe ifosfamide‐induced renal toxicity tends to be chronic in a substantial number of treated children, it should be balanced carefully against efficacy. Cumulative ifosfamide doses of 45 g/m2 and above should be carefully considered, especially in children younger than age 3.

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

“…3,4). Recent reports have shown that the frequency of renal damage is remarkably higher than had been appreciated, and IFO-induced nephropathy is likely underestimated because of the inherent flaws in the evaluation methods commonly used and the time dependence of IFO-induced nephrotoxicity (6,7,9). This is especially true in cases of lateonset glomerular dysfunction (5,6,9).…”

Osteonecrosis in children with acute lymphoblastic leukemia

“…58 Ifosfamide can induce renal tubulopathy/Fanconi syndrome, and may subsequently manifest as hypophosphatemic rickets, compromising bone structure. 59 Due to hypercoagulability, vascular endothelial damage, and disruption of bone formation, purine antimetabolites can impair proliferation of chondrocytes.…”

Renal Dysfunction and Elevated Blood Pressure in Long-Term Childhood Cancer Survivors

“…Chemotherapeutic agents with well documented early nephrotoxicity are ifosfamide, cisplatin, and carboplatin (5)(6)(7)(8)(9)(10).…”