Glomerular toxicity persists 10 years after ifosfamide treatment in childhood and is not predictable by age or dose

This prospective longitudinal single institution cohort study evaluated the natural history of and risk factors for chronic nephrotoxicity 10 years after ifosfamide treatment in childhood.

Twenty-five patients (16 males) treated with ifosfamide were investigated at end of treatment (End), 1 and 10 years later. Glomerular filtration rate (GFR), serum phosphate (PO4) and bicarbonate (HCO3) and renal tubular threshold for phosphate (Tmp/GFR) were measured, and total nephrotoxicity score (Ns) graded.

More patients had a low GFR at 1 (72%) and 10 (50%) years than at End (26%) (P = 0.006 for End vs. 1 year). Electrolyte supplementation requirements for tubular toxicity resolved by 10 years (0% vs. 32% at End and 24% at 1 year; both P < 0.05). At 10 years, 17% of patients had moderate overall nephrotoxicity and 13% clinically significant reduction of GFR (<60 ml/min/1.73 m2). Neither dose nor age at treatment predicted any measure of toxicity at 10 years or reduced GFR at any timepoint. Higher cumulative ifosfamide dose correlated with greater tubular and overall nephrotoxicity at End and/or 1 year (P < 0.05 for each of PO4, HCO3, Tmp/GFR, Ns), but age at treatment did not differ between patients with normal or abnormal results.

Although clinically significant tubular toxicity had resolved by 10 years, GFR was <60 ml/min/1.73 m2 in 13% of patients, raising concerns about very long-term glomerular function. Higher cumulative dose was associated with greater tubular and overall toxicity at End and 1 year, but not at 10 years. Age at treatment did not predict nephrotoxicity at any timepoint.