title: Glomerular toxicity persists 10 years after ifosfamide treatment in childhood and is not predictable by age or dose.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Paediatric and Adolescent Oncology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom. roderick.skinner@ncl.ac.uk
authors.forename: Roderick
authors.initials: R
authors.lastname: Skinner
authors.forename: Annie
authors.initials: A
authors.lastname: Parry
authors.forename: Lisa
authors.initials: L
authors.lastname: Price
authors.forename: Michael
authors.initials: M
authors.lastname: Cole
authors.forename: Alan W
authors.initials: AW
authors.lastname: Craft
authors.forename: Andrew D J
authors.initials: AD
authors.lastname: Pearson
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects*; D007223:Infant; D007674:Kidney Diseases / Q000139:chemically induced*; D007678:Kidney Glomerulus / Q000187:drug effects*; D008297:Male; D009369:Neoplasms / Q000188:drug therapy; D012307:Risk Factors
chemical_list: D000970:Antineoplastic Agents; D007069:Ifosfamide