Efforts to establish an animal model of Fanconi syndrome after ifosfamide administration to rats

Abstract

About 10% of children develop Fanconi syndrome (FS) a few months after ifosfamide (IFO) treatment. To establish an animal model, IFO was injected as 4 or 5 treatment courses (TCs, once daily for 3 consecutive days), to adult female rats (AF, 8 mg 100 g(-1) body wt, 4 TCs), to young female rats (YF, 8 mg 100 g(-1) body wt, 5 TCs) and to male rats (M, 6 mg 100 g(-1) body wt, 4 TCs). In the adult female rats, polyuria with electrolyte and albumin wasting occurred acutely, 2 days after the first treatment course. After the third treatment course, 30% of the rats died, but survivors showed a reduced excretion of electrolytes and glucose. The body weight increase was significantly diminished in adult female and male rats by about 25% or 70%, respectively. Up to 5 months after 5 TCs in young female rats, 15% of the animals died but the survivors did not show any sign of renal failure. In males, 28% of the rats died and in surviving animals the excretion of electrolytes, proteins and glucose as well as GFR were reduced 7 weeks after the last treatment course. There were no pathomorphological changes in kidney and liver. Determination of renal and hepatic cytochrome P450 activities indicated that results of adult female and male rats could be caused by starving, known as a common side effect of IFO, and not by its nephrotoxicity. Altogether, it was not possible to establish a model of a Fanconi syndrome persisting after cessation of IFO treatment in our rat strain, whereas acute, FS-like IFO effects on the kidney could be shown.