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.

N‐Acetylcysteine prevents ifosfamide‐induced nephrotoxicity in rats

“…This was best explained by the animals losing body weight significantly due to wastage in muscle mass, as shown in the histology. This is a well‐described side effect in patients treated with anticancer drugs ( Appenroth et al , 2007 ) and was also reported in ifosfamide‐treated rats ( Springate and Van Liew, 1995 ; Sener et al , 2004 ). As a result, the serum creatinine concentration could not be used adequately to reflect changes in renal function at the higher dose of ifosfamide (80 mg kg −1 ).…”

“…To date, all recent papers addressing ifosfamide‐induced nephrotoxicity also used an acute animal model ( Sener et al , 2004 ). An attempt to establish an animal model for long‐lasting ifosfamide‐induced Fanconi syndrome was unsuccessful by Appenroth et al . (2007) .…”

Effects of aristolochic acid I and/or hypokalemia on tubular damage in C57BL/6 rat with aristolochic acid nephropathy

“…Glycosuria and proteinuria were more pronounced in groups III and IV than the other groups ( p < 0.05) ( Table 4 ), as were polyuria and urinary alkalization ( Table 2 ). These results are similar to previous animal studies of aFS [ 23 , 24 ]. Therefore, aFS appears to have been induced by the administration of AA-I (10 mg/kg) in groups III and IV despite the fact that K + was 3.9 ± 0.4 mEq/L in group III.…”