Ifosfamide‐induced nephrotoxicity : Mechanism and prevention

Abstract

Ifosfamide (IFO) is an anti-tumor prodrug effective against many solid tumors. Therapeutic efficacy is limited by a high incidence of renal damage. We examined the effect of IFO on renal mitochondrial function. We hypothesized that IFO metabolites inhibit NADH:ubiquinone oxidoreductase (complex I; C-I), which is sensitive to free radicals, thereby impairing the respiratory chain (RC) and oxidative phosphorylation (OP). We further hypothesized that provision of substrate to complex-II (C-II) would prevent IFO-induced injury by bypassing C-I. We tested RC activity in renal cortical mitochondria from rats treated with IFO, IFO+agmatine (a stimulator of fatty acid oxidation) or IFO+glutamine. Mitochondria of IFO-treated rats show a 50% decrease in State 3 respiration with C-I substrates but not with C-II substrates. Inhibition of C-I significantly increased [NADH] and decreased [NAD] in kidney cortex of these rats. The in vivo supplementation with agamatine or glutamine reversed inhibition of the RC and OP. Agmatine may furnish more FADH2 to C-II. Glutamine may supply succinate to C-II after conversion to glutamate and 2-oxo-glutarate. In in vitro studies we found that chloroacetaldehyde (CAA), a IFO metabolite, inhibited C-I and OP by 60% without affecting C-II. Disruption of C-I by CAA probably is the primary lesion of IFO-induced nephrotoxicity. Supplementation with C-II substrates ameliorates - and even might prevent - renal damage. Supported by NIH, DK-53761 and CA-79495 (to I.N.)