Effects of deferasirox on renal function and renal epithelial cell death.

Abstract Iron-chelating therapyresults in a significant improvement in the life expectancy of patients with transfusional iron overload. However, alterations of renal function have been observed in some patients undergoing chelation therapy. In the present study we evaluated the effect of treatment with deferasirox iron chelatoron the renal function in normal Wistar rats and in mouse and human cultured tubular cell lines. Results indicate that deferasiroxgiven daily via intraperitoneal route for 7 days induced: (1) an increased urinary protein, albumin and glucose excretion, (2) tubular necrosis/apoptosis, (3) and increased tubular damage markers, in spite of normal glomerular function. Moreover, in vitro studies revealed that: (1) mouse MCT cultures resulted more susceptible to the antiproliferative/cytotoxic effect of deferasirox, mainly at 24 h after treatment, than human HK-2 cultures, (2) MCT cell content of damage molecules increased after 24 h of iron chelatortreatment with slight changes in their excretion into the culture medium and (3) MCT cultures showed a significant evidence of apoptotic cell death through an increased expression and activation of caspase-3 and marked DNA fragmentation. In conclusion, this renal side effect of deferasirox- chelating therapyseems to be based on direct toxic effects of deferasiroxon renal tubular cells.