Cyclosporine A sensitizes the kidney to tubulointerstitial fibrosis induced by renal warm ischemia

Background. Renal warm ischemic injury and immunosuppression with cyclosporin A (CsA) may contribute to chronic allograft nephropathy after cadaveric transplantation. This study establishes whether CsA can sensitize the kidney to injury and fibrosis induced by renal warm ischemia (RWI). Methods. The left kidney of Sprague-Dawley rats was subjected to 30 min of warm ischemia and/or intraperitoneal CsA (15 mg/kg/d) for 30 days (n=6 per group). Renal injury and fibrosis were assessed histologically together with immunohistochemistry for collagen III, transforming growth factor (TGF)-β1, ED1 (macrophage marker), and α-smooth muscle actin. Renal mRNAs for collagen III, TGF-β1, matrix metalloproteinase (MMP-2, and tissue inhibitor of metalloproteinase-1 together with MMP enzyme activity were also determined. Results. RWI or CsA alone produced only minor effects on renal injury and fibrosis. However, in CsA-treated rats, RWI produced a marked increase in tubulointerstitial fibrosis, as shown by the potentiation of collagen III and TGF-β1 determined by immunochemistry and mRNA analysis. The up-regulation of tissue inhibitor of metalloproteinase-1 mRNA was associated with a decrease in MMP enzyme activity. In CsA-treated rats, RWI was also associated with an increase in inflammatory infiltrates, elevated immunostain for ED1 (indicating extensive macrophage influx), and elevated immunostain for α-smooth muscle actin (indicating myofibroblast activation). Conclusions. In the rat, CsA can sensitize the kidney to fibrosis induced by renal warm ischemia. In renal transplantation, when cadaveric donor kidneys have been subjected to a period of warm ischemia, CsA may be an inappropriate choice for immunosuppressive therapy.