New insight of immunosuppressive drugs related nephrotoxicity

Even though the incidence of acute rejection episode has been dramatically lowered after organ transplantation, long-term results have not improved consequently. Nephrotoxicity is a major side effect of the powerful immunosuppressive drugs used and may precluded long-term outcome. This side effect is well-recognized for calcineurine inhibitors but sirolimus (SRL), a mTOR inhibitor, also exhibit nephrotoxicity especially after delayed graft function. For calcineurine inhibitors, in vivo and in vitro data demonstrate that P-glycoproteine may play a critical role in protecting renal epithelial cells from cyclosporine A (CsA) toxicity. Regarding the molecular mechanisms, transcriptional profiles of human proximal tubular cells exposed to CsA found that it preferentially alters biological processes located at the cell membrane, such as ion transport or signal transduction. Wide expression analysis suggested that CsA may induce an endoplasmic reticulum (ER) stress in tubular cells in vitro and in vivo, because of cyclophilin A inhibition. Furthermore, CsA induces epithelial phenotypic changes reminiscent of an incomplete epithelial-to-mesenchymal transition in a TGF-b independent manner, as did various ER stress inducers. Finally, in primary cultured human tubular cells CsA induces autophagy dependant of ER stress. SRL modifies biological processes within the nucleus and related to transcriptional activity. It inhibits the proliferative response to mitogenic stimuli, and causes cell cycle arrest in the early G(1) phase, by a nonspecifi c process due to inhibition of the p70(S6k) pathway and by a direct effect on cyclin D3 mRNA stability. All these data demonstrate that new pathways have been defined recently to better understand the immunosuppressive drug associated nephrotoxicity giving possible clues to prevent this complication.

Keywords: Organ Transplantation, nephrotoxicity, carcinomatosis, intraperitoneal chemotherapy, cancer