The Role of Immunosuppressive Drugs in Aggravating Renal Ischemia and Reperfusion Injury

• Published in: Transplantation proceedings 2007-03, Vol.39 (2), p.417-420
• Main Authors: Gonçalves, G.M, Cenedeze, M.A, Feitoza, C.Q, de Paula, C.B, Marques, G.D, Pinheiro, H.S, de Paula Antunes Teixeira, V, Antônia dos Reis, M, Pacheco-Silva, A, Câmara, N.O.S
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cyclosporine - adverse effects; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immunosuppressive Agents - adverse effects; Kidney Function Tests; Kidney Transplantation - immunology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Models, Animal; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Postoperative Complications - chemically induced; Renovascular diseases; Reperfusion Injury - chemically induced; Sirolimus - adverse effects; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Tissue, organ and graft immunology; Transplantation, Isogeneic; Treatment Outcome
• ISSN: 0041-1345; 1873-2623
• DOI: 10.1016/j.transproceed.2007.01.027

Abstract Renal ischemia followed by reperfusion leads to acute renal failure in both native kidneys and renal allografts. Cyclosporine has known nephrotoxic effects. Thus, cyclosporine therapy subsequent to ischemia/reperfusion (I/R) injury may further exacerbate graft dysfunction. Rapamycin is a newer agent that suppresses the immune system by a different mechanism. In the present study, the effects of Cyclosporine and rapamycin at low and higher concentrations were investigated in an I/R-induced injury model. Methods Cyclosporine (100 mg/kg or 50 mg/kg), rapamycin (3 mg/kg per day or 1.5 mg/kg), or both were administered to mice before being subjected to 45 minutes of ischemia. Blood and kidney samples were collected at 24, 48, and 120 hours after surgery. We quantified acute tubular necrosis and tubular regeneration. Results Animals subjected to I/R showed impaired renal function that peaked at 24 hours (2.05 ± 0.23 mg/dL), decreasing thereafter. Treatment with higher concentrations of cyclosporine or rapamycin caused even more renal dysfunction at 48 hours, which was sustained up to 120 hours after reperfusion (1.53 ± 0.6 mg/dL), when compared to the low concentrations of cyclosporine or rapamycin (1.08 ± 0.19 mg/dL; 0.99 ± 0.14 mg/dL, P < .05, respectively). Cyclosporine delayed tubular regeneration, which was higher in controls at day 5 (67.0% vs 37.6%, P < .05). Conclusions These results demonstrated that cyclosporine or rapamycin might further aggravate ischemically injured organs, negatively affecting posttransplantation recovery in a concentration-dependent fashion.