The role of immunosuppressive drugs in aggravating renal ischemia and reperfusion injury.
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.
Gonçalves
G M
GM
Laboratório de Imunologia Clínica e Experimental, Division of Nephrology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil.
Cenedeze
M A
MA
Feitoza
C Q
CQ
de Paula
C B
CB
Marques
G D
GD
Pinheiro
H S
HS
de Paula Antunes Teixeira
V
V
Antônia dos Reis
M
M
Pacheco-Silva
A
A
Câmara
N O S
NO
D000818:Animals; D016572:Cyclosporine / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011183:Postoperative Complications / Q000139:chemically induced; D015427:Reperfusion Injury / Q000139:chemically induced*; D020123:Sirolimus / Q000009:adverse effects*; D014185:Transplantation, Isogeneic; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus