Long-term effects of cyclosporine A to rapamycin conversion on testicular function and morphology in rat models of kidney transplantation

Abstract

Objective To investigate the long-term effects of cyclosporine A(CsA) to rapamycin (Rapa) conversion on testicular function and morphology in rat models of kidney transplantation. Methods Left orthotopic renal transplantation in rats was performed using standard model approach, namely, using Fisher rats as donor and male Lewis rats as recipient. Thirty-six Lewis rat models were randomized into the Rapa group (group R, n=10), CsA continuous use group (group A, n=10), CsA withdrawal group (group B, n=8) and control group (group C, n=8). In addition, the Lewis rats receiving donor Lewis rat kidney were assigned into a syngeneic transplantation group (group T, n=6). Immediately after surgery, Groups R,A, B and C were subjected to gavage of CsA (1.5 mg·kg-1 ·d-1) till day 10. Thereafter, groups R, A and B were given a larger dose of CsA ( 10 mg· kg-1· d-1 ) gavage from day 11 to week 7. From weeks 8 to week 24,CsA was converted to Rapa (0.5 mg· kg-1 ·d-1 ) in group R and to normal saline (10 ml· kg-1· d-1 ) in group B,and remained unchanged in group A. Gavage of normal saline was also given to group C from day 11 to week 24, and to group T immediately after surgery till week 24. At week 24 after surgery, the rats were sacrificed and phlebotomized for determination of testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH). Moreover, the testosterone/LH ratio was calculated. The weights of right testis were then recorded in every group. Thereafter, the seminiferous tubule diameter (STD) was randomly measured under light microscope, and a quantitative histological score criteria was used to evaluate the histological injury of testis. Every two specimens of testis were randomly selected from groups R, A and T for examination of ultrastructure using transmission electron microscopy. Results The serum level of testosterone in group R was lowered as compared with group T, group A [(0.85±0.09) μg/L vs (1.05±0.17) μg/L, (0.94+0.13) μg/L,all P＜0.05]but was not significantly different among the other groups. There were no differences in FSH and LH among the five groups. The testosterone/LH ratio was highest in T group and lowest in R group (0.59±0.03). Compared with T group, the weights of right testis and mean STD in groups R, A, B and C were significantly reduced, and were lowest in group R. Groups R, A, B and C had increased histological injury scores as compared with group T. Under electron microscopy, group R showed edematous mitochondria,dilated endoplasmic reticulum in Leydig cells and significantly reduced organelles in Sertoli cells, and group A showed edematous mitochondra in Leydig cells and reduced organelles in Sertoli cells, while group T did not show any abnormalities in ultrastructure of testis tissues. Conclusion Compared with continuous use of CsA, the long-term effect of CsA to Rapamycin conversion may not compromise the function of testis but can lead to more severe histological injury. Key words: Kidney transplantation; Testis; Cyclosporine A ; Rapamycin; Histology