Sex hormones and gender-related differences: Their influence on chronic renal allograft rejection

Background. Renal hemodynamics and immune responses differ between males and females. Thus, sex hormones and genetically determined gender differences may determine the process of chronic rejection to some extent. Methods. Female (F) or male (M) F344 kidneys were orthotopically transplanted into ovariectomized female Lewis recipients and were treated for 16 weeks with either estradiol, testosterone, or vehicle. Results. Testosterone treatment resulted in increased urinary protein excretion independently of the donor gender, as well as extended glomerular sclerosis, interstitial fibrosis, and severe vascular lesions. Additionally, mononuclear cell infiltration was most pronounced in these animals, in parallel to an increased expression of intercellular adhesion molecule-1 (ICAM-1), fibronectin, laminin, and transforming growth factor-β (TGF-β) in the grafts. Estradiol treatment resulted in an improved graft function, reduced glomerular sclerosis, and a diminished cellular infiltration, in parallel to a reduced ICAM-1, fibronectin, laminin, and TGF-β expression. In animals treated with vehicle, the gender of the donor influenced the outcome. Grafts of male origin had good graft function and histology, whereas grafts from female donors developed severe proteinuria and glomerular, interstitial, and vascular damage. Conclusions. These results suggest that a protective effect of estradiol on the progression of chronic rejection exists that is independent of donor gender. Additionally, a male kidney may benefit from the absence of testosterone, whereas the function of a female kidney deteriorates in the absence of estradiol.