Bootcongres

Steroid-refractory acute rejection is a risk factor for inferior renal allograft outcome. We investigated the relationship between the genotype of glucocorticoid signaling and metabolism genes and the response to steroid treatment in renal allograft recipients with acute rejection.

One hundred and fifty three kidney transplant recipients (1995-2005), who were treated with high dose i.v. methylprednisolone during a first rejection episode, were included in the study. Maintenance therapy consisted of a double regimen (prednisone, calcineurin inhibitor: Cyclosporine or Tacrolimus) or triple regimen (also with MMF). We analyzed single nucleotide polymorphism genotype of genes involved in glucocorticoid signaling (Glucocorticoid Receptor, GLCCI1) and drug metabolism (CYP3A5, ABCB1, PXR) in both recipients and donors.

CYP3A5 genotype of the donor kidney was the only variable showing a significant association (P=0.039) with response to steroid treatment. In subanalyses, similar trends were observed between patients receiving Cyclosporine and patients receiving Tacrolimus. Patients who had received a renal allograft from a CYP3A5*1-allele-expressing donor had a 3.3 times lower risk of resistance to steroid treatment during acute rejection (odds ratio=0.3; 95% confidence interval, 0.10–1.0; P=0.047). CYP3A5*1 donor grafts (n=20) displayed significantly higher intragraft CYP3A5 mRNA expression levels than allografts from CYP3A5*3/*3 carriers (n=105; P<0.00001). Accordingly, significantly higher CYP3A5 mRNA levels were seen in steroid responsive patients compared to steroid resistant patients (P=0.006). By immunohistochemistry, distal and proximal tubules were found to abundantly express CYP3A5 protein. In a panel of different cell types, proximal tubular epithelial cells and activated macrophages showed the highest CYP3A5 mRNA expression. 

Our study shows that resistance to steroid treatment during acute rejection is associated with donor genotype and intragraft expression levels of CYP3A5. We speculate that recipients receiving kidneys with a high expressing CYP3A5*1 genotype are better protected against rejection injury and therefore are less resistant to steroid treatment.