Donor genotype and intragraft expression of CYP3A5 reflect the response to steroid treatment during acute renal allograft rejection.

Background: Glucocorticoid-refractory acute rejection is a risk factor for inferior renal allograft outcome. We investigated genetic predisposition to the response to steroid treatment of acute allograft rejection. Methods: Single nucleotide polymorphisms of genes involved in glucocorticoid signaling (GR, GLCCI1) and drug metabolism and transport (CYP3A5, ABCB1, and PXR) were analyzed in kidney transplant recipients (1995-2005, Leiden cohort, n=153) treated with methylprednisolone. Significant associations were verified in a second cohort (Berlin cohort, n=66). Results: Patients who received a CYP3A5*1 allele expressing allograft had a lower risk of resistance to methylprednisolone during acute rejection (odds ratio 0.29, 95% confidence interval 0.11-0.79; P=0.016 in combined cohorts analysis). No differences were observed for glucocorticoid signaling or other drug metabolism/transport-related genes. Both before transplantation (n=69) and at time of acute rejection (n=88), tissue CYP3A5 mRNA expression was significantly higher in CYP3A5*1 allele expressing donor kidneys than in CYP3A5*3/*3 allografts (P

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