title: CYP2C8*3 polymorphism and donor age are associated with allograft dysfunction in kidney transplant recipients treated with calcineurin inhibitors.
abstract: Epoxieicosatrienoic acids (EETs) play a protective role against damaging processes in the kidney. We have assessed the effect of polymorphisms in EETs-producing enzymes (CYP2C8 and CYP2J2) and other proteins involved in calcineurin inhibitors (CNIs) disposition (CYP3A4, CYP3A5, and ABCB1) on graft function and clinical outcome in 166 renal transplant recipients treated with CNIs. Both CYP2C8*3 and donor age greater than 48 years were associated to a higher incidence of delayed graft function (DGF) [OR = 2.01 (1.1-4.1), P = .04 and 5.14 (2.4-10.9), P < .0001; respectively] and worse creatinine clearance 1 year after grafting (P < .05 and P < .001, respectively). In addition, carrying 4-6 variants in the 3 ABCB1 loci and older donor age were individually associated to higher incidence of calcineurin-inhibitor-induced nephrotoxicity [OR = 2.38 (1.1-5.4), P = .03 and OR = 1.03 (1.01-1.06), P = .038]. Regression analyses confirmed the relevant effect of both CYP2C8*3 and donor age on graft dysfunction. Carrying the 2C8*3 allele and having a donor older than 48 years was defined as a high-risk status and observed to be highly related to DGF [OR = 3.91 (1.46-10.48), P < .01] and worse creatinine clearance (P = .033). Our results show that genetic and clinical parameters can be combined to identify risk factors for allograft dysfunction in renal transplant recipients.
authors: Division of Pharmacology, Department of Medical and Surgical Therapeutics, Medical School, University of Extremadura, Badajoz, Spain. ggervasi@unex.es
authors: Guillermo
authors: G
authors: Gervasini
authors: Montserrat
authors: M
authors: Garcia
authors: Rosa María
authors: RM
authors: Macias
authors: Julio
authors: J
authors: Benitez
authors: Francisco
authors: F
authors: Caravaca
authors: Juan Jose
authors: JJ
authors: Cubero
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000367:Age Factors; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000627:therapeutic use; D065727:Cytochrome P-450 CYP2C8; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8