title: Donor Genotype and Intragraft Expression of CYP3A5 Reflect the Response to Steroid Treatment During Acute Renal Allograft Rejection.
abstract: Glucocorticoid (GC)-refractory acute rejection (AR) is a risk factor for inferior renal allograft outcome. We investigated genetic predisposition to the response to steroid treatment of acute allograft rejection.
  
  
  
  Single nucleotide polymorphisms of genes involved in GC 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).
  
  
  
  Patients who received a CYP3A5*1 allele expressing allograft had a lower risk of resistance to methylprednisolone during AR (odds ratio, 0.29; 95% confidence interval, 0.11-0.79; P = 0.016 in combined cohorts analysis). No differences were observed for GC signaling or other drug metabolism/transport-related genes. Both before transplantation (n = 69) and at time of AR (n = 88), tissue CYP3A5 mRNA expression was significantly higher in CYP3A5*1 allele expressing donor kidneys than in CYP3A5*3/*3 allografts (P < 0.00001). Moreover, steroid-responsive patients (n = 64) expressed significantly higher intragraft CYP3A5 mRNA levels compared to steroid-refractory patients (n = 42) in AR (P = 0.006).
  
  
  
  CYP3A5 protein expression was detected in tubular epithelial cells and inflammatory cells within the grafts. Our findings show that steroid resistance during AR is associated with donor genotype and intragraft expression levels of CYP3A5.
authors.affiliation: 1 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. 2 Obesity R&D Center, Novo Nordisk Inc., Seattle, WA. 3 Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany. 4 Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. 5 Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. 6 Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands. 7 Department of Nephrology, Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany. 8 HLA Laboratory, Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany.
authors.forename: Niels Vincent
authors.initials: NV
authors.lastname: Rekers
authors.forename: Tanja M
authors.initials: TM
authors.lastname: Flaig
authors.forename: Marko J K
authors.initials: MJK
authors.lastname: Mallat
authors.forename: Marijke J
authors.initials: MJ
authors.lastname: Spruyt-Gerritse
authors.forename: Malu
authors.initials: M
authors.lastname: Zandbergen
authors.forename: Jacqueline D H
authors.initials: JDH
authors.lastname: Anholts
authors.forename: Ingeborg M
authors.initials: IM
authors.lastname: Bajema
authors.forename: Marian C
authors.initials: MC
authors.lastname: Clahsen-van Groningen
authors.forename: Jianxin
authors.initials: J
authors.lastname: Yang
authors.forename: Johan W
authors.initials: JW
authors.lastname: de Fijter
authors.forename: Frans H J
authors.initials: FHJ
authors.lastname: Claas
authors.forename: Susanne
authors.initials: S
authors.lastname: Brakemeier
authors.forename: Nils
authors.initials: N
authors.lastname: Lachmann
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
authors.forename: Emile
authors.initials: E
authors.lastname: de Heer
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.forename: Juliane
authors.initials: J
authors.lastname: Bolbrinker
authors.forename: Michael
authors.initials: M
authors.lastname: Eikmans
mesh_terms: D000208:Acute Disease; D064591:Allografts; D016009:Chi-Square Distribution; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005858:Germany; D005938:Glucocorticoids / Q000378:metabolism / Q000627:therapeutic use*; D006084:Graft Rejection / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D006801:Humans; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000601:surgery*; D016030:Kidney Transplantation / Q000009:adverse effects*; D016015:Logistic Models; D008297:Male; D008775:Methylprednisolone / Q000378:metabolism / Q000627:therapeutic use*; D008875:Middle Aged; D009426:Netherlands; D016017:Odds Ratio; D010597:Pharmacogenetics; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors; D014019:Tissue Donors; D016896:Treatment Outcome
chemical_list: D005938:Glucocorticoids; D012333:RNA, Messenger; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D008775:Methylprednisolone