title: Impact of tacrolimus intraindividual variability and CYP3A5 genetic polymorphism on acute rejection in kidney transplantation.
abstract: BACKGROUND
  Wide variation in tacrolimus concentrations and low tacrolimus exposure have been reported to be associated with poor renal graft outcomes in non-Asians. The CYP3A5 polymorphism is a representative genetic factor that might affect this association, together with environmental factors. We investigated whether tacrolimus variability or the mean tacrolimus trough concentration can influence kidney allograft outcomes in Asians and whether the CYP3A5 polymorphism (rs776746) can affect this relationship.
  
  
  METHODS
  Data from renal transplant patients between 2000 and 2010 were analyzed retrospectively. The tacrolimus intraindividual variability (IIV) and the mean tacrolimus trough concentration were calculated from the tacrolimus concentrations between 6 and 12 months after transplantation.
  
  
  RESULTS
  A total of 249 renal transplant patients were enrolled. The patients with higher tacrolimus IIV had shorter rejection-free survival (P = 0.002). However, there was no difference in rejection-free survival between CYP3A5 expressers and nonexpressers. The tacrolimus IIV was not associated with the CYP3A5 polymorphism. High IIV of tacrolimus was an independent risk factor of biopsy-proven acute rejection after adjusting for mean tacrolimus concentration, HLA mismatch, induction therapy, donor type, and CYP3A5 polymorphism (hazard ratio 2.655, 95% confidence interval 1.394-5.056). Interestingly, the impact of tacrolimus IIV on acute rejection was significant in CYP3A5 expressers, whereas it was not in CYP3A5 nonexpressers.
  
  
  CONCLUSIONS
  The IIV of tacrolimus trough concentrations had a significant impact on rejection-free survival. The effect was influenced by CYP3A5 polymorphism, although the tacrolimus variability itself was not determined by the CYP3A5 polymorphism.
authors.affiliation: Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.
authors.forename: Han
authors.initials: H
authors.lastname: Ro
authors.forename: Sang-Il
authors.initials: SI
authors.lastname: Min
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Yang
authors.forename: Kyung Chul
authors.initials: KC
authors.lastname: Moon
authors.forename: Yon Su
authors.initials: YS
authors.lastname: Kim
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Kim
authors.forename: Curie
authors.initials: C
authors.lastname: Ahn
authors.forename: Jongwon
authors.initials: J
authors.lastname: Ha
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D006084:Graft Rejection / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000627:therapeutic use*; D007438:Introns; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D056910:Republic of Korea; D012189:Retrospective Studies; D016019:Survival Analysis; D016559:Tacrolimus / Q000097:blood / Q000627:therapeutic use*
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus