title: Factors increasing quantitative interstitial fibrosis from 0 hr to 1 year in living kidney transplant patients receiving tacrolimus.
abstract: BACKGROUND
  This study investigated the increase in interstitial fibrosis (IF) from 0 hr to 1 month and 1 year posttransplantation in biopsy sections and assessed the risk of developing IF in 118 living kidney recipients.
  
  
  METHODS
  A quantitative analysis of IF was performed using computer-assisted imaging. The percent IF (%IF) in the cortical region at 0 hr was defined as the baseline, and the increases in %IF at 1 month and 1 year were calculated. Demographics, higher (regimen 1) and lower (regimen 2) target trough concentrations of tacrolimus, and the cytochrome P450 (CYP) 3A5 polymorphism were tested as risk factors.
  
  
  RESULTS
  The mean %IF at 0 hr, 1 month, and 1 year was 10.3%+/-4.2%, 15.0%+/-5.8%, and 19.0%+/-7.7%, respectively. %IF increased 1.7- and 2.2-fold from 0 hr to 1 month and 1 year posttransplantation, respectively. At 1 year, the increase was higher in patients with the CYP3A5*3/*3 genotype (nonexpressers), those treated with regimen 1, and those with a lower estimated glomerular filtration rate and higher body mass index. In a multivariate analysis, CYP3A5 nonexpression correlated with the development of IF (odds ratio 2.63, P=0.018). Tacrolimus blood levels in the early stage posttransplantation were higher in nonexpressers than CYP3A5 expressers in both regimens 1 and 2, despite therapeutic drug monitoring.
  
  
  CONCLUSIONS
  The higher concentrations of tacrolimus, especially in the nonexpressers treated with regimen 1, might influence the development of IF. This study suggested that a new regimen with lower and narrow target trough levels of tacrolimus or a dosing strategy based on the CYP3A5 genotype is needed to reduce the risk of developing IF.
authors: Department of Urology, Akita University School of Medicine, Akita, Japan.
authors: Yoshiko
authors: Y
authors: Miura
authors: Shigeru
authors: S
authors: Satoh
authors: Mitsuru
authors: M
authors: Saito
authors: Kazuyuki
authors: K
authors: Numakura
authors: Takamitsu
authors: T
authors: Inoue
authors: Takashi
authors: T
authors: Obara
authors: Hiroshi
authors: H
authors: Tsuruta
authors: Shintaro
authors: S
authors: Narita
authors: Yohei
authors: Y
authors: Horikawa
authors: Norihiko
authors: N
authors: Tsuchiya
authors: Atsushi
authors: A
authors: Komatsuda
authors: Hideaki
authors: H
authors: Kagaya
authors: Masatomo
authors: M
authors: Miura
authors: Tomonori
authors: T
authors: Habuchi
mesh_terms: D000328:Adult; D000368:Aged; D015992:Body Mass Index; D002908:Chronic Disease; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005355:Fibrosis; D005919:Glomerular Filtration Rate; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D007668:Kidney / Q000473:pathology*; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000276:immunology / Q000473:pathology*; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus