title: Association of the combination of time-weighted variability of tacrolimus blood level and exposure to low drug levels with graft survival after kidney transplantation.
abstract: The variability of tacrolimus blood levels has been shown to be associated with inferior graft survival. However, the effect of variability during the early post-transplantation period has not been evaluated. We sought to evaluate the association between time-weighted variability in the early post-transplantation period and graft survival. We also explored the interaction between drug level variability and exposure to inadequate drug levels.
  
  
  
  This retrospective cohort study included all patients who underwent kidney transplantation in the Rabin Medical Center and were treated with tacrolimus. Time-weighted coefficient of variability (TWCV) was defined as time-weighted standard deviation divided by the mean drug level. Univariate and multivariate Cox proportional hazard model was used with the primary outcome of patients and graft survival.
  
  
  
  The study population included 803 patients who underwent kidney transplantation between 1 January 2000 and 29 September 2013. The high tertile of TWCV of tacrolimus blood levels was associated with reduced graft survival by univariate and multivariate analyses [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.14-2.53, P = 0.01 and HR 1.74, 95% CI 1.14-2.63, P = 0.01, respectively]. The interaction between high TWCV and exposure to inadequately low drug levels was significantly associated with reduced survival (P = 0.004), while the interaction between TWCV and high drug blood levels was not. One hundred and thirty patients (16.2%) had the combination of high TWCV and exposure to low drug values (<5 ng/mL). These patients had reduced graft survival by univariate and multivariate analyses (HR 2.42, 95% CI 1.57-3.74, P < 0.001 and HR 2.6, 95% CI 1.65-4.11, P < 0.001, respectively).
  
  
  
  The combination of high TWCV and exposure to low drug levels might identify high-risk patients in the early post-transplantation period.
authors.affiliation: Department of Nephrology, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.|Sacker School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Benaya
authors.initials: B
authors.lastname: Rozen-Zvi
authors.affiliation: Department of Nephrology, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.|Sacker School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Department of Nephrology, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.|Sacker School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shelly
authors.initials: S
authors.lastname: Lichtenberg
authors.affiliation: Sacker School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Internal Medicine B, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.
authors.forename: Hefziba
authors.initials: H
authors.lastname: Green
authors.affiliation: Sacker School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Internal Medicine D, Rabin Medical Center-Hasharon Hospital, Petach Tikva, Israel.
authors.forename: Ori
authors.initials: O
authors.lastname: Cohen
authors.affiliation: Sacker School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Uzi
authors.initials: U
authors.lastname: Gafter
authors.affiliation: Department of Nephrology, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.|Sacker School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Avry
authors.initials: A
authors.lastname: Chagnac
authors.affiliation: Sacker School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Transplantation, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.
authors.forename: Eytan
authors.initials: E
authors.lastname: Mor
authors.affiliation: Department of Nephrology, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.|Sacker School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Transplantation, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rahamimov
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D016903:Drug Monitoring; D005260:Female; D006084:Graft Rejection / Q000097:blood* / Q000188:drug therapy / Q000209:etiology; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: graft survival; immunosuppression; kidney transplantation; variability