title: Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival.
abstract: BACKGROUND
  Erratic tacrolimus blood levels are associated with liver and kidney graft failure. We hypothesized that erratic tacrolimus exposure would similarly compromise lung transplant outcomes. This study assessed the effect of tacrolimus mean and standard deviation (SD) levels on the risk of chronic lung allograft dysfunction (CLAD) and death after lung transplantation.
  
  
  METHODS
  We retrospectively reviewed 110 lung transplant recipients who received tacrolimus-based immunosuppression. Cox proportional hazard modeling was used to investigate the effect of tacrolimus mean and SD levels on survival and CLAD. At census, 48 patients (44%) had developed CLAD and 37 (34%) had died.
  
  
  RESULTS
  Tacrolimus SD was highest for the first 6 post-transplant months (median, 4.01; interquartile range [IQR], 3.04-4.98 months) before stabilizing at 2.84 μg/liter (IQR, 2.16-4.13 μg/liter) between 6 and 12 months. The SD then remained the same (median, 2.85; IQR, 2.00-3.77 μg/liter) between 12 and 24 months. A high mean tacrolimus level 6 to 12 months post-transplant independently reduced the risk of CLAD (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.63-0.86; p < 0.001) but not death (HR, 0.96; 95% CI, 0.83-1.12; p = 0.65). In contrast, a high tacrolimus SD between 6 and 12 months independently increased the risk of CLAD (HR, 1.46; 95% CI, 1.23-1.73; p < 0.001) and death (HR, 1.27; 95% CI, 1.08-1.51; p = 0.005).
  
  
  CONCLUSIONS
  Erratic tacrolimus levels are a risk factor for poor lung transplant outcomes. Identifying and modifying factors that contribute to this variability may significantly improve outcomes.
authors.affiliation: Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia; Respiratory Medicine, Waikato Hospital, Hamilton, New Zealand.
authors.forename: Harry M
authors.initials: HM
authors.lastname: Gallagher
authors.affiliation: Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia.
authors.forename: Ghulam
authors.initials: G
authors.lastname: Sarwar
authors.affiliation: Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia.
authors.forename: Tracy
authors.initials: T
authors.lastname: Tse
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Sladden
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Esmond
authors.initials: E
authors.lastname: Hii
authors.affiliation: Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia; School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Yerkovich
authors.affiliation: Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia; School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Hopkins
authors.affiliation: Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia; School of Medicine, The University of Queensland, Brisbane, Queensland, Australia. Electronic address: daniel.chambers@health.qld.gov.au.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chambers
mesh_terms: D000328:Adult; D064591:Allografts; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000097:blood / Q000453:epidemiology / Q000517:prevention & control*; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009520:New Zealand / Q000453:epidemiology; D011379:Prognosis; D016016:Proportional Hazards Models; D011793:Queensland / Q000453:epidemiology; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: CLAD; chronic lung allograft dysfunction; death; erratic tacrolimus levels; lung transplant