title: Lower tacrolimus trough levels are associated with subsequently higher acute rejection risk during the first 12 months after kidney transplantation.
abstract: The premise that lower TAC trough levels are associated with subsequently higher first BPAR risk during the first 12 mo post-transplant was recently questioned. Using our prospectively followed cohort of 528 adult, primary kidney transplant recipients (pooled across four randomized trials) who received reduced TAC dosing plus an IMPDH inhibitor, TAC trough levels measured at seven time points, 7, 14 days, 1, 2, 3, 6 and 9 months post-transplant, were utilized along with Cox's model to determine the multivariable significance of TAC level(t) (a continuous time-dependent covariate equaling the most recently measured TAC level prior to time t) on the hazard rate of developing first BPAR during the first 12 months post-transplant. The percentage developing BPAR during the first 12 months post-transplant was 10.2% (54/528). In univariable analysis, lower TAC level(t) was associated with a significantly higher BPAR rate (P = 0.00006), and its significance was maintained even after controlling for 2 significant baseline predictors (African-American/Hispanic Recipient and Developed DGF) in Cox's model (multivariable P = 0.0003). Use of a cutpoint, TAC level(t) <4.0 vs. ≥4.0 ng/ml, yielded an even greater association with BPAR rate (univariable and multivariable P < 0.000001), with an estimated hazard ratio of 6.33. These results suggest that TAC levels <4.0 ng/ml should be avoided during the first 12 months post-transplant when TAC is used in combination with fixed-dose mycophenolate with or without corticosteroids and induction therapy.
authors.affiliation: Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Gaynor
authors.affiliation: Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Ciancio
authors.affiliation: Miami Transplant Institute, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Giselle
authors.initials: G
authors.lastname: Guerra
authors.affiliation: Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Sageshima
authors.affiliation: Miami Transplant Institute, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: David
authors.initials: D
authors.lastname: Roth
authors.affiliation: Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goldstein
authors.affiliation: Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Chen
authors.affiliation: Miami Transplant Institute, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Kupin
authors.affiliation: Miami Transplant Institute, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Adela
authors.initials: A
authors.lastname: Mattiazzi
authors.affiliation: Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Lissett
authors.initials: L
authors.lastname: Tueros
authors.affiliation: Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Flores
authors.affiliation: Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Lois
authors.initials: L
authors.lastname: Hanson
authors.affiliation: Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.affiliation: Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Vianna
authors.affiliation: Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: George W
authors.initials: GW
authors.lastname: Burke
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D051799:Delayed Graft Function / Q000209:etiology; D005260:Female; D006084:Graft Rejection / Q000209:etiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: biopsy-proven acute rejection; kidney transplant recipient; tacrolimus trough level