title: Early tacrolimus exposure after liver transplantation: relationship with moderate/severe acute rejection and long-term outcome.
abstract: OBJECTIVE
  Liver transplant (LT) patients might be overimmunosuppressed as recommendations for tacrolimus trough concentrations (TC) within 4-6 weeks after liver transplantation are set too high (10-15 ng/ml). Early tacrolimus exposure was evaluated in relation to acute rejection and long-term outcomes.
  
  
  METHODS
  Four hundred and ninety-three consecutive LT patients receiving tacrolimus as primary immunosuppression (1995-2008) were analyzed. Acute rejection was diagnosed using protocol biopsies at day 6.1 ± 2.5. Median follow-up was 7.3 years (IQR 3.9-10.5). Early tacrolimus exposure (<15 days) was evaluated against moderate/severe acute rejection, chronic rejection, graft loss, chronic renal impairment and mortality using multiple logistic and Cox regression.
  
  
  RESULTS
  Maintenance immunosuppression was tacrolimus monotherapy (48.1%), double therapy combination with antimetabolites or steroids (18%), or triple therapy combination with antimetabolites and steroids (33.9%). Histological grade of acute rejection was moderate in 157 cases (31.8%) and severe in 19 cases (3.9%). Tacrolimus TC>7 ng/ml on the day of protocol biopsy was associated with less moderate/severe rejection (23.8%) compared with<7 ng/ml (41.2%) (p = 0.004). Mean tacrolimus TC 7-10 ng/ml within 15 days after LT were associated with reduced risk of graft loss (RR = 0.46; p = 0.014) compared to TC 10-15 ng/ml. A peak TC>20 ng/ml within this period was independently related to higher mortality (RR = 1.67; p = 0.005), particularly due to cardiovascular events, infections and malignancy (RR = 2.15; p = 0.001). Early tacrolimus exposure did not influence chronic rejection (p = 0.58), or chronic renal impairment (p = 0.25).
  
  
  CONCLUSIONS
  During the first 2 weeks after LT, tacrolimus TC between 7 and 10 ng/ml are safe in terms of acute rejection and are associated with longer graft survival.
authors.affiliation: The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, Royal Free Hospital, London, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodríguez-Perálvarez
authors.forename: Giacomo
authors.initials: G
authors.lastname: Germani
authors.forename: Vasilios
authors.initials: V
authors.lastname: Papastergiou
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tsochatzis
authors.forename: Evangelos
authors.initials: E
authors.lastname: Thalassinos
authors.forename: Tu Vinh
authors.initials: TV
authors.lastname: Luong
authors.forename: Nancy
authors.initials: N
authors.lastname: Rolando
authors.forename: Amar Paul
authors.initials: AP
authors.lastname: Dhillon
authors.forename: David
authors.initials: D
authors.lastname: Patch
authors.forename: James
authors.initials: J
authors.lastname: O'Beirne
authors.forename: Douglas
authors.initials: D
authors.lastname: Thorburn
authors.forename: Andrew Kenneth
authors.initials: AK
authors.lastname: Burroughs
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D006526:Hepatitis C / Q000601:surgery; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D017114:Liver Failure, Acute / Q000601:surgery; D008113:Liver Neoplasms / Q000601:surgery; D016031:Liver Transplantation / Q000276:immunology* / Q000401:mortality; D016015:Logistic Models; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012720:Severity of Illness Index; D015996:Survival Rate; D016559:Tacrolimus / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus