title: Tacrolimus exposure and evolution of renal allograft histology in the first year after transplantation.
abstract: Tacrolimus has a narrow therapeutic window and is characterized by a large inter-individual variability in bioavailability. The impact of tacrolimus exposure on subclinical evolution of graft histology has not been studied in renal recipients. This analysis included 239 protocol biopsies (obtained at implantation, 3 and 12 months) of 120 consecutive kidney recipients treated with tacrolimus, mycophenolate mofetil (MMF) and corticosteroids. Biopsies were scored according to the Banff 2001 criteria and a chronicity score was calculated. Prospective pharmacokinetic data were included in the analysis (5544 tacrolimus predose blood concentrations and tacrolimus AUC(0-12) at 3 and 12 months). Higher donor age and higher number of human leukocyte antigen-DR (HLA-DR) mismatches were independent predictors of subclinical acute rejection at 3 months, present in 8.7% of patients. The number of HLA-DR mismatches was independently associated with biopsy-proven clinical acute rejection. Biopsy-proven acute rejection episodes and low mean tacrolimus exposure were independently associated with higher increase in chronicity scores between 3 and 12 months after transplantation. This observational study suggests that rejection phenomena and immune-mediated mechanisms remain important in the early progression of chronic allograft pathology. Tacrolimus doses or systemic exposure were not associated with lesions of calcineurin inhibitor nephrotoxicity, suggesting that other factors determine susceptibility to tacrolimus nephrotoxicity.
authors.affiliation: Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Naesens
authors.forename: E
authors.initials: E
authors.lastname: Lerut
authors.forename: B V
authors.initials: BV
authors.lastname: Damme
authors.forename: Y
authors.initials: Y
authors.lastname: Vanrenterghem
authors.forename: D R J
authors.initials: DR
authors.lastname: Kuypers
mesh_terms: D000328:Adult; D001706:Biopsy; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids / Q000627:therapeutic use; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus