title: High Intrapatient Variability of Tacrolimus Concentrations Predicts Accelerated Progression of Chronic Histologic Lesions in Renal Recipients.
abstract: High intrapatient variability (IPV) of tacrolimus concentrations is increasingly recognized as a predictor of poor outcome in solid organ recipients. How it relates to evolution of histology has not been explored. We analyzed tacrolimus IPV using the coefficient of variability (CV) from months 6-12 after transplantation in a cohort of 220 renal recipients for whom paired protocol biopsies at 3 mo and 2 years were available. Recipients in the highest CV tertile had an increased risk of moderate to severe fibrosis and tubular atrophy by 2 years compared with the low-IPV tertile (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.09-5.60, p = 0.031; and OR 2.40, 95% CI 1.03-5.60, p = 0.043, respectively). Other predictors were donor age, severity of chronic lesions at 3 mo, and presence of borderline or subclinical rejection at 3 mo. Chronicity score increased significantly more in the high CV tertile group than in the middle and low tertiles (mean increase 1.97 ± 2.03 vs. 1.18 ± 2.44 and 1.12 ± 1.80, respectively; p < 0.05). CV did not predict evolution of renal function, which did not deteriorate within the 2-year follow-up period. These results indicate that high IPV is related to accelerated progression of chronic histologic lesions before any evidence of renal dysfunction.
authors.affiliation: Department of Microbiology and Immunology, KU Leuven - University of Leuven, and Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: T
authors.identifier: 0000-0001-5712-6294
authors.initials: T
authors.lastname: Vanhove
authors.affiliation: Department of Microbiology and Immunology, KU Leuven - University of Leuven, and Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Vermeulen
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Annaert
authors.affiliation: Department of Imaging and Pathology, KU Leuven - University of Leuven, and Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Lerut
authors.affiliation: Department of Microbiology and Immunology, KU Leuven - University of Leuven, and Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: D R J
authors.initials: DRJ
authors.lastname: Kuypers
mesh_terms: D001284:Atrophy / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D005355:Fibrosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000601:surgery*; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000627:therapeutic use*; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: calcineurin inhibitor: tacrolimus; clinical research/practice; fibrosis; immunosuppressant; immunosuppression/immune modulation; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; pharmacokinetics/pharmacodynamics; pharmacology