title: Tacrolimus Concentration/Dose Ratio is Associated with Renal Function After Liver Transplantation.
abstract: BACKGROUND
  The calcineurin inhibitor (CNI) tacrolimus (Tac) is an effective immunosuppressant used after liver transplantation (LTx), but is often associated with CNI nephrotoxicity. Currently, there is no simple clinical predictor for CNI nephrotoxicity after LTx. We hypothesized that the Tac metabolism rate - defined as the blood concentration normalized by its daily dose (the C/D ratio) - is associated with post-LTx renal impairment.
  
  
  METHODS
  We analyzed the relationship between the C/D ratio and post-transplant renal function in 179 patients who underwent LTx between 2000 and 2012 and were initially immunosuppressed with Tac, mycophenolate mofetil, and prednisolone. Six months after LTx, 115 patients were categorized into 1 of 2 groups based on their Tac C/D ratio (<1.09 or ≥1.09): fast (n=58) or slow (n=57) metabolizers. The renal function was determined 36 months after LTx using the estimated glomerular filtration rate (eGFR) as described by Cockcroft and Gault.
  
  
  RESULTS
  At the time of LTx there was no statistically significant difference between the eGFR of fast and slow metabolizers. Six months (P=0.016), 12 months (P=0.001), and 36 months (P=0.018) after LTx, fast Tac metabolizers had significantly more impaired renal function than slow metabolizers. Because of a presumption of CNI nephrotoxicity, 32.8% of fast metabolizers and 14.0% of slow metabolizers were switched from Tac to other immunosuppressants (P=0.027).
  
  
  CONCLUSIONS
  In this study, the Tac metabolism rate appears to influence renal function after LTx, suggesting that a C/D ratio of <1.09 is associated with increased CNI nephrotoxicity in LTx recipients.
authors.affiliation: Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital Münster, Münster, Germany.
authors.forename: Gerold
authors.initials: G
authors.lastname: Thölking
authors.affiliation: Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital Münster, Münster, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Siats
authors.affiliation: Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital Münster, Münster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Fortmann
authors.affiliation: Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany.
authors.forename: Raphael
authors.initials: R
authors.lastname: Koch
authors.affiliation: Department of Transplant Medicine, University Hospital of Münster, Münster, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Hüsing
authors.affiliation: Department of Transplant Medicine, University Hospital of Münster, Münster, Germany.
authors.forename: Vito R
authors.initials: VR
authors.lastname: Cicinnati
authors.affiliation: Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Münster, Germany.
authors.forename: Hans Ulrich
authors.initials: HU
authors.lastname: Gerth
authors.affiliation: Department of General Surgery, University Hospital of Münster, Münster, Germany.
authors.forename: Heiner H
authors.initials: HH
authors.lastname: Wolters
authors.affiliation: Department of General Surgery, University Hospital of Münster, Münster, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Anthoni
authors.affiliation: Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Münster, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.affiliation: Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Münster, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Suwelack
authors.affiliation: Department of Transplant Medicine, University Hospital of Münster, Münster, Germany.
authors.forename: Hartmut H
authors.initials: HH
authors.lastname: Schmidt
authors.affiliation: Department of Transplant Medicine, University Hospital of Münster, Münster, Germany.
authors.forename: Iyad
authors.initials: I
authors.lastname: Kabar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D008658:Inactivation, Metabolic; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011183:Postoperative Complications / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D051437:Renal Insufficiency / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D012189:Retrospective Studies; D016559:Tacrolimus / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus