title: Relationship of tacrolimus exposure and mycophenolate mofetil dose with renal function after renal transplantation.
abstract: BACKGROUND
  The most common immunosuppressive treatment in de novo renal transplantation is a triple regimen that includes tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, and that may also include antibody induction. Whether nephrotoxicity is an issue with tacrolimus at the currently used dosages remains an open question.
  
  
  METHODS
  We pooled data from three large, randomized, de novo renal transplantation studies (Symphony, Fixed Dose Concentration Controlled [FDCC], and OptiCept) that used variations of the triple regimen with respect to tacrolimus target levels, MMF dosing, and antibody induction. We used multivariate linear regression to explore the relationship of renal function at 1 year after transplantation (estimated glomerular filtration rate) with tacrolimus levels and MMF dose measured over the previous 6 months. The model included also a series of possible confounders. RESULTS.: The analysis population consisted of 998 patients. On average, tacrolimus levels were in a range considered low (mean ± standard deviation 7.2 ± 2.54 ng/mL), and MMF dose was 1.5 ± 0.61 g/day. Lower tacrolimus levels and higher MMF doses were associated with significantly better renal function. There were other variables associated with renal function, most notably acute rejection, donor age, and delayed graft function. Subanalyses in each of the three studies gave a consistent picture. There was no overt difference in the effect sizes when patients with stage II (estimated glomerular filtration rate 60-89 mL/min) or stage III (30-59 mL/min) chronic kidney disease were assessed separately.
  
  
  CONCLUSIONS
  Tacrolimus seems to have a moderate but consistent nephrotoxic effect even in modern efficient immunosuppressive regimens where it is used at lower doses than in previous years.
authors.affiliation: Department of Nephrology and Transplantation, Skane University Hospital, Malmö, Sweden. henrik.ekberg@med.lu.se
authors.forename: Henrik
authors.initials: H
authors.lastname: Ekberg
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
authors.forename: Bruce
authors.initials: B
authors.lastname: Kaplan
authors.forename: Corrado
authors.initials: C
authors.lastname: Bernasconi
mesh_terms: D000328:Adult; D065095:Calcineurin Inhibitors; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000502:physiology*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus