title: Early withdrawal of calcineurin inhibitor from a sirolimus-based immunosuppression stabilizes fibrosis and the transforming growth factor-β signalling pathway in kidney transplant.
abstract: OBJECTIVE
  The focus in renal transplantation is to increase long-term allograft survival. One of the limiting factors is calcineurin inhibitor (CNI)-induced fibrosis. This study attempted to examine the histological aspect of interstitial fibrosis and the modulation of the transforming growth factor-β (TGF-β) canonical signalling pathway following early withdrawal of CNI from sirolimus-based immunosuppressive therapy.
  
  
  METHODS
  Forty-five kidney transplant recipients with low-medium immunologic risk were randomized and underwent protocol biopsies obtained at the time of transplantation and at 3 and 12 months thereafter. The recipients were taking tacrolimus, sirolimus and prednisone. After the 3rd month, patients were randomized into two groups: sirolimus (SRL) (removed CNI and increased sirolimus) and tacrolimus (TAC) (maintained CNI). Renal biopsies were analyzed according to Banff's 2007 criteria. The sum of Banff's ct and ci constituted the chronicity index. Fibrosis was evaluated by the histomorphometrical analysis of the total collagen and myofibroblast deposition. Immunohistochemical characterization and quantification of TGF-β, TGF-β receptor 1 (TGF-β-R1), receptor 2 (TGF-β-R2) and phospho-Smad2/3 (p-Smad2/3) were performed.
  
  
  RESULTS
  Maintenance of CNI was associated with the increase of the surface density of collagen and α-smooth muscle actin (α-SMA), (P = 0.001). Furthermore, increased TGF-β (P = 0.02), TGF-β-R1 (P = 0.02), p-Smad2/3 (P = 0.03) and stabilized TGF-β-R2. On the other hand, the removal of CNI with increase in the dose of sirolimus limited the enhancement of the chronicity index at 12 m (SRL, 2.18 vs TAC, 3.12, P = 0.0007), diminished the deposition of fibrosis and promoted the stabilization of TGF-β, TGF-β-R2, p-Smad2/3 and myofibroblasts as well as the reduction of TGF-β-R1 (P = 0.01).
  
  
  CONCLUSIONS
  The early withdrawal of CNI limited the fibrosis progression through the stabilization of chronicity index and of the canonical TGF-β signalling pathway.
authors.affiliation: Faculty of Medicine, Federal University of Rio de Janeiro, CEP 21941-902, Rio de Janeiro, Brazil; Nephrology Service, University Hospital Clementino Fraga Filho, Federal University of Rio de Janeiro, CEP 21941-902, Rio de Janeiro, Brazil.
authors.forename: Regiane F
authors.initials: RF
authors.lastname: Rivelli
authors.forename: Renato T
authors.initials: RT
authors.lastname: Gonçalves
authors.forename: Maurilo
authors.initials: M
authors.lastname: Leite
authors.forename: Marcos André R
authors.initials: MA
authors.lastname: Santos
authors.forename: Alvimar G
authors.initials: AG
authors.lastname: Delgado
authors.forename: Lucio R
authors.initials: LR
authors.lastname: Cardoso
authors.forename: Christina M
authors.initials: CM
authors.lastname: Takiya
mesh_terms: D000328:Adult; D001706:Biopsy; D001938:Brazil; D065095:Calcineurin Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D003094:Collagen / Q000378:metabolism; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005355:Fibrosis; D006084:Graft Rejection / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011446:Prospective Studies; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D003094:Collagen; D020123:Sirolimus; D016559:Tacrolimus
keywords: calcineurin inhibitors; chronic allograft nephropathy; fibrosis; kidney transplantation and transforming growth factor β