AIM: 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). CONCLUSION: The early withdrawal of CNI limited the fibrosis progression through the stabilization of chronicity index and of the canonical TGF-β signalling pathway.
RCT Entities:
AIM: 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). CONCLUSION: The early withdrawal of CNI limited the fibrosis progression through the stabilization of chronicity index and of the canonical TGF-β signalling pathway.
Authors: Deirdre Hahn; Elisabeth M Hodson; Lorraine A Hamiwka; Vincent Ws Lee; Jeremy R Chapman; Jonathan C Craig; Angela C Webster Journal: Cochrane Database Syst Rev Date: 2019-12-16
Authors: Gerold Thölking; Nils Hendrik Gillhaus; Katharina Schütte-Nütgen; Hermann Pavenstädt; Raphael Koch; Barbara Suwelack; Stefan Reuter Journal: J Clin Med Date: 2020-01-23 Impact factor: 4.241