从基于西罗莫司的免疫抑制方案中早期停用钙调神经磷酸酶抑制剂可稳定肾移植中的纤维化和转化生长因子-β信号通路。

Early withdrawal of calcineurin inhibitor from a sirolimus-based immunosuppression stabilizes fibrosis and the transforming growth factor-β signalling pathway in kidney transplant.

作者信息

Rivelli Regiane F, Gonçalves Renato T, Leite Maurilo, Santos Marcos André R, Delgado Alvimar G, Cardoso Lucio R, Takiya Christina M

机构信息

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.

出版信息

Nephrology (Carlton). 2015 Mar;20(3):168-76. doi: 10.1111/nep.12368.

DOI:10.1111/nep.12368

PMID:25404086

Abstract

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.

摘要

目的

肾移植的重点是提高移植肾的长期存活率。限制因素之一是钙调神经磷酸酶抑制剂（CNI）诱导的纤维化。本研究试图探讨基于西罗莫司的免疫抑制治疗中早期停用CNI后间质纤维化的组织学特征以及转化生长因子-β（TGF-β）经典信号通路的调节情况。

方法

45例中低免疫风险的肾移植受者被随机分组，并在移植时、移植后3个月和12个月进行方案活检。受者服用他克莫司、西罗莫司和泼尼松。在第3个月后，患者被随机分为两组：西罗莫司（SRL）组（停用CNI并增加西罗莫司剂量）和他克莫司（TAC）组（维持CNI）。根据2007年班夫标准对肾活检组织进行分析。班夫ct和ci的总和构成慢性指数。通过对总胶原蛋白和肌成纤维细胞沉积的组织形态计量分析来评估纤维化。对TGF-β、TGF-β受体1（TGF-β-R1）、受体2（TGF-β-R2）和磷酸化Smad2/3（p-Smad2/3）进行免疫组织化学表征和定量分析。

结果

维持CNI与胶原蛋白和α平滑肌肌动蛋白（α-SMA）的表面密度增加相关（P = 0.001）。此外，TGF-β（P = 0.02）、TGF-β-R1（P = 0.02）、p-Smad2/3（P = 0.03）增加，TGF-β-R2稳定。另一方面，停用CNI并增加西罗莫司剂量可限制12个月时慢性指数的升高（SRL组为2.18，TAC组为3.12，P = 0.0007），减少纤维化沉积，并促进TGF-β、TGF-β-R2、p-Smad2/3和肌成纤维细胞的稳定，以及TGF-β-R1的减少（P = 0.01）。