title: Everolimus immunosuppression reduces the serum expression of fibrosis markers in liver transplant recipients.
abstract: OBJECTIVE
  To evaluate the expression of serum fibrosis markers in liver transplantation (LT) recipients on everolimus monotherapy compared to patients on an anti-calcineurin regimen.
  
  
  METHODS
  This cross-sectional case-control study included LT patients on everolimus monotherapy (cases) (E) (n = 30) and matched controls on an anti-calcineurin regimen (calcineurin inhibitors, CNI), paired by etiology of liver disease and time since LT (n = 30). Clinical characteristics, blood tests and elastography were collected. Serum levels of transforming growth factor-β (TGF-β), angiopoietin-1, tumor necrosis factor (TNF), platelet derived growth factor, amino-terminal propeptide of type III procollagen (PIIINP), hyaluronic acid (HA), VCM-1 (ng/mL), interleukin (IL)-10, interferon-inducible protein 10 (IP-10), vascular endothelial growth factor and hepatocyte growth factor (HGF) (pg/mL) were determined by enzyme-linked immunosorbent assay. Expression of these markers between E and CNI was compared. Stratified analysis was done according to factors that may influence liver fibrosis. Variables are described with medians (interquartillic range) or percentages.
  
  
  RESULTS
  A total of 60 patients [age: 59 (49-64), hepatitis C virus (HCV): n = 21 (35%), time from LT: 73 mo (16-105)] were included. Patients had been on everolimus for a median of 15 mo. No differences in inflammatory activity, APRI test or liver elastography were found between the groups. No significant differences were observed between the groups in serum levels of PIIINP, metalloproteinase type = 1, angiopoietin, HGF, IP-10, TNF-α, IL-10 and vascular cell adhesion molecule. Patients on E had a lower expression of TGF-β [E: 12.7 (3.7-133.6), CNI: 152.5 (14.4-333.2), P = 0.009] and HA [E: 702.89 (329.4-838.2), CNI: 1513.6 (691.9-1951.4), P = 0.001] than those on CNI. This difference was maintained in the stratified analysis when recipient age is more than 50 years (TFG-β1: P = 0.06; HA: P = 0.005), in patients without active neoplasia (TFG-β1, P = 0.009; HA: P = 0.01), according to time since LT (> than 5 years, TFG-β1: P = 0.001; HA: P = 0.002), related to previous history of biliary complications (HA: P = 0.01) and HCV recurrence (HA: P = 0.004). Liver transplant recipients with everolimus monotherapy had less serum expression of TGF-β y HA than matched patients with anti-calcineurins. This difference remains when classifying patients according to donor age and time since LT. Due to the small sample size, when examining patients with a prior history of biliary complications or recurrent HCV, the difference was non-significant but trends towards the lower expression of TFG-β1 in the everolimus group. Mammalian target of rapamycin (mTOR) plays a role in the transformation of quiescent hepatocellular stellate cell to their active profibrotic state, and experimental models have demonstrated the potential activity of mTOR inhibition in attenuating fibrogenesis.
  
  
  CONCLUSIONS
  This study supports a possible role of everolimus in liver fibrosis modulation after LT in a clinical setting and suggests that tailoring immunosuppression could avoid fibrosis progression in the allograft.
authors.affiliation: Ainhoa Fernández-Yunquera, Cristina Ripoll, Rafael Bañares, Diego Rincón, Ismael Yepes, Vega Catalina, Magdalena Salcedo, Department of Liver Transplantation, Hospital General Gregorio Marañón, 28028 Madrid, Spain.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Fernández-Yunquera
authors.affiliation: Ainhoa Fernández-Yunquera, Cristina Ripoll, Rafael Bañares, Diego Rincón, Ismael Yepes, Vega Catalina, Magdalena Salcedo, Department of Liver Transplantation, Hospital General Gregorio Marañón, 28028 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ripoll
authors.affiliation: Ainhoa Fernández-Yunquera, Cristina Ripoll, Rafael Bañares, Diego Rincón, Ismael Yepes, Vega Catalina, Magdalena Salcedo, Department of Liver Transplantation, Hospital General Gregorio Marañón, 28028 Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Bañares
authors.affiliation: Ainhoa Fernández-Yunquera, Cristina Ripoll, Rafael Bañares, Diego Rincón, Ismael Yepes, Vega Catalina, Magdalena Salcedo, Department of Liver Transplantation, Hospital General Gregorio Marañón, 28028 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Puerto
authors.affiliation: Ainhoa Fernández-Yunquera, Cristina Ripoll, Rafael Bañares, Diego Rincón, Ismael Yepes, Vega Catalina, Magdalena Salcedo, Department of Liver Transplantation, Hospital General Gregorio Marañón, 28028 Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Rincón
authors.affiliation: Ainhoa Fernández-Yunquera, Cristina Ripoll, Rafael Bañares, Diego Rincón, Ismael Yepes, Vega Catalina, Magdalena Salcedo, Department of Liver Transplantation, Hospital General Gregorio Marañón, 28028 Madrid, Spain.
authors.forename: Ismael
authors.initials: I
authors.lastname: Yepes
authors.affiliation: Ainhoa Fernández-Yunquera, Cristina Ripoll, Rafael Bañares, Diego Rincón, Ismael Yepes, Vega Catalina, Magdalena Salcedo, Department of Liver Transplantation, Hospital General Gregorio Marañón, 28028 Madrid, Spain.
authors.forename: Vega
authors.initials: V
authors.lastname: Catalina
authors.affiliation: Ainhoa Fernández-Yunquera, Cristina Ripoll, Rafael Bañares, Diego Rincón, Ismael Yepes, Vega Catalina, Magdalena Salcedo, Department of Liver Transplantation, Hospital General Gregorio Marañón, 28028 Madrid, Spain.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Salcedo
keywords: Everolimus; Liver fibrosis; Mammalian target of rapamycin; Rapamycin; Transplantation