Everolimus immunosuppression reduces the serum expression of fibrosis markers in liver transplant recipients

Fernández‐Yunquera, Ainhoa; Ripoll, Cristina; Bañares, Rafael; Puerto, Marta; Rincón, Diego; Yepes, Ismael; Catalina, Vega; Salcedo, Magdalena

doi:10.5500/wjt.v4.i2.133

Cited by 20 publications

(15 citation statements)

References 52 publications

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“…Progressive IPTH has been correlated with steroid continuation, even if this association needs confirmation. On the other hand, mTOR inhibitors seem to play a role in preventing fibrosis progression . Histological findings of F2 fibrosis on protocol biopsies and/or a liver stiffness of >5.6 kPa should prompt a reconsideration of the immunosuppression regimen of individual patients, even in the absence of biochemical abnormalities.…”

Section: Discussionmentioning

confidence: 99%

“…Correlations of the TE results in patients stratified by mild-to-moderate (METAVIR F<2) or significant (METAVIR F ≥ 2) fibrosis at histological staging been correlated with steroid continuation,38 even if this association needs confirmation. On the other hand, mTOR inhibitors seem to play a role in preventing fibrosis progression 53. Histological findings of F2 fibrosis on protocol biopsies and/or a liver stiffness of >5.6 kPa should prompt a reconsideration of the immunosuppression regimen of individual patients, even in the absence of biochemical abnormalities.5 | CONCLUSIONSTE is an accurate, non-invasive tool for the detection of significant graft fibrosis in pediatric LT recipients, and we suggest that it should be included in the standard follow-up of these patients.…”

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confidence: 99%

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Transient elastography for non‐invasive evaluation of post‐transplant liver graft fibrosis in children

Vinciguerra

Brunati

David

et al. 2018

Pediatric Transplantation

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As graft survival in pediatric LT is often affected by progressive fibrosis, numerous centers carry out protocol liver biopsies. Follow-up biopsy protocols differ from center to center, but all biopsies are progressively spaced out, as time from transplant increases. Therefore, there is a need for non-invasive techniques to evaluate graft fibrosis progression in those children who have no clinical or serological signs of liver damage. Indirect markers, such as the APRI, should be relied on with caution because their sensitivity in predicting fibrosis can be strongly influenced by the etiology of liver disease, severity of fibrosis, and patient age. A valid alternative could be TE, a non-invasive technique already validated in adults, which estimates the stiffness of the cylindrical volume of liver tissue, 100-fold the size of a standard needle biopsy sample. The aims of this study were to evaluate the reliability of TE in children after LT and to compare both the TE and the APRI index results with the histological scores of fibrosis on liver biopsies. A total of 36 pediatric LT recipients were studied. All patients underwent both TE and biopsy within a year (median interval -0.012 months) at an interval from LT of 0.36 to 19.47 years (median 3.02 years). Fibrosis was assessed on the biopsy specimens at histology and staged according to METAVIR. There was a statistically significant correlation between TE stiffness values and METAVIR scores (P = .005). The diagnostic accuracy of TE for the diagnosis of significant fibrosis (F ≥ 2) was measured as the area under the curve (AUROC = 0.865), and it demonstrated that the method had a good diagnostic performance. APRI was not so accurate in assessing graft fibrosis when compared to METAVIR (AUROC = 0.592). A liver stiffness cutoff value of 5.6 kPa at TE was identified as the best predictor for a significant graft fibrosis (METAVIR F ≥ 2) on liver biopsy, with a 75% sensitivity, a 95.8% specificity, a 90% positive predictive value, and an 88.5% negative predictive value. These data suggest that TE may represent a non-invasive, reliable tool for the assessment of graft fibrosis in the follow-up of LT children, alerting the clinicians to the indication for a liver biopsy, with the aim of reducing the number of protocol liver biopsies.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Transient elastography for non‐invasive evaluation of post‐transplant liver graft fibrosis in children

Vinciguerra

Brunati

David

et al. 2018

Pediatric Transplantation

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“…In addition, the antiproliferative effect of everolimus has been reported to reduce the likelihood of hepatocellular carcinoma (HCC) recurrence or de novo cancer development . Furthermore, the antiproliferative activity of everolimus has been reported to confer an advantage in reducing fibrosis progression in hepatitis C virus transplant recipients …”

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confidence: 99%

Renal function improvement in liver transplant recipients after early everolimus conversion: A clinical practice cohort study in Spain

et al. 2015

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A national, multicenter, retrospective study was conducted to assess the results obtained for liver transplant recipients with conversion to everolimus in daily practice. The study included 477 recipients (481 transplantations). Indications for conversion to everolimus were renal dysfunction (32.6% of cases), hepatocellular carcinoma (HCC; 30.2%; prophylactic treatment for 68.9%), and de novo malignancy (29.7%). The median time from transplantation to conversion to everolimus was 68.7 months for de novo malignancy, 23.8 months for renal dysfunction, and 7.1 months for HCC and other indications. During the first year of treatment, mean everolimus trough levels were 5.4 (standard deviation [SD], 2.7) ng/mL and doses Additional supporting information may be found in the online version of this article.

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“…Moreover, reduction of fibrosis up to 70%, numbers of cholangiocytes and myo fibroblasts, and hepatic extracellular matrix deposition was observed [39,40]. Moreover, in post liver transplant patients, the use of mTOR inhibitors was associated with slower rate of liver fibrosis [41].…”

Section: Discussionmentioning

confidence: 93%

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

Lashen¹

2017

JLRDT

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Background: In chronic hepatitis C (CHC) infection, liver disease progression results from viral persistence. Deregulation of target of rapamycin (TOR) signaling and autophagy is detected in viral infections and cancer. We studied the role of TOR and autophagy in the progression of CHC infection.Methods: 54 patients infected with HCV, [27 with CHC; 13 with cirrhosis and 14 with hepatocellular carcinoma (HCC)]; and 15 healthy subjects were included. Quantification of serum TOR was determined using enzyme linked immunosorbent assay. Tissue samples were immune-stained using TOR and autophagy protein 5 (Atg5) polyclonal antibodies. Expression of TOR and Atg5 was scored semi-quantitatively.Results: Expression and serum TOR were higher in HCC patients compared to patients without HCC (P< 0.05). Serum and expression of TOR were positively correlated to inflammation, fibrosis, steatosis and tumor characteristics (Alpha-fetoprotein, maximum diameter, tumor grade and CLIP stage) (P<0.05). Expression of Atg5 was inversely correlated with inflammation, fibrosis and tumor characteristics (P<0.05), Atg5 showed significant inverse correlation with serum and intra-hepatic expression of TOR (P<0.05). Serum TOR showed high sensitivity and specificity in discriminating infected patients with and without HCC at a cut-off value of 4.55 ng/ml [Area under ROC curve = 0.970]. Conclusion:Activation of TOR plays an important role in progression of HCV related liver disease possibly though autophagy suppression and they could be a potential therapeutic target. Serum TOR is a potential seromarker in discriminating HCV infected patients with and without HCC with high sensitivity and specificity.

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Everolimus immunosuppression reduces the serum expression of fibrosis markers in liver transplant recipients

Abstract: 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.

Cited by 20 publications

References 52 publications

Transient elastography for non‐invasive evaluation of post‐transplant liver graft fibrosis in children

Transient elastography for non‐invasive evaluation of post‐transplant liver graft fibrosis in children

Renal function improvement in liver transplant recipients after early everolimus conversion: A clinical practice cohort study in Spain

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

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