Significant Graft Fibrosis Research Articles

Diagnostic performance of 2D-shear wave elastography and serum fibrosis markers for evaluation of hepatic graft fibrosis in pediatric liver-inclusive transplant recipients: A prospective pilot study.

Liver biopsy is the gold standard for hepatic fibrosis staging, but it is invasive and has potential severe complications. We aimed to determine the diagnostic performance of 2D-SWE and serum markers to predict significant hepatic graft fibrosis (≥F2) in pediatric liver-inclusive transplant recipients. This prospective, cross-sectional pilot study included children younger than 19years who had received a LT or LSBT and underwent a liver biopsy performed for clinical indications. LS was measured using 2D-SWE. The AUROC was calculated to evaluate the diagnostic performance of 2D-SWE and biomarkers (AST/ALT ratio, APRI, FIB4) for predicting significant fibrosis. Twenty-two children (13males, 8 LSBT) were included. Eighteen (81.8%) children received a whole liver graft. Thirteen (59.1%) patients had hepatic fibrosis (≥F1) and four (18.2%) had significant fibrosis. The AUROCs of AST/ALT ratio, APRI, and FIB4 for predicting significant hepatic graft fibrosis were 0.71 (p=.29), 0.85 (p=.0001), and 0.76 (p=.03), respectively. When FIB4 was calculated using the hepatic graft's age, its AUROC improved to 0.85 (p<.0001). The AUROC of 2D-SWE for predicting significant hepatic graft fibrosis was 0.80 (p=.046). When 2D-SWE was combined with APRI or FIB4, its AUROC improved to 0.82 (p=.08) and 0.87 (p=.002), respectively. APRI and FIB4 can accurately predict significant hepatic graft fibrosis. 2D-SWE may serve as a valuable adjunct tool to detect significant graft fibrosis, especially when combined with these serum markers.

Preoperative Splenomegaly Is a Risk Factor for Prolonged Splenomegaly after Liver Transplantation and Can Result in Hypersplenism and Graft Fibrosis

Background: Splenomegaly (SM) often persists after liver transplantation (LT), however, its predictors and clinical significance are unknown. Methods: We analyzed 415 LT recipients in our institution to clarify this issue. First, predictors and clinical consequences of persistent SM three years after LT were analyzed among spleen-preserved recipients. Second, the clinical data of surviving recipients three years after LT were compared between splenectomized and spleen-preserved recipients using propensity score matching (PSM). Third, survival outcomes were compared between splenectomized and spleen-preserved recipients after PSM. SM was determined as a splenic volume (SV)/body surface area (BSA) > 152 ml/m2 based on the CT splenic volumetry data of 140 donors. Results: In the first analysis, among 119 recipients with preoperative SM, 86 (73.6%) recipients had persistent SM 3 years after LT. Preoperative SV/BSA was the only independent predictor for the persistent SM and it was associated with lower platelet (PLT) and white blood cell (WBC) counts and significant graft fibrosis (≥ Metavir F2) (21.4% vs. 2.8%, p = 0.01). In the second analysis, spleen preservation was related to lower PLT and WBC counts and a higher proportion of significant graft fibrosis (26.7% vs. 7.1%, p = 0.022) three years after LT. In the third analysis, spleen-preserved recipients showed worse survival than splenectomized recipients (73.3% vs. 84.5% at 3 years after LT, p = 0.04). Conclusions: Preoperative SM frequently persists more than three years after LT and is associated with subclinical hypersplenism, graft fibrosis and even death.

Post-transplant hepatic fibrosis in pediatric liver-small bowel transplant recipients: A single-center, retrospective, observational study.

Little is known about the prevalence of hepatic graft fibrosis in combined LSBT children. We aimed to determine the prevalence of and identify potential predictors for hepatic graft fibrosis in LSBT children and to compare them with those in LT children. We retrospectively included children younger than 19years who had received a primary LT/LSBT between 2000 and 2018 and had a liver biopsy performed at least 6months post-transplant. A Cox proportional hazards regression model was used to determine predictors associated with significant hepatic graft fibrosis (≥F2) in LSBT vs LT children. Ninety-six children (47 LSBT, 54 females) were included. The median post-transplant follow-up (years) was 12.8 in LT vs 10.5 in LSBT patients (P=.06). Hepatic graft fibrosis was found in 81.6% of LT vs 70.2% of LSBT children (P=.19), after a median time of 2.5years and 2.6years, respectively. On multivariate analyses, having post-transplant biliary complications was found to be associated with significant graft fibrosis in LT children, whereas AST/ALT ratio was found to predict significant hepatic graft fibrosis in LSBT children. The use of parenteral nutrition after transplant was not associated with significant hepatic graft fibrosis. The prevalence of hepatic graft fibrosis in LSBT children did not significantly differ from that in LT children, but the predictors may differ. Future studies should investigate the role of post-transplant autoimmune antibodies and donor-specific antibodies in the development and progression of hepatic graft fibrosis in LSBT children.

Pretransplantation splenomegaly frequently persists after liver transplantation and can manifest as hypersplenism and graft fibrosis - a retrospective study.

The risk factors and clinical impact of post-transplantation splenomegaly (SM) are poorly understood. We investigated the predictors and impacts of post-transplantation SM in 415 LT patients at Kyoto University Hospital from April 2006 to December 2015. First, the predictors and clinical consequences of SM three years post-transplantation were analyzed among spleen-preserved recipients. Second, the clinical data of surviving recipients three years post-transplantation were compared between splenectomized and spleen-preserved recipients. There was no difference in indication for liver transplantation between these two groups. Third, survival outcomes were compared between splenectomized and spleen-preserved recipients. SM was determined as a SV/body surface area (BSA) higher than 152ml/m2 . In the first analysis, preoperative SM occurred in 79.9% recipients and SM persisted three years post-transplantation in 72.6% recipients among them. Preoperative SV/BSA was the only independent predictor of three year post-transplantation SM, which was associated with lower platelet (PLT), white blood cell (WBC) counts and significant graft fibrosis (21.4% vs. 2.8%). In the second analysis, spleen-preservation was related to lower PLT, WBC counts and a higher proportion of significant graft fibrosis (26.7% vs. 7.1%) three years post-transplantation. In the third analysis, spleen-preserved recipients showed worse survival than splenectomized recipients. In conclusion, preoperative SM frequently persists more than three years post-transplantation and is associated with subclinical hypersplenism, graft fibrosis, graft loss, and even death.

Transient elastography assessment of liver allograft fibrosis in pediatric transplant recipients.

TE measures liver stiffness to assess fibrosis. Its use in post-transplant patients was reported in few small pediatric studies. We evaluated TE ability to predict liver graft fibrosis in a large cohort while comparing it to the performance of APRI and FIB-4. We also investigated the effect of graft type on LSMs. Patients at Boston Children's Hospital who underwent LT and LSM≤1year from biopsy (2007-2018) were eligible. Ninety-four patients (45%M) aged 1-21years (89%<18years; 13%<2years) were eligible. Median time between transplant/biopsy and LSM was 5.1years and 52days, respectively. Thirty-nine percent received whole-liver grafts, 54% TV grafts, and 6% as part of MV. At LSM, median ALT was 25 [IQR 16-33]IU/L. Twenty-one percent had METAVIR≥F2. LSM was statistically higher among those with significant fibrosis (METAVIR≥F2) compared to those with METAVIR F0/F1 (median [IQR] 7.5 [4.6, 13.6] vs 5.1 [4.0, 6.4]kPa, respectively) (P=.005 by Wilcoxon rank-sum test). APRI and FIB-4 distributions were not different across METAVIR stages. The AUROC for LSM was 0.71 (95% CI 0.56-0.85) with an optimal cut-point of 6.5kPa. Graft type had no influence on the AUROC for LSM. TE is useful for assessing significant graft fibrosis in children and young adult LT recipients and performs better than APRI and FIB-4. TV grafts demonstrate similar correlation with histology as whole-liver grafts.

Non-Invasive Assessment of Graft Fibrosis After Living Donor Liver Transplantation: Is There Still a Role for Liver Biopsy?

Non-invasive methods have evolved as a surrogate for liver biopsy such as indirect markers (aspartate transaminase to platelet ratio index, fibro-α score), transient elastography (TE), and magnetic resonance elastography (MRE).The aim of this study is to prospectively compare the value of MRE, TE, and indirect markers in detecting and staging allograft fibrosis compared to liver biopsies in patients who have undergone living donor liver transplantation for complications related to hepatitis C virus.A total of 31 living donor liver transplantation recipients with hepatitis C virus recurrence underwent a liver biopsy, TE, and MRE within 3 months of a liver biopsy. Fibrosis was assessed according to the biopsy and staged according to Metavir criteria.There was a significant correlation between both MRE and fibro-α scores, as well as histologic classification by liver biopsy (P = .02, .002). The diagnostic accuracy of MRE and fibro-α scores in diagnosing significant fibrosis (F ≥ 3) was measured as the area under the curve (.708 and .833, respectively). Both methods showed good diagnostic performance. TE and aspartate transaminase to platelet ratio index were insignificantly correlated with the degree of fibrosis in liver biopsy (P value of .134, .535). At a cutoff value of 5.5 kPa, MRE predicted graft fibrosis (Metavir stage ≥ 3) with 71.43% sensitivity, 75% specificity, 45.5% positive predictive value, and 90% negative predictive value; at a cutoff value > 1.47, fibro-α scores predicted significant graft fibrosis (Metavir stage ≥ 3) with 85.7% sensitivity and 70.83% specificity, with a positive predictive value of 46.2% and a negative predictive value of 94.4%. These data suggest that non-invasive methods could be considered a reliable tool in assessing significant graft fibrosis post-living donor liver transplantation.

Clinical utility of complement-dependent C3d assay in kidney recipients presenting with late allograft dysfunction.

The objective of this study was to evaluate the utility of a complement-dependent C3d assay to risk stratify donor-specific antibodies (DSA) in a multicenter cohort of kidney recipients presenting with new-onset clinical dysfunction. A total of 106 subjects with evidence of DSA at a mean period of 5.3±5.0years posttransplant underwent testing using C3d reagents. C3d positivity was strongly associated with both the peak and sum IgG DSA MFI, with 98.3% (n=57/58) of strongly reactive sera (peak MFI>10000) eliciting a positive signal. Patients with C3d+ DSA had a higher creatinine (P=.03), more significant graft fibrosis (P=.035), and a faster rate of graft loss posttest compared to those with C3d- DSA (P=.05). Subanalysis of patients with low-moderate level DSA confirmed the inferior outcome associated with C3d positivity. Despite the prognostic value of C3d as a stand-alone test, the assay did not provide independent risk prediction after incorporation of graft fibrosis in a multivariate model (P=.94). Overall, C3d offered limited discriminatory value for strong DSA with peak IgG MFI >10000 and in patients where histologic data is available, but its utilization may be considered in those with low-moderate level DSA and where an allograft biopsy is not accessible.

AST-to-platelet ratio index in non-invasive assessment of long-term graft fibrosis following pediatric liver transplantation.

Long-term graft fibrosis occurs in the majority of pediatric liver transplant recipients. Serial biopsies to monitor graft health are impractical and invasive. The APRI has been evaluated in pediatric liver disease, but not in the context of post-transplantation fibrosis. We aimed to investigate the validity of APRI as a predictor of long-term graft fibrosis in pediatric liver transplant recipients. This was a retrospective, observational study of a cohort of children who underwent liver transplantation at King's College Hospital between 1989 and 2003, with a relevant dataset available. Protocol liver biopsies were performed at 10-yr follow-up and fibrosis was graded using the Ishak scoring system, with S3-6 denoting "significant fibrosis." APRI was calculated concurrently with biopsy. A total of 39 asymptomatic patients (20 males; median age at transplant, 1.43 yr) underwent protocol liver biopsies at a median of 10.39 yr post-transplantation. APRI was associated with significant fibrosis (p = 0.012). AUROC for APRI as a predictor of significant fibrosis was 0.74 (p = 0.013). The optimal cutoff APRI value for significant fibrosis was 0.45 (sensitivity = 0.67; specificity = 0.79; PPV = 0.67; NPV = 0.79). APRI appears to be a useful non-invasive adjunct in the assessment of significant graft fibrosis in the long-term follow-up of pediatric liver transplant survivors.

Sirolimus Reduces the Risk of Significant Hepatic Fibrosis After Liver Transplantation for Hepatitis C Virus: A Single-Center Experience

IntroductionHepatitis C virus (HCV) recurrence following orthotopic liver transplantation is an expected outcome in all patients transplanted for a primary diagnosis of HCV. HCV recurrence has been shown to be associated with graft fibrosis and graft loss. Recent studies suggest that sirolimus (SRL) therapy may slow or inhibit hepatic fibrosis following liver transplant in patients positive for HCV at the time of transplant. MethodsAmong 313 patients who underwent orthotopic liver transplantation for HCV between 2000 and 2009, 251 qualified for inclusion in the study. Per protocol liver biopsies were performed on all patients at 1 year following liver transplantation and/or at the time of a clinical diagnosis of HCV recurrence. Biopsies were scored for fibrosis using the Batts-Ludwig staging system (0–4); significant fibrosis was defined as fibrosis ≥ stage 2. ResultsOverall, there was no difference in overall survival or graft loss in the SRL compared with the control group. Multivariate analysis revealed SRL therapy to be associated with decreased odds of significant hepatic fibrosis at year 1 postoperatively and over the study duration. ConclusionsThis retrospective, single-center study showed sirolimus-based immunosuppression to be associated with a lower risk of significant graft fibrosis, both at year 1 and throughout the study period, following liver transplantation in HCV-infected recipients.