Yuta Hirata

Protocol liver biopsy is the only examination that can detect mid-term graft fibrosis after pediatric liver transplantation

AIM To assessed the clinical significance of protocol liver biopsy (PLB) in pediatric liver transplantation (LT). METHODS Between July 2008 and August 2012, 89 and 55 PLBs were performed in pediatric patients at two and five years after LT, respectively. We assessed the histopathological findings using the Metavir scoring system, including activity (A) and fibrosis (F), and we identified factors associated with scores of ≥ A1 and ≥ F1. Our results clarified the timing and effectiveness of PLB. RESULTS The incidences of scores of ≥ A1 and ≥ F1 were 24.7% and 24.7%, respectively, at two years after LT and 42.3% and 34.5%, respectively, at five years. Independent risk factors in a multivariate analysis of a score of ≥ A1 at two years included ≥ 2 h of cold ischemic time, no acute cellular rejection and an alanine amino transaminase (ALT) level of ≥ 20 IU/L (P = 0.028, P = 0.033 and P = 0.012, respectively); however, no risk factors were identified for a score of ≥ F1. Furthermore, no independent risk factors associated with scores of ≥ A1 and ≥ F1 at five years were identified using multivariate analysis. A ROC curve analysis of ALT at two years for a score of ≥ A1 demonstrated the recommended cutoff value for diagnosing ≥ A1 histology to be 20 IU/L. The incidence of scores of ≥ A2 or ≥ F2 at two years after LT was 3.4% (three cases), and all patients had an absolute score of ≥ A2. In contrast to that observed for PLBs at five years after LT, the incidence of scores of ≥ A2 or ≥ F2 was 20.0% (11 cases), and all patients had an absolute score of ≥ F2. In all cases, the dose of immunosuppressants was increased after the PLB, and all ten patients who underwent a follow-up liver biopsy improved to scores of ≤ A1 or F1. CONCLUSION PLB at two years after LT is an unnecessary examination, because the serum ALT level reflects portal inflammation. In addition, immunosuppressive therapy should be modulated to maintain the ALT concentration at a level less than 20 IU/L. PLB at five years is an excellent examination for the detection of early reversible graft fibrosis because no serum markers reflect this finding.

Maternal grafts protect daughter recipients from acute cellular rejection after pediatric living donor liver transplantation for biliary atresia

Some studies have found that gender mismatch between donors and recipients are related to poor graft prognosis after liver transplantation. However, few studies have investigated the impact of gender mismatch on acute cellular rejection (ACR) in pediatric living donor liver transplantation (LDLT). This retrospective study investigated the clinical significance of these factors in ACR after pediatric LDLT. Between November 2001 and February 2012, 114 LDLTs were performed for recipients with biliary atresia (BA) using parental grafts. We performed univariate and multivariate analyses to identify the factors associated with ACR. The donor–recipient classifications included mother donor to daughter recipient (MD; n = 43), mother to son (n = 18), father to daughter (FD; n = 33), and father to son (n = 20) groups. The overall incidence rate of ACR in the recipients was 36.8%. Multivariate analysis showed that gender mismatch alone was an independent risk factor for ACR (P = 0.012). The FD group had a higher incidence of ACR than the MD group (P = 0.002). In LDLT, paternal grafts with gender mismatch were associated with a higher increased incidence of ACR than maternal grafts with gender match. Our findings support the possibility that maternal antigens may have an important clinical impact on graft tolerance in LDLT for patients with BA.

The impact of rituximab in ABO‐incompatible pediatric living donor liver transplantation: The experience of a single center

Previous studies have demonstrated the safety of ABO‐incompatible pediatric LDLT using preoperative plasmapheresis and rituximab; however, no reports have described the timing and dosage of rituximab administration for pediatric LDLT. This study aimed to describe a safe and effective dosage and timing of rituximab for patients undergoing pediatric ABO‐incompatible LDLT based on the experience of our single center. A total of 192 LDLTs in 187 patients were examined. These cases included 29 ABO‐incompatible LDLTs in 28 patients. Rituximab was used beginning in January 2004 in recipients older than two yr of age (first period: 375 mg/m2 in two cases; second period: 50 mg/m2 in two cases; and 200 mg/m2 in eight cases). Two patients who received 375 mg/m2 rituximab died of Pneumocystis carinii pneumonia and hemophagocytic syndrome. One patient who received 50 mg/m2 rituximab required retransplantation as a consequence of antibody‐mediated complications. All eight patients administered 200 mg/m2 survived, and the mean CD20+ lymphocyte count was 0.1% at the time of LDLT. In the preoperative management of patients undergoing pediatric ABO‐incompatible LDLT, the administration of 200 mg/m2 rituximab three wk prior to LDLT was safe and effective.

Selection of living donor liver grafts for patients weighing 6kg or less

In the field of pediatric living donor liver transplantation (LDLT), physicians sometimes must reduce the volume of left lateral segment (LLS) grafts to prevent large‐for‐size syndrome. There are 2 established methods for decreasing the size of an LLS graft: the use of a segment 2 (S2) monosegment graft and the use of a reduced LLS graft. However, no procedure for selecting the proper graft type has been established. In this study, we conducted a retrospective investigation of LDLT and examined the strategy of graft selection for patients weighing ≤6 kg. LDLT was conducted 225 times between May 2001 and December 2012, and 15 of the procedures were performed in patients weighing ≤6 kg. We selected S2 monosegment grafts and reduced LLS grafts if the preoperative computed tomography (CT)–volumetry value of the LLS graft was >5% and 4% to 5% of the graft/recipient weight ratio, respectively. We used LLS grafts in 7 recipients, S2 monosegment grafts in 4 recipients, reduced S2 monosegment grafts in 3 recipients, and a reduced LLS graft in 1 recipient. The reduction rate of S2 monosegment grafts for use as LLS grafts was 48.3%. The overall recipient and graft survival rates were both 93.3%, and 1 patient died of a brain hemorrhage. Major surgical complications included hepatic artery thrombosis in 2 recipients, bilioenteric anastomotic strictures in 2 recipients, and portal vein thrombosis in 1 recipient. In conclusion, our graft selection strategy based on preoperative CT‐volumetry is highly useful in patients weighing ≤6 kg. S2 monosegment grafts are effective and safe in very small infants particularly neonates. Liver Transpl 21:233‐238, 2015.

Risk factors and treatments for hepatic arterial complications in pediatric living donor liver transplantation

Hepatic artery complications (HAC) are a serious complication in pediatric liver transplant recipients because its incidence is high and it can occasionally lead to graft liver failure. We herein present a retrospective analysis of our 10‐year experience with pediatric living donor liver transplantation (LDLT) focusing on the risk factors and treatments for HAC.

Pretransplant levels of endotoxin can predict the risk of bacterial infections and graft liver function after liver transplantation.

BACKGROUND Although endotoxin (Et) has been used as a biological index of bacterial infections, Et can also be used to evaluate liver functions because Et present in the portal vein blood is processed by the hepatic reticuloendothelial system. In the field of posttransplant management, it is important for liver transplant recipients to monitor the presence of posttransplant bacterial infections and graft liver functions because these results are directly correlated with a graft prognosis. Therefore, the measurement of Et during liver transplantation (LT) may be the detection of posttransplant infections and graft liver functions. This retrospective study investigated whether Et measured by the Et activity assay (EAA) in the peripheral venous blood during living donor LT (LDLT) can predict the incidence of posttransplant bacterial infections and graft liver functions. MATERIALS AND METHODS The study subjects consisted of 21 patients who underwent LDLT between April 2010 and February 2011. Et activity (EA) was measured using the EAA in peripheral venous blood samples collected 1 or 2 days before LDLT, and on postoperative days (PODs) 1, 5, 7, and 14. We included LDLT recipients with intra-abdominal infections, respiratory infections, and bacteremia in the group with posttransplant bacterial infections. RESULTS The incidence rates of posttransplant bacterial infections or hyperbilirubinemia after LDLT were 57.1%. The LDLT recipients with posttransplant bacterial infections or hyperbilirubinemia had significantly higher levels of EA in comparison with patients without complications before LDLT (0.22 ± 0.10 vs. 0.07 ± 0.05, p < 0.001), but they had no statistically significant increase of EA between PODs 1 and 14. Based on a receiver operating characteristic curve analysis of pretransplant levels of EA in patients with posttransplant bacterial infections or hyperbilirubinemia, the recommended cutoff value to diagnose posttransplant bacterial infections or hyperbilirubinemia was set at 0.16 (sensitivity 83.3%, specificity 88.9%, and area under the curve 0.940). CONCLUSION At a pretransplant level of EA greater than 0.16, patients had an augmented risk for developing posttransplant bacterial infections or hyperbilirubinemia.

Pediatric living donor liver transplantation for congenital hepatic fibrosis using a mother’s graft with von Meyenburg complex: A case report

This is the first report of living donor liver transplantation (LDLT) for congenital hepatic fibrosis (CHF) using a mother’s graft with von Meyenburg complex. A 6-year-old girl with CHF, who suffered from recurrent gastrointestinal bleeding, was referred to our hospital for liver transplantation. Her 38-year-old mother was investigated as a living donor and multiple biliary hamartoma were seen on her computed tomography and magnetic resonance imaging scan. The mother’s liver function tests were normal and she did not have any organ abnormality, including polycystic kidney disease. LDLT using the left lateral segment (LLS) graft from the donor was performed. The donor LLS graft weighed 250 g; the graft recipient weight ratio was 1.19%. The operation and post-operative course of the donor were uneventful and she was discharged on post-operative day (POD) 8. The graft liver function was good, and the recipient was discharged on POD 31. LDLT using a graft with von Meyenburg complex is safe and useful. Long-term follow-up is needed with respect to graft liver function and screening malignant tumors.

Antenatal immunoglobulin for prevention of neonatal hemochromatosis

Neonatal hemochromatosis (NH) is a rare disease with a poor prognosis, particularly prior to 2008. Antenatal maternal high‐dose immunoglobulin (Ig) is effective in preventing NH recurrence, but the adverse effects of this treatment have not been documented as yet. Here, we report on a patient who underwent high‐dose Ig treatment to prevent NH recurrence. The patient was a 31‐year‐old pregnant Japanese woman. Her first child died of NH after receiving living donor liver transplantation. The patient received high‐dose Ig treatment to prevent recurrence of NH from gestational weeks 16 to 35. During the treatment, platelet count gradually decreased, and cesarean section was required at 35 gestational weeks. The child did not develop liver failure. High‐dose Ig prevented the recurrence of NH. Caution should be exercised due to possible adverse effects of this treatment.

Donor age and operational tolerance in living donor liver transplantation

Some studies have found that recipient age is related to operational tolerance (OT) after living donor liver transplantation (LDLT) (1). However, few studies have investigated the impact of donor age on OT in LDLT. We reported that our pilot study indicated that donor age is a crucial factor affecting telomere length sustainability in hepatocytes after LDLT and that the telomeres in grafted livers may be elongated somewhat longer when the grafts are immunologically well controlled (2). Therefore, we think that there is a clinical significance of donor age in OT after LDLT. As to a surveillance after OT, it has recently been reported that histopathological assessments using protocol liver biopsy (PLB) are important (1). Because graft liver dysfunction does not occur if the fibrosis does not become advanced, it is not possible to predict the occurrence of graft liver fibrosis or portal inflammation using standard liver function test alone (3). We reported that our pilot study indicated that PLB in patients with the long-term survival is an excellent examination for detecting early reversible graft fibrosis because no serum markers reflect this finding (4). Therefore, we think that there is a clinical significance of PLB in patients with OT after LDLT as a surveillance tool. Between June 1991 and November 2004, 109 LDLTs were performed for patients with nonrecurrence of original diseases using parental and grandparental grafts in our department and other facilities. We performed univariate analyses to identify the factors associated with OT. We performed a PLB after OT and assessed the histopathological findings using the METAVIR scoring system, including A (activity) and F (fibrosis). The overall incidence rate of OT after LDLT in the patients was 21.1%. The median period between LDLT and withdrawal of immunosuppressants was 7.4 yr (0.4–11.8), and the median observation period after OT was 7.0 yr (4.7–15.5). An independent risk factor of OT by univariate analyses was donor age alone (p = 0.049). A receiver operating characteristic curve analysis of donor age in OT demonstrated the recommended cutoff value for getting OT to be 34.5 yr. The <35 yr donor age group had a higher incidence of OT than the ≥35 yr group (p = 0.015; Table 1). In two patients (8.7%) with OT, as both histopathological findings in PLB were A1 and F2, the reintroduction of immunosuppressants was performed at 13.3 and 7.8 yr after OT, respectively. Our findings support the possibility that the factor of donor age has an important clinical impact on OT after LDLT, and PLB after OT is an excellent examination for detecting early graft fibrosis. In addition, we have reported the possibility that maternal antigens may have an important clinical impact on graft tolerance in LDLT (5). Including our reports and findings, we are currently planning a retrospective analysis of telomere and maternal chimerism using hepatic tissues of PLB in patients with OT to clarify the association between telomere and maternal chimerism and OT as a new parameter of OT.

Living donor liver transplantation from an asymptomatic donor with mild coagulation factor IX deficiency: Report of a case

The use of donors with coagulation FIX deficiency is controversial, and there are no current protocols for peri‐transplant management. We herein describe the first reported case of a pediatric LDLT from an asymptomatic donor with mild coagulation FIX deficiency. A 32‐yr‐old female was evaluated as a donor for her 12‐month‐old daughter with biliary atresia. The donors pretransplant coagulation tests revealed asymptomatic mild coagulation FIX deficiency (FIX activity 60.8%). Freeze‐dried human blood coagulation FIX concentrate was administered before the dissection of the liver and 12 h afterwards by bolus infusion (40 U/kg) and was continued on POD 1. The bleeding volume at LDLT was 590 mL. On POD 1, 3, 5, and 13, the coagulation FIX activity of the donor was 121.3%, 130.6%, 114.6%, and 50.2%, respectively. The donors post‐transplant course was uneventful, and the recipient is currently doing well at 18 months after LDLT. The FIX activity of the donor and recipient at nine months after LDLT was 39.2% and 58.0%, respectively. LDLT from donors with mild coagulation FIX deficiency could be performed effectively and safely using peri‐transplant short‐term coagulation FIX replacement and long‐term monitoring of the plasma FIX level in the donor.