Long-Term Outcomes of Living-Donor Liver Transplantation for Primary Biliary Cirrhosis: A Japanese Multicenter Study.

The factors that influence long-term outcomes after living-donor liver transplantation (LDLT) for primary biliary cirrhosis (PBC) are not well known. Compared with deceased-donor transplantation, LDLT has an increased likelihood of a related donor and a decreased number of human leukocyte antigen (HLA) mismatches. To clarify the effects of donor relatedness and HLA mismatch on the outcomes after LDLT, we retrospectively analyzed 444 Japanese patients. Donors were blood relatives for 332 patients, spouses for 105, and "other" for 7. The number of HLA A-B-DR mismatches was none to two in 141, three in 123, and four to six in 106 patients. The 15-year survival rate was 52.6%, and PBC recurred in 65 patients. Recipient aged 61 years or older, HLA mismatches of four or more (maximum of six), graft:recipient weight ratio less than 0.8, and husband donor were adverse indicators of patient survival. IgM 554 mg/dL or greater, donor-recipient sex mismatch, and initial immunosuppression with cyclosporine were significant risks for PBC recurrence, which did not affect patient survival. In subgroup analysis, conversion to cyclosporine from tacrolimus within 1 year diminished recurrence. Prospective studies are needed to determine the influence of pregnancy-associated sensitization and to establish an optimal immunosuppressive regimen in LDLT patients.

Practices for Supporting and Confirming Decision-Making Involved in Kidney and Liver Donation by Related Living Donors in Japan: A Nationwide Survey.

This nationwide survey investigated the actual practices for supporting and confirming the decision-making involved in related living-organ donations in Japan, focusing on organ type and program size differences. Answers to a questionnaire survey were collected from 89 of the 126 (71%) kidney and 30 of the 35 (86%) liver transplantation programs in Japan that were involved in living-donor transplantations in 2013. In 70% of the kidney and 90% of the liver transplantation programs, all donors underwent "third-party" interviews to confirm their voluntariness. The most common third parties were psychiatrists (90% and 83%, respectively). Many programs engaged in practices to support decision-making by donor candidates, including guaranteeing the right to withdraw consent to donate (70% and 100%, respectively) and prescribing a set "cooling-off period" (88% and 100%, respectively). Most donors were offered care by mental health specialists (86% and 93%, respectively). Third parties were designated by more of the larger kidney transplant programs compared with the smaller programs. In conclusion, the actual practices supporting and confirming the decision to donate a living organ varied depending on the organ concerned and the number of patients in the program.

Impact of rituximab desensitization on blood-type-incompatible adult living donor liver transplantation: a Japanese multicenter study.

We evaluated the effects of rituximab prophylaxis on outcomes of ABO-blood-type-incompatible living donor liver transplantation (ABO-I LDLT) in 381 adult patients in the Japanese registry of ABO-I LDLT. Patients underwent dual or triple immunosuppression with or without B cell desensitization therapies such as plasmapheresis, splenectomy, local infusion, intravenous immunoglobulin and rituximab. Era before 2005, intensive care unit-bound status, high Model for End-Stage Liver Disease score and absence of rituximab prophylaxis were significant risk factors for overall survival and antibody-mediated rejection (AMR) in the univariate analysis. After adjustment for era effects in the multivariate analysis, only absence of rituximab prophylaxis was a significant risk factor for AMR, and there were no significant risk factors for survival. Rituximab prophylaxis significantly decreased the incidence of AMR, especially hepatic necrosis (p < 0.001). In the rituximab group, other B cell desensitization therapies had no add-on effects. Multiple or large rituximab doses significantly increased the incidence of infection, and early administration had no advantage. In conclusion, outcomes in adult ABO-I LDLT have significantly improved in the latest era coincident with the introduction of rituximab.

Effect of maintenance therapy with low-dose peginterferon for recurrent hepatitis C after living donor liver transplantation.

Approximately 30% of patients who have recurrent hepatitis C after liver transplantation achieve sustained virological response (SVR) by taking a combination therapy of pegylated interferon and ribavirin. For the remaining non-SVR patients, an effective management treatment has not yet been established. In this study, efficacy of long-term peginterferon maintenance therapy for non-SVR patients was evaluated. Forty patients who had previously received the combination therapy for hepatitis C after living donor liver transplantation were classified into one of the following three groups: the SVR group (n = 11); the non-SVR-IFN group (n =17), which received low-dose peginterferon maintenance therapy for non-SVR patients; and the non-SVR-Withdrawal group (n = 12), which discontinued the interferon treatment. We then compared histological changes among these three groups after 2 or more years follow-up. Activity grade of liver histology improved or remained stable in patients in the SVR and non-SVR-IFN groups, but deteriorated in half of the patients in the non-SVR-Withdrawal group. Fibrosis improved or remained stable in 10 of 11 SVR patients and in 13 of 17 non-SVR-IFN patients, but deteriorated in all non-SVR-Withdrawal patients. Mean changes in fibrosis stage between pretreatment and final liver biopsy were -0.18, +0.06 and +2.2 in the SVR, non-SVR-IFN and non-SVR-Withdrawal groups, respectively. Fibrosis stage deteriorated to F3 or F4 significantly more rapidly in the non-SVR-Withdrawal group than in the other two groups. In conclusion, continuing long-term maintenance therapy with peginterferon prevented histological progression of hepatitis C in patients who had undergone living donor liver transplantation.

Current status of organ transplantation in Japan.

To overcome severe donor shortage, Japanese doctors over the years have developed innovative strategies to maximize organs transplanted per brain death donor and expanded the donor pool using living donors. They also used living and marginal organs and drastically improved living donor lung, liver, pancreas and kidney transplantations. Moreover, they initiated ABO blood type incompatible liver transplantation advancements and succeeded in overcoming the blood type barrier in kidney and liver transplantations. Similar efforts are underway for pancreas transplantation. Furthermore, Japanese doctors have developed a nonaggressive step to achieve immunosuppression following organ transplantation by carefully monitoring donor-specific hyporesponsiveness and infectious immunostatus. However, the institution of amendments to allocation systems and the intensification of efforts to decrease living donor morbidity and to increase the number of brain death donors have remained important issues needing attention. Overall, the strategies Japan has adopted to overcome donor shortage can provide useful insights on how to increase organ transplantations.

Risk factors for recurrence of primary sclerosing cholangitis after living donor liver transplantation in Japanese registry.

The outcomes of primary sclerosing cholangitis (PSC) after living donor liver transplantation (LDLT) in a large series have not been reported. We aimed to determine long-term patient and graft survival, risk factors for PSC recurrence, and the significance of recurrence after LDLT in a Japanese registry. Questionnaires concerning patient characteristics, treatments, and clinical courses were used. Data of 114 patients undergoing primary LDLT for PSC from July 1996 to December 2008 in 29 institutions were evaluated. For strict diagnoses of recurrence, patients with hepatic artery thrombosis (n = 8), ABO-blood-type-incompatible transplantation (n = 8), and established ductopenic rejection (n = 2) were excluded and 96 patients were analyzed for risk factors. Recurrence was diagnosed in 26 patients (27%) at 8 to 79 months after transplantation. Patient, graft, and recurrence-free survivals were 78, 74 and 57% at 5 years after LDLT, respectively. The graft loss rate was 69 versus 23% in patients with versus without recurrence, respectively. Multivariate analysis revealed that high MELD scores, first-degree-relative donors, postoperative CMV infection, and early biliary anastomotic complications were significant risk factors for recurrence. PSC recurrence was a significant risk factor of graft loss but not patient death. PSC recurrence was frequent and had significant impacts on outcomes after LDLT.

Graft loss and poor outcomes after living-donor liver transplantation owing to arterioportal shunts caused by liver needle biopsies.

BACKGROUND: Arterioportal shunts (APS) are well-known critical complications after liver transplantation (OLT). The aims of this study were to assess the frequency and causes of APS after OLT and to analyze APS patients with poor outcomes. PATIENTS: We evaluated 1415 OLT recipients retrospectively investigating APS cases. RESULTS: APS were detected in at least 9 patients (0.6%). All patients with APS had a history of posttransplant invasive procedures; percutaneous transhepatic cholangio drainage (n = 6) or needle biopsy (LNB; n = 3). Two patients with poor outcomes showed proximal APS caused by LNBs. The other 7 patients with distal APSs, showed stable conditions. Imaging findings in the 2 proximal APS patients revealed drastic changes in graft hemodynamics. Although they finally underwent re-OLT, their outcomes were poor, owing to fatal complications associated with advanced collaterals. CONCLUSION: We concluded that even careful LNBs can cause APS at unexpected points. Earlier, more aggressive treatments are required, especially for proximal APS patients.

Hashimoto's encephalopathy after interferon therapy for hepatitis C virus in adult liver transplant recipient accompanied by post-transplant lymphoproliferative disorder related to Epstein-Barr virus infection.

A 55-year-old woman underwent living-donor liver transplantation (LDLT). She had no history of autoimmune diseases. Spleen was preserved. Steroids were withdrawn at 3 months after LDLT. Epstein-Barr virus (EBV) infection occurred at 3.5 years after LDLT. Recurrent hepatitis C virus infection was confirmed at 4.5 years after LDLT, and pegylated interferon was introduced. Diagnosis of EBV-positive post-transplant lymphoproliferative disorder (PTLD) was made at 4.8 years after LDLT, and tacrolimus (Tac) was stopped completely. Then, unconsciousness, convulsion, and cervical stiffness appeared suddenly. Electroencephalography, cerebrospinal fluid analysis, and image studies revealed normal or only nonspecific findings. The patient was in a state of exhaustion; therefore, steroid pulse therapy (SPT) was attempted. Surprisingly, her general condition, including consciousness disturbance, was improved markedly, and Hashimoto's encephalopathy (HE) was suspected, based on this reaction to SPT. Elevations of anti-thyroglobulin antibody and anti-thyroid peroxidase antibody were confirmed. After withdrawal of Tac, and treatment with acyclovir and steroids, EBV-positive PTLD and HE improved, although they recurred at 5.1 years after LDLT. SPT improved only neurological symptoms. Molecular-targeted therapy was given for recurrent PTLD, based on analysis of sampling specimens. This therapy was effective, but tumor lysis syndrome occurred, and the patient died at 5.3 years after LDLT.

Coupled regulation of interleukin-12 receptor beta-1 of CD8+ central memory and CCR7-negative memory T cells in an early alloimmunity in liver transplant recipients.

This study investigated how CD8(+) T cell subsets respond to allo- and infectious immunity after living donor liver transplantation (LDLT). Early alloimmunity: 56 recipients were classified into three types according to the post-transplant course; type I demonstrated uneventful post-transplant course, type II developed severe sepsis leading to multiple organ dysfunction syndrome or retransplantation and type III with acute rejection. In 23 type I recipients, the interleukin (IL)-12 receptor beta-1 (R beta 1)(+) cells of central memory T cells (Il-12R beta 1(+) T(CM)) were increased above the pretransplant level. In 16 type II recipients, IL-12R beta 1(+) T(CM) was decreased markedly below the pretransplant level on postoperative day (POD) 5. In 17 type III recipients, IL-12R beta 1(+) T(CM) was decreased for a more prolonged period until POD 10. Along with down-regulation of IL-12R beta 1(+) T(CM), the IL-12R beta 1(+) cells of CCR7-negative subsets (CNS) as well as perforin, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha decreased gradually, resulting in the down-regulation of effectors and cytotoxicity. The down-regulation of IL-12R beta 1(+) T(CM) was suggested to be due to the recruitment of alloantigen-primed T cells into the graft, and then their entry into the secondary lymphoid organ, resulting in graft destruction. Infectious immunity: immunocompetent memory T cells with the capacity to enhance effectors and cytotoxicity were generated in response to post-transplant infection along with both up-regulation of the IL-12R beta 1(+) T(CM) and an increase in the CNS showing the highest level of IL-12R beta 1(+) cells. In conclusion, this work demonstrated that the IL-12R beta 1(+) cells of T(CM) and CNS are regulated in a tightly coupled manner and that expression levels of IL-12R beta 1(+) T(CM) play a crucial role in controlling allo- and infectious immunity.

Herpes simplex virus hepatitis after pediatric liver transplantation.

Herpes simplex virus (HSV) hepatitis has a fatal impact on the outcome of organ transplanted recipients. Here, we present a thought-provoking case of HSV hepatitis in a high-risk recipient after living-related liver transplantation (LRLT). A 1-month-old female newborn infant was affected by HSV encephalitis. Fulminant hepatic failure (FHF) of unknown etiology occurred suddenly at 4.4 years of age. Viral infections were ruled out as the cause of FHF. Intensive care including plasma exchange (PE) was started, and the preoperative treatments for ABO incompatibility were performed. Thereafter, LRLT was performed emergently. Although strong immunosuppression for ABO incompatibility was continued after LRLT, antibody-mediated rejection (AMR) occurred on postoperative day (POD) 4. PE was repeated and improvements were obtained. However, liver dysfunction appeared on POD 8. Histopathological findings of liver needle biopsy clearly revealed HSV hepatitis, although the results of HSV DNA and antibody titer in blood sample did not clearly indicate HSV infection. On POD 21, thrombotic microangiopathy (TMA) occurred and the plasma and immunoglobulin were replenished. Our pediatric recipient recovered successfully from AMR, HSV hepatitis, TMA, and repeated sepsis. We conclude that well considered therapy based on the real-time detection of HSV hepatitis is indispensable for the further improvements of outcome in HSV hepatitis after LRLT.

Clinical features of biochemical cholestasis in patients with recurrent hepatitis C after living-donor liver transplantation.

Recurrent hepatitis C after liver transplantation (HepC-LT) progresses faster than hepatitis C in non-transplant settings. Cholestasis has been suggested to be one characteristic of HepC-LT related to the rapid progression. We investigated the clinical features of biochemical cholestasis, which we defined as high serum concentrations of alkaline phosphatase and gamma-glutamyl transpeptidase, in patients with recurrent hepatitis C after living-donor liver transplantation. Eighty patients were diagnosed with post-transplant recurrent hepatitis C after exclusion of other aetiologies of cholestasis by liver biopsy and imaging. The clinical features of biochemical cholestasis in the patients with HepC-LT, including histological changes, the efficacy of interferon therapy and helper T-cell (Th) subsets in the peripheral blood, were analysed. Fifty-five of the 80 patients with HepC-LT (69%) had evidence of biochemical cholestasis. Progression of liver fibrosis to stage F3 or F4 was significantly accelerated in patients with biochemical cholestasis compared with patients without cholestasis. The biochemical cholestasis in patients with HepC-LT improved after interferon therapy in 22 of 39 patients (56%) who showed a virological response to the therapy, suggesting that hepatitis C virus (HCV) caused the biochemical cholestasis in these patients. Patients with biochemical cholestasis who had a biochemical response to interferon therapy showed an increased Th1 responses in peripheral blood. In conclusion, biochemical cholestasis is the characteristic feature of HepC-LT and is related to progression of liver fibrosis. An increased Th1 response is associated with cholestasis caused by HCV after liver transplantation.

Resolution of preoperative portal vein thrombosis after administration of antithrombin III in living donor liver transplantation: case report.

A 59-year-old man with hepatitis C virus-associated liver cirrhosis was transferred to our hospital to undergo living donor liver transplantation. Coagulation was impaired (prothrombin time [International Normalized Ratio], 3.27), and antithrombin III (AT-III) activity was 23% (normal, 87%-115%). Contrast-enhanced computed tomography scans revealed portal vein thrombosis (PVT) from the junction between the splenic and superior mesenteric vein to the porta hepatica; the portal vein was completely obstructed (PVT). To prevent further development of PVT, 1500 U of AT-III was administered for 3 days, elevating the AT-III activity to 50%. A contrast-enhanced computed tomography scan obtained 9 days after AT-III administration showed resolution of PVT. Living donor liver transplantation was safely performed without portal vein grafting. Thus, a low AT-III concentration may have an important role in the pathogenesis of PVT in patients with cirrhosis.

Portal vein complications in pediatric living donor liver transplantation using left-side grafts.

The aim of this report is to assess the rate of portal vein complications (PVCs), the success rate of treatment for PVCs and the prognosis of patients with PVCs for pediatric living donor liver transplantation (LDLT). Pre- and postoperative records of 521 pediatric LDLTs, using left-side grafts were retrospectively reviewed. The overall rate of PVC was 9%, with early PVC occurring in nine patients (1.7%) with a mortality rate of 67% and late PVC in 38 patients (7.3%). Fifteen of these patients with late PVC showed complete portal vein occlusion despite various treatments, and in six of them the graft was lost. Histological examination revealed fibrosis in portal areas in 13 patients, around the central veins associated with cholestasis in the parenchyma in 10, and hepatocyte ballooning in 12. Correction of portal vein flow or retransplantation is necessary for the rescue of patients with early PVCs. Graft loss in the long term may be high with the occurrence of liver failure or portal hypertension related causes, such as hepatopulmonary syndrome and gastrointestinal bleeding in patients with late PVCs. For the rescue of these patients, especially for patients with body weight < 6 kg, regular monitoring of portal vein flow is essential.

Evidence of immune tolerance to blood group antigens in a case of ABO-incompatible pediatric liver transplantation.

In a 12-year-old patient with blood group O, who had received a partial liver graft 10 years ago from his father with blood group A, the levels of anti-A-specific antibodies (Abs) were persistently undetectable after the transplantation, while the levels of anti-B-specific Abs gradually increased and attained a plateau. Peripheral blood mononuclear cells (PBMCs) from this patient were engrafted into NOD/SCID mouse in order to investigate the immune response to donor-type blood group antigens. Even after sensitization with blood group-A erythrocytes, no anti-A Abs were detected in the serum samples of the mouse that received PBMCs from the blood group-O recipient of group-A liver allograft, however, immunoglobulins specific for antigens other than the A antigens were produced. Thus, we provide a possible evidence of immune tolerance to blood group antigens in this ABO-incompatible pediatric liver transplantation.

Rapid and accurate measurement of anti-A/B IgG antibody in ABO-unmatched living donor liver transplantation by surface plasmon resonance.

High anti-blood group A or B (anti-A/B) immunoglobulin G (IgG) haemagglutination titres are associated with poor graft survival in ABO-unmatched liver transplantation. We have previously reported that the surface plasmon resonance (SPR) method can be used to measure anti-A/B IgG levels in the plasma very quickly and quantitatively. The aim of this study was to brush up this SPR method. The anti-A/B IgG antibodies (Abs) were purified from the plasma of healthy volunteers by affinity chromatography and used to establish standard curves for the SPR and flow cytometry (FCM) methods. The haemagglutination test tube (TT), FCM and SPR methods were then used to measure the changes over time in the anti-A/B IgG titres of 25 ABO-unmatched living donor liver transplantation (LDLT) recipients. The standard curve permitted the SPR values for the anti-A/B IgG titres to be expressed in microg mL(-1) units. The SPR measurements of the anti-A/B IgG levels in the LDLT recipients correlated very well with the FCM values, whereas the TT values correlated poorly with either method. Furthermore, the SPR method accurately detected the effects of plasma exchange. In conclusion, the SPR method is an accurate, time- and labour-saving method for measuring anti-A/B IgG titres that can be easily standardized.

Cytomegalovirus infection with perineal pain after living donor liver transplantation: report of four cases.

We report on 4 adult cases of presumptive cytomegalovirus (CMV) disease with perineal pain after living donor liver transplantation. Patients presented with severe perineal pain without any other symptoms related to CMV infection, except pyrexia. All patients had an episode of acute cellular rejection (ACR) before the onset of perineal pain, and 1 patient needed OKT3 therapy. The severe perineal pain was not well controlled with medication, and 1 patient needed epidural anesthesia. In the first 3 patients, pp65 CMV antigenemia (pp65CMV-Ag) test results were positive and intravenous administration of ganciclovir (GCV) therapy was initiated. In the last patient, GCV therapy was preemptively administered before a positive pp65CMV-Ag test result was confirmed. After administration of GCV, the pain gradually disappeared and all patients had negative pp65CMV-Ag test results. In conclusion, unusual perineal pain can be a symptom related to CMV infection. CMV infection needs to be kept in mind when a liver transplant recipient has severe perineal pain, especially after receiving treatment for ACR.