Kazuaki Tokodai

C5a-Inhibitory Peptide Combined with Gabexate Mesilate Prevents the Instant Blood-Mediated Inflammatory Reaction in a Rat Model of Islet Transplantation

BACKGROUND The instant blood-mediated inflammatory reaction (IBMIR), in which the activation of both the coagulation and the complement cascades plays a key role, is one of the main obstacles to successful islet transplantation. At present, however, no useful protocol is clinically available. Therefore the aim of this study was to examine whether complementary peptides against an active region of C5a were safe to suppress IBMIR, owing to their extremely low molecular mass, when combined with a clinically available anticoagulant. METHODS Complement receptors on pancreatic tissues and isolated islets were analyzed by immunohistochemical staining and flow cytometry. Two-and-a-half islet equivalents per gram of syngeneic rat islet grafts were transplanted intraportally into 4 groups of 10-13 animals each after streptozotocin induction of diabetes: control, gabexate (Gab), C5a-inhibitory peptide (C5aINH), and C5aINH plus Gab. Recipients injected with equivalent amounts of saline solution served as control subjects. Plasma samples were collected at 0, 0.5, 1, 3, 6, and 24 h after transplantation for analysis. We also evaluated the curative rate, intravenous glucose tolerance test, and insulin amounts in the liver of the recipients. RESULTS C3a receptor (C3aR) was scarcely expressed on the isolated islets with relatively strong expression of C5a receptor (C5aR): C3aR: 0.44 +/- 0.38%; C5aR: 7.91 +/- 2.83%). However, C5aR was not expressed on pancreatic tissues before the isolation procedures. Thrombin-antithrombin complex was significantly suppressed in the 3 treated groups (P = .0015). The curative rate was also significantly improved (0% vs 33% vs 67% vs 100%, respectively; P = .03). Glucose tolerance was significantly improved among the 3 treated groups (P < .0005). Insulin amounts in the liver were considerably higher among treated versus control hosts. Notably, the treatment did not affect the increased body weight of the recipient. CONCLUSIONS This study suggested that C5a-inhibitory peptide combined with gabexate mesilate may be a useful approach to control the IBMIR induced in clinical islet transplantation and one that is free of side effects.

The relationship between recurrences and immunosuppression on living donor liver transplantation for hepatocellular carcinoma.

OBJECTIVES Living donor liver transplantation (LDLT) offers timely transplantation for patients with hepatocellular carcinoma (HCC). If ABO-incompatible LDLT is feasible, the needs for pretransplantation treatments may be eliminated. It is known that negative impacts of immunosuppression are limited among LDLT for HCC, however, we believe that excessive immunosuppression is one of the risk factors for recurrence. We compared the impacts of immunosuppression for LDLT with hepatectomy outcomes for HCC. METHODS From 1991 to 2010, we performed 144 LDLTs including 14 patients with HCC. Seven met the Milan criteria. Immunosuppressive therapies were based on tacrolimus plus methylprednisolone plus CD25 antibody. For ABO-incompatible cases, we also used mycophenolate mofetil and rituximab. Five cases underwent strong imunosuppressive therapy (steroid pulse or rituximab) within 180 days. In addition, we performed hepatectomy for 180 HCC cases from 1997 to 2010. RESULTS Overall survival rates of the LDLT cohort and hepatectomy groups were similar, but disease-free 5-year survival rates (DFS) of the LDLT cohort were significantly better than those of the hepatectomy group (total = 54.4% versus 27.4%, within the Milan criteria cases, 71.4% versus 33.8%). Thus, the negative impact of immunosuppression on recurrence was less than the benefit of a whole liver resection. Among strongly immunosuppressed cases, 5-years DFS rates were significantly worse than among other immunosuppressed cases (20.0% versus 76.2%). Upon univariate analysis, the factors associated with HCC recurrence were alpha-fetoprotein levels and steroid doses within 180 days, but multivariate analysis did not show a predictor for recurrence. CONCLUSION Patients who are strongly immunosuppressed may have several negative impacts for recurrences. More careful indications must be selected for ABO-incompatible cases.

Prevalence and risk factors of obesity, hypertension, dyslipidemia and diabetes mellitus before and after adult living donor liver transplantation.

The development of metabolic abnormalities after liver transplantation (LTx) contributes to cardiovascular events and mortality. We analyzed the prevalence and risk factors of obesity, hypertension, dyslipidemia and diabetes mellitus (DM) after adult living donor liver transplantation.

Expression of receptors for anaphylatoxins C3a and C5a on rat islet preparations.

BACKGROUND Complement activation has been implicated in the development of the instant blood-mediated inflammatory reaction (IBMIR). In particular, anaphylatoxins C3a and C5a elicit a broad range of proinflammatory effects, including chemotaxis of inflammatory cells and cytokine release. We have previously shown that 2 types of receptors for C5a are expressed on isolated islets. In the present study, we investigated this component in detail. METHODS C3aR, C5aR, and C5L2, together with CD11b and CD31, on freshly isolated islets (fresh group) and islets cultured with (cytokine group) or without (culture group) TNF-α, IL-1β, and IFN-γ for ∼12 hours were analyzed by flow cytometry. In addition, these 3 kinds of receptors were analyzed on nonendocrine cells. RESULTS C5aR and C5L2 were expressed on the isolated islets (C5aR: 7.91 ± 2.83%; C5L2: 2.45 ± 1.34%) and the expression of both C5a receptors was markedly attenuated by culture for 12 hours (C5aR: P < .005; C5L2: P < .05). Compared with the culture group, the expression was significantly up-regulated in the cytokine group (C5aR: P < .05; C5L2: P = .05). C5aR-positive cells expressed CD11b but not CD31. In contrast to islets, nonendocrine cells expressed C5L2 predominantly. C3aR was scarcely expressed on isolated islets or nonendocrine cells. CONCLUSIONS These data suggest that C5aR and C5L2 are expressed on CD11b-positive leukocytes in islet preparations. Depletion of C5a receptors by culturing appropriately could be an attractive therapeutic strategy in clinical islet transplantation.

Rituximab therapy and reduction of immunosuppression to rescue graft function after renal posttransplantation lymphoproliferative disorder found by macrohematuria in a pancreas and kidney transplant recipient: a case report.

INTRODUCTION Posttransplantation lymphoproliferative disorder (PTLD) remains an uncommon complication of solid organ transplantation, with a high mortality rate reported after conventional therapies. Epstein-Barr virus (EBV) may cause PTLD, but most EBV infections after transplantation are clinically silent reactivations, so the detection of PTLD is often delayed. Recently we experienced the rare case of intrarenal graft PTLD found by macrohematuria in a simultaneous pancreas and kidney transplant recipient. The grafts were saved by treatments with rituximab, cyclophosphamide, hydroxydaunorubicin, and prednisone-based chemotherapy (R-CHOP) after reduction of immunosuppression (IR). METHODS This 37-year-old man with insulin-dependent diabetes underwent simultaneous pancreas and kidney transplantation (SPK) with enteric drainage. Six months after transplantation, he displayed macrohematuria, which we investigated by blood tests, computer tomography (CT) scan, positron emission tomography (PET)-CT, and magnetic resonance imaging, recognizing a tumor in the transplanted renal graft. An open biopsy showed a CD20-positive PTLD. We started treatments with IR, rituximab (375 mg/m(2), weekly for 2 cycles) and R-CHOP therapy: rituximab (375 mg/m(2)) plus CHOP every 3 weeks for 6 cycles. RESULTS IR and R-CHOP therapy achieved a complete remission (CR). CR has continued for 14 months at the time of writing. The maximum level of EBV DNA was 259 copies/μg DNA, but 2 months after these therapies, the level had decreased to normal. The patient had no impairment of pancreas and kidney graft functions. CONCLUSIONS The outcome of intragraft PTLD in the kidney of an SPK recipient suggested that the negative impact of IR on graft function may be compensated by the immunosuppressive effects of rituximab, allowing reduced immunosuppression during chemotherapy.

Long-Term Survival with Growth Hormone Replacement after Liver Transplantation of Pediatric Nonalcoholic Steatohepatitis Complicating Acquired Hypopituitarism

Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease (NAFLD). In adult patients, liver transplantation (LT) is the treatment of choice for end-stage liver disease secondary to NASH. However, little information is available regarding outcomes of LT in pediatric patients with NASH. We describe here a pediatric patient with NASH associated with hypopituitarism who underwent living donor liver transplantation (LDLT). An 11-year-old boy was diagnosed with a pituitary tumor, which was removed by trans-interhemispheric approach following bifrontal craniotomy. Histopathological examination revealed a mature teratoma. Eighteen months later, magnetic resonance imaging showed recurrence of the pituitary tumor, which was found to be a germinoma. He underwent 3 months of chemoradiotherapy, with a complete response. He gradually became obese, with elevated transaminase levels. At age 15 years, he developed fatigue and dyspnea and was found to have liver cirrhosis secondary to NASH with severe hepatopulmonary syndrome. He underwent LDLT using a right liver graft from his mother. Twelve months later, abdominal computed tomography showed recurrence of NAFLD. Five years after the LDLT, transaminases were slightly elevated. Growth hormone replacement therapy was started, reducing transaminase levels to their normal ranges. Ten years after LDLT, fatty liver remains stable, although his body mass index has not been reduced. Growth hormone replacement therapy may be effective in graft maintenance. This is the first case report of a patient with maintained stable liver function 10 years after LDLT for pediatric NASH.

Risk factors for recurrence in stage II/III colorectal cancer patients treated with curative surgery: The impact of postoperative tumor markers and an infiltrative growth pattern.

We evaluated the capacity of clinicopathological factors to predict recurrence in stage II/III colorectal cancer (CRC) patients after curative resection.

Arterial and biliary complications after living donor liver transplantation: a single-center retrospective study and literature review

AimThe mortality of patients on the waiting list for deceased donor liver transplantation (DDLT) is high, especially in countries where donation rates are low. Thus, living donor liver transplantation (LDLT) is an attractive option. However, compared with DDLT, LDLT is associated with increased rates of arterial and biliary complications. We examined the rates of complications and risk factors following LDLT.MethodsWe retrospectively investigated and compared the rates of complications of DDLT and LDLT in our institute. We also performed univariate and multivariate analyses to identify the independent risk factors for these complications. The complications and specific disadvantages of LDLT were reviewed and discussed.ResultsThe incidence rate of arterial complications in LDLT was 6.0%, compared with 3.2% (13/441) in DDLT. A multivariate analysis identified low body weight (P = 0.032) as the only independent risk factor for hepatic artery thrombosis. The rate of all biliary complications in LDLT was 17.3%, compared with 18.7% in DDLT. The risk factors for biliary stricture identified by the multivariate analysis were recurrent cholangitis and the number of bile ducts. The durations of hospital stay and overall survival rates were similar between the two groups.ConclusionGiven the shortage of deceased donor organs, we believe that LDLT is acceptable in an attempt to meet demand.

Effect of Recipient Age at Liver Transplantation on Prevalence of Post-Transplant Donor-Specific HLA Antibody

BACKGROUND Post-transplant donor-specific HLA antibodies (DSA) may have a detrimental effect on long-term outcomes of organ transplantation. The aim of this study was to specifically evaluate the effect of recipient age on the prevalence of DSA over a long-term follow-up after living donor liver transplantation (LDLT). MATERIAL AND METHODS A retrospective analysis of DSA evaluations was performed in 50 pediatric patients with HLA data available. Patients were divided into 2 groups based on their age at the time of LDLT: younger (Y) group, age <3 years; older (O) group, age ≥3 years. DSA evaluation was performed using Luminex single-antigen bead assays, with a mean fluorescence intensity ≥1000 used as a cut-off for positive results. RESULTS There were no between-group differences in terms of sex, ABO incompatibility or acute rejection. Only one of our 50 patients tested positive for class I DSA. Significantly more patients tested positive for HLA-DR DSA in group Y (40.6%) than in group O (11.1%; p=0.02). Recipients <3 years of age at the time of LDLT may be at a higher risk of testing positive for class II DSA. CONCLUSIONS These findings can inform the implementation of cost-effective screening of post-transplant DSA in pediatric LDLT recipients.

Indications and outcomes of an endoscopic approach under laparotomy for the treatment of bilioenteric anastomotic strictures

BAS is a potentially life‐threatening complication of LDLT. The aim of this study was to report on the indications and outcomes of an endoscopic approach under laparotomy being used in our institution to treat BAS after LDLT, using hepaticojejunostomy, for a small case series. Eighty‐three patients underwent an LDLT in our institution between 1991 and 2014. Retrospective chart review indicated that 10 of these patients developed BAS and were included in our analysis. The endoscopic approach under laparotomy was used in three patients who developed BAS 10 yr or more after their LDLT and in whom a percutaneous transhepatic approach and an endoscopic approach had failed. The course of recovery post‐operatively was unremarkable for two of the three patients who underwent the endoscopic approach under laparotomy. One patient required follow‐up laparotomy to treat a perforation of the bowel causing acute peritonitis. At follow‐up one yr post‐operatively, the stent tube was removed in two patients who recovered fully. The other patient had full recovery with the stent remaining in situ. The endoscopic approach under laparotomy could be a safe and promising option in the treatment of BAS to avoid surgical re‐anastomosis.