K. Ishiyama

Attenuation of portal hypertension by continuous portal infusion of PGE1 and immunologic impact in adult-to-adult living-donor liver transplantation.

Background Small-for-size syndrome remains the greatest limiting factor of expanding segmental liver transplantation from living donors. Portal hyperperfusion is considered to substantially contribute to small-for-size syndrome. We investigated the impact of continuous portal infusion of prostaglandin E1 (PGE1) on small-for-size grafts (SFSGs) in adult-to-adult living-donor liver transplantation (LDLT). Methods From July 2003 to December 2009, LDLT was performed in 122 patients. We introduced continuous portal infusion of PGE1 to five SFSG patients (PG group) from November 2007 to December 2009 and retrospectively compared them with a historical control group of eight relevant SFSG patients without PGE1 infusion (non-PG group) from July 2003 to October 2007 to determine the safety and efficacy of continuous PGE1 portal infusion for SFSGs. Splenectomy cases were excluded from analysis. Results The PG group demonstrated significantly lower postoperative portal pressure than the non-PG group. Moreover, the PG group demonstrated significantly improved liver function in the early posttransplantation period and significantly better recovery from hyperammonemia at 1 week after transplantation and from hyperbilirubinemia in the late posttransplantation period. Overall survival was significantly better in the PG group than in the non-PG group. Three patients in the non-PG group died of rejection-related reasons. Interestingly, immunomonitoring assay revealed that antidonor immune responses were significantly accelerated in the non-PG group compared with the PG group after LDLT. In contrast, the PG group showed well-suppressed antidonor immune responses. Conclusion Continuous portal infusion of PGE1 for SFSG attenuated portal hypertension, improved graft function, and suppressed antidonor immune responses, resulting in better survival.

Optimization of Immunosuppressive Therapy Based on a Multiparametric Mixed Lymphocyte Reaction Assay Reduces Infectious Complications and Mortality in Living Donor Liver Transplant Recipients

AIM We investigated the clinical relevance of immune monitoring by a multiparametric mixed lymphocyte reaction (MLR) assay, wherein the number and phenotype of alloreactive precursors can be quantified by combining the results of carboxyfluorescein diacetate succinimidyl ester labeling and flow cytometry analysis. METHODS In 51 adult patients undergoing living donor liver transplantation (OLT), immunosuppressive drugs were dosed on the basis of immune monitoring by the MLR assay (optimized protocol: group O). In 64 other patients, the agents were prescribed according to empirical regimens (empirical protocol: group E). In group O, MLR assays were performed at 2- to 4-week intervals until 3 months after OLT and thereafter at 3- to 6-month intervals. Therapeutic adjustments for immunosuppressants were determined by tapering the doses in cases of anti-donor hyporesponsiveness for both CD4+ and CD8+ T-cell subsets. RESULTS The 1-year patient and graft survivals in groups O versus E were 90.2% versus 76.6%, respectively. The incidence of acute rejection episodes (ARE) among group O (13.7%) were lower than in cohort E (28.1%). None of the patients in group O while four patients (3%) in group E already have shown chronic rejection to date. The incidences of bacteremia and fungal infections in group O (9.8% and 7.5%, respectively) were lower than in cohort E (18.8% and 12.6%, respectively). CONCLUSION A multiparametric MLR assay may facilitate the development of adequate immunosuppressive regimens.

Fc-Gamma Receptor Polymorphisms Predispose Patients to Infectious Complications After Liver Transplantation

We investigated the impact of polymorphisms in host innate immunoregulatory genes on the development of infectious complications after liver transplantation (LT). The single‐nucleotide polymorphisms (SNPs) of C1QA [276A/G], FCGR2A [131H/R], and FCGR3A [158F/V], genes encoding the Fc gamma receptor (FcγR), were analyzed in 89 living donor LT recipients in relation to the occurrences of postoperative infectious complications within 30 days after LT. Consistent with a lower affinity of the isoform encoded by FCGR3A [158F] to both IgG1 and IgG3, a significantly higher incidence of bloodstream infections (BSI) was observed in the FCGR3A [158F/V or F/F] than in the FCGR3A [158V/V] individuals. The combination of FCGR2A and FCGR3A SNPs further stratified the incidence of BSI, regardless of C1QA SNP. The predominant causative pathogen of BSI in the FCGR3A [158F/F or F/V] patients was gram‐positive cocci (73.3%), of which one third was methicillin‐resistant Staphylococcus aureus. No differences were observed in the incidence of fungal infections or in cytomegalovirus infections with respect to the three gene polymorphisms. Our findings indicate that FcγR SNPs are predisposing factors for BSI and can predict mortality after LT. This study provides a foundation for further prospective studies on a larger scale.

Two patients treated with pegylated interferon/ribavirin/telaprevir triple therapy for recurrent hepatitis C after living donor liver transplantation

It is difficult to use protease inhibitors in patients with recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) due to interaction with immunosuppressive drugs. We report our experience with two patients treated with telaprevir (TVR) combined with pegylated interferon/ribavirin (PEG IFN/RBV) for recurrent HCV genotype 1 infection after LT. The first was a 63‐year‐old man with HCV‐related liver cirrhosis, who failed to respond to IFN‐β plus RBV after LT. Treatment was switched to PEG IFN‐α‐2b plus RBV and TVR was started. The donor had TT genotype of interleukin (IL)‐28 single nucleotide polymorphisms (SNP) (rs8099917). The recipient had TT genotype of IL‐28 SNP (rs8099917). Completion of 12‐week triple therapy was followed by PEG IFN‐α‐2b plus RBV for 36 weeks. Finally, he had sustained viral response. The second was a 70‐year‐old woman with HCV‐related liver cirrhosis and hepatocellular carcinoma. She failed to respond to PEG IFN‐α‐2b plus RBV after LT, and was subsequently switched to PEG IFN‐α‐2b/RBV/TVR. Genotype analysis showed TG genotype of IL‐28 SNP for the donor, and TT genotype of IL‐28 SNP for the recipient. Serum HCV RNA titer decreased below the detection limit at 5 weeks. However, triple therapy was withdrawn at 11 weeks due to general fatigue, which resulted in HCV RNA rebound 4 weeks later. Both patients were treated with cyclosporin, starting with a small dose to avoid interactions with TVR. TVR is a potentially suitable agent for LT recipients who do not respond to PEG IFN‐α‐2b plus RBV after LT.

Three patients treated with daclatasvir and asunaprevir for recurrent hepatitis C after liver transplantation: Case report

We previously reported our data on telaprevir or simeprevir used in combination with pegylated interferon (PEG IFN) and ribavirin (RBV) for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). Here, we report three patients who achieved viral responses with no effect on the blood concentrations of immunosuppressive agents following daclatasvir and asunaprevir treatment. The first patient was a 57‐year‐old man with HCV‐related liver cirrhosis who failed to respond to PEG IFN/RBV after living donor LT. He had been treated with 1 mg/day of tacrolimus. The second was a 63‐year‐old man with HCV‐related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG IFN/RBV after living donor LT. He had been treated with 1 mg/day of tacrolimus. The third was a 61‐year‐old man with HCV‐related liver cirrhosis. He had been treated with mycophenolate mofetil (MMF). Serum HCV RNA became undetectable by TaqMan polymerase chain reaction test after 4 weeks of daclatasvir and asunaprevir treatment in all patients, and no remarkable fluctuations in blood concentration were observed either in tacrolimus or in MMF during 24 weeks of therapy. No adverse events were observed, and all patients received the full dose of daclatasvir and asunaprevir over 24 weeks. Serum HCV RNA remained negative at 12 weeks after the end of treatment in all patients. The daclatasvir and asunaprevir treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT.

Renal vein extension using an autologous renal vein in a living donor with double inferior vena cava: a case report.

BACKGROUND When the kidney from a living donor with a double inferior vena cava (IVC) is harvested for renal transplantation, the short length of the renal vein may eventually create a technical problem for graft implantation. Herein, we have reported a rare case of renal vein extension using an autologous renal vein in a living donor with a double IVC. CASE REPORT A 70-year-old man with end-stage renal disease owing to autosomal-dominant polycystic kidney disease underwent a living donor kidney graft from his wife who had a double IVC. Because of the enlarged kidneys, the patient underwent a bilateral native nephrectomy with concomitant renal transplantation to create space in the pelvis. At nephrectomy, the recipients renal vein was used to extend the donor renal vein. On the back table, the vein graft was sutured to the donor renal vein, permitting a 3.0-cm extension. RESULTS The transplantation was performed safely without any complications; the recipients renal function and blood flow were excellent after the operation. CONCLUSION This case illustrated that an autologous renal vein graft is a preferable option to extend of short donor renal vein for recipients who require a simultaneous native nephrectomy.

Two patients treated with simeprevir plus pegylated-interferon and ribavirin triple therapy for recurrent hepatitis C after living donor liver transplantation: case report.

We previously reported our data on telaprevir (TVR) used in combination with pegylated-interferon and ribavirin (PEG-IFN/RBV) for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). TVR substantially increases the blood levels of immunosuppressive agents such as cyclosporine and tacrolimus for drug-drug interactions. On the other hand, the effect of simeprevir (SMV) on the blood levels of these immunosuppressive agents is unclear. We report 2 patients who achieved viral responses with little effect on the blood levels of cyclosporine and tacrolimus using SMV plus PEG-IFN/RBV treatment. The first was a 71-year-old woman with HCV-related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG-IFN/RBV after living donor LT. She was treated with 40 mg/d of cyclosporine, and received SMV plus PEG-IFN/RBV treatment. The second was a 65-year-old man with HCV-related liver cirrhosis who failed to respond to PEG-IFN/RBV after living donor LT. He was treated with 3 mg/d of tacrolimus, and received SMV plus PEG-IFN/RBV treatment. Serum HCV RNA became undetectable using TaqMan polymerase chain reaction (PCR) test after 4 weeks of treatment in both patients, and no remarkable fluctuation in blood concentration was observed either in cyclosporine or tacrolimus during the 12 weeks of SMV treatment. Completion of 12-week SMV triple therapy was followed by PEG-IFNα2b plus RBV, and both patients achieved sustained virological response 12 weeks after the end of treatment. SMV plus PEG-IFNRBV treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT.