Koji Miyazawa

Risk Factors for Hepatic Artery Thrombosis After Microsurgical Vascular Reconstruction in Liver Transplantation

OBJECTIVE In liver transplantation, microsurgical reconstruction of a hepatic artery is essential but requires challenging techniques. Especially in living-donor liver transplantation, the recipient artery is short and located deep in the abdominal cavity. Furthermore, hepatic artery thrombosis (HAT) can be a lethal complication. This study sought to uncover the risk factors for HAT after microsurgical vascular reconstruction. METHODS From 1991 to 2011, we performed 151 microsurgical vascular reconstructions, including 3 deceased-donor liver transplantations. We retrospectively investigated the cases, performing univariate and multivariate analyses to identify independent risk factors for HAT. The patients had undergone ultrasonographic examinations for HAT over the first 14 days after transplantation. RESULTS Upon univariate analysis, the risk factors identified to be associated with P < .20 were young age (P = .0484), low body weight (P = .0466), short height (P = .0128), high graft-to-recipient weight ratio (P = .0031), small liver graft volume (P = .0416), small amounts of gabexate mesilate infusion (P = .0516), and the conventional technique (without a back-wall support suture; P = .1326). A multiple logistic regression analysis identified low body weight to be the only independent risk factor for HAT. CONCLUSION On the univariate analysis, we found that using the back-wall support suture technique contributed to the reduction of HAT, whereas on multivariate analysis, the only independent risk factor for HAT was low body weight.

Edaravone, a Free Radical Scavenger, Improves the Graft Viability on Liver Transplantation From Non–heart-beating Donors in Pigs

BACKGROUND Although liver transplantation from non-heart-beating donors (NHBDs) is an effective way to overcome shortage of donors, primary graft nonfunction is often noted in these grafts. We have previously reported that edaravone, a free radical scavenger, has a cytoprotective effect on warm ischemia-reperfusion injury and improves the function of liver grafts from NHBDs in a rat model of ischemia-reperfusion. The purpose of this study was to investigate the effects of edaravone on liver transplantations from NHBDs. METHODS Pigs were divided into three groups: (1) a heart-beating (HB) group (n = 5), in which liver grafts were retrieved from HB donors; (2) a non-heart-beating (NHB) group (n = 4), in which liver grafts were retrieved under apnea-induced NHB conditions; and (3) an edaravone-treated (ED) group (n = 5), in which liver grafts were retrieved in the same manner as the NHB group and treated with edaravone at the time of perfusion (3 mg/L in University of Wisconsin [UW] solution), cold preservation (1 mg/L in UW solution), and after surgery (1 mg/kg/d). The grafts from all groups were transplanted after 4 hours of cold preservation. RESULTS In the ED group, the 7-day survival rate was significantly higher than that in the NHB group (80% versus 0%, P = .0042, Kaplan-Meier log-rank test). Furthermore, on histologic examination, the structure of sinusoids in the ED group was well preserved and similar to that in the HB group. CONCLUSIONS Edaravone may improve the viability of liver grafts from NHBDs.

Short Oxygenated Warm Perfusion With Prostaglandin E1 Administration Before Cold Preservation as a Novel Resuscitation Method for Liver Grafts From Donors After Cardiac Death in a Rat In Vivo Model.

Background We previously demonstrated that short oxygenated warm perfusion (SOWP) prevented warm ischemia-reperfusion injury in rat livers from donors after cardiac death (DCDs) in an ex vivo model. In the present study, we aimed to examine the in vivo effects of SOWP and SOWP with prostaglandin E1 (PGE1) in DCD rat liver transplants. Methods We performed liver transplantation after 6-hour cold preservation using grafts retrieved from DCD rats, divided into nontreatment (NT), SOWP, and SOWP with PGE1 (SOWP + PG) treatment groups. The SOWP grafts were perfused with oxygenated buffer at 37°C for 30 minutes before cold preservation. Prostaglandin E1 was added to the SOWP + PG group perfusate. Eleven liver transplants from each group were performed to evaluate graft function and survival; 5 rats were used for data collection after 1-hour reperfusion, and 6 rats were used for the survival study. As a positive control, the same experiment was performed in a heart-beating donor group. Results In both the SOWP and SOWP + PG groups, serum liver enzymes, intercellular adhesion molecule 1 levels, and cellular damage were significantly decreased compared with the NT group. In the SOWP + PG group, bile production and energy status were significantly improved compared with the NT group. The 4-week survival was 0% (0/6), 67% (4/6), 83% (5/6), and 100% (6/6) in the NT, SOWP, SOWP + PG, and heart-beating donor group, respectively. Conclusions Short oxygenated warm perfusion before cold preservation and the addition of PGE1 to SOWP were thus beneficial in an in vivo rat model.

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.

Surgical resection of recurrent extrahepatic hepatocellular carcinoma with tumor thrombus extending into the right atrium under cardiopulmonary bypass: a case report and review of the literature

BackgroundRecurrent hepatocellular carcinoma accompanied by a right atrial tumor thrombus is rare. No standard treatment modality has been established. Surgical treatment may be the only curative treatment; however, surgery has been considered high risk. We herein describe a patient who underwent resection of a recurrent right atrial tumor thrombus under normothermic cardiopulmonary bypass on a beating heart.Case presentationA 60-year-old man underwent a right hepatectomy for hepatocellular carcinoma with diaphragm invasion. During the preoperative cardiac screening, he was diagnosed with an old myocardial infarction with triple-vessel coronary disease. Percutaneous coronary intervention was performed for the left anterior descending artery and left circumflex coronary artery. High-grade stenosis remained in his right coronary artery. Nine months later, computed tomography showed recurrent hepatocellular carcinoma in the diaphragm and a tumor thrombus extending from the suprahepatic inferior vena cava into the right atrium. Surgical resection of the recurrent tumor was performed through a right subcostal incision with xiphoid extension and median sternotomy. The recurrent tumor was incised with the diaphragm and pericardium. Intraoperative ultrasonography revealed that the tumor thrombus was free from right atrium wall invasion and that the right atrium could be clamped just proximal to the tumor thrombus. The right atrium, infrahepatic vena cava, left and middle hepatic veins, and hepatoduodenal ligament were encircled. Cardiopulmonary bypass was performed to prevent ischemic heart disease caused by intraoperative hypotension. Total hepatic vascular exclusion was then performed under normothermic cardiopulmonary bypass on heart beating. The inferior vena cava wall was incised. The tumor thrombus with the diaphragmatic recurrent tumor was resected en bloc. The patient had a favorable clinical course without any complications.ConclusionThe recurrent hepatocellular carcinoma in the diaphragm and the right atrial tumor thrombus were safely resected using normothermic cardiopulmonary bypass on heart beating.

The Reconstruction of Hepatic Arteries Using Extra-Anatomical Free Autografts in Living Donor Liver Transplantation

Objectives: In living-donor liver transplantation (LDLT), microsurgical reconstruction of a hepatic artery is essential but requires challenging techniques, because graft arteries are short and usable vessel grafts are limited. Furthermore, hepatic artery thrombosis can be a lethal complication. Extra-anatomical jump graft reconstruction using free grafts is reported to have a high reocclusion rate. However, this technique is necessary when there is no other option. We report 4 cases of LDLT that required extra-anatomical reconstruction technique using free autografting from the aorta to the hepatic artery. In this technique, we used the systemic administration of gabexate mesilate that is the strong serine protease inhibitor. Methods: From 1991 to 2015, we performed 164 LDLTs. We retrospectively investigated 4 cases of extraanatomical reconstruction of the hepatic artery using free autografting from the aorta to the hepatic artery. Results: Two cases initially underwent anatomical reconstruction, but the arteries occluded early, because of the dissection of recipient’s artery. There was no arterial graft, so we performed extra-anatomical reconstruction by using free autografting from the aorta to the hepatic artery. In the other two cases, the recipient arteries could not be used. Therefore, we initially performed extra-anatomical reconstruction by using radial artery free autografting as jump grafts from the aorta to the hepatic artery. In all cases, we used the systemic administration of gabexate mesilate, and could rescue all cases. Conclusion: We experienced and were able to salvage 4 cases that required free autografts. When there is no other means of reconstructing arteries, it is necessary to perform this procedure, depending on the condition of the intima of the recipient artery.

Analysis of the Association of Posttransplant Donor-Specific HLA Antibody with Liver Fibrosis After Pediatric Liver Transplantation

Objectives Although the short-term outcomes of pediatric liver transplantation (LT) have improved, the long-term outcomes, which are especially important in pediatric LT, have not improved to the same extent. This is partly caused by immunological progression of liver graft fibrosis. However, liver function test results are commonly normal even among patients with liver fibrosis; therefore, the indication and timing of liver graft biopsy have not been established. The aim of this study was to identify predictive factors of immunological graft fibrosis during long-term follow-up after pediatric LT. Methods We retrospectively identified 90 patients who underwent pediatric living donor LT (LDLT) at our institution between July 1991 and October 2013. Out of 90 LDLT patients, donor-specific antibody (DSA) screening was performed for 71 patients. After the DSA screening, liver biopsies were subsequently performed and graft fibrosis plus findings of chronic rejection were evaluated for 18 patients. Patients were divided into two groups based on histological findings, and clinical characteristics among patients with immunological graft fibrosis were assessed. The degree of fibrosis was diagnosed based on the Metavir fibrosis staging, and the fibrosis group included patients with fibrosis of F2 or more and patients with F1 fibrosis plus findings of chronic rejection, especially including C4d deposition. The cut-off for a positive reaction of Single Antigen Beads assay was set at a mean fluorescence intensity (MFI) of 1,000 or more. Results Of 18 patients, seven were included in the fibrosis group. No significant between-group differences were found regarding pretransplant characteristics, including age, sex, primary disease, ABO incompatibility, and immunosuppressive regimen. Episodes of biopsy-proven acute rejection and non-adherence to immunosuppressive drugs were comparable between the two groups. The mean fluorescence intensity (MFI) for anti-DR DSAs was significantly higher in the fibrosis group than the non-fibrosis group (1655 vs. 216; p = 0.019). There were significant between-group differences regarding the positive rate of anti-DR DSAs (86% vs. 28%; p = 0.012). The MFI for anti-DQ DSA was higher among patients with liver fibrosis, although this between-group difference did not reach statistical significance. The immunosuppression minimization rate was more prevalent among patients with liver fibrosis, although this between-group difference did not reach statistical significance (71% vs. 45%; p = 0.37). Conclusion Posttransplant development of anti-DR DSA is a risk factor of liver fibrosis during long-term follow-up. This finding provides useful information for the implementation of valid histological examinations of liver grafts for patients with higher MFI, especially for anti-DR DSA, after pediatric LT. JSPS KAKENHI Grant Numbers JP17K16502. JSPS KAKENHI Grant Numbers JP26861036.

The Effects of Short-Term Subnormothermic Perfusion after Cold Preservation on Liver Grafts from Donors after Cardiac Death

Background We previously reported that short oxygenated warm perfusion before cold storage (CS) had improved the graft viability of rat livers from donors after cardiac death (DCD). In this study, we investigated the effectiveness of short-term oxygenated subnormothermic perfusion for different durations after CS in a rat DCD model, and investigated the effects of 30-min subnormothermic perfusion for DCD livers in pigs. Methods In Study 1: We used an isolated rat liver perfusion system. The grafts were retrieved from Wistar rats 30min after cardiac arrest (thoracotomy), preserved in CS for 6h, and perfused with oxygenated subnormothermic (23-26°C) Krebs-Henseleit buffer for different durations (0, 30, 60, and 90min). After that, 15min incubation at 23-26°C, the grafts were reperfused under normothermic condition for 60min as a model of liver transplantation (0, 30, 60, and 90min groups; n=5 in each). In Study 2, landrace pigs (25-30kg) were randomly allocated into three types of groups (n = 5 per group): heart-beating (HB) graft, transplanted after a 4-h period of cold storage (CS); DCD graft, retrieved 20min after apnea induced cardiac arrest (respiratory withdrawal) and transplanted after a 4-h period of CS; and subnormothermic ex vivo liver perfusion (SELP) graft, retrieved in the same manner as the DCD graft but perfused with a subnormothermic oxygenated Krebs-Henseleit buffer (21-25°C, 10-15cmH2O) for 30min in the simplified dripping manner, without a machine perfusion system, after the 4-h period of CS, and subsequently transplanted. Results In Study 1, performing SELP groups significantly improved portal flow volume (P <0.05), and bile production (P <0.05), decreased liver enzymes (P <0.05), and increased tissue ATP (P <0.01) compared to DCD group. In the histological examinations, additional SELP ameliorated tissue deterioration, preserved the parenchymal structure, and decreased apoptosis compared to DCD group (P <0.01). In Study 2, the survival rate in the SELP group was significantly better than that in the DCD group (P = 0.0016). In the histological examination, preserved structure of the parenchyma was observed in the SELP group, and SELP significantly decreased apoptosis compared to DCD group (P <0.0001). Conclusion Even 30min of subnormothermic perfusion after CS recovered DCD livers from ischemia-reperfusion injury and might improve the viability of the grafts. Although 30min SELP was not sufficient to improve the survival rate as a level of HB group and to prevent primary graft non-function completely, this simple technique has the potential to expand the donor liver pool.

Association of post-transplant donor-specific HLA antibody with liver graft fibrosis during long-term follow-up after pediatric liver transplantation

The aim of this study was to evaluate the significance of post‐transplant DSA as a predictor of liver fibrosis during long‐term follow‐up after pediatric LT. We evaluated the histological findings in 18 LT recipients who underwent liver biopsy after DSA screening. Liver fibrosis was scored based on the METAVIR fibrosis staging. Patients were divided into 2 groups based on histological findings, and clinical characteristics among patients with liver fibrosis were assessed. Of 18 patients, 7 were included in the fibrosis group. No significant between‐group differences were found regarding peritransplant characteristics, including age, sex, primary disease, ABO incompatibility, and immunosuppressive regimen. Episodes of acute rejection and non‐adherence to immunosuppressive drugs were comparable between both groups. The MFI for anti‐DR DSA and positive rate were significantly higher in the fibrosis group (1655 vs 216; P = .019, 86% vs 27%; P = .012, respectively). MFI for anti‐DQ DSA was higher in the fibrosis group, but non‐significantly (2052 vs 384; P = .46). Post‐transplant anti‐DR DSA is associated with graft fibrosis during long‐term follow‐up. This finding seems useful for the implementation of valid histological examinations of liver grafts for patients with higher MFI, especially for anti‐DR DSA, after pediatric LT.

A Case of Successful Simultaneous Pancreas-Kidney Transplantation Using the Injured Pancreas Graft

OBJECTIVE Graft injuries sometimes occur and may cause complications such as the leakage of pancreatic secretions, which is often lethal. We report our experience of a case of successful simultaneous pancreas-kidney transplantation using injured pancreas graft. PATIENTS AND METHODS The recipient was a 57-year-old woman with type 1 diabetes mellitus, and the donor was a 30-year-old man with a brain injury. In the donation, the pancreas parenchyma, splenic artery, and gastroduodenal artery were injured iatrogenically. We therefore reconstructed these arteries using vessel grafts and then performed simultaneous pancreas-kidney transplantation. RESULTS Five days after transplantation, we noted a high titer of amylase in the ascites; therefore, we performed an urgent laparotomy. The origin of the amylase was the injured pancreatic parenchyma, and continued washing and drainage were carried out. We reconstructed the duodenojejunostomy using the Roux-en-Y technique to separate the passage of food from the pancreas graft to prevent injury to other organs due to exposure to pancreatic secretions. Thereafter, we inserted a decompression tube into the anastomosis thorough the blind end of the jejunum. Finally, we inserted 3 drainage tubes for lavage. Following this procedure, the patient recovered gradually and no longer required hemodialysis and insulin therapy. She was discharged from our hospital 56 days after transplantation. CONCLUSION The restoration of the injured graft was possible by management of pancreatic secretions and use of the donors vessel grafts. Shortage of donors is a problem throughout the world; thus, it is important to use injured grafts for transplantation if possible.