T. Kashiwadate

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.

A new liver graft preparation method for uncontrolled non-heart-beating donors, combining short oxygenated warm perfusion and prostaglandin E1

BACKGROUND To resolve the shortage of donors associated with liver transplantation, the potential uncontrolled non-heart-beating donor (UNHBD) pool is expected to increase. However, warm ischemia-reperfusion injury leads to inferior survival in transplantation using the grafts from UNHBD compared with those from heart-beating donors. To overcome this problem, we developed a new method for preparation of liver grafts from UNHBDs consisting of a combination of short oxygenated warm perfusion (SOWP) and prostaglandin E1 (PGE1). METHODS Using an ex vivo perfusion rat model, we examined the effectiveness of this new method. RESULTS Using SOWP and PGE1 treatment, the total amount of bile production during reperfusion in UNHBD grafts was increased to the same level as that in the heart-beating donor grafts. The addition of PGE1 to SOWP buffer decreased aspartate aminotransferase/alanine aminotransferase and tumor necrosis factor α levels during 1 h of reperfusion. Necrosis and apoptosis were significantly decreased by SOWP + PGE1 treatment. SOWP + PGE1 ameliorated induction of mitochondrial permeability transition, and the total amount of mitochondrial cytochrome c in the SOWP + PGE1 group after reperfusion was kept significantly higher than that in the no treatment group. Cytosolic c-Jun N-terminal protein kinase activation was significantly suppressed by SOWP + PGE1. Decrease in mitochondrial Bcl-2 was suppressed by SOWP alone and SOWP + PGE1 treatment, and Bax in the mitochondria was significantly suppressed by SOWP + PGE1. CONCLUSION SOWP and PGE1 prior to cold preservation significantly improved the function of liver grafts that underwent warm ischemia-reperfusion injury. Therefore, this method might be useful in liver transplantation using UNHBD grafts.

Recombinant Human Soluble Thrombomodulin (ART-123) Prevents Warm Ischemia-Reperfusion Injury in Liver Grafts from Non-Heart- Beating Donors

BACKGROUND Liver transplantation is an established treatment for end-stage liver disease. However, an ongoing problem worldwide concerning this treatment is the shortage of grafts. Although transplantation using grafts from non-heart-beating donors (NHBDs) is considered a promising solution, some researchers have reported that these liver grafts are associated with primary graft nonfunction and biliary complications. The purpose of this study was to establish a safe technique procuring liver grafts from marginal donors such as NHBDs. MATERIALS AND METHODS Male Wistar rats were divided into three groups: (1) the heart-beating (HB) group, whose livers were retrieved from HB donors; (2) the non-HB (NHB) group, whose livers were retrieved from NHBDs that had experienced an apnea-induced agonal condition (for this group, livers were subjected to warm ischemia for 30 minutes after cardiac arrest); and (3) the recombinant human soluble thrombomodulin (ART-123) group, whose livers were retrieved in the same manner as the NHB group but pretreated with ART-123 (1 mg/kg) at the agonal stage. The livers were reperfused for 60 minutes with oxygenated Krebs-Henseleit bicarbonate buffer after cold preservation for 6 hours. RESULTS Bile production and portal flow volume in the ART-123 group were significantly higher than those in the NHB group. Alanine aminotransferase levels in the ART-123 group were significantly lower than those in the NHB group. Histological findings showed the narrowing of sinusoidal spaces and necroses in the NHB group were more severe than those in the ART-123 group. CONCLUSIONS These results suggest that thrombomodulin may improve the viability of liver grafts from NHBDs.

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.

Pretransplant HbA1c Is a Useful Predictor for the Development of New-Onset Diabetes in Renal Transplant Recipients Receiving No or Low-Dose Erythropoietin.

Aims. To evaluate the predictive power of pretransplant HbA1c for new-onset diabetes after transplantation (NODAT) in kidney transplant candidates, who had several predispositions for fluctuated HbA1c levels. Methods. We performed a retrospective study of 119 patients without diabetes who received kidney transplantation between March 2000 and January 2012. Univariate and multivariate logistic regression analyses were used to investigate the association of several parameters with NODAT. Predictive discrimination of HbA1c was assessed using a receiver-operating characteristic curve. Results. Seventeen patients (14.3%) developed NODAT within 1 year of transplantation. Univariate logistic regression analysis revealed that recipient age, gender, and HbA1c were predictors of NODAT. In the multivariate analysis, the association between pretransplant HbA1c and NODAT development did not reach statistical significance (P = 0.07). To avoid the strong influence of high-dose erythropoietin on HbA1c levels, we performed subgroup analyses on 85 patients receiving no or low-dose (≤6000 IU/week) erythropoietin. HbA1c was again an independent predictor for NODAT. Receiver-operating characteristic analysis revealed a cut-off value of 5.2% with an optimal sensitivity of 64% and specificity of 78% for predicting NODAT. Conclusions. Our results reveal that the pretransplant HbA1c level is a useful predictor for NODAT in patients receiving no or low-dose erythropoietin.

Soluble Thrombomodulin Ameliorates Ischemia-Reperfusion Injury of Liver Grafts by Modulating the Proinflammatory Role of High-Mobility Group Box 1

Transplantation using grafts obtained after cardiac death (CD) is considered a promising solution for graft shortages. However, no standard criteria for organ preservation have been established for CD donors. High-mobility group box 1 (HMGB1) is a DNA-binding protein that is released from dying hepatocytes as an early mediator of inflammation and organ tissue damage. HMGB1 stimulates immunocytes to produce inflammatory cytokines, thereby amplifying the inflammatory response. Thrombomodulin is an integral membrane protein that functions as an endothelial anticoagulant cofactor, and it binds HMGB1 through the extracellular domain. We investigated the effects of ART-123, recombinant human soluble thrombomodulin, on warm ischemia-reperfusion injury in liver grafts. Male Wistar rats were divided into four ex vivo groups: heart-beating (HB) group, in which livers were isolated from HB donors; CD group, in which livers were isolated from CD donors exposed to apnea-induced conditions and warm ischemic conditions for 30 min after cardiac arrest; and two CD groups pretreated with ART-123 (1 or 5 mg/kg). Each isolated liver was reperfused for 1 h after cold preservation for 6 h. The perfusate levels of HMGB1, LDH, TNF-α, and IL-6 were significantly lower in the CD group pretreated with ART-123 (5 mg/kg) than in the CD group. Bile production was significantly higher in the CD group pretreated with ART-123 (5 mg/kg) than in the CD group. The sinusoidal spaces were significantly narrower in the CD group than in the other groups. We propose that ART-123 maintains sinusoidal microcirculation by reducing endothelial cell damage during warm ischemia-reperfusion injury.

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.

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.

Limited utility of blood cultures in the management of febrile outpatient kidney transplant recipients

BACKGROUND/PURPOSE Blood cultures for patients suspected of having bacteremia are standard practice, although several studies demonstrate that blood cultures have limited utility because of a low true-positive rate and infrequent resultant changes in antibiotic treatment. However, most reports exclude immunocompromised patients such as transplant recipients. We assessed the utility of blood cultures in transplant recipients hospitalized for community-acquired infections and evaluated clinical characteristics to predict bacteremia. METHODS This retrospective study included 136 febrile cases in 97 kidney transplant recipients admitted to our hospital for whom blood cultures were performed between February 2001 and March 2013. RESULTS Among the 136 cases, blood cultures were positive, contaminated, and negative in seven (5.1%) cases, 12 (8.8%) cases, and 117 cases (86.1%), respectively. All bacteria detected in the seven cases were sensitive to the initial empirical antibiotics. Antibiotic treatment was changed based on the blood culture results only in one case for which the coverage was narrowed. The white blood cell count and C-reactive protein level were significantly higher in the patients with bacteremia. The predictive model based on these two factors successfully identified the high-risk group with a sensitivity and specificity of 86% and 91%, respectively. CONCLUSION Among the outpatient kidney transplant recipients, positive blood cultures were uncommon and scarcely affected antibiotic therapy, especially in patients with upper respiratory tract or urinary tract infections. Therefore, it may be reasonable to perform blood cultures only for patients with marked leukocytosis and high C-reactive protein level, even among transplant recipients.