Tatsuya Fukumori

The mechanism of injury in a steatotic liver graft during cold preservation.

BACKGROUND Fatty livers are more prone to primary nonfunction after transplantation. It is known that cell injury is strongly associated with alterations in the content and composition of membrane lipids. We assumed that plasma membrane (PM) fluidity, which is the most important property of the membrane, differed between fatty and normal livers. METHODS The livers from obese and lean Zucker rats were flushed with cold Ringers lactate and University of Wisconsin (UW) solution via the portal vein and preserved in cold UW solution for 24 hr. Histological examinations of electron microscopy were performed to investigate of sinusoidal lining cells (SLCs). PMs were isolated using a discontinuous density gradient of Percoll, and the lipid compositions were determined by chromatography. RESULTS SLCs of fatty livers were markedly injured compared with control livers even after short preservation time. Moreover, many blebs were observed in the obese rats even after short preservation time. As for PM lipid composition, the cholesterol/phospholipid (PL) ratio of total PM was 0.14+/-0.03 in the obese rats and 0.21+/-0.03 in the lean rats (P<0.05). The relative proportions of polyunsaturated fatty acids among PLs in PM were 35.7+/-1.2% vs. 45.9+/-1.5% (P<0.0001). These results indicated that the fluidity of the PM in the obese rats is decreased after exposure to low temperatures. CONCLUSIONS Our results suggest that steatotic livers from obese donors are more susceptible to cold preservation injury than livers without steatosis because of the severe deterioration of SLCs, and it is associated with PM fluidity even after short-term cold preservation.

Successful use of anti-CD20 monoclonal antibody (rituximab) for ABO-incompatible living-related liver transplantation

Background. Humoral rejection after ABO-incompatible liver transplantation often causes graft loss and a life-threatening situation. We used rituximab, which can eliminate B cells highly selectively, as an additional therapy for ABO-incompatible living-related liver transplantation. Cases. Patient 1 was a 1-year-old girl with biliary atresia. Her blood type was O, and the donor’s was A. She underwent two plasma exchanges before liver transplantation and had triple immunosuppressants (mycophenolate mofetil, tacrolimus, and methylprednisolone). She was diagnosed with humoral rejection by needle biopsy on postoperative day 6. Rituximab was used for 3 days at 375, 187, and 187 mg/m2 and successfully reduced the antibody titer, transaminase, and CD19+ cells count in peripheral blood lymphocytes. The patient has not had any severe rejection, infection, or serious complications 2 years posttransplantation. Patient 2 was a 42-year-old woman with primary biliary cirrhosis. The blood type was O, and the donor’s was B. She received three plasma exchanges, triple immunosuppressants, splenectomy, intraarterial anticoagulant therapy, and rituximab (375 mg/m2 immediately after transplantation). The titer and CD19+ cells count remained persistently low throughout the recovery course. She did not develop humoral rejection 1 year after transplantation. Conclusions. Rituximab efficiently reduces anti-ABO antibody titer by selectively eliminating B cells and is safe and effective against humoral rejection after ABO-incompatible liver transplantation.

Use of older controlled non-heart-beating donors for liver transplantation.

Background. Use of liver grafts from non–heart-beating donors (NHBDs) warrants consideration so to expand the donor pool. Because the results of controlled NHBDs (CNHBDs) were acceptable, we have recently tried to expand the criteria to older CNHBDs. Here, we report our experience using liver grafts from older CNHBDs. Methods. We retrospectively studied our donor records from June 1994 through December 2001. CNHBDs were divided into two groups by age: older donors (O) were more than or equal to 55 years old, and younger donors (Y) were less than 55 years old. We compared donor and recipient demographics and peak laboratory values during the first postoperative week. Results. Twenty-five grafts from CNHBDs were transplanted in our center. Five livers were harvested from O (63±6 years) and 20 were from Y (32±15 years). No differences other than age in donor characteristics were noted between O and Y. Mean age of recipients was 50 years in both groups. Mean cold ischemic time (CIT) was 5.4 hours in O and 7.3 hours in Y (P <.05). Peak glutamic oxaloacetic transaminase (U/L), glutamic pyruvic transaminase (U/L), bilirubin (mg/dL), and prothrombin time (sec) during the first postoperative week were 611, 500, 3.9, and 16 in O and 846, 593, 5.9, and 17 in Y. There were no significant differences between the two groups. The graft survival at 1 year was 80% in O and 70% in Y. Conclusions. In our preliminary experience, recipients of liver grafts from older CNHBDs had an outcome equivalent to that of younger CNHBDs. With the strict evaluation of the donors and brief CIT, liver grafts from older CNHBDs may be used to expand the donor pool.

Risks of donation and quality of donors’ life after living donor liver transplantation

The purpose is to clarify risks of donation and quality of the donors life after living‐related donor liver transplantation (LDLTx). Sixty‐eight donors were classified into four groups: lateral segment group (n = 30); left lobe group (n = 18); left lobe with the middle hepatic vein group (n = 11); right lobe group (n = 9). We investigated (i) the risks of donation, and evaluated the following: blood loss, operation time, postoperative liver function and duration of hospitalization; (ii) quality of donors’ life: donors were mailed a structured questionnaire and the Short‐Form Health Survey (SF‐36), a generic measure assessing quality of life using eight scales. The results were: (i) there were no differences in liver function and duration of hospitalization between four groups; (ii) 48 donors (71%) responded. All donors returned to normalcy. The donors did not regret their decision to donate except two cases whose recipients had died. The donors’ life was almost guaranteed regardless of the lobe we used as the graft.

Elimination of Kupffer cells and nafamostat mesilate rinse prevent reperfusion injury in liver grafts from agonal non-heart-beating donors.

BACKGROUND We hypothesized that microcirculatory disturbance was an obstacle to liver transplantation (LTx) from non-heart-beating donors (NHBDs) and that it was attributed mainly to a deterioration of sinusoidal endothelial cells (SECs) and sinusoidal narrowing. This study was designed to examine porcine orthotopic LTx using livers obtained from pretreated agonal NHBDs, and to determine whether the maintenance of the liver microcirculation would result in successful LTx from agonal NHBDs. METHODS Pigs were allocated to five groups: (i) control group; (ii) NM group, in which grafts were rinsed with nafamostat mesilate (NM) rinse; (iii) LD group, in which Kupffer cells in grafts were eliminated by liposome-encapsulated dichloromethylene diphosphonate (L-DMDP); (iv) LDNM group, in which grafts pretreated with L-DMDP were rinsed with NM rinse; (v) heart-beating donor (HBD) group. In all groups, but the HBD group, the livers were pretreated with FK506 and prostaglandin I2 analogue, and were preserved in University of Wisconsin solution after cardiac arrest. Thereafter orthotopic LTx was performed. RESULTS After reperfusion, it was histologically demonstrated that elimination of Kupffer cells prevented SECs deterioration and NM rinse prevented sinusoidal narrowing. The hepatic energy charge recovered in all groups except the control group. In the LDNM group, three of four recipients survived more than 7 days. CONCLUSIONS For a successful LTx from agonal NHBDs, it is important to prevent microcirculatory disturbance caused by SEC deterioration and sinusoidal narrowing after reperfusion. Combination therapy consisting in the elimination of Kupffer cells and NM rinse prevented primary graft non-function in liver grafts from agonal NHBDs.

Host-derived enterocytes in intestinal grafts.

Replacement of donor lymphoid tissue by lymphocytes of recipient origin is an established phenomenon in small bowel transplants. However, replacement of donor epithelial cells of bowel grafts by host cells has not been demonstrated. The objective of our study was to determine whether donor enterocytes are replaced by host-derived enterocytes in the intestinal allograft. Graft biopsy specimens, obtained from five human male recipients of female intestine, were examined for the presence of male enterocytes. The biopsies dated from 90 to 770 days posttransplant. Formalin-fixed 3-microm specimen sections were stained for X and Y chromosomes by fluorescent in situ hybridization technique. Fluorescent microscopy of the stained sections identified male enterocytes in four patients, with a percentage of male cells ranging from 0.09% to 0.26% of the total enterocyte mass. Using the fluorescent in situ hybridization technique, we demonstrated the presence of host-derived male (XY) enterocytes in the female intestinal graft.

Efficacy of a liver resection for hepatocellular carcinoma in patients with chronic renal failure

PurposeAs there is still little information available on hepatic resection in patients with chronic renal failure (CRF) in the literature, it is believed that a liver resection for HCC in CRF patients with various related complications is always risky.MethodsWe retrospectively reviewed the clinical and pathological records of 17 patients with CRF who had undergone hepatectomy for HCC, and of 51 non-CRF patients subjected to hepatectomy for HCC during the same period.ResultsThe operative and pathological findings were comparable between the two groups. Postoperative circulatory insufficiency occurred more frequently in the CRF group (P = 0.013). Although the disease-free survival rates were comparable between the two groups, the overall survival rates were significantly lower in the CRF group than in the non-CRF group (P = 0.031).ConclusionsA hepatectomy for HCC should be considered even for CRF patients with various complications if careful perioperative management and suitable multidisciplinary treatment for recurrent disease are provided.

Mechanism of primary graft non-function in a rat model for fatty liver transplantation

Abstract We established a fatty liver model in rat suitable for the model of human liver with steatosis by cholesterol enriched chow, and investigated the mechanism of primary graft non‐function in fatty liver transplantation (LTx) using this model. Grafts with steatosis caused primary graft dysfunction after LTx following even short cold preservation; however, no significant difference was recognized in mitochondrial function of the graft during preservation. Morphological findings were not different at 1 h after reperfusion between non‐steatotic and steatotic livers. Focal necrosis of hepatocytes was seen and the sinusoidal endothelial cells were injured 24 h after reperfusion. In addition, the fluidity of the plasma membrane decreased in fatty liver. Our results indicate that deterioration of sinusoidal endothelial cells after reperfusion causes graft dysfunction in LTx of steatotic liver.

Pneumonia Due to Varicella-Zoster Virus Reinfection in a Renal Transplant Recipient

Varicella pneumonia is one of the serious complications of primary varicella zoster virus (VZV) infection in adults. A 36-year-old woman with end-stage renal disease underwent renal transplantation from a living donor in 1998, receiving immunosuppressive treatment with cyclosporine, mycophenolate mofetil, and methylprednisolone. She had a history of VZV infection during childhood. The patient developed an intractable cough on December 10, 2006, but there were no abnormalities in the laboratory data or chest radiograph for several weeks. On January 1, 2007, she was admitted to our hospital with cutaneous vesicles covering the entire body. We learnt that when her symptoms developed, her son was diagnosed with varicella. The chest radiograph at this stage showed a diffuse miliary pattern in the entire lung field. We started intravenous administration of acyclovir. VZV antigen was detected in the cutaneous lesions and VZV antibody in the serum after the start of these treatments, so we continued to administer acyclovir for 18 days. The cutaneous lesions healed and the pneumonia improved based on the chest radiograph. She was discharged from the hospital on January 19, 2007. In conclusion, this report documents VZV reinfection in a transplant patient.

A Free Radical Scavenger, Edaravone, Prevents Ischemia-Reperfusion Injury in Liver Grafts From Non–Heart-Beating Donors

BACKGROUND Due to the increase in liver transplantation, the donor shortage has become a serious problem, requiring marginal, non-heart-beating donors (NHBDs). The aims of this study were to evaluate the cytoprotective effect of edaravone, a free radical scavenger, on warm ischemia-reperfusion (I/R) injury of liver grafts from NHBDs. METHODS Rat livers were harvested from heart-beating donors (HB group) or from NHBDs undergoing cardiac arrest for 30 minutes led by thoracotomy (NHB group), and reperfused for 60 minutes with Krebs-Henseleit bicarbonate buffer after cold preservation for 6 hours. In another group (ED group), warm ischemic livers from NHBDs were reperfused with buffer containing edaravone (1 mg/L) after cold preservation. RESULTS In the ED group, portal flow volume, bile production, and energy charge were significantly ameliorated. Lipid peroxidation, elevation of hepatic enzymes, and release of tumor necrosis factor-alpha and interleukin-1 beta were significantly alleviated, compared with the NHB group. CONCLUSIONS These results suggested that edaravone has suppressive effects on warm I/R injury in liver grafts from NHBDs.