Yorihiro Akamatsu

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.

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.

Liver transplantation for severe hypoxemia caused by patent ductus venosus

The authors describe the case of a 9-year-old girl who underwent liver transplantation because she suffered from severe hypoxemia caused by patent ductus venosus (PDV). Generally, severe hypoxemia (PaO2 < 50 mm Hg in room air or < 300 mm Hg in pure oxygen) is not an indication for liver transplantation because the hypoxemia may not be improved, and may lead to a fatal outcome. PDV, which is associated with mild liver dysfunction, is not an indication for liver transplantation by itself. But in our patient, most of the mesenteric venous flow directly entered the systemic circulation through the PDV just like the portosystemic shunt, and this caused the pulmonary arteriovenous shunt and hypoxemia. Thus, the authors operated on the patient in an attempt to restore her pulmonary function. Nitric oxide (10 to 20 ppm) was added to the inhaled gas to dilate the functional pulmonary capillaries and to deliver sufficient oxygen after the transplantation. Although the patient suffered various complications after the operation, the final results were excellent.

The Significance of Preserving the Energy Status and Microcirculation in Liver Grafts from Non-Heart-Beating Donor:

To complete a successful liver transplantation (LTx) from non-heart-beating donors (NHBD), it is necessary to both improve the energy status in liver grafts and to reduce the exposure to free radicals. This study investigated the effects of short perfusion with oxygenated buffer on the grafts prior to cold preservation. In addition, the effects of the antioxidant, biliverdin, for reduction of free radicals was investigated. Male Wistar rats were used. Livers were retrieved, preserved in UW solution, and perfused for 60 min with oxygenated Krebs-Henseleit solution. Rats were allocated to six groups as follows (n = 5): i) control group—no warm ischemia (WI) and cold preservation, ii) HBD group—no WI with cold preservation for 6 h; iii) NHBD group—with 30 min of WI and cold preservation, iv) NM group—with WI including nafamostat mesilate infusion before cardiac arrest and cold preservation; v) PRE group—with WI, 30-min pre-cold preservation perfusion with oxygenated buffer after cardiac arrest, and cold preservation, vi) BV group—with the same treatment as the PRE group plus the addition of biliverdin to the pre-cold preservation perfusion. The portal flow volume, bile production, AST, and TNF-α in perfusate, energy charge (EC), and ATP level in the tissue, and histological findings were investigated. The portal flow volume in the NM, PRE, and BV groups were higher than in the NHBD group. The bile production in the PRE and BV groups were also higher than in the NHBD group. The EC and ATP level of the BV group after reperfusion were higher than those of the NHBD group. Pre-cold preservation perfusion and addition of biliverdin to perfusate improved viability of grafts from NHBD. The results indicate that the preservation of the energy status and microcirculation of the graft is important for successful LTx from NHBD.

Quality of Life and Problems Affecting Recipients More Than 10 Years After Living Donor Liver Transplantation

BACKGROUND We initiated living donor liver transplantation (LDLT) in 1991, allowing us to examine issues related to long-term survival. The aim of this study was to review the long-term outcomes of LDLT in children. PATIENTS AND METHODS We performed 116 LDLT from 1991 to present, including 17 recipients who survived >10 years. They were evaluated for growth, immunosuppressive therapy, complications, and quality of life (QOL). RESULTS The average age at LDLT was 5.4 years (range, 6 months to 17 years), with a present average age of 17.2 years (range, 11-28 years). At the time of LDLT, 6 recipients had growth retardation with body weights low for age by 2 standard deviations (SD). However, 4 of 6 recipients who underwent LDLT before age of 2 years caught up, reaching average heights and body weights for their ages. Among 6 recipients who were diagnosed with acute rejections by biopsy >5 years after LDLT, 5 improved after steroid pulse therapy. One recipient with a steroid-resistant acute rejection was administered deoxyspergualin after steroids. Chronic rejection was not observed in this series. One recipient has not required immunosuppressive therapy for >4 years with a good present condition. CONCLUSION The majority of LDLT recipients achieved a good QOL during long-term survival; they are pursuing normal studies.

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.

Long-term outcome of ABO-incompatible living-donor liver transplantation: a single-center experience

PURPOSE We report the long-term outcome of ABO-incompatible living donor liver transplantation (LDLT) performed in our hospital. METHODS We started the LDLT program in 1991 and from that year up to now (2008) 11 patients have received an ABO-incompatible graft. RESULTS Nine out of the 11 cases have survived from 3.7 years to 13.9 years (mean 7.3 years) and they are in good conditions at present. Seven patients were subjected to preoperative apheresis. Eight patients experienced acute rejection and of them, 6 experienced steroid-resistant rejection that was treated with deoxyspergualin and apheresis. One patient who suffered rapidly progressing rejection died due to liver failure. Three patients who were administered rituximab did not suffer severe rejection nor adverse effects. During the long-term follow up 5 recipients had major complications such as postoperative lymphoproliferative disease, post-transplantation diabetes mellitus, portal vein occlusion and biliary stenosis. But those complications were controlled under stable conditions. CONCLUSIONS We concluded that long-term survival can be expected after ABO-incompatible LDLT provided perioperative complications such as humoral rejection are overcome.

Management of Anti-allogeneic Antibody Elimination by Apheresis in Living Donor Liver Transplantation

Abstract:  In this study, we report on the indications and efficacy of the elimination of antiallogeneic antibodies in living donor liver transplant recipients. Seven patients incompatible with the ABO‐blood type were subjected to apheresis before transplantation. The procedure resulted in titers being decreased to less than a score of 8. After transplantation, apheresis was also performed in 6 cases and continuous hemodiafiltration in 1 case. In addition, three out of 11 ABO‐blood type incompatible recipients were administered anti‐CD20 antibody (rituximab). Two crossmatch positive patients were subjected to apheresis before transplantation, and in these cases the titers were reduced to less than a score of 2. Moreover, these two patients had no acute rejections after transplantation. We concluded that apheresis is effective for preventing acute rejection induced by pre‐existing anti‐A and/or anti‐B antibodies, as well as antidonor specific antibodies, but is not effective in some patients who had accelerated humoral rejection.

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.

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.