Kazushige Satoh

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.

Attenuation of cross-talk between the complement and coagulation cascades by C5a blockade improves early outcomes after intraportal islet transplantation.

Background. Complement 5a factor (C5a) elicits a broad range of proinflammatory effects, including chemotaxis of inflammatory cells and cytokine release. C5a is also linked to the coagulant activity in autoimmune diseases. Therefore, C5a most likely plays a crucial role in the instant blood-mediated inflammatory reaction. Methods. Intraportal transplantation of 2.5 islet equivalents/g of syngeneic rat islet grafts was performed in two groups of streptozotocin-induced diabetic rats: controls and C5a inhibitory peptide (C5aIP)-treated group. Results. The thrombin-antithrombin complex was significantly suppressed in the C5aIP group (P=0.003), and both the curative rate and the glucose tolerance were significantly improved in the C5aIP group (P<0.05 and P<0.005, respectively). Expression of tissue factor on granulocytes in recipient livers was up-regulated 1 h after islet infusion (P<0.0001), which was significantly suppressed by C5aIP (P<0.005). However, C5aIP was unable to regulate tissue factor expression on isolated islets. Furthermore, no differences were detected between the groups, regarding infiltration of CD11b-positive cells and deposition of C5b-9 on the islet grafts. Conclusions. These data suggest that C5aIP attenuates cross-talk between the complement and coagulation cascades through suppressing up-regulation of tissue factor expression on leukocytes in recipient livers but not on islet grafts, a process leading to improvement in islet engraftment. Therefore, C5aIP in combination with conventional anticoagulants could be a strong candidate strategy to control the instant blood-mediated inflammatory reaction induced in clinical islet transplantation.

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.

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.

Nonmarginal-Donor Duodenal Ulcers Caused by Rejection After Simultaneous Pancreas and Kidney Transplantation: A Case Report

OBJECTIVE Pancreas transplantation has been associated with the highest surgical complication rate among routinely performed organ transplant procedures. Complications can be caused not only from the pancreas itself but also from the simultaneously transplanted duodenum: gastrointestinal bleeding, duodenal ulcer, pseudoaneurysm, arterioenteric fistula, and severe rejection. Herein we report a patient who underwent simultaneous pancreas-kidney transplantation (SPKT) and experienced a duodenal perforation because of rejection. METHODS The 60-year-old man with insulin-dependent diabetes underwent SPKT with enteric drainage. At 15 days there after he displayed melena. RESULTS We suspected it to be caused by rejection and ischemic changes. We slightly increased the doses, of tacrolimus and methylprednisolone. But 17 days after SPKT, the ulcer perforated, requiring a repair operation and increased dose of mycophenolate mofetil. However, the ulcers perforated repeatedly, requiring 4 repair operations. Unfortunately the patient developed pneumonia that mitigated continues repairs or rejection therapies, so we expated the duodenum and pancreas but saved the kidney. The pathologic findings showed the ulcer to have been caused by severe rejection. Despite those episodes, the patient was weaned from hemodialysis. CONCLUSIONS Perforation of the transplanted duodenum is one of the most difficult complications among SPKT patients. This potentially lethal complication may be caused by mucosal rejection, ischemic changes, and the exocrine output from the pancreatic graft.

Rituximab therapy and reduction of immunosuppression to rescue graft function after renal posttransplantation lymphoproliferative disorder found by macrohematuria in a pancreas and kidney transplant recipient: a case report.

INTRODUCTION Posttransplantation lymphoproliferative disorder (PTLD) remains an uncommon complication of solid organ transplantation, with a high mortality rate reported after conventional therapies. Epstein-Barr virus (EBV) may cause PTLD, but most EBV infections after transplantation are clinically silent reactivations, so the detection of PTLD is often delayed. Recently we experienced the rare case of intrarenal graft PTLD found by macrohematuria in a simultaneous pancreas and kidney transplant recipient. The grafts were saved by treatments with rituximab, cyclophosphamide, hydroxydaunorubicin, and prednisone-based chemotherapy (R-CHOP) after reduction of immunosuppression (IR). METHODS This 37-year-old man with insulin-dependent diabetes underwent simultaneous pancreas and kidney transplantation (SPK) with enteric drainage. Six months after transplantation, he displayed macrohematuria, which we investigated by blood tests, computer tomography (CT) scan, positron emission tomography (PET)-CT, and magnetic resonance imaging, recognizing a tumor in the transplanted renal graft. An open biopsy showed a CD20-positive PTLD. We started treatments with IR, rituximab (375 mg/m(2), weekly for 2 cycles) and R-CHOP therapy: rituximab (375 mg/m(2)) plus CHOP every 3 weeks for 6 cycles. RESULTS IR and R-CHOP therapy achieved a complete remission (CR). CR has continued for 14 months at the time of writing. The maximum level of EBV DNA was 259 copies/μg DNA, but 2 months after these therapies, the level had decreased to normal. The patient had no impairment of pancreas and kidney graft functions. CONCLUSIONS The outcome of intragraft PTLD in the kidney of an SPK recipient suggested that the negative impact of IR on graft function may be compensated by the immunosuppressive effects of rituximab, allowing reduced immunosuppression during chemotherapy.

Two cases in one family of living donor liver transplantation for homozygous familial hypercholesterolemia

To the Editor: We experienced two pediatric patients homozygous for familial hypercholesterolemia (FH) who received living donor liver transplantation (LDLT) from their parents, who were heterozygous for FH. The elder brother presented orange cutaneous xanthomas and was diagnosed homozygous FH at the age of 1 year. The plasma lipidogram showed that total cholesterol was 898 mg/dl, LDL cholesterol was 756 mg/dl, and the triglycerides level was 60 mg/dl. Cardiac ultrasonography showed no abnormal findings. He and his father had the same gene mutation of the LDL receptor. There were no ABO-compatible living donors with a normal LDL receptor in their family, and it was difficult to find a deceased donor in Japan; thus, he underwent LDLT with his father as the donor. The donor was heterozygous for FH, but we speculated that after LDLT total cholesterol could be controlled with anticholesterol agents. The graft was the lateral segment, and he was administered methylprednisolone and tacrolimus as immunosuppressive therapy. His liver function tests (LFTs) normalized immediately after transplantation, and his cholesterol has remained controlled at about 280mg/dl with HMG-CoA reductase for 5 years after LDLT. His sister was born 2 years after his LDLT. The family had been well informed of the risk of having another baby heterozygous for FH. The plasma lipidogram showed that her total cholesterol was 857 mg/dl, LDL cholesterol was 689 mg/dl, and the triglycerides level was 173 mg/dl just after birth. She had symmetrical skin lesions on her hands. We informed the family that it was going to be very difficult to find a deceased donor, and the baby underwent ABO-incompatible LDLT with her mother as the donor at the age of 2 years. We performed plasma exchange twice before treatment to reduce the IgM and IgG hemagglutinin titers. One year after LDLT, her cholesterol remained stable at about 240mg/dl under treatment with HMG-CoA reductase. At present, the four patients, including the two donors, are leading a normal daily life. FH is a disease caused by a mutant gene on chromosome 19 coding for the structure of the LDL receptor.1 In the homozygous state, which occurs in only 1 in 1 million people, atherosclerosis progresses much more rapidly, producing cardiovascular disease and even causing death within the first two decades of life. LDL apheresis was introduced even for small children, but it has many difficulties such as long-term maintenance of blood access and a poor quality of life. Gene therapy has also been attempted, but it proved to be inefficient. Liver transplantation as a curative treatment for homozygous FH was introduced in 19842 because approximately 70% of LDL receptors are located in the liver. In Japan deceased donors are scarce, so LDLT is more feasible for homozygous FH.3 Our patients showed that LDLT from a heterozygous or even an ABO-incompatible donor is effective for patients with homozygous FH, provided they are maintained on cholesterol-lowering drugs after transplantation.

Improved quality of life and unchanged magnetic resonance brain imaging after living donor liver transplantation for late-onset ornithine transcarbamylase deficiency: report of a case.

We report the case of a 7-year-old girl with ornithine transcarbamylase deficiency whose quality of life (QOL) improved greatly after a living donor liver transplantation (LDLT). Ornithine transcarbamylase deficiency had been diagnosed when she was 2 years old and she finally underwent LDLT, with her father as the donor, when she was 7 years old. The patient had suffered episodes of hyperammonemic encephalopathy ranging from lethargy to coma, treated by hemodialysis twice before LDLT, and her intelligence quotient was borderline for her age. Preoperative magnetic resonance imaging (MRI) showed an atrophic area in the subcortical white matter of the frontal lobe. After LDLT, the patient suffered acute rejection with hyperamylasemia, but not hyperammonemia. Postoperative MRI and quantitative MR spectroscopy showed no changes in the subcortical lesion. She has been followed up carefully for 16 months and has had no further complications or any sign of hyperammonemia.

Obstructive jaundice caused by biliary stone formation around the stent after liver transplantation

Abstract:  We report an unusual case of obstructive jaundice caused by a biliary stone, which developed in the stump of a Roux‐en‐Y hepaticojejunostomy after undergoing LT. The patient was a 13‐yr‐old male. At 74 days after birth, a hepaticojejunostomy (Kasais procedure) was performed for the treatment of biliary atresia. He underwent a reduced size deceased donor LT in the left subphrenic space twice at the age of one and three years in Australia. Eleven years after his second LT, he developed liver dysfunction and jaundice with a low grade fever. Computed tomography showed a marked jejunal loop enlargement by a rugby ball‐shaped stone and the bile duct in the graft was thus dilated. A surgical exploration revealed the jejunal loop to be bent sharply while its stump side was dilated by stagnated bile including a biliary stone. The stone included a stent that had been previously used for the hepaticojejunostomy. This case suggests that a retained stent used for hepaticojejunostomy had thus caused biliary stone formation because of a combination of various conditions in the jejunal loop.