Hideaki Okajima

Current status of organ transplantation in Japan and worldwide

Recent advances in immunosuppressant therapy have dramatically reduced the frequency of acute rejection of organ transplants. Subsequently, the short-term graft survival rate has been improved, and ABO blood type-incompatible and existing anti-HLA antibody-positive kidney transplantation has been enabled, which has increased the availability of living kidney donors. Japan has a unique history and strategies of liver transplantation (LT) for various liver diseases. The outcomes of living donor liver transplantation (LDLT) in Japan is comparable to that of deceased donor liver transplantation (DDLT) in Western countries despite the relatively short history of LT. The main disadvantage of LT in Japan is donor shortage mainly due to the small number of available deceased donors. There are some disadvantages with LDLT in autoimmune liver diseases because of the dependence on blood relative donors. The first brain-dead pancreas transplantation (PTx) was performed in 2000. Since that time, 42 brain-dead PTx, 2 non-heart beating PTx, and 14 living donor PTx had been performed by the end of 2007. One of the 44 recipients of deceased donor PTx died of unknown causes 11 months after transplantation. Although most of the deceased donors in Japan were marginal and their condition was not favorable, the results of these cases were comparable to those of Western countries. Fourteen intestinal transplantations (ITx) had been performed by the end of 2007 in four transplant centers. There were 3 deceased donor and 11 live donor transplants. The original diseases included short bowel syndrome (n = 6), intestinal function disorder (n = 6), and retransplantation (n = 2). The graft and patient survival rate are 60% and 69%, respectively. Eight recipients survived and stopped parenteral nutrition with full-functioning grafts. Amendment of the Japanese law for the utilization of deceased donors should increase the number available donors in the future.

Coefficient factor for graft weight estimation from preoperative computed tomography volumetry in living donor liver transplantation

In the clinical setting of living donor liver transplantation (LDLT), it is common to find a discrepancy between the graft volume estimated by preoperative computed tomography volumetry and the actual graft weight (AGW) measured on the back‐table. In this study, we attempt to find the coefficient factor that correlates the estimated graft volume to the AGW. Whole livers explanted in 25 LDLT recipients (17 cirrhotic and 8 morphologically normal with familial amyloid polyneuropathy) were evaluated to compare cirrhotic livers and noncirrhotic normal livers. In addition, right lobe grafts (n = 39) and left lobe grafts (n = 35) used in LDLTs were also evaluated to further determine the correlation between estimated graft volume and AGW. The correlation coefficient between estimated liver volume and actual liver weight was 1.01 in whole cirrhotic livers, whereas it was 0.85 in whole livers with familial amyloid polyneuropathy. In the partial liver grafts, it was 0.84 in right lobe grafts and 0.85 in left lobe grafts. In conclusion, we suggest that a correlation coefficient of 0.85 should be applied for the accurate calculation of the graft weight from the volume estimated by preoperative computed tomography in LDLT. Liver Transpl, 2011.

The Efficacy and Safety of High-Dose Mizoribine in ABO-Incompatible Kidney Transplantation Using Anti-CD20 and Anti-CD25 Antibody Without Splenectomy Treatment

BACKGROUNDnMizoribine (MZR) has been developed as an immunosuppressive agent in Japan, but it shows less potent immunosuppressive effects at doses up to 3 mg/kg/d. In this study, we investigated whether high-dose MZR (6 mg/kg/d) was effective for ABO-incompatible (ABO-i) living donor kidney transplantation (LKT) using treatment with anti-CD25 and anti-CD20 monoclonal antibodies without splenectomy.nnnMETHODSnSince 2007, we encountered 24 cases of ABO-i LKT using anti-CD20 and anti-CD25 monoclonal antibody without splenectomy. The pretransplant immunosuppressive regimen consisted of two doses of anti-CD20 antibody, mycophenolate mofetil (MMF), prednisolone, a calcineurin inhibitor (cyclosporine [7 mg/kg] or tacrolimus [0.2 mg/kg] and two doses of anti-CD25 antibody. Antibody removal by plasmapheresis was performed before LKT up to several times according to the antibody titer. The posttransplant regimen consisted of high-dose mizoribine (6 mg/kg/d) instead of MMF (MZR group, n = 12).nnnRESULTSnThe 1-year graft survival rates for the MZR and MMF groups were both 100%. The rejection rate in the MZR group (eight %) was not significantly higher than that in the MMF group (seventeen %) Serum creatinine level was not significantly different between the two groups. In the MZR group 6 (50%) patients developed CMV antigenemia-positivity versus 11 (92%) in the MMF group (P < .05). The number of patients who developed CMV disease was 0 in the MZR group and 1 (8%) in the MMF group. The number of patients treated with ganciclovir was 0% and 8%, respectively (not significant).nnnCONCLUSIONSnWe obtain good clinical results with high-dose MZR in ABO-i LKT using anti-CD20 and anti-CD25 antibody treatment without splenectomy.

Fatty liver and anti-oxidant enzyme activities along with peroxisome proliferator-activated receptors γ and α expressions in the liver of Wilson's disease

BACKGROUNDnThe mechanisms of liver damage and steatosis in Wilsons disease (WD) presenting accumulation of copper generating oxidants remain unclear. Recent studies have shown that peroxisome proliferator-activated receptors (PPARs), in particular PPARs α and γ, regulate fat content of the liver together with the anti-oxidant and anti-inflammation systems. However, such PPARs have never been studied in WD.nnnMETHODSnWe examined PPARs along with the liver damage and steatosis of WD using liver specimens from affected patients exhibiting mild liver damage (group I, n = 5), moderate or greater liver damage (group II, n = 10) and fulminant hepatic failure (group III, n = 5), and from asymptomatic carriers (group H, n = 4).nnnRESULTSnPPAR α expression was increased over the control levels in groups H and I but was decreased in groups II and III in parallel with the progression of liver damage (group H = I>II>III). PPAR γ expression was inversely increased (group H<I<II<III). Mn-dependent superoxide dismutase (Mn-SOD), CuZn-SOD, and catalase activities were decreased in the affected three groups, and were increased in group H. Among group II exhibiting substantial inter-individual variances in parameters, the severity of steatosis showed a significant positive correlation with PPAR γ expression (p<0.001) but not PPAR α expression. CuZn-SOD activity was positively correlated with PPARα expression (p<0.05) but not PPAR γ expression.nnnCONCLUSIONnThese results suggest that changes of PPARs γ and α are associated with the steatosis and the impairment of anti-oxidant system in the liver of WD.

Percutaneous transluminal venoplasty after venous pressure measurement in patients with hepatic venous outflow obstruction after living donor liver transplantation

PurposeThe aim of this study was to evaluate retrospectively the outcome of percutaneous transluminal venoplasty (PTV) after venous pressure measurement in patients with hepatic venous outflow obstruction following living donor liver transplantation (LDLT).Materials and methodsWe studied 24 consecutive patients suspected of having hepatic venous outflow obstruction after LDLT. Pressure gradients were measured proximal and distal to the lesion, and gradient values >3 mmHg were considered hemodynamically significant. We evaluated the technical success, complications, outcome of venoplasty and recurrence, and the patency rate.ResultsIn all, 11 female patients manifested a pressure gradient >3 mmHg across the anastomotic site; they underwent subsequent PVT. The initial balloon venoplasty procedure was technically successful in 10 of the 11 patients (91%), and the pressure gradient was reduced from 5.8 to 1.1 mmHg (P < 0.01). Clinical improvement was observed in 9 of these 10 patients; one patient failed to improve and underwent retransplantation. Recurrent obstruction occurred in four patients; they underwent PTV with (n = 2) or without (n = 2) stent placement. There were no major procedural complications.ConclusionPTV following venous pressure measurement is an effective and safe treatment for venous outflow obstruction in patients subjected to LDLT. In patients with recurrent obstruction, re-venoplasty is recommended.

The Excellent Outcomes of ABO-Incompatible Kidney Transplantation With High Titer (>×2048) Using Anti-CD20 and Anti-CD25 Antibody Without Splenectomy: Two Case Reports

BACKGROUNDnDue to the shortage of deceased donors, we have expanded the indications for living-donor kidney transplantation (LKT) to include ABO-incompatible (ABO-i) individuals. However, which patients with high-titer anti-blood-group antibody can be transplanted successfully is unclear.nnnMETHODSnSince 2009 we have performed 2 high-titer ABO-i spousal LKT using anti-CD20 and anti-CD25 monoclonal antibody without splenectomy. In both cases, anti-type A antibody was 2048-fold before antibody removal. The immunosuppressive regimen consisted of 2 doses of anti-CD20 antibody (200 mg/body, day -14 to day -7), mycophenolate mofetil (1000 mg), prednisolone (10 mg starting from day -14), calcineurin inhibitor (cyclosporine [7 mg/kg] or tacrolimus [0.2 mg/kg] starting from day -7), and 2 doses of anti-CD25 antibody (20 mg/body, days 0 and 4). Antibody removal by plasmapheresis was performed up to 4 times before LKT according to the antibody titer. The posttransplantation regimen consisted of mycophenolate mofetil or mizoribine as antimetabolite. A protocol biopsy was performed at 1 month and 1 year after LKT.nnnRESULTnThe 60- and 62-year-old men had renal graft transplantation performed in the right hemipelvis without complication. After LKT, urinary output and serum creatinine decrease were within acceptable ranges without evidence of an acute rejection episode for 12 and 7 months, respectively. Patient and graft survival rates were 100%. A protocol biopsy at 1 month after LKT showed additional treatment to be unnecessary. Serious viral infection was not seen, even in the 1 patient who temporarily experienced positive changes in cytomegalovirus antigenemia.nnnCONCLUSIONSnWe obtained good clinical results among 2 high-titer ABO-i LKT using anti-CD20 and anti-CD25 antibodies without splenectomy, in conjunction with a calcineurin inhibitor plus mycophenolate mofetil or mizoribine.

Re-evaluation of the indications for liver transplantation in Wilson's disease based on the outcomes of patients referred to a transplant center.

The aim of this study was to re‐evaluate the indications and timing of LT for WD. From 2000 to 2009, eight patients with WD who had been referred to our institution for LT were enrolled in this study. The mean patient age was 15.9 yr (range, 7–37 yr). Four patients could not receive LT, because there were no available donors. All four patients were treated with chelating agent medication. Three of them (two of two patients with fulminant WD and one of two with cirrhotic WD) who did not undergo LT are still alive and doing well with stable liver functional tests. Only one of the patients with cirrhotic WD who did not undergo LT died of hepatic failure. Even among the four patients who underwent LT, one with fulminant WD recovered from hepatic encephalopathy with apheresis therapy and chelating agent. He later required LT because of severe neutropenia from d‐penicillamine. The other three patients who underwent LT recovered and have been doing well. Some of the patients with WD can recover and avoid LT with medical treatment. Even when WD has progressed liver cirrhosis and/or fulminant hepatic failure at the time of diagnosis, medical treatment should be tried before considering LT.

Excellent Results of High-Dose Mizoribine Combined With Cyclosporine, Basiliximab, and Corticosteroids in Renal Transplant Recipients—4-Year Results

BACKGROUNDnMizoribine (MZR) at 3 mg/kg/d shows less potent immunosuppressive effects, but high-dose MZR (6 mg/kg/d) was effective and safe in a 2-year study in conjunction with a regimen of cyclosporine (CsA), basiliximab, and corticosteroids.nnnMETHODSnWe compared 40 living-related kidney recipients administered MZR (6 mg/kg/d), CsA (7 mg/kg/d), prednisolone (maintenance dose 10 mg/d), and basiliximab (20 mg/body) with control group (n = 38) treated with CsA, mycophenolate mofetil (MMF; 25 mg/kg/d), basiliximab, and corticosteroids.nnnRESULTSnThe 4-year graft survival rates for the MZR vs MMF groups were 92.5% vs 94.7%, respectively, with serum creatinine levels of 1.66 ± 1.0 mg/dL vs 1.41 ± 0.42 mg/dL at 3 years, and 1.72 ± 1.16 mg/dL vs 1.56 ± 1.26 mg/dL at 4 years. There was no significant difference in serum creatinine levels between the 2 groups. The MZR group demonstrated a significantly higher rate of elevated serum uric acid values (29.7%). The numbers of patients treated with allopurinol at 4 years were 11/37 (29.7%) for MZR vs 2/36 (5.6%) for the MMF subjects (P < .05). Mean serum uric acid levels of the MZR vs MMF group at 4 years were 7.1 ± 1.9 mg/dL vs 7.0 ± 1.6 mg/dL, respectively (NS). There was no significant difference between the 2 groups regarding bone marrow suppression or liver dysfunction. Severe cytomegalovirus infection was not observed at 3 and 4 years in either group. There were no severe gastrointestinal symptoms among the MZR or the MMF group at 3 or 4 years.nnnCONCLUSIONSnThe combination of high-dose MZR with CsA, basiliximab, and corticosteroids displayed excellent results over a 4-year follow-up.

A case of living-donor renal transplantation for chronic renal failure caused by secondary amyloidosis.

In Japan, amyloidosis is a rare cause of renal failure and of renal transplantation. We treated a patient who underwent a renal transplantation because of chronic renal failure caused by secondary amyloidosis with a good result. The patient was a 50-year-old woman who was diagnosed with secondary amyloidosis and an amyloid kidney. She underwent living donor renal transplantation after about 7 years of hemodialysis. During the 3-year posttransplantation period, she maintained good allograft function with a serum creatinine level about 1.2 mg/dL. Because of amyloidosis is a systemic disease, amyloid kidney patients often experience fatal complications, so the indications for renal transplantation in amyloid patients are still controversial. But if the patients general condition is good, renal transplantation can be an effective therapy for patients with kidney failure caused by amyloidosis.

Current state and future evolution of pancreatic islet transplantation

Pancreatic islet transplantation provides an effective treatment option for patients with type 1 diabetes (T1D) with intractable impaired awareness of hypoglycemia and severe hypoglycemic events. Currently, the primary goal of islet transplantation should be excellent glycemic control without severe hypoglycemia, rather than insulin independence. Islet transplant recipients were less likely to achieve insulin independence, whereas solid pancreas transplant recipients substantially had greater procedure‐related morbidity. Excellent therapeutic effects of islet transplantation as a result of accurate blood glucose level–reactive insulin secretion, which cannot be reproduced by current drug therapy, have been confirmed. Recent improvement of islet transplantation outcome has been achieved by refinement of the pancreatic islet isolation technique, improvement of islet engraftment method, and introduction of effective immunosuppressive therapy. A disadvantage of islet transplantation is that donors are essential, and donor shortage has become a hindrance to its development. With the development of alternative transplantation sites and new cell sources, including porcine islet cells and embryonic stem/induced pluripotent stem (ES/iPS)‐derived β cells, “On‐demand” and “Unlimited” cell therapy for T1D can be established.