The Japanese Liver Transplantation Society (JLTS) was established in 1980 in order to characterize and follow trends in patient characteristics and graft survival among all liver transplant patients in Japan. This study analyzed the comprehensive factors that may influence the outcomes of pediatric patients who undergo living donor liver transplantation (LDLT) by evaluating the largest cohort in the world. Between November 1989 and December 2010, 2224 pediatric patients underwent LDLT in Japan. There were 998 male (44.9%) and 1226 female donors (55.1%) without donor mortalities related to transplant surgery. There were 946 male (42.5%) and 1278 female (57.5%) recipients with a median age of 4.0 years (range: 13 days to 17.9 years). Cholestatic liver disease was the leading indication for LDLT (n = 1649; 76.2%), followed by metabolic disorders (n = 194; 8.7%), acute liver failure (n = 192; 8.6%) and neoplastic liver disease (n = 66; 3.0%). The 1-, 5-, 10- and 20-year patient survival rates were 88.3%, 85.4%, 82.8% and 79.6%, respectively. Blood-type incompatibility, recipient age, etiology of liver disease and transplant era were found to be significant predictors of overall survival. We are able to achieve satisfactory long-term pediatric patient survival outcomes in the JLTS series without compromising the living donors.
graft-to-recipient body weight
Japanese Liver Transplantation Society
living donor liver transplantation
left lateral segment
Living donor liver transplantation (LDLT) was introduced in Japan in 1989 as a life-saving procedure for a patient with biliary atresia due to the absolute scarcity of organs available for deceased donor transplantation . The shortage of deceased organ donors led to the development of unique technical, physiological and logistical innovations in LDLT [2, 3]. Experience with and technical improvements in living donor surgery have led to the generalization of pediatric LDLT with excellent patient and graft survival outcomes. These techniques have expanded the potential donor pool and decreased waiting list mortality in the setting of pediatric liver transplantation (LT) .
Recently, there have been technical and immunological refinements in the Japanese pediatric LDLT program, such as resolving graft size matching and overcoming blood-type mismatches. The Kyoto group reported that ideal grafts, defined as grafts with a graft-to-recipient body weight ratio (GRWR) of 0.8–4.0%, are associated with small- and large-for-size syndrome, which results in poor patient survival [5, 6]. ABO-incompatible LDLT was introduced in Japan to overcome the potential donor shortage. It has been reported that, despite the application of preoperative plasma exchange, splenectomy and enhanced immunosuppression, the 5-year graft survival rate is less than 70% in the pediatric population [7, 8]. Specific diseases and preoperative patient conditions are associated with transplantation outcomes [9-11].
The JLTS, the Japanese Liver Transplantation Society, a cooperative research consortium, was established in 1980 in order to characterize and follow trends in patient characteristics and graft survival outcomes at all liver transplant centers in Japan. The JLTS is a mandatory data registry, and 100% of the LDLT cases were enrolled in this study. All data were validated by cross-checking the information with the national registry of the Japanese Transplantation Society and the national clinical database of the Japan Surgical Society. The aim of this preliminary study was to evaluate the largest cohort of pediatric patients who have undergone LDLT in the world. The use of annual LT registry data was approved by the ethical committee of the JLTS.
Patients and Methods
We analyzed data for all living donors and recipients who underwent isolated LDLT and were enrolled in the JLTS between the registry's inception in November 1989 and December 2010. The study patients were followed before LDLT, then yearly after transplantation. The following donor data were obtained from the JLTS database: age, sex, blood type, relationship to the recipient and graft type. The following recipient data were collected: age, sex, blood type, original liver disease and outcome at last follow-up (survival or death). Data regarding perioperative patient conditions, immunosuppression protocols, postoperative complications and cause of death were not available due to limitations in the information contained within the JLTS database.
The number of LDLTs performed in Japan showed an initial increase to a maximum of 562 in 2005 followed by a decrease and return to the status quo of approximately 450 annually (Figure 1). During the study period (November 1989 to December 2010), 6097 LDLTs were performed in Japan with a minimum follow-up of 2 years. Of these cases, 2224 involved children less than 18 years of age (36.5%) who were enrolled in the present study. The annual number of pediatric LDLT cases has been 130–140 over the past 5 years. During the same study period, 96 deceased LTs, including 13 split LTs in pediatric patients were performed, and these patients were excluded from the present study.
Continuous variables are reported as medians and interquartile ranges, and categorical variables are reported as proportions. The cumulative survival is shown with Kaplan–Meier curves, and differences in survival between groups were analyzed using the log-rank test. Medians were compared using the Wilcoxon test and proportions were compared using the chi-square test. Factors associated with long-term patient survival were analyzed with Cox regression analyses. The backward stepwise procedure was used for variable selection with retention criteria at a p value of <0.1 level of significance. Variables with p < 0.1 in the univariate analysis were included in the multivariate analysis. All recipients were followed until death and/or graft loss or until December 2010. The median follow-up period was 10.6 years (range: 2.0–21.1 years). All statistical tests were two-sided, and p < 0.05 was considered to be significant. The statistical analyses were performed with the SPSS version19.0 software program.
The characteristics of the 2224 donors and recipients are summarized in Table 1. The potential donors were evaluated using liver function tests, and blood type, anatomical variations and graft size were evaluated with computed tomography (CT) volumetry. All patients received grafts from family members. There were 998 male (44.9%) and 1226 female donors (55.1%) with a median age of 35.2 years (range: 17–70 years) and a median body weight of 59 kg (range: 36–103 kg). The donors were parents in 95.3% cases, including fathers and mothers in 42.9% and 52.4% of cases, respectively, followed by grandparents in 2.7% of cases. The blood-type combination was identical in 1484 (66.7%) cases and compatible in 446 (20.1%) cases, while 294 (13.2%) recipients received ABO-incompatible grafts. The graft types included reduced left lateral segment (LLS; n = 96; 4.3%), LLS (n = 1549; 69.6%), left lobe (n = 500; 22.5%), posterior segment (n = 3; 0.1%) and right lobe grafts (n = 76; 3.4%). There were no donor mortalities related to surgery in this study population.
|Body weight (kg)||59.0||36.0–103.4|
|Male sex (n [%])||998||44.9%|
|Relationship to recipient|
|Type of graft|
|Reduced left lateral segment||96||4.3|
|Left lateral segment||1549||69.6|
|Age||4.0 years||13 days–17.9 years|
|Body weight (kg)||16.6||2.6–90.0|
|Male sex (n [%])||946||42.5%|
There were 946 male (42.5%) and 1278 female (57.5%) recipients with a median age of 4.0 years (range: 13 days to 17.9 years) and a median body weight of 16.6 kg (range: 2.6–90 kg). Table 2 lists the indications for LDLT observed in the present study. Cholestatic liver disease was the leading indication for LDLT (n = 1649; 76.2%), followed by metabolic disorders (n = 194; 8.7%), acute liver failure (n = 192; 8.6%) and neoplastic liver disease (n = 66; 3.0%). Biliary atresia (n = 1471; 66.1%) was the most common indication in patients with cholestatic liver disease, followed by Alagille syndrome (n = 70; 3.1%). Wilson's disease (n = 59; 2.6%) was the most common indication in patients with metabolic liver disease, followed by Ornithine transcarbamylase deficiency (n = 40; 1.8%) and Methylmalonic academia (n = 20, 0.9%). Nearly 85% of the children who underwent LDLT for acute liver failure had disease of unknown etiology (163 out of 192 cases). Hepatoblastoma (n = 52, 2.3%) was the most common indication in patients with neoplastic liver disease. Retransplantation using living donors was indicated in 76 patients (3.4%), including two cases of third LDLT.
|Cholestatic liver disease||1649||76.2|
|Primary sclerosing cholangitis||20||0.9|
|Congenital bile duct dilatation||5||0.2|
|Metabolic liver disease||194||8.7|
|Ornithine transcarbamylase deficiency||40||1.8|
|Carbamoyl phosphate synthetase 1 deficiency||9||0.4|
|Glycogen storage disease||15||0.7|
|Primary hyperoxaluria type 1||9||0.4|
|Acute liver failure||192||8.6|
|Auto immune hepatitis||2||0.1|
|Congenital absence of portal vein||21||0.9|
The 1-, 5-, 10- and 15-year survival rates for adult and pediatric patients undergoing LDLT were 80.7%, 71.9%, 65.5% and 56.9% and 88.3%, 85.4%, 82.8% and 80.0%, respectively. There were significant differences in survival between the adult and pediatric patients (p < 0.0001).
Recipient and donor factors were analyzed for overall recipient survival. The results of the univariate and multivariate analyses are shown in Table 3. According to the univariate analysis, donor age, ABO incompatibility, recipient age, etiology of liver disease and transplant era were significant predictors of survival. The univariate analysis of the factors predicting patient survival showed no significant associations between survival and donor sex, gender combination, relationship of the donor, graft type or recipient sex. Factors with p < 0.1 were included in the multivariate analysis, and ABO incompatibility, recipient age, etiology of liver disease and transplant era were found to be significant predictors of overall survival.
|Hazard ratio||95% Confidence interval||p-value|
|Donor age: ≥40 years vs. <40 years||1.015||1.003||1.027||0.013|
|Donor sex: male vs. female||1.086||0.884||1.334||0.433|
|Gender combination: male to male vs. male to female vs. female to male vs. female to female||0.990||0.970||1.011||0.343|
|ABO compatibility: identical vs. compatible vs. incompatible||0.748||0.656||0.853||<0.001|
|Graft type: monosegment vs. left lateral segment vs. left lobe vs. left with caudate lobe vs. right lobe||1.064||0.935||1.210||0.346|
|Recipient age: <6 months vs. ≤6 months, <1 year vs. 1–5 years vs. 6–10 years vs. ≤11 years, <18 years||1.146||1.044||1.257||0.004|
|Recipient age: ≥1 years vs. <1 years||1.100||0.879||1.378||0.405|
|Recipient sex: male vs. female||0.914||0.825||1.013||0.087|
|Etiology of liver disease||1.040||0.948||1.141||0.404|
|Cholestatic liver disease vs. others||0.453||0.367||0.558||<0.001|
|Acute liver failure vs. others||2.405||1.823||3.173||<0.001|
|Metabolic disease vs. others||0.851||0.575||1.260||0.422|
|Neoplastic disease vs. others||1.747||1.073||2.843||0.025|
|Vascular disease vs. others||0.787||0.294||2.109||0.634|
|Re-transplantation vs. others||4.433||3.152||6.235||<0.001|
|Transplant era: 1989–1995 vs. 1996–2000 vs. 2001–2005 vs. 2006–2010||0.698||0.629||0.775||<0.001|
|Donor age: ≥40 years vs. <40 years||1.003||0.989||1.017||0.675|
|ABO compatibility: identical vs. compatible vs. incompatible||0.776||0.677||0.890||<0.001|
|Recipient age: <6 months vs. ≤6 months, <1 year vs. 1–5 years vs. 6–10 years vs. ≤11 years, <18 years||0.562||0.387||0.816||0.002|
|Recipient sex: male vs. female||0.921||0.745||1.137||0.344|
|Etiology of liver disease||0.661||0.462||0.945||0.395|
|Cholestatic liver disease vs. others||0.273||0.173||0.433||0.348|
|Acute liver failure vs. others||3.063||2.304||4.071||<0.001|
|Neoplastic disease vs. others||2.634||1.598||4.339||<0.001|
|Re-transplantation vs. others||5.746||3.978||8.299||<0.001|
|Transplant era: 1989–1995 vs. 1996–2000 vs. 2001–2005 vs. 2006–2010||0.651||0.584||0.726||<0.001|
When the data were analyzed separately, there were distinct differences in outcomes based on graft-type and blood-type combination. In this study, patients with reduced LLS and left lobe grafts exhibited a trend toward lower patient survival than those who received LLS and right lobe grafts over the long term. Similarly, the age of the recipient was found to be a predicting factor for patient survival, and recipients less than 6 months or older than 10 years of age demonstrated significantly worse patient survival, with 15-year survival rates of 70.5% and 68.4%, respectively (Figure 2).
ABO compatibility had a significant impact on overall patient survival, with a 15-year survival rate of 68.5% among patients who received ABO-incompatible grafts (Figure 3). When the cumulative patient survival in patients with ABO-incompatible grafts (n = 294) was analyzed according to the recipient age at LDLT, a significantly better 20-year patient survival rate of 81.4% was achieved in the recipients less than 2 years of age (p < 0.01).
When the survival rates were analyzed according to the original liver disease, patients with cholestatic liver disease showed a significantly better patient survival rate than those with metabolic disease, neoplastic disease or acute liver failure, with a 20-year survival rate of 84% (Figure 4). After assessing the patient survival rate of the patients with biliary atresia, the leading indication for LT, according to the age at LDLT, a significantly worse 15-year survival rate of 68.4% was seen in the patients over 10 years of age. The patients with metabolic liver disease, Wilson's disease and urea cycle disorders showed significantly better patient survival than patients with other metabolic liver diseases, with 15-year survival rates of 73.4% and 95.9%, respectively. Among the acute liver failure patients, who showed a 15-year survival rate of 67.0%, those under 1 year of age exhibited a decreased 15-year survival rate of 54.2% (Table 4).
|Number||%||Patient survival (%)|
|1 year||5 years||10 years||15 years||20 years|
|Donor age (p = NS; median 35.2 [range 17–70 years])|
|20 years ≤ <40 years||1646||74||88.9||86.4||83.9||81.7||81.2|
|40 years ≤ <60 years||543||24.4||86.5||82.8||79.7||74.7||74.7|
|Donor relation (p = NS)|
|Gender mismatch (p = NS)|
|Graft type (p = NS)|
|Reduced left lateral segment||96||4.3||79.1||74.2||74.2||—||—|
|Left lateral segment||1549||69.6||89.8||87.6||85.1||83.4||82.9|
|ABO compatibility (p < 0.01)|
|Age at incompatible LT (p < 0.01)|
|2 years ≤ <10 years||36||13.3||76.7||72.3||66.7||48.6||—|
|10 years ≤ <18 years||73||24.8||72.2||63.7||59.2||49.3||—|
|Recipient sex (p = NS)|
|Recipient age (p < 0.01; median 4.0 years [range 13 days to 17.9 years])|
|6 months ≤ <1 year||613||27.6||89.2||87.6||86.1||85.3||85.3|
|1 year ≤ <5 years||789||35.5||90.2||88.7||85.8||85.1||84.1|
|5 years ≤ <10 years||320||14.4||90.0||85.3||81.3||76.1||76.1|
|10 years ≤ <18 years||396||17.8||83.5||79.1||76.5||68.4||68.4|
|Indication of liver transplantation (p < 0.01)|
|Cholestatic diseases (p = NS)||1649||76.2||91.2||89.4||86.5||84.0||84.0|
|Biliary atresia (age at LDLT; p < 0.01)||1471||66.1||91.3||89.5||86.9||84.8||84.8|
|6 months ≤ <1 year||503||34.2||92.2||91.4||89.6||84.8||84.8|
|1 year ≤ <5 years||535||36.4||93.1||91.6||88.8||87.9||87.9|
|5 years ≤ <10 years||177||8||92.6||91.2||87.7||83.4||—|
|10 years ≤ <18 years||212||14.4||83.5||79.0||75.4||68.4||—|
|Primary sclerosing cholangitis||20||0.9||100.0||94.4||63.0||—||—|
|Metabolic disease (p < 0.001)||194||8.7||92.2||87.9||87.0||77.5||—|
|Urea cycle disorders||49||2.2||95.9||95.9||95.9||95.9||—|
|Glycogen storage diseases||15||0.7||92.9||69.3||—||—||—|
|Acute liver failure (age at LDLT; p < 0.01)||192||8.6||72.6||69.0||67.0||67.0||—|
|Primary vs. re-transplantation (p < 0.01)|
|Center volume (p = NS)|
|High volume (≥50)||2033||91.4||88.1||85.2||82.5||79.7||79.3|
|Low volume (<50)||191||8.6||90.0||88.3||85.8||85.8||—|
|Transplantation era (p < 0.01)|
Retransplantation with living donors remains a controversial undertaking, given the scarcity of organs from relatives. In the present series, retransplantation with living donors accounted for 3.3% of cases, and third transplantation accounted for 0.2% of cases. Patient survival was significantly worse in the retransplant recipients compared with that observed in children receiving single grafts (48.1% and 84.0% at 10 years, respectively).
Liver transplant centers can be categorized as low- or high-volume. The overall number of liver transplants is less than 50 for low-volume centers (26 centers) and greater than 50 for high-volume centers (23 centers). There were no significant differences between the low- and high-volume centers with regard to patient survival (p = 0.2584).
The number of pediatric LDLTs has remained static, with 130–140 transplants performed annually. The two decades comprising the study period can be categorized into four eras. Although there were no significant differences, the proportions of recipients with ABO-incompatible grafts and those less than 6 months of age increased from 13.5% to 16.0% and 4.7% to 12.2% over the past two decades, respectively. Significant improvements in patient survival were obtained within the most recent 5 years, with a 5-year patient survival rate of 91.8% (Figure 5). Comparing the recipient 1- and 3-year survival rates according to the two dominant graft types (LLS grafts and left lobe grafts) by transplant era reveals significant improvements within the past 5 years (93.9% and 92.9% for 1- and 3-year survival in patients with LLS grafts and 90.8% and 89.9% for 1- and 3-year survival in patients with left lobe grafts; p < 0.01). The survival rates over the past 5 years among patients with ABO-incompatible grafts demonstrate significantly superior survival, with rates of 87.9% and 87.9% at 1 and 3 years, respectively (p < 0.01). There were significant differences in the 1- and 3-year survival rates for recipients according to age (less than 6 months and over 10 years) and transplant era. Among the patients who received LDLT within the past 5 years, the 1- and 3-year survival rates were 91.8% and 88.7% among the patients less than 6 months of age and 88.7% and 86.7% among the patients over 10 years of age (p < 0.01).
We reviewed the outcomes of 2224 pediatric LDLT recipients, the largest pediatric LDLT cohort in the world. The survival rates observed in the Japanese pediatric LDLT series were excellent, approaching 88.3%, 85.4%, 82.8% and 79.6% for patients at 1, 5, 10 and 20 years post-LDLT, respectively. The present results compare favorably with recently published data from an outstanding series regarding deceased LT [10, 11]. In this study, ABO incompatibility, recipient age, etiology of liver disease and the transplant era were found to be significant predictors of overall survival. Liver graft size matching is one of the major factors determining a successful outcome. Relative to older pediatric recipients, infants had worse overall patient survival rates in the present study. The use of small-for-size grafts leads to lower graft survival due to insufficient metabolic and synthetic functions and portal hypertension in older recipients 5). Although the patients with left lobe grafts showed significantly lower survival rates in the present study, there might be considerable historical perspectives. For example, the success of pediatric LDLT using LLS for children led to the use of the same procedure in adolescent recipients in the early 1990s. With occasional patient mortalities from small-for-size grafts impeding the wider use of LDLT in adolescents, many centers began to use the right lobe from the donor to provide a greater amount of actual graft mass for the recipient in order to achieve a better outcome without compromising the living donor . It has been reported nonadherence with recommended immunosuppressant medication is associated with poor medical outcomes in adolescent transplant recipients in the world [13, 14]. Nonadherence might not be a common cause of graft failure in Japan, in part due to national healthcare coverage for all pediatric patients who become adults, although prospective investigations of transition process might be necessary.
On the other hand, the disadvantage of using large-for-size grafts in infants is that insufficient tissue oxygenation and graft compression are observed in association with a relatively high incidence of vascular complications that result in poor outcomes . To address the problems of large-for-size grafts in small babies, the use of reduced LLS was introduced with acceptable results, including a 10-year survival rate of 74.2% in the present series. The proportion of recipients less than 6 months of age, who may potentially receive large-for size grafts has increased to 12.2% over the past 5 years. Tailoring the graft size is essential for obtaining better outcomes in small infants and large adolescents with end-stage liver disease. Children with liver disease are particularly susceptible to malnutrition, which is reported to be one of the few pretransplantation variables with a known detrimental impact on posttransplantation mortality [16, 17]. Optimizing the pretransplantation status with nutritional management would be essential.
ABO-incompatible LDLT has been performed to mitigate the problems of the organ shortage in Japan. The graft survival rate of children younger than 2 years of age receiving ABO-incompatible grafts was similar to that of children receiving compatible grafts in the present series. Survival is gradually affected in association with age by specific complications related to antibody-mediated rejection such as focal hepatic necrosis caused by microcirculatory disturbances and the development of multiple non-anastomotic biliary strictures attributable to arteriole insufficiency . ABO-incompatible grafts were used in 13.2% of the recipients in the present series. Despite the application of preoperative plasma exchange, splenectomy and enhanced immunosuppression, the 15-year graft survival rate was less than 50% in children over 2 years of age. The recent introduction of rituximab in ABO-incompatible cases has improved graft survival in older recipients by inducing B cell desensitization [18, 19]. Recently, rituximab prophylaxis has become widely used, with improved outcomes. The percentage of patients receiving ABO-incompatible grafts has increased to 16.0%. Although providing long-term follow-up, including monitoring for late-onset neutropenia, is necessary in order to offer clear recommendations, children over 2 years of age can receive this alternative treatment modality . Moreover, operational immunosuppressant tolerance protocol, not limited to ABO-incompatible cases, was initiated in the early 1990s at Kyoto University, with a complete withdrawal rate of 38.1% in selected pediatric patients with monitoring gamma–delta T cells [21, 22]. Operational tolerance is one of the recent innovations in pediatric LDLTs.
It has been reported that the cause of liver disease is a strong predictor of patient outcomes, and patients with cholestatic liver disease fair far better than those with other indications . Similar to the findings of the deceased LT series, patients with biliary atresia had a consistently better 20-year patient survival rate of 84.8% in the present series. Significantly worse patient survival, however, was observed in the patients with biliary atresia over 10 years of age, with a 20-year survival rate of 68.4%. The timing of LDLT in older patients with biliary atresia is crucial.
The present study confirmed that LDLT performed to treat metabolic disease can provide an acceptable survival rate of 77.5% over 15 years, although most donors in the present series were heterozygous for their respective recipients' disorders. While neither mortality nor morbidity related to heterozygosis were observed, an intensive investigation should be conducted in this donor population.
There are several reports of the use of deceased LT to treat acute liver failure in children, with reported overall patient survival rates of 60–75% [23, 24]. The overall survival rate of the patients with acute liver failure in the present study is comparable with 67.0% over 15 years. However, among acute liver failure patients less than 1 year of age, the patient survival rates were significantly lower in the short and long term (61.4% and 54.2% at 1 and 15 years, respectively) despite relatively appropriate availability of donors compared to deceased LT. The reasons for this difference are not well documented; however, long-lasting unknown hepatitis viral infections may cause accelerated immune responses, and the incidence of refractory acute or chronic rejection is higher in patients with acute liver failure of unknown etiology in infancy [25, 26]. Further immunological refinements and advances in perioperative intensive care are required for LT patients with infantile acute liver failure.
The patients undergoing LDLT for hepatic malignancy demonstrated a poorer 20-year survival rate of 69.9%. The potential advantage of LDLT is that it allows for optimal timing of LT, given the absence of delay between the completion of effective chemotherapy and planned LT .
Re-LT remains controversial in the setting of LDLT given the limitation of donors and the fact that previous reports have demonstrated poorer outcomes with re-LT than primary LT . Taking into consideration the recipient 10-year survival rate of 48.1% observed in the present study, determining clear indications and limitations for re-LDLT is necessary in order to avoid unequivocal morbidity and even mortality in potential living donor candidates.
Despite the increasing proportion of small children and ABO-incompatible cases, patient survival was significantly better among the patients undergoing LDLT more recently (5-year survival rate: 91.8%) due to perioperative patient management by pediatric specialists and surgical innovations and advances in immunosuppression, such as overcoming graft size matching and ABO incompatibility. In addition, the outcomes after LDLT observed in the present study were comparable to those of deceased LT [9-11]. In our country, small deceased donors are less likely to become available, and LDLT is often the only treatment modality for patients with pediatric liver disease. Due to the unequivocal risks, efforts should be made to increase deceased LT in order to minimize the need for living donors.
Over the past two decades, medical and surgical innovations have established pediatric LDLT as the optimal therapy for patients suffering from acute or chronic liver disease. Our study, however, was limited by the restrictions, accuracy and consistency of the information contained within the JLTS database. We did not have access to preoperative patient conditions, recipient and donor laboratory data, immunosuppression protocols, morbidity, cause of death, growth or quality of life measures. As LDLT has been revealed to increase the donor pool and decrease pediatric waiting list mortality, conducting further investigations of the most important remaining causes of death in liver-transplanted children is essential. The JLTS started a new online detailed registration system in January 2013 that can be explored in detail. We hope that increased experience with and refinement of this procedure will lead to further improvements in outcomes among patients undergoing LT for pediatric liver diseases.
This work was supported in part by grants from the Scientific Research Fund of the Ministry of Education and by a Research Grant for Immunology, Allergy and Organ Transplant from the Ministry of Health, Labour and Welfare, Japan (Nos. 21591403, H21-04, H21-042, H24-014) and the Foundation for Growth Science, Japan.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
The following constitute the pediatric JLTS research group enrolled in this study:
Shinji Uemoto (Kyoto University, Kyoto), Norihiro Kokudo (Tokyo University, Tokyo), Susumu Satomi (Tohoku University, Miyagi), Yukihiro Inomata (Kumaoto University, Kumamoto), Tastuo Kuroda (Keio University, Tokyo), Masahiro Fukuzawa (Osaka University, Osaka), Koichi Mizuta (Jichi University, Tochigi), Go Wakabayashi (Iwate University, Iwate), Yasutsugu Takada (Ehime University, Ehime), Shoji Kubo (Osaka City University, Osaka), Miyuki Kouno (Kanazawa Medical University, Kanazawa), Seiji Kawasaki (Juntendo University, Tokyo), Tatsuya Suzuki (Fujita Health University, Nagoya), Takahito Yagi (Okayama University, Okayama), Norio Yoshimura (Kyoto Prefectural University of Medicine, Kyoto), Tomoaki Taguchi (Kyushu University, Fukuoka), Hiroyuki Kuwano (Gunma University, Gunma), Izumi Takeyoshi (Gunma University, Gunma), Kenichi Hakamada (Hirosaki University, Hirosaki), Koji Aoyama (National Okayama Medical Center, Okayama), Kimikazu Hamano (Yamaguchi University, Yamaguchi), Masaaki Oka (Yamaguchi University, Yamaguchi), Hiroto Egawa (Tokyo Women's Medical University, Tokyo), Shinichi Miyagawa (Shinshu University, Nagano), Hidetoshi Mastunami (Matsunami General Hospital, Gifu), Katsuyoshi Hatakeyama (Niigata University, Niigata), Masato Shinkai (Kanagawa Children's Medical Center, Kanagawa), Nobuhiro Ohkochi (Tsukuba University, Ibaragi), Susumu Eguchi (Nagasaki University, Nagasaki), Yoshitsugu Tajima (Shimane University, Shimane), Akihiko Tsuchida (Tokyo Medical College, Tokyo), Hiroshi Matsufuji (Kagoshima University, Kagoshima), Tetsuo Ota (Kanazawa University, Kanazawa), Masanori Kon (Kansai Medical University, Osaka), Satoshi Kaihara (Kobe City Medical Center, Kobe), Katsuhiko Yanaga (Jikei Medical University, Tokyo), Shigeki Arii (Tokyo Medical and Dental University, Tokyo), Syuji Isa (Mie University, Mie), Itaru Endo (Yokohama City University, Kanagawa), Masaru Miyazaki (Chiba University, Chiba), Mistuo Shimada (Tokushima University, Tokushima), Keiichi Kubota (Dokkyo Medical University, Tochigi), Yoshiyuki Nakajima (Nara Medical University, Nara), Mitsukazu Goto (Fukushima Medical University, Fukushima), Jiro Fujimoto (Hyogo College of Medicine, Hyogo), Akinobu Taketomi (Hokkaido University, Hokkaido), Masahiko Watanabe (Kitasato University, Kanagawa), Hiromitsu Takeyama (Nagoya City University), Yasuhiro Ogura (Nagoya University, Nagoya), Seisuke Sakamoto, Mureo Kasahara (National Center for Child Health and Development, Tokyo).