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Original Clinical Science—Liver

Outcomes of Pediatric Liver Transplantation in Japan: A Report from the Registry of the Japanese Liver Transplantation Society

Kasahara, Mureo MD, PhD1; Umeshita, Koji MD, PhD2; Eguchi, Susumu MD, PhD3; Eguchi, Hidetoshi MD, PhD2; Sakamoto, Seisuke MD, PhD1; Fukuda, Akinari MD, PhD1; Egawa, Hiroto MD, PhD4; Haga, Hironori MD, PhD5; Kokudo, Norihiro MD, PhD6; Sakisaka, Shotaro MD, PhD7; Takada, Yasutsugu MD, PhD8; Tanaka, Eiji MD, PhD9; Uemoto, Shinji MD, PhD10; Ohdan, Hideki MD, PhD11

Author Information
doi: 10.1097/TP.0000000000003610

Abstract

INTRODUCTION

Living donor liver transplantation (LDLT) was introduced in Japan in 1989 as a life-saving procedure for pediatric patients with post-Kasai biliary atresia due to the absolute scarcity of organs available for deceased donor transplantation (DDLT).1 The shortage of deceased organ donors led to the development of unique technical, logistical, and physiological innovations in LDLT.2,3 Experience and technical improvements in living donor surgery have led to the general acceptance of pediatric LDLT, and even adult LDLT, with excellent long-term patient and graft outcomes.4 These techniques have expanded the potential donor pool and reduced waiting list mortality in pediatric liver transplantation (LT).5 Although the Organ Transplantation Law was established in 1997, the demand of patients waiting for organ transplantation has not been sufficiently satisfied in Japan, and most pediatric recipients received LDLT.6

The indications for LT include chronic liver disease, metabolic liver disease, acute liver failure, neoplastic disease, vascular disease, graft failure, and other indications. Specific diseases and preoperative patient conditions might be associated with transplantation outcomes.6,7 During the past 3 decades, medical and surgical innovations have established pediatric LT to be the optimal therapy for patients suffering from the end-stage liver disease. This has allowed expansion of the indications for LT to assess patient severity and body weight in association with various diseases. The profiles of current pediatric LT recipients differ significantly from those of earlier eras.8,9

The Japanese Liver Transplantation Society (JLTS), a cooperative research consortium, was established in 1980 to characterize and follow trends in patient characteristics and graft survival outcomes at all liver transplant centers in Japan. The JLTS has a mandatory data registry, and all data are validated by cross-checking with the national registry of the Japanese Transplantation Society and the National Clinical Database of the Japan Surgical Society. Previously published studies that have analyzed these data have examined specific factors affecting outcomes.10-12 This report aims to describe the most current information about pediatric LT from data in the JLTS registry. The use of the annual LT registry data was approved by the ethics committee of the JLTS.

MATERIALS AND METHODS

Study Design

We analyzed data for all donors and recipients who underwent LT and who were enrolled in the JLTS between the registry’s inception in November 1989 and December 2018. The study patients were followed before LT, then yearly after transplantation. The system of case registration shifted from the conventional paper document system to web-based registration as of January 1, 2012.

The following donor data were obtained from the JLTS database: age, sex, blood type, relationship to the recipient in LDLT, and graft type. The following recipient data were collected: age, sex, blood type, original liver disease, and outcome at the last follow-up (survival or death). The preoperative recipient data, immunosuppression, surgical complications, such as vascular and biliary complications, and the cause of graft failure were not available in the JLTS datasets.

The number of LTs performed in Japan showed an initial increase to a maximum of 570 in 2005 followed by a decrease and return to approximately 400–450 annually. During the study period, 9642 LTs were performed in Japan with a minimum follow-up period of 1 y. Among these cases, 3347 involving children <18 y of age (34.7%) from 51 centers in Japan were enrolled in the present study. The annual number of pediatric LT cases has been 100–120 for the past 5 y (Figure 1).

F1
FIGURE 1.:
Number of pediatric liver transplantation cases in Japan (N = 3347). DDLT, deceased donor LT; LDLT, living donor LT; LT, liver transplantation.

Statistical Analysis

Continuous variables are reported as the median and interquartile range, and categorical variables are reported as proportions. Cumulative survival is shown with Kaplan–Meier curves, and the differences in survival between groups were analyzed using the log-rank test. Factors associated with long-term patient survival were analyzed with Cox regression analyses. Variables with P values of <0.1 in a univariate analysis were included in a multivariate analysis. All recipients were followed until death and/or graft loss, or until December 2019. The median follow-up period was 9.4 y (range: 1–31.1 y). All statistical tests were two-sided, and P values of <0.05 were considered to indicate statistical significance. All statistical analyses were performed using the SPSS software program (version 22.0; IBM, Armonk, NY).

RESULTS

Donor Characteristics

The characteristics of the 3347 donors and recipients are summarized in Table 1. In LDLT, the potential donors were evaluated using liver function tests; blood type, anatomical variations, and graft size were evaluated by computed tomography volumetry. Living donor candidates were strictly limited to relatives up to the third civil degree, or spouses of the recipient who showed a strong voluntary will to donate. There were 44.7% male donors with a median age of 34.0 y (range: 17.0–70.0 y) and a median body weight of 58.0 kg (range: 36.0–105.0 kg). The donors were parents in 95.2% of cases, including fathers and mothers in 42.9% and 52.3% of cases, respectively, followed by grandparents (2.7%), uncle/aunt (1.4%), siblings (0.5%), and cousins (0.1%). The blood type combination was identical in 2110 (64.5%) cases and compatible in 682 (20.9%) cases, whereas 479 (14.6%) recipients received ABO-incompatible grafts. The graft types included left lateral segment (n = 2238; 68.4%), reduced left lateral segment (n = 169; 5.2%), left lobe (n = 761; 23.3%), posterior segment (n = 5; 0.2%), and right lobe grafts (n = 98; 3.0%). There was no living donor mortality related to surgery in this study population (Table 1).

TABLE 1. - Characteristics of the patients undergoing pediatric liver transplantation in Japan (N = 3347)
LDLT (n = 3271) DDLT (n = 69) Domino LT (n = 7) Total (N = 3347)
Donor Median IQR Median IQR Median IQR Median IQR
Male sex (%) 44.7 65.2 57.1 45.1
Age (y) 34.0 17.0–70.0 42.0 1.0–65.0 3.0 1.0–63.0 34.0 1.0–70.0
Body weight (kg) 58.0 36.0–105.0 57.4 8.8–75.0 38.6 9.1–51.5 58.0 8.8–105
Height (cm) 163.0 137.0–198.0 168.5 70.0–180.0 132.0 79.4–163.0 163.0 70.0–198.0
BMI 21.6 14.7–43.0 20.2 18.0–23.1 19.4 14.5–22.7 21.6 13.2–43.2
Relationship to recipient n (%) n (%) n (%) n (%)
Identical 2110 64.5 47 68.1 2 28.6 2159 64.5
Compatible 682 20.9 13 18.8 2 28.6 697 20.8
Incompatible 479 14.6 9 13.0 3 42.9 491 14.7
Type of graft n (%) n (%) n (%) n (%)
Reduced left lateral segment 169 5.2 2 2.9 171 5.1
Left lateral segment 2238 68.4 25 36.2 1 14.3 2264 67.6
Left lobe 761 23.3 10 14.5 1 14.3 772 23.1
Posterior segment 5 0.2 5 0.1
Right lobe 98 3.0 5 7.2 1 14.3 104 3.1
Whole 29 42.0 4 57.1 33 1
Recipient Median Range Median Range Median Range Median Range
Male sex (%) 43.2 46.6 42.9 43.3
Age (y) 1.6 9d–17.9 7.7 19d–17.9 2.9 0.7–17.0 1.7 9d–17.9
Body weight (kg) 9.8 2.6–90.0 20 3.0–70.0 30.8 6.4–45.0 9.9 2.6–90
Height (cm) 76.1 43.3–183.7 114 44.0–175.0 130.9 63.1–160.3 77 43.3–183.7
BMI, body mass index; DDLT, deceased donor liver transplantation; IQR, interquratile range; LDLT, living donor liver transplantation; LT, liver transplantation.

Transplant centers offer LDLT and DDLT simultaneously when receiving the initial informed consent from the patient and/or the patient’s family. Once informed consent has been obtained, assessment for either LDLT or DDLT is initiated. The final decision concerning registration on the DDLT waiting list is made according to the family’s wishes. When a patient is registered as a DDLT and domino LT candidate in the Japan Organ Transplant Network, the patient’s clinical and laboratory data, including the Child–Pugh score, Model for End-Stage Liver Disease score, and Pediatric End-Stage Liver Disease score, or disease-oriented prognostic score (such as primary sclerosing cholangitis, Wilson’s disease, or acute liver failure) are revised. The indications for LT in metabolic liver disease were evaluated according to a grading score system based on the guidelines recommended by the Japanese Ministry of Health, Labour and Welfare.12 Briefly, the metabolic disorders were divided into groups based on the following: whether the disorder predominantly involved the liver (liver-oriented disease; Wilson’s disease, urea cycle disorder, citrullinemia, tyrosinemia type 1, bile acid synthetic defects, and Crigler-Najjar syndrome type 1) or partly involved the liver; the effectiveness of conventional medical treatment; the quality of life; and the mental/physical status. Each candidate is allocated a clinical priority score by the National Assessment Committee for Indications for LT.10

In Japan, the Organ Transplantation Law was established in 1997; since that time, DDLT became legally available. The “Revised Brain Death Law” in 2010 allowed organ donations from individuals ≤15 y of age (but >6 mo of age) with the consent of their relatives, resulting in a marginally increased tendency for deceased donor organ donation in Japan. There were 69 DDLTs in the study period with median donor age of 42.0 y and a median body mass index (BMI) of 20.2. Split LT has been considered by each transplant center for donors <50 y of age without significant steatosis of the graft liver. In addition, each transplant center may decide to perform split LT according to the recipient’s medical condition, the characteristics of the deceased donor, the estimated ischemic time, and other factors. Split-liver transplantation was indicated in 42 cases (60.9%). All split procedures were performed in an ex situ manner. To prevent the prolonged organ retrieval time, which can be a burden to the donor hospital and an inconvenience for other surgical teams at a multiorgan retrieval, ex situ splitting has been recommended by the Japanese Organ Transplantation Network. Domino LT was indicated in 7 patients from pediatric donors with maple syrup urine disease. Two recipients received split LT and one recipient reduced left lobe LT from a domino donor.

Recipient Characteristics

The study population included 1448 male (43.3%) and 1899 female recipients with a median age (shown as LDLT, DDLT, and domino LT, respectively) of 1.6, 7.7, and 2.9 y, and a median body weight of 9.8, 20.0, and 30.8 kg. Table 2 lists the indications for LT according to the type of LT observed in the present study. Immunosuppression consisted of tacrolimus and low-dose steroids in most cases.13 Patients who received blood type incompatible transplants had preoperative Rituximab, plasma exchange to reduce the anti-ABH antibody titer.14

TABLE 2. - Indications for liver transplantation and graft survival following pediatric liver transplantation in Japan (N = 3347)
LDLT (n = 3271) DDLT (n = 69) Domino LT (n = 7) Total (3347) Recipient age at LT (y) Recipient BW at LT (kg) Graft survival (%) P
n % n % n % n % Median IQR Median IQR 1 y 5 y 10 y 15 y 20 y 25 y 30 y
Chronic liver disease 2332 71.3 22 31.9 4 57.1 2358 70.5 1.4 1.7 m–17.9 9.0 2.6–88 91.3 88.7 85.6 83.1 80.7 78.7 78.7 <0.0001
Biliary atresia 2102 64.3 13 18.8 3 42.9 2118 63.3 1.3 2 m–17.9 8.8 2.6–71 91.7 89.4 86.9 84.5 82.1 80.2 80.2
Alagille syndrome 95 2.9 95 2.8 1.6 5 m–15.6 8.1 4.0–46.0 90.5 89.4 83.8 83.8 80.9 80.9 80.9
Cryptogenic cirrhosis 39 1.2 1 1.4 40 1.2 3.2 4 m–17.5 12.8 2.8–55.0 84.6 76.1 72.1 67.3 67.3 56.1
Primary sclerosing cholangitis 26 0.8 7 10.1 33 1.0 11.3 9 m–17.3 25.0 7.0–62.0 97 83.2 54.2 45.2 30.1
Congenital bile duct dilatation 6 0.2 6 0.2 2.9 0.4–12.0 11.8 5.5–35.9 100 100 100 100 100
Caroli disease 11 0.3 11 0.3 7.2 1.1–16.6 19.3 6.8–51.2 90 78.8 78.8 78.8
Congenital hepatic fibrosis 31 0.9 1 14.3 32 1.0 7.7 2 m–17.6 20.4 2.7–45.0 90.6 87.4 87.4 87.4 87.4 87.4 87.4
Autoimmune hepatitis 7 0.2 1 1.4 8 0.2 16.6 12.9–17.2 44.3 30.9–62.5 62.5 62.5 62.5 31.3 31.3 31.3
Nonalcoholic steatohepatitis 2 0.1 2 0.1 12.7 9.8–15.5 51.7 15.3–88 100 100 100 50 50
GVHD (post bone marrow Tx) 5 0.2 5 0.1 10.1 1.0–13.6 28.8 3.8–31.6 60 40 40
Intestinal failure associated liver disease 5 0.2 5 0.1 11.0 0.9–17.4 26.9 3.1–34.2 60 20 20
COACH syndrome 1 0.0 1 0.0 7.6 20.0 100 100
Langerhans cell histiocytosis 1 0.0 1 0.0 3.4 11.3 0
Hepatitis C 1 0.0 1 0.0 14.6 59.0 0
Metabolic liver disease 362 11.1 19 27.5 2 28.6 38 11.4 3.2 23d–17.9 13.0 30–74 92.1 88.8 86.1 80.3 77.9 77.9 71.5 <0.0001
Wilson’s disease 68 2.1 6 8.7 74 2.2 12.0 6.2–17.3 42.8 20.0–74.0 92.3 91.2 89 79 75.8 75.8 75.8
Ornithine transcarbamylase deficiency 70 2.1 8 11.6 78 2.3 3.2 23d–17.9 13.0 3.5–53.8 97.4 97.4 97.4 97.4 97.4 97.4
Carbamoyl phosphate synthetase 1 deficiency 22 0.7 22 0.7 0.6 4 m–11.0 7.2 5.8–29.0 100 95.5 95.5 95.5
Citrullinemia 17 0.5 2 2.9 19 0.6 4.1 6 m–17.0 12.0 6.0–51.0 100 100 100 100
Argininosuccinic aciduria 2 0.1 2 0.1 2.3 1.4–3.3 9.3 8.6–10.0 100 100 100 100
Methylmalonic academia 40 1.2 40 1.2 1.3 2 m–12.2 9.3 4.5–27.1 90 90 90 90
Propionic academia 14 0.4 14 0.4 1.0 6 m–5.1 9.5 6.1–16.6 93.3 80 80 80 80 80
Tyrosinemia 15 0.5 15 0.4 0.7 1 m–1.8 6.4 3.1–13.0 93.3 80 80 80 80 80
Bile acid synthesis disorder 52 1.6 1 1.4 53 1.6 2.0 5 m–17.7 10.0 3.1–30.8 90.4 84.2 78.2 69.4 69.4 69.4 69.4
Glycogen storage disease 24 0.7 24 0.7 3.5 5 m–14.3 13.0 5.0–47.5 83.3 74.8 74.8 49.8
Primary hyperoxaluria type 1 14 0.4 14 0.4 8.5 6 m–17.8 23.0 7.3–51.4 71.4 71.4 71.4 71.4 71.4
Mitochondrial DNA depletion syndrome 7 0.2 7 0.2 0.8 3 m–6.3 7.4 3.0–14.0 71.4 28.6 28.6
Maple syrup urine disease 6 0.2 6 0.2 2.3 10 m–13.0 24.5 9.1—39.8 83.3 83.3
Crigler-Najjar 3 0.1 3 0.1 5.5 4 m–6.0 15.8 7.9–22.0 100 100 100 100 100
Niemann Pick disease type C 2 0.1 2 0.1 0.4 1 m–6 m 4.8 4.6–5.0 100 100
Hyper cholesterolemia 2 0.1 1 1.4 1 14.3 4 0.1 2.6 2.1–2.9 11.5 10.0–12.6 100 100 100 100 100
Cystic fibrosis 1 0.0 1 0.0 13.8 21.2 100 100
Protoporphyria 1 0.0 1 0.0 15.5 52.5 0
Refsum disease 1 0.0 1 0.0 3.8 12.2 100 100
ECHS1 deficiency 1 0.0 1 0.0 1 m 3.0 0
Protein C deficiency 1 1.4 1 14.3 2 0.1 8.8 2.0–15.5 31.3 10.0–52.5 100 100
Acute liver failure 289 8.8 9 13 0 0 298 8.9 1.1 9 d–17.9 9.5 2.6–90 76.4 71.4 68.9 67.3 65.9 65.9 n.s.
Hemochromatosis 11 0.3 1 1.4 12 0.4 27.5 d 9–84 d 2.7 2.6–4.3 83.3 75 75
Hepatitis B 7 0.2 1 1.4 8 0.2 1.0 2 m–17.8 7.7 6.0–67.2 100 100 100 100 100 100
Drug induced 2 0.1 2 0.1 15.6 15.0–16.2 53.2 47.4–59.0 100 100 100 100 100 100
EBV 2 0.1 1 1.4 3 0.1 5.0 2.2–9.4 15.9 11.0–32.0 100 100 100 100
Unknown 263 8.0 6 8.7 269 8.0 1.1 12 d–17.9 9.6 2.6–74 75.5 70.4 67.6 65.8 64.2 64.2
Heat stroke 1 0.0 1 0.0 16.8 90.0 100 100 100 100 100
Others 3 0.1 3 0.1 1 m 29 d–3 m 3.7 3.5–4.0 50 50 50 50
Neoplastic disease 126 3.9 1 1.4 1 14.3 128 3.8 3.1 2.9 m–16.9 12.9 3.1–49.8 87.3 75.7 71.5 71.5 71.5 0.039
Hepatoblastoma 108 3.3 1 14.3 109 3.3 3.1 6 m–16.9 12.5 5.3–49.8 89.1 76.8 75.4 75.4 75.4
Hepatocellular carcinoma 5 0.2 5 0.1 12.3 1.9–13.9 26.1 9.4–48.0 80 80 53.3 53.3 53.3
Hemangioma 6 0.2 1 1.4 7 0.2 2.6 3 m–14.9 10.4 5.5–26.7 83.3 83.3 55.6 55.6 55.6
Hemangioendothelioma 3 0.1 3 0.1 4.1 4 m–13.7 10.6 3.1–16.8 100 66.7 66.7
Sarcoma 2 0.1 2 0.1 9.9 4.5–15.3 27.5 14–41 50 50 0
Choriocarcinoma 1 0.0 1 0.0 4 m 14.0 100
Metastatic liver tumor (pancreas Solid papillary tumor) 1 0.0 1 0.0 14.3 47.0 100 100 100 100
Vascular disease 51 1.6 0 0 0 0 51 1.5 5.0 4.8 m–17.4 15.0 4.3–70 94.1 89.5 89.5 89.5 89.5 89.5 n.s.
Congenital absence of portal vein 42 1.3 42 1.3 4.7 4 m–17.1 14.5 4.3–70.0 95.2 92.4 92.4 92.4 92.4 92.4
Budd–Chiari syndrome 7 0.2 7 0.2 11.5 3.3–17.4 32.0 11.5–53.0 85.7 71.4 71.4 71.4 71.4 71.4
Veno occulusive diease 2 0.1 2 0.1 1.1 8 m–1.4 9.4 8.8–10.0 100 100 100 100 100
Retransplantation 111 3.4 18 26.1 0 0 129 3.9 5.8 24 d–17.9 18.0 5.3–68 63.6 55.9 43.5 43.5 29.0 n.s.
Second transplantation 106 3.2 15 21.7 121 3.6 5.7 24 d–17.9 18.0 5.3–68.0 62.8 54.6 43.8 42.1 36.1
Third transplantation 5 0.2 3 4.3 8 0.2 7.0 2.0–13.5 17.4 10.2–53.4 87.5 75 60 60 25
Total 3271 97.7 69 0.2 7 0.2 3347 100.0 1.7 9 d–17.9 9.9 2.6–90 88.9 85.9 82.2 79.5 77.1 75.4 75.4
DDLT, deceased donor liver transplantation; EBV, Epstein-Barr virus; GVHD, graft-versus-host disease; IQR, interquratile range; LDLT, living donor liver transplantation; LT, liver transplantation.

Chronic liver disease was the leading indication for LDLT (n = 2332; 71.3%), followed by metabolic disorders (n = 362; 11.1%), acute liver failure (n = 289; 8.8%), and neoplastic liver disease (n = 126; 3.9%). Biliary atresia (n = 2102; 64.3%) was the most common indication in patients with chronic liver disease, followed by Alagille syndrome (n = 95; 2.9%). Due to the early diagnosis and treatment, urea cycle deficiency (n = 121; 3.6%) was the leading indication in patients with metabolic liver disease, followed by Wilson’s disease (n = 68; 2.1%) and bile acid synthesis disorder (n = 52; 1.6%). The number of cases in which LDLT was performed for metabolic disorders increased over the past 3 decades from 8.0% to 14.2% (Figure 2A). Although there were no significant differences, the number of cases of recipients with urea cycle deficiency, organic acidemia, and glycogen storage disease increased, whereas the number of transplant recipients with Wilson’s disease decreased, according to the transplant era (Figure 2B).

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FIGURE 2.:
Percentage of pediatric living donor liver transplantation cases according to the transplant era. A, Percentage of pediatric living donor liver transplantation cases according to the transplant era (n = 3271). B, Percentage of pediatric living donor liver transplantation cases for metabolic disorders according to the transplant era (n = 362).

Nearly 91% of the children who underwent LDLT for acute liver failure had a disease of unknown etiology (263/289 cases). Hepatoblastoma (n = 108; 3.3%) was the most common indication in patients with neoplastic liver disease. Although the number of cases was limited, congenital absence of the portal vein (n = 42; 1.3%) was the most common indication in patients with vascular disease. Retransplantation using living donors was indicated in 111 patients (3.4%), including 5 cases of third LDLT.

LT candidates are offered LDLT and DDLT simultaneously when receiving informed consent from the patient and the family in most transplant centers. The reasons for registration for DDLT included familial hereditary disease (eg, protein C deficiency, heterozygous hypercholesterolemia, and heterozygote mother ornithine transcarbamylase deficiency [OTCD]) and factors known to be associated with a poor prognosis in LDLT (eg, primary sclerosing cholangitis [PSC]).6 The indications for DDLT included retransplantation for graft failure (n = 18; 26.1%), biliary atresia (n = 13; 18.8%), OTCD (n = 8; 11.6%), and primary sclerosing cholangitis (n = 7; 10.1%).

Potential candidates for domino LT are patients on DDLT waiting lists with a good physical size match to a donor. In these 7 domino LT cases, all second recipients were unable to undergo LDLT for social or medical reasons. Domino LT was indicated for biliary atresia (n = 3; 42.9%) and familial hereditary diseases. There were significant differences in the indications for LT between the LDLT and DDLT groups with regard to the rates of chronic disease, metabolic liver disease, and retransplantation (P < 0.001).

Graft Survival

The graft survival curves for LDLT, DDLT, and domino LT patients are shown in Figure 3. Although the follow-up times were different, there were significant differences in survival between the LDLT, DDLT, and domino LT patients (P = 0.03).

F3
FIGURE 3.:
Graft survival in pediatric liver transplantation in Japan according to the type of transplant. DDLT, deceased donor LT; LDLT, living donor LT; LT, liver transplantation.

When the graft survival rates were analyzed according to the original liver disease, patients with chronic liver disease, metabolic liver disease, and vascular disease showed significantly better graft survival rates (77.5%, 77.9%, and 89.5%, respectively) than those with neoplastic disease, acute liver failure, and retransplantation, with long-term graft survival rates of 65.9%, 46.1%, and 29.0%, respectively (P < 0.0001). After assessing the graft survival according to each liver disease in chronic liver disease, autoimmune hepatitis, and PSC were associated with significantly worse survival in comparison to other diseases, with 20-y graft survival rates of 31.2% and 30.1%, respectively (P < 0.0001).

Patients with metabolic liver disease, urea cycle disorders (OTCD, carbamoyl phosphate synthetase-1 deficiency, citrullinemia, and argininosuccinic aciduria), organic acidemia (methylmalonic acidemia and propionic acidemia), and Wilson’s disease showed significantly better graft survival than patients with other metabolic liver diseases, with 25-y survival rates of 97.5%, 87.7%, and 75.8%, respectively (P < 0.0001). Patients with mitochondrial DNA depletion syndrome showed worse graft survival at 10 y (27.3%). Regarding the patients with neoplastic liver disease, patients with hepatoblastoma showed significantly better graft survival than nonhepatoblastoma patients, with 25-y survival rates of 76.8% and 47.2%, respectively (P = 0.039). Among the acute liver failure patients, who showed a 25-y survival rate of 65.9%, those with an unknown origin exhibited a decreased 25-y survival rate of 64.2%, although the difference was not statistically significant (P = 0.22) (Table 2).

Recipient and donor factors were analyzed to identify factors associated with overall graft survival. According to the univariate analysis, donor age, donor BMI, ABO incompatibility, recipient age, etiology of liver disease, transplant center experience, and transplant era were significant predictors of graft survival. The univariate analysis of factors predicting graft survival showed no significant associations between graft survival and gender combination, relationship of the donor, graft type, or recipient sex. Factors with P values of <0.1 were included in a multivariate analysis, and the results of the multivariate analyses are shown in Table 3. The multivariate analysis of factors predicting graft survival showed significant associations between graft survival and donor age, donor BMI, ABO incompatibility, recipient age, recipient body weight, transplant type, transplant center experience, and transplant era.

TABLE 3. - Factors associated with poor graft survival after pediatric liver transplantation in Japan
Multivariate analysis n Hazard ratio (95% Confidence interval) P
Donor age: <50 y vs ≥50 y 3189 vs 158 0.397 0.268 0.588 <0.0001
Donor BMI: <25 vs ≥25 2624 vs 723 0.745 0.610 0.908 0.004
ABO compatibility: identical/compatible vs incompatible 2857 vs 490 0.649 0.521 0.807 <0.0001
Recipient age: <10 y vs ≥10 y 2796 vs 551 0.459 0.370 0.569 <0.0001
Recipient body weight: <20 kg vs ≥20 kg 2293 vs 728 0.557 0.459 0.675 <0.0001
Transplant type: LDLT vs DDLT and Domino LT 2371 vs 76 0.532 0.289 0.981 0.043
Center experience: <100 cases vs ≥100 cases 854 vs 2493 1.254 1.031 1.526 0.024
Transplant era: 1989–2004 vs 2005–2018 1143 vs 1904 1.828 1.548 2.159 <0.0001
BMI, body mass index; DDLT, deceased donor liver transplantation; LDLT, living donor liver transplantation; LT, liver transplantation.

The 3 decades in the study period can be categorized into 3 eras: 1989–2000, 2001–2010, and 2011–2018. If we compare available deceased donor according to era, there was a progressive increase in the percentage of DDLT during these 3 decades, with percentage of 0.34%, 0.81%, and 4.82%, respectively (P < 0.0001).

ABO-incompatible LT was increasingly implemented during these 3 decades, with rates of 10.9%, 14.6%, and 17.5%, respectively. Although there was a significant difference in long-term graft survival between recipients with ABO-identical/compatible donors versus incompatible donors, the graft survival rate in the most recent era did not differ to a statistically significant extent, with 5-y survival rates of 89.9% and 88.8%, respectively (Figure 4). Overall, 1-y graft survival increased from a mean of 63.6% in 1990 to 94.5% in 2018 (P < 0.0001) (Figure S1, SDC, https://links.lww.com/TP/C101). Significant improvements in patient survival were obtained in the most recent years, with a 10-y graft survival rate of 89.0%.

F4
FIGURE 4.:
Graft survival in Japan according to ABO compatibility and transplant era.

DISCUSSION

We reviewed the outcomes of 3271 pediatric LT recipients included in the JLTS dataset. The graft survival rates observed in the Japanese pediatric LT series were excellent, approaching 88.9%, 85.9%, 82.2%, 77.1%, and 75.4% at 1, 5, 10, 20, and 30 y post-LT, respectively. The present results compare favorably with published data from a noteworthy Western series on pediatric LT.15,16

In Japan, the “Revised Brain Death Law” in 2010 resulted in a marginally increased tendency for deceased donor organ donation. However, the demand from patients waiting for LT has not been sufficiently satisfied. Given this lack of significant progression in DDLT, LT in Japan has largely been centered on LDLT (97.7%) using partial liver grafts from healthy relative donors. One of the interesting findings of this study is that DDLTs and domino LTs were applied as alternative treatments to LDLT for specific pediatric liver diseases, for which LDLT is challenging to perform. Parental LDLT is difficult for patients with certain conditions, particularly with a potentially heterozygous parental donor, such as inherited metabolic liver disease (X-linked maternal donor of OTCD, homozygous hypercholesterolemia, protoporphyria, and protein C deficiency), and autoimmune liver disease (primary sclerosing cholangitis). In patients with pediatric liver disease for which LDLT is known to be associated with an unsatisfactory prognosis, DDLT should be considered as first-line treatment. Overall promotion of deceased donor organ transplantation is still an alternative in solid organ transplantation in Japan.

In this study, donor age ≥50 y, donor BMI ≥25.0, ABO incompatible LT, recipient age ≥10 y, recipient body weight ≥20 kg, etiology of liver disease, transplant type (DDLT), transplant center experience (<100 cases in total), and transplant era (year 1989–2004) were found to be significant predictors of overall poorer graft survival. Japan is witnessing an aging of the population (in 2019, it was estimated that 28.4% of the population was >65 y of age) and a decline in the birth rate (total fertility rate: 1.42 births per woman according to 2019 statistics) at a rate that is unparalleled in the world.17 Due to the background of a “superaging” society with low birth rate, the annual number of pediatric LT procedures has been steadily decreasing in recent years, although the median donor age and BMI have not changed appreciably during these 30 y. According to the World Health Organization Asia Pacific guidelines, BMI > 25 was considered as obese, and 51.4% of Japanese obese population showed fatty liver.18,19 Therefore, preoperative exercise and diet in the donors will be an important issue, especially in LDLT.

ABO-incompatible LDLT has been performed to mitigate the problems of the organ shortage in Japan since the early 1990s.20 The graft survival rate of children <2 y of age receiving ABO-incompatible grafts was reported to be similar to that of children receiving compatible grafts.11 However, graft 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 nonanastomotic biliary strictures attributable to arteriole insufficiency.21 ABO-incompatible grafts were used in 14.7% of the recipients in the present study and have been increasingly indicated in recent years. The recent introduction of rituximab and preoperative plasma exchange to reduce the isoagglutinin titer in ABO-incompatible cases has improved graft survival by inducing B-cell desensitization.22 The current immunosuppression protocol for ABO-incompatible LT in Japan consists of Rituximab infusion (200–375 mg/m2) 2–3 wks before LT, pre-LT plasma exchange (targeted at recipient isoagglutinin titer ≤1:8), and mycophenolate mofetil as an additional immunosuppressant.11 Recently, rituximab prophylaxis with preoperative plasma exchange has been widely applied in Japan, and ABO incompatibility did not affect graft survival.

Although short-term graft survival has significantly improved during the 3 decades, adolescent age at the time of solid organ transplantation has been recognized as a risk factor for poor long-term graft survival in liver, kidney, heart, and lung transplantation.23 Our findings are consistent with a prior study demonstrating that recipients ≥10 y of age and ≥20 kg at the time of LT had a higher risk of graft failure than other age groups. It has been hypothesized that the increased risk of graft loss during adolescence is due to the transition from pediatric care to adult care, a lack of adherence to immunosuppression, changes in health insurance coverage, and adverse effects of the long-term use of immunosuppression.24 Several reports have demonstrated that there are developmental differences in the immune function in each generation, with regard to adaptive immunity. While Th2/anti-inflammatory cytokines (IL-10)/T-reg is high in young children, Th1/proinflammatory cytokines (IL-1β and TNF-α) increase with age.25,26 It is conceivable that this age window represents a period of heightened immunologic risk with decreased immune tolerance, although there is no evidence to support this hypothesis regarding the change in immune function. The increased risk of graft loss during adolescence is most likely multifactorial, and prospective studies of the transition process are now underway to clarify these points in the JLTS.

With the accumulation of experience, the indications for LT have changed over the 3 decades. BA was previously a leading indication; however, there are numerous other diseases that may become clinically evident in various age groups and which may lead to the decision to perform LT. The study population included patients with several diseases that are associated with a poor prognosis, such as PSC and autoimmune hepatitis with LDLT, chronic hepatic graft-versus-host disease, Langerhans cell histiocytosis, mitochondrial depletion syndrome, protoporphyria, ECHS1 deficiency, and hepatic sarcoma. A precise diagnosis and the timing of transplantation are crucial, and the indications for LT should be discussed on a case-by-case basis to improve the prognosis, especially for patients with rare diseases.

Because the percentage of DDLT has been progressively increased, LDLT is still a major treatment modality for the end-stage liver disease children in Japan. Although LDLT and DDLT are complementary and not competitive strategies, DDLT may be the only treatment modality for recipients with poor prognostic factors for LDLT. Of note, we could not achieve sufficient graft survival in pediatric DDLT or split LT in comparison to LDLT in the present study. We need to learn from experienced countries regarding donor selection criteria, indications, procurement technique, preservation methods, and immunosuppression for pediatric DDLT and split LT.27-29

The present study was associated with some limitations, including restrictions on information contained within the JLTS dataset, as well as the accuracy and consistency of that information. We did not have access to preoperative patient conditions, including the Pediatric End-Stage Liver Disease score, recipient or donor laboratory data, immunosuppression protocols, recipient or donor morbidity, surgical complications, and cause of death, growth, or quality of life (QOL) measures. Recently, Korean multicenter study demonstrated that live liver donors have increased long-term mortality risk compared with similar healthy controls. Therefore, long-term follow-up, including psychosocial support, is needed for live liver donors.30 As LDLT and domino LT have been revealed to increase the donor pool and decreased pediatric waiting list mortality, the pediatric population will possibly remain dependent on the additional LDLT and domino LT program to further reduce the waiting list mortality. Further investigations are required to determine the most important causes of death during long-term follow-up after LT.

We hope that the refinement of procedures and immunosuppression protocols will lead to the further improvement of long-term outcomes and QOL in patients undergoing LT for pediatric liver diseases. We should always remember that we are trying to obtain excellent long-term outcomes in pediatric liver transplant recipients with a favorable QOL for all who are involved in the process.

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