Waiting list mortality for pediatric deceased donor liver transplantation in a Japanese living‐donor–dominant program

Living donor liver transplantation (LDLT) has become a major life‐saving procedure for children with end‐stage liver disease in Japan, whereas deceased donor liver transplantation (DDLT) has achieved only limited success. The annual number of pediatric liver transplantations is approximately 100‐120, with a patient 20‐year survival rate of 81.0%. In 2005, the liver transplantation program at the National Center for Child Health and Development in Tokyo, Japan, was initiated, with an overall number of 560 pediatric patients with end‐stage liver disease to date. In July 2010, our center was qualified as a pediatric DDLT center; a total of 132 patients were listed for DDLT up until February 2019. The indications for DDLT included acute liver failure (n = 46, 34.8%), metabolic liver disease (n = 26, 19.7%), graft failure after LDLT (n = 17, 12.9%), biliary atresia (n = 16, 12.1%), and primary sclerosing cholangitis (n = 10, 7.6%). Overall, 25.8% of the patients on the waiting list received a DDLT and 52.3% were transplanted from a living donor. The 5‐year patient and graft survivals were 90.5% and 88.8%, respectively, with an overall waiting list mortality of 3.0%. LDLT provides a better survival compared with DDLT among the recipients on the DDLT waiting list. LDLT is nevertheless of great importance in Japan; however, it cannot save all pediatric recipients. As the mortality of children on the waiting list has not yet been reduced to zero, both LDLT and DDLT should be implemented in pediatric liver transplantation programs.     

Pediatric liver retransplantation from living donors can be considered as a therapeutic option for patients with irreversible living donor graft failure

Liver retransplantation (re-LT) is required in patients with irreversible graft failure, but it is a significant issue that remains medically, ethically, and economically controversial, especially in living donor liver transplantation (LDLT). The aim of this study was to evaluate the outcome, morbidity, mortality, safety and prognostic factors to improve the outcome of pediatric living donor liver retransplantation (re-LDLT). Six of 172 children that underwent LDLT between January 2001 and March 2010 received a re-LDLT and one received a second re-LDLT. The overall re-LDLT rate was 3.5%. All candidates had re-LDLT after the initial LDLT. The overall actuarial survival of these patients was 83.3% and 83.3% at one and five yr, respectively. These rates are significantly worse than the rates of pediatric first LDLT. Vascular complications occurred in four patients and were successfully treated by interventional radiologic therapy. There were no post-operative biliary complications. One case expired because of hemophagocytic syndrome after re-LDLT. Although pediatric re-LDLT is medically, ethically, and economically controversial, it is a feasible option and should be offered to children with irreversible graft failure. Further investigations, including multicenter studies, are therefore essential to identify any prognostic factors that may improve the present poor outcome after re-LDLT.     

Impact of liver transplantation on HRQOL in children less than 5 years old

Our primary goal was to assess health related quality of life (HRQOL) at transplantation and 1 yr after transplantation in pediatric liver transplant patients aged less than 5 years. We conducted a prospective longitudinal study of HRQOL in pediatric liver transplant recipients, aged less than 5 years to define the impact of liver transplantation on HRQOL and identify factors that predict HRQOL after transplantation. The infant toddler health status questionnaire (ITHQ) was completed at the time of listing for liver transplantation and at 6 and 12 months after liver transplantation. The primary outcome measures were the subscale scores that comprise ITHQ. The mean age (+/-s.e.m.) of the enrolled patients (n = 45) at transplantation was 1.4 (+/-1.2) yr. Thirty-eight (84%) of the enrolled patients completed the study. The highest mean baseline scores of 78.6 (+/-3.3) were for global mental health (GlobalMH). ITHQ subscale scores increased steadily after transplantation. The greatest increase was in the first 6 months after transplant. At 1 yr after transplantation, there were significant increases in all of the ITHQ subscale scores except for GlobalMH. ITHQ subscales were similar for patients who received LDLT compared with those who received cadaver donor liver transplantation (CDLT) at baseline and a year after transplant. Time elapsed as transplantation was a significant predictor of functional health in all of the models generated. Scores for general health (GH), global health (GGH), parental time-impact (PT) and parental time-emotion (PE) were higher for male children. Family cohesion (FC) improved with time elapsed since transplant and increased number of inpatient days. HRQOL improves after transplantation in all of our patients irrespective of the donor type. Functional health scores were higher in patients with normal serum bilirubin at 1 yr post-transplant. Assessment of HRQOL should be an integral part of care for liver transplant patients and their caregivers.     

Hepatic artery reconstruction in pediatric living donor liver transplantation under 10 kg, without microscope use

Enne M, Pacheco-Moreira L, Balbi E, Cerqueira A, Alves J, Valladares MA, Santalucia G, Martinho J-M. Hepatic artery reconstruction in pediatric living donor liver transplantation under 10 kg, without microscope use.
Pediatr Transplantation 2010: 14: 48–51. © 2009 John Wiley & Sons A/S.
Abstract:  Arterial reconstructions are pivotal, particularly in pediatric LDLT. We describe microsurgical reconstruction technique with 6× loupes and the clinical course of the first 23 less than 10 kg recipients in an initial LDLT program at a developing country. From March 2002 to October 2008, 286 liver transplantation were performed in 279 patients at our unit. There were 73 children and 206 adults. Among the children, 23 weighing less than 10 kg were recipients from living donors. Arterial reconstructions were with end-to-end interrupted suture using a 6× magnification loupe, according to the untied suture technique. All patients were prospectively followed by color Doppler ultrasound protocol. In our initial experience there were no arterial complications. With mean 24 months of follow-up, 19 patients (82%) are alive with good graft function. Hepatic artery in LDLT can be safely reconstructed with microsurgical techniques without microscope using, with 6× loupe magnification, and can achieve good results in patients under 10 kg.     

Early graft failure due to a veno-occlusive disease after a pediatric living donor liver transplantation

A 10-month-old boy with biliary atresia after Kasai procedure underwent a living donor liver transplantation (LDLT). Five days after the LDLT, high fever and increased ascites followed by poor bile drainage was accompanied by elevation of serum liver enzymes. Liver biopsy showed occlusion of the central veins by fibro-edematous endothelium and submassive necrosis of the parenchyma. Veno-occlusive disease (VOD) was suspected, and re-LDLT was urgently performed because of deterioration of hepatic failure. There are few cases of VOD after liver transplantation and this is the first one in an infant after LDLT.     

Biliary reconstruction before clamp removal to avoid portal vein thrombosis in pediatric living‐donor liver transplantation using hyper‐reduced left lateral segment grafts: A novel technical strategy

LT has become the treatment of choice for children with end‐stage liver disease. The scarcity of donors and the considerable mortality on waiting lists have propelled the related living‐donor techniques, especially in small children. This population need smaller and good quality grafts and are usually candidates to receive a LLS from a related donor. Many times this grafts are still large and do not fit in the receptor's abdomen, so a further hyper‐reduction may be required. Despite all advances in LT field, vascular complications still occur in a considerable proportion remaining as a significant cause of morbidity, graft loss, and mortality. Technical issues currently play an essential role in its genesis. The widely spread technique for biliary and vascular reconstruction in living donor LT (LDLT) nowadays implies removal of the portal vein (PV) clamp after the venous anastomosis, then the arterial reconstruction is done, followed by the biliary reconstruction. However, due to the posterior location of the LLS bile duct, for its reconstruction, a rotation of the liver is required risking a potential transient PV occlusion leading to thrombosis afterward. We describe a new technique that involves performing biliary reconstruction after the PV anastomosis and before removing the vascular clamp, thus allowing to freely rotate the liver with less risk of PV occlusion and thrombosis.     

Living donor liver transplantation in Alagille syndrome—Single center experience from south Asia

To analyze the clinical characteristics and the outcomes of living donor liver transplantation in children with Alagille syndrome (AGS). Clinical data of children with AGS who underwent liver transplantation between July 2009 and May 2019 in our unit were retrospectively analyzed. Primary end‐points were patient and graft survival. Ten children with AGS underwent living donor liver transplantation at a median age of 28 months (range, 12‐84 months). Jaundice was the most common initial symptom and was noted after a median duration of 20 days after birth (range, 7‐60 days). Two patients had undergone Kasai porto‐enterostomy for misdiagnosis of biliary atresia. The most common indication for transplantation was severe pruritus with poor quality of life. Explant livers in three children showed cirrhosis with early well‐differentiated hepatocellular carcinoma. We have 100% patient and graft survival at a mean follow‐up of 32 months (range 3‐72 months). The median z‐score for weight and height at liver transplantation was ?2.66 (range: ?6.44 to ?0.9) and ?3.6 (range: ?7.96 to ?0.93) while at follow‐up was ?1.7 (range: ?3.4 to ?0.35) and ?2.1 (range: ?3.9 to ?1.4), respectively. The estimated glomerular filtration rate was normal pretransplant and follow‐up. This is the first series of LDLT for Alagille syndrome in the Indian sub‐continent. We report excellent post‐transplant outcomes in contrast to outcomes reported from Western literature.     

Lymphocytotoxic crossmatch in pediatric living donor liver transplantation

Abstract:  To investigate the relationship between the pretransplant LCT results and the outcome after pediatric LDLT in a single center. The clinical data of 76 children undergoing 79 LDLTs including three retransplantations from May 2001 to January 2006 were retrospectively analyzed. All of the children had end-stage liver disease, and their median age was 1.4 yr (range, six months to 16.5 yr). Immunosuppressive therapy consisted of cyclosporine- or FK-based regimens with steroids. The children were classified into two groups (positive or negative) according to the pretransplant LCT results. The incidences of post-transplant surgical complications and of rejection episodes were compared. The relationship between the pretransplant LCT results and patient and graft survival rates was also analyzed. Seventy-nine pretransplant crossmatch tests were done; 13 (16.5%) were positive, and 66 (83.5%) were negative. No significant difference was found in the pretransplant clinical factors between two crossmatch groups. There was no significant difference between the groups in the incidence of vascular and biliary tract complications, in the rate of early or steroid-resistant cellular rejections, or in one- and three-yr patient (91.7%, 91.7%, respectively, in the positive group, 93.5%, 93.5%, respectively, in the negative group, p = 0.80) and graft (92.3%, 92.3%, respectively, in the positive group, 88.8%, 86.4%, respectively, in the negative group, p = 0.63) survival. The present study demonstrates that there is no reason to do pretransplant LCT to select the living donor for pediatric LDLT.     

Liver graft volumetric changes after living donor liver transplantation with segment 2 graft for small infants

Urahashi T, Mizuta K, Sanada Y, Wakiya T, Yasuda Y, Kawarasaki H. Liver graft volumetric changes after living donor liver transplantation with segment 2 graft for small infants. Abstract: LT for small infants weighing <5 kg with liver failure might require innovative techniques for size reduction and transplantation of small grafts to avoid large‐for‐size graft, but little is known about post‐transplant graft volumetric changes. Five of 172 children who underwent LDLT received monosegment or reduced monosegment grafts using a modified Couinaud’s segment II (S2) graft for LDLT. Serial CT was used to evaluate the changes in the GV and other factors before LDLT and one and three months after LDLT. The shape of these grafts was classified into an OL type and an LL type. The GV increased in all patients one month after LDLT, whereas the GV decreased three months after LDLT in OL in comparison with one month after LDLT. The GRWR of the OL type has tended to decrease at three months, whereas the LL type showed a continuous increase with time, but finally they had adapted graft size for their body size. In conclusion, the volume of S2 grafts after LDLT had unique changes toward the ideal volume for the child weight when they received the appropriate liver volume.     

Selection of donors for living donor liver transplantation in a single center of a developing country: lessons learned from the first 100 cases

The selection of donors for living donor liver transplantation (LDLT) is one of the most important features in this kind of surgery. The aim of this study is to describe our initial experience in the donor evaluation process. From December 2001 to January 2005, 104 donors were evaluated for 70 recipients (65 potential donors were evaluated for 39 adult recipients, and 39 donors for 31 pediatric recipients). Only 30 donors were able to donate: 13 for the adult group, and 17 for the pediatric one. In general, the utilization rate of potential donors was 28.8% (30/104). For the adult patients, 65 potential donors were seen to perform 13 LDLT, which represents a utilization rate of potential donors of 20%. For the pediatric patients, this rate was 43.6%. The exclusion criteria were clinical in 22 cases (21%), anatomical in 13 cases (13%), psychosocial in nine cases (9%), and others in 12 (12%). Death of recipients led to exclusion 18 of donors (17%). Thirty-three percent of adults and 55% of pediatric recipients who had at least one potential donor to start the evaluation process were able to identify a living donor. In conclusion, the first limit for LDLT is the rigorous donor evaluation.     

Hyperammonemia in ornithine transcarbamylase‐deficient recipients following living donor liver transplantation from heterozygous carrier donors

Ornithine transcarbamylase deficiency (OTCD) is a urea cycle disorder of X‐linked inheritance, affecting the detoxification of excess nitrogen and leading to hyperammonemia (hyper‐NH₃). Living donor liver transplantation (LDLT) has been applied for the treatment of OTCD. This case series retrospectively reviewed two OTCD patients who experienced hyper‐NH₃ following LDLT. The first case was a 5‐year‐old girl who had onset of OTCD at 2 years of age. Ornithine transcarbamylase (OTC) enzyme activity was 62% for the donor and 15% for the recipient. The patient suffered from recurrence of hyper‐NH₃ within 2 months following LDLT. The second case was a 5‐year‐old girl who had onset of OTCD at 3 years of age. OTC enzyme activity was 42.6% for the donor and 9.7% for the recipient. The patient suffered hyper‐NH₃ for 12 days starting on the date of surgery. Both of the patients transiently required continuous veno‐venous hemodialysis; however, they are currently doing well without intensive medical treatment. The use of asymptomatic OTCD heterozygous donors in LDLT has been accepted with careful examination. However, an OTCD heterozygous carrier donor should be avoided if there is another donor candidate, due to the potentially fatal condition of hyper‐NH₃ following LDLT.     

Long‐term outcomes of pediatric living donor liver transplantation at a single institution

Oh SH, Kim KM, Kim DY, Lee YJ, Rhee KW, Jang JY, Chang SH, Lee SY, Kim J‐S, Choi BH, Park S‐J, Yoon CH, Ko G‐Y, Sung K‐B, Hwang G‐S, Choi K‐T, Yu E, Song G‐W, Ha T‐Y, Moon D‐B, Ahn C‐S, Kim K‐H, Hwang S, Park K‐M, Lee Y‐J, Lee S‐G. Long‐term outcomes of pediatric living donor liver transplantation at a single institution.
Pediatr Transplantation 2010: 14:870–878. © 2010 John Wiley & Sons A/S. Abstract: There have only been a few studies on the long‐term outcomes and prognostic factors after pediatric LDLT. We conducted a retrospective, single‐center assessment of the outcomes as well as the demographic and clinical factors that influenced the poor outcomes in 113 children aged <16 (median age 21 months; 6 months–15.5 yr) who underwent 115 LDLTs, predominantly for biliary atresia (60.9%) and FHF (14.8%), between 1994 and 2006 at Asan Medical Center. Left lateral segment or left lobe grafts were implanted into most of these children (86.9%) according to routine procedures. The overall rates of graft survival at one, five, and 10 yr were 89.6%, 83.0%, and 81.5%, respectively, and the overall rates of patient survival were 92.9%, 86.3%, and 84.8%, respectively. Virus‐related disease (41.2%) and chronic rejection (29.4%) were the major causes of mortality. On multivariate analysis, UNOS status 1a and 1b and chronic rejection were significant risk factors for both graft and patient loss, whereas the PELD score >25 was a significant risk factor for graft loss. Patient and graft survival may be related not only to post‐operative complications, but also to the patient’s preoperative clinical condition.     

Transfusion requirements during cadaveric and living donor pediatric liver transplantation

Surgical techniques that have been used during liver transplantation (LT) together with patient's coagulation profile and institutional practices are reported to have an effect on transfusion requirements. The aim of this study is to evaluate the transfusion requirement in both cadaveric (CDLT, n = 22) and living donor (LDLT, n = 24) pediatric LT performed in our institution. Balanced general anesthesia was used for all patients. Transfusion requirements were met to maintain a hemoglobin concentration of 8-10 g/dL, platelet level >50 x 10(3)/mL, prothrombin time <20 s and hemodynamic course with observing heart rate, arterial and central venous blood pressures and hourly urine output. Blood loss was replaced by using whole blood. Both groups' perioperative total blood and fresh-frozen plasma (FFP) volumes transfused, fluid requirements and hemodynamic courses, standard coagulation profile and metabolic variables determined in time periods of operations, patients' preoperative characteristics, operative features and postoperative events were compared. The mean transfusion requirements were 37.1 +/- 33.4 and 74.8 +/- 90.8 mL/kg of whole blood (p = 0.059) and 34.5 +/- 24.9 and 51.5 +/- 59.7 mL/kg of FFP for CDLT and LDLT, respectively (p = 0.519). The mean ages and mean body weights of the CDLT patients were higher than LDLT patients (9.7 +/- 5.3 vs. 6.6 +/- 4.4 yr, p = 0.015 and 32.4 +/- 17.7 vs. 21.0 +/- 14.8 kg, p = 0.032, respectively) while the mean operation time (493 +/- 135 vs. 323 +/- 93 min, p = 0.0001) and PELD score (13.1 +/- 11.2 vs. 20.1 +/- 11.8, p = 0.036) were higher for LDLT. In the entire population, multiple regression analysis showed that age, body weight and operation time have a significant combined effect on blood consumption (r2= 0.29, p = 0.003) meanwhile operation time was found to be an effective single variable (p = 0.002). None of the single or combined variables was found to have a significant effect on FFP consumption (r2= 0.17, p = 0.63) and crystalloid use (r2= 0.19, p = 0.11). Hemodynamic courses of both groups were similar. The incidences of metabolic acidosis and hypothermia during the anhepatic periods were higher in the CDLT group (p < 0.05). However, transfusion requirement in the ICU were higher in LDLT group [6.9 +/- 2.2 (n = 6) vs. 18.6 +/- 19 (n = 11) mL/kg, p < 0.05] after LT. As a result of this study in a pediatric patient population, no statistical significance was found in whole blood transfusion and FFP requirements between CDLT and LDLT. Duration of the operation was the primary factor effecting transfusion volume showing the importance of continued small volume losses during uncomplicated LT in this small sized patient population. Transfusion need for pediatric LT should be individualized for each patient based on the intraoperative conditions including surgical and patient features.     

Current status of liver transplantation

Liver transplantation is accepted therapy for acute or chronic liver failure. Survival after LT has improved significantly in developed countries and this has increased the awareness of this treatment modality in the developing world. Successful LT in both children and adults have now been reported from India. Chronic liver failure secondary to cholestatic liver disease in the most frequent indication for LT, with biliary with atresia as the single commonest cause. Innovative techniques such as reduced size, splint, and living donor liver transplantation are being applied more often to decrease long waiting times and reduce associated morbidity and mortality. Early postoperative complications include primary graft failure, venous thrombosis, rejection, biliary complications and infections. Late complication includes CMV or EBV infections, side effects of immunosuppression, post transplantation lymphoproliferative disease and late biliary strictures. Most children achieve good quality of life. There are still many lessons to learn and there are future challenges such as the ever increasing problems of donor scarcity and the search for potent but less toxic immunosuppressive agents.     

Hepatobiliary scintigraphy for the assessment of biliary stricture after pediatric living donor liver transplantation for hepaticojejunostomy reconstruction: the value of the excretion rate at 60 min

HBS is performed to determine the presence of biliary stricture after liver transplantation. We focused on the Ex-60 after an intravenous injection of tracer during HBS. The aim of this study was to review the cutoff values for the diagnosis of biliary stricture by HBS after pediatric LDLT. We analyzed 114 HBS studies using (99m) Tc-PMT in 80 cases after pediatric LDLT. HBS was performed three months after LDLT on a routine basis and/or was performed when ultrasonography and blood test findings indicated biliary stricture. A ROC curve analysis was performed to identify the cutoff value for the correlation between Ex-60 and biliary stricture. The Ex-60 (mean ± s.d.) in the cases diagnosed as having biliary stricture and in normal subjects were 49.1 ± 20.2% vs. 78.0 ± 9.7% (p < 0.01), respectively. As a result of an ROC curve analysis of the Ex-60, the recommended cutoff value to diagnose biliary stricture was set at 69.2% (sensitivity 87.0%, specificity 81.8%). In cases where the Ex-60 by (99m) Tc-PMT HBS is <69.2%, it is recommended that further treatment for biliary stricture should be provided.     

A case of classical maple syrup urine disease that was successfully managed by living donor liver transplantation

Classical MSUD is often fatal without appropriate medical interventions because of metabolic crisis. There are numerous reports suggesting the therapeutic potential of deceased donor liver transplantation for MSUD. However, the usefulness of LDLT for MSUD is unknown. We report a case of classical MSUD, which was successfully managed by LDLT from the patient's father at 1 year of age. Abnormal brain findings, which were cured with effective treatment, gradually disappeared after LDLT. The patient then developed normally. Findings from this case suggest the importance of LDLT for maintaining low leucine levels and subsequent normal neurological development. Although LDLT involves a modest surgical insult, LDLT with a related donor achieves acceptable leucine levels for life.     

肝移植术后完全停用免疫抑制剂三例儿童临床特点分析

目的 探讨肝移植术后完全停用免疫抑制剂儿童的临床特征,寻找可能与术后免疫耐受形成有关的因素.方法 回顾性分析我院2008年7月至2009年6月间完成的儿童肝移植中完全停用免疫抑制剂的3例患儿资料,包括:移植年龄、原发疾病、供肝来源、术后免疫抑制剂、随访检查结果等.结果 3例完全停药儿童的原发病均为胆道闭锁,平均移植年龄7个月17 d,均为母体活体供肝肝移植,肝移植术后免疫抑制剂方案均为强的松龙+环孢素A,服药至少2年以上,完全停药1年以上.结论 移植年龄＜1岁、原发病为胆道闭锁、母体供肝、服药2年以上、服用环孢素A是这些完全停药儿童的共同特征.     

Living-donor liver transplantation for carbamoyl phosphate synthetase 1 deficiency

CPS1 is a mitochondrial matrix enzyme that catalyzes the first committed step of the urea cycle, the primary system for removing nitrogen produced by protein metabolism using N-acetylglutamate. Patients with CPS1 deficiency have severe hyperammonemia that results in serious neurologic sequelae and sometimes death. LT has been indicated for neonatal-onset CPS1 deficiency. This study retrospectively reviewed five children with a diagnosis of CPS1 deficiency who underwent LDLT from heterozygous donors. Between November 2005 and May 2010, 124 children underwent LDLT with an overall patient and graft survival of 91.0%. Five patients were indicated for LDLT because of CPS1 deficiency. All recipients achieved resolution of their metabolic derangement, without donor complication, with a normal feeding regimen without medication for their original metabolic liver disease. LDLT, even from heterozygous donors, appears to be a feasible option, associated with a better quality of life for treating patients with CPS1 deficiency. Long-term observation may therefore be necessary to collect sufficient data to confirm the efficacy of this treatment modality.     

Bowel obstruction due to diaphragmatic hernia in an elder child after pediatric liver transplantation

A 10-yr-old boy with end-stage liver cirrhosis due to Wilson's disease received a living donor liver transplantation (LDLT) at our institution. The donor was his father and the graft was a left lateral segment. The liver transplantation procedure and the postoperative course were uneventful. Two months after the procedure, he developed a first episode of bowel obstruction that was treated with conservative therapy. During a second episode of bowel obstruction, he also presented respiratory distress. A plain chest X-ray revealed the presence of small intestine loops in the right thoracic cavity and bowel obstruction due to diaphragmatic hernia was diagnosed. Repair of the diaphragmatic hernia was performed and the patient has been doing well after the surgery. Diaphragmatic hernia after LDLT is rare but should be recognized as a possible complication when a left lobe or a left lateral segment graft is used.     

Hepatic artery reconstruction with inferior mesenteric vein graft in pediatric living donor liver transplantation

Abstract:  We report a transplant of the left lateral liver segments with two arteries for a pediatric recipient from a live donor. A six-month-old female patient was diagnosed with liver cirrhosis secondary to biliary atresia and scheduled for LDLT (father as donor). Left lateral hepatectomy was performed at the donor site. The dissection of the left HA, which divided immediately after its origin, showed two branches for segments II and III. The artery for segment III was anastomosed to the recipient HA. The artery for segment II was too short for direct anastomosis with the gastroduodenal artery. After an unsuccessful attempt to use of the recipient's saphenous vein, the recipient's IMV was used as an interposition graft. No post-operative complications were observed. The outcome of this case demonstrates that left lateral segments with two arteries can be successfully used if proper surgical techniques are applied. From this experience we can recommend the IMV as an alternative to the saphenous vein for an interposition graft.