Living-donor liver transplantation for methylmalonic acidemia patient with hepatocellular carcinoma: A case report and literature review.

BACKGROUND: Methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by defects in propionyl-CoA (P-CoA) catabolism; of note, liver neoplasms rarely occur as a long-term complication of the disorder. Herein, we report the case of a patient with MMA and hepatocellular carcinoma (HCC) who was successfully treated with a living-donor liver transplant (LDLT) following prior kidney transplantation. CASE REPORT: A 25-year-old male patient with MMA underwent LDLT with a left lobe graft because of metabolic instability and liver neoplasms. He had presented with chronic symptoms of MMA, which had been diagnosed by genetic testing. Additionally, he had undergone living-donor kidney transplantation with his father as the donor due to end-stage kidney disease 6 years before the LDLT. He had an episode of metabolic decompensation triggered by coronavirus disease in 2019. Imaging studies revealed an intrahepatic neoplasm in the right hepatic lobe. Due to concerns about metabolic decompensation after hepatectomy, LDLT was performed using a left lobe graft obtained from the patient's mother. Pathological findings were consistent with the characteristics of well-to-moderately differentiated HCC. The postoperative course was uneventful, and the patient was discharged 48 days after the LDLT without any complications. At the 9-month follow-up, the patient's condition was satisfactory, with sufficient liver graft function and without metabolic decompensation. CONCLUSION: This case indicates that although HCC is a rare complication in patients with MMA, clinicians should be aware of hepatic malignancies during long-term follow-up.

"Reduced Size Liver Grafts in Pediatric Liver Transplantation; Technical Considerations".

Liver transplantation (LT) has become a vital treatment option for children with end-stage liver disease. Left lateral segment (LLS) grafts are particularly common in split and living donor LT for pediatric patients. However, challenges arise in small infants receiving LLS grafts, primarily due to graft-size mismatches, resulting in "large-for-size" grafts. To overcome this issue, the practice of further reducing grafts from the LLS to diminish graft thickness has been explored. Currently, the indication for reducing the thickness of LLS grafts includes recipients with a body weight (BW) under 5.0 kg, neonates with acute liver failure, or those with metabolic liver disease. At the National Center for Child Health and Development in Tokyo, Japan, among 131 recipients of reduced-size LLS grafts, a remarkable 15-year graft survival rate of 89.9% has been achieved in small infants. This success indicates that with experience and refinement of the technique, there's a trend towards improved graft survival in recipients with reduced-thickness LLS grafts. This advancement underscores the importance of BW-appropriate methods in graft selection to ensure exceptional outcomes in vulnerable pediatric patients in need of LT. These techniques' ongoing development and refinement are crucial in enhancing the survival rates and overall outcomes for these young patients.

The role of liver transplantation in COACH syndrome (Joubert syndrome with congenital hepatic fibrosis): A review of the literature.

BACKGROUND: COACH syndrome is a rare autosomal recessive genetic disease characterized by liver fibrosis, which leads to severe complications related to portal hypertension. However, only a few patients with COACH syndrome undergoing liver transplantation (LT) have been reported. MATERIALS AND METHODS: We herein report the outcomes of four children who underwent LT for COACH syndrome at our institute and review three previously reported cases to elucidate the role of LT in COACH syndrome. RESULTS: All four patients in our institute were female, and three received living donors LT. All patients were diagnosed with COACH syndrome by genetic testing. LT was performed in these patients at 3, 7, 9, and 14 years old. The indication for LT was varices related to portal hypertension in all patients. One showed an intrapulmonary shunt. Blood tests revealed renal impairment due to nephronophthisis in three patients, and one developed renal insufficiency after LT. The liver function was maintained in all patients. A literature review revealed detailed information for three more patients. The indication for LT in these three cases was portal hypertension, such as bleeding from esophageal varices. One patient had chronic renal failure on hemodialysis at LT and underwent combined liver and kidney transplantation. Of these three previous patients, one died from hepatic failure due to de novo HCV infection 3 years after LT. CONCLUSIONS: LT should be considered an effective treatment for COACH syndrome in patients with severe portal hypertension. However, a detailed follow-up of the renal function is necessary.

Optimal liver transplant procedure in progressive familial intrahepatic cholestasis type 1 treated with biliary diversion or intestinal transplantation: Lessons learned from three cases treated with different approaches.

BACKGROUND: Progressive familial intrahepatic cholestasis type 1 (PFIC1) is an autosomal recessive cholestatic liver disorder caused by ATP8B1 gene mutations. Although liver transplantation (LT) is indicated for progressive liver disease, postoperative complications, including severe diarrhea and graft steatohepatitis leading to graft loss, have been reported. CASES: The first patient had jaundice, pruritus, diarrhea, and growth retardation (weight z-score: -2.5; height z-score: -3.7). She underwent LT with total internal biliary diversion (TIBD) to the colon at 2 years of age. Graft biopsy at the 7-year follow-up examination revealed microvesicular steatosis (60%). Her diarrhea improved, and her growth failure was recovering (weight z-score: -1.0; height z-score: -1.7). The second patient underwent sequential intestine-liver transplantation at 8 years of age due to end-stage liver disease (ESLD) and short bowel syndrome caused by massive bowel resection for internal hernia after partial external biliary diversion (PEBD) at 21 months of age. She developed severe pancreatitis induced by steroid-bolus therapy for rejection after transplantation. She died 1.7 years after intestinal transplantation due to an uncontrollable pancreatic abscess and acute respiratory distress syndrome. The third patient underwent PEBD at 15 months of age and received LT with TEBD at 15 years of age due to ESLD with hepatic encephalopathy. Throughout the perioperative period, she showed no abdominal symptoms, including diarrhea and pancreatitis. Graft biopsy at the 2-year follow-up examination revealed macrovesicular steatosis (60%) with inflammation. CONCLUSIONS: The patients showed different outcomes. Effective therapeutic options to mitigate post-LT complications in patients with PFIC1 must be considered individually.

Gallstone ileus at 17 years after living donor liver transplantation: A case report.

BACKGROUND: Gallstone ileus (GI) occurs in <0.1% of all cases of mechanical bowel obstruction. There have been a few reports of GI occurring after Kasai procedures or Roux-en-Y anastomosis for bariatric surgery. We herein report a case of GI that occurred over 17 years after liver transplantation (LT). CASE REPORT: A 33-year-old woman who had undergone living donor LT for biliary atresia at 16 years old and had been regularly followed on an outpatient basis in our hospital presented with the sudden onset of increased abdominal distension, pain, and nausea. Enhanced abdominal computed tomography showed dilatation of the intrahepatic bile duct and the whole intestinal tract of the Roux limb as well as ischemic changes near the jejuno-jejunal anastomosis. On laparotomy, a movable and hard foreign body was palpated in the intestinal tract close to the jejuno-jejunal anastomosis site. Enterotomy was performed, and a 4-cm gallstone was removed. The patient had a good postoperative course and was discharged on postoperative day 12. CONCLUSIONS: Although GI after LT is a rare complication, it may need to be differentiated as a cause of ileus. An accurate differential diagnosis and early reliable intervention for stone removal will help prevent serious bowel complication, which may lead to graft dysfunction.

Successful pediatric liver transplantation case with a positive SARS-CoV-2 test at the time of transplant.

AIM: We report a successful liver transplantation (LT) in a child with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. CASE PRESENTATION: A 3-year-old female patient with decompensated cirrhosis due to Alagille syndrome underwent a split LT with a left lateral segment graft. She had a history of SARS-CoV-2 infection 4 months before LT. She was exposed to SARS-CoV-2 after the decision for organ acceptance. We repeatedly confirmed the negative SARS-CoV-2 test by polymerase chain reaction (PCR) before LT. Liver transplantation was carried out in the negative pressure operational theater with full airborne, droplet, and contact precautions as the patient was considered to be within the incubation period of SARS-CoV-2. The SARS-CoV-2 PCR test became positive in the nasopharyngeal swab specimen at the operation. Remdesivir, the antiviral treatment, was held off due to potential hepatotoxicity and no exacerbation of COVID-19. She received tacrolimus and low-dose steroids per protocol. She remained SARS-CoV-2 positive on postoperative days (PODs) 1, 2, and 5. The presence of antibodies for SARS-CoV-2 at LT was confirmed later. On POD 53, she was discharged without any symptomatic infection. CONCLUSION: This case demonstrated that a positive SARS-CoV-2 result was not an absolute contraindication for a life-saving LT. Liver transplantation could be safely performed in a pediatric patient with asymptomatic COVID-19 and S-immunoglobulin G antibodies for SARS-CoV-2.

Strategy for hepatoblastoma with major vascular involvement: A guide for surgical decision-making.

BACKGROUND: Surgical management of tumor thrombus extending to the major vascular system for children with hepatoblastoma is challenging and insufficiently discussed. METHODS: We conducted a retrospective review of hepatoblastoma with tumor thrombus extending to the major vascular system (inferior vena cava, 3 hepatic veins, and portal vein trunk) treated at our center between May 2010 and June 2021. We describe our preoperative assessment, surgical strategies, and outcomes. RESULTS: We identified 9 patients (median age at the diagnosis: 3.4 years). All patients received chemotherapy before liver surgery. At the time of the diagnosis, tumor thrombus extended to the portal vein trunk (n = 6), inferior vena cava (n = 3), and 3 hepatic veins (n = 2). Among the 9 patients, 4 underwent liver resection. Liver transplantation was performed in 5 patients. The inferior vena cava wall was circumferentially resected for tumor removal in 1 patient and partially resected in 2 patients. One patient underwent liver transplantation using veno-venous bypass. Patients with tumor thrombus extending to the portal vein trunk were more likely to be managed by liver transplantation in comparison to those with tumor thrombus spreading to the inferior vena cava. The median follow-up period was 5.5 years. One patient underwent transhepatic balloon dilatation for biliary stricture after liver resection. Tumor recurrence was seen in 3 patients (33.3%; lung, n = 2; lymph node and liver, n = 1). No patients died during the follow-up period. CONCLUSION: Surgical intervention for pediatric hepatoblastoma with tumor thrombus extending into the major vascular system is safe, feasible, and achieves excellent outcomes.

Preemptive liver transplant in two patients with primary hyperoxaluria type 1: Clinical significance of nephrolithiasis and nephrocalcinosis.

BACKGROUND: Although nephrolithiasis (NL) and nephrocalcinosis (NC) are very common features of primary hyperoxaluria type 1 (PH1), the long-term prognosis of NL and NC after preemptive liver transplantation (PLT) has not been elucidated. MATERIAL AND METHODS: We describe the cases of two chronic kidney disease (CKD) stage three patients with different clinical courses after PLT for PH1. RESULTS: The first patient underwent PLT at 7 years of age with an estimated glomerular filtration rate (eGFR) of 47.8 ml/min/1.73 m2 . Two years later, she experienced several episodes of obstructive pyelonephritis due to urolithiasis, and developed septic shock in one of these episodes. At the same time as these episodes, preexisting NL and NC progressively improved, with disappearance on X-ray disappeared at 8 years after transplantation. Her renal function has been maintained with an eGFR of 58.7 ml/min/1.73 m2 . The second patient received PLT at 10 years of age with an eGFR of 58.9 ml/min/1.73 m2 . Her renal function has been maintained with an eGFR of 65.9 ml/min/1.73 m2 . She had repeated urolithiasis which started to appear at 3 years after LT. The radiological findings still show bilateral NL and NC, but the stones in the renal pelvis have shown mild improvement. CONCLUSIONS: Regardless of the regression in NC seen on X-ray, long-term maintenance of the renal function in patients with PH1 with CKD stage 3 can be achieved with PLT. In patients with NL, there is a risk of serious complications due to posttransplant immunosuppressive therapy when obstructive pyelonephritis occurs after LT.

Acute Antibody-mediated Rejection Coexisting With T Cell-mediated Rejection in Pediatric ABO-incompatible Transplantation.

The management and outcome of ABO-incompatible (ABO-I) liver transplantation (LT) has been improving over the past few decades. Recently, the introduction of a pathological evaluation of acute antibody-mediated rejection (AMR) for liver allograft has provided a new recognition of allograft rejection in LT. Methods: One hundred and one pediatric ABO-I LTs performed in our institute were retrospectively analyzed. We assessed the clinical manifestations, diagnosis, and treatment of acute AMR, focusing on the recipient age and pathological findings. Results: Twelve cases (11.9%) of acute AMR related to ABO-I were observed. Nine cases developed mixed T cell-mediated rejection (TCMR)/AMR. These consisted of 6 patients in the younger age group for whom the preconditioning treatment was not indicated and 4 patients in the older age group to whom rituximab was administered as planned. Two patients in the older age group to whom preoperative rituximab was not administered as planned developed isolated AMR. Acute AMR in the older group required plasma exchange for treatment, regardless of the coexistence of TCMR. In contrast, those in the younger group were successfully treated by intravenous methylprednisolone pulse and intravenous immunoglobulin without plasma exchange, accounting for mild immune reaction. Conclusions: Acute ABO-I AMR can develop simultaneously with TCMR, even in young patients with a compromised humoral immune response following ABO-I LT. Establishing the accurate diagnosis of AMR with a pathological examination, including component 4d staining, is crucial for optimizing treatment.

Effect of a C5a receptor antagonist on macrophage function in an intestinal transplant rat model.

BACKGROUND: C5a promotes alloreactivity via the C5a receptor 1 (C5aR1) on immune cells, but this has not been confirmed in the case of small intestine transplantation immunity. In the present study, we examined the effect of C5aR1 antagonist (PMX53) on macrophage function in small intestinal transplantation. METHODS: The model was created by heterotopic intestinal transplantation using donor Dark Agouti and recipient Lewis rats. PMX53 was administered starting on the day of operation until postoperative day 7. The graft survivals were compared, and HE staining of grafts, lymphocyte mixed reaction test (MLR, mixed culture of T cells from lymph nodes and spleen cells from donors), and changes in macrophage and T cell accumulation in grafts on day 6 after transplantation were evaluated. In addition, the effect of PMX53 on macrophage differentiation and activation was assessed using macrophages derived from bone marrow (BMDM). RESULTS: Graft survival was significantly prolonged in the therapeutic group compared to the untreated group. Histological evaluation showed that PMX53 inhibited the shortening of the graft villus, and the stimulation index of MLR was significantly lower in the therapeutic group compared to the untreated group. In the therapeutic group, the accumulation of macrophages in intestinal graft and monocyte in blood were reduced, compared with the untreated group. PMX53 decreased the differentiation in BMDM and the mRNA expression of IL-1ß and TNF-α in activated BMDM. CONCLUSION: Inhibition of C5a/C5aR1 signaling appears to regulate macrophage differentiation and suppress rejection in small intestine transplantation immunity.

Clinical outcomes of surgical management for rare types of progressive familial intrahepatic cholestasis: a case series.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of genetic autosomal recessive diseases that cause severe cholestasis, which progresses to cirrhosis and liver failure, in infancy or early childhood. We herein report the clinical outcomes of surgical management in patients with four types of PFIC. CASE PRESENTATION: Six patients diagnosed with PFIC who underwent surgical treatment between 1998 and 2020 at our institution were retrospectively assessed. Living-donor liver transplantation (LDLT) was performed in 5 patients with PFIC. The median age at LDLT was 4.8 (range: 1.9-11.4) years. One patient each with familial intrahepatic cholestasis 1 (FIC1) deficiency and bile salt export pump (BSEP) deficiency died after LDLT, and the four remaining patients, one each with deficiency of FIC1, BSEP, multidrug resistance protein 3 (MDR3), and tight junction protein 2 (TJP2), survived. One FIC1 deficiency recipient underwent LDLT secondary to deterioration of liver function, following infectious enteritis. Although he underwent LDLT accompanied by total external biliary diversion, the patient died because of PFIC-related complications. The other patient with FIC1 deficiency had intractable pruritus and underwent partial internal biliary diversion (PIBD) at 9.8 years of age, pruritus largely resolved after PIBD. One BSEP deficiency recipient, who had severe graft damage, experienced recurrence of cholestasis due to the development of antibodies against BSEP after LDLT, and eventually died due to graft failure. The other patient with BSEP deficiency recovered well after LDLT and there was no evidence of posttransplant recurrence of cholestasis. In contrast, recipients with MDR3 or TJP2 deficiency showed good courses and outcomes after LDLT. CONCLUSIONS: Although LDLT was considered an effective treatment for PFIC, the clinical courses and outcomes after LDLT were still inadequate in patients with FIC1 and BSEP deficiency. LDLT accompanied by total biliary diversion may not be as effective for patients with FIC1 deficiency.

A study of the mechanisms responsible for the action of new immunosuppressants and their effects on rat small intestinal transplantation.

In a series of studies, using an identical rat intestinal transplantation model, we evaluated the effects of several drugs. FK-506 caused a significant attenuation in the proliferation of allogeneic CD4+ T cells and IFN-γ secreting effector functions. FYT720 resulted in a marked reduction in the numbers of lymphocytes, associated with a reduction of T cell recruitment, in grafts. An anti-MAdCAM antibody was next reported to significantly down-regulate CD4+ T cell infiltration in intestinal grafts by blocking the adhesion molecule, and could be useful as an induction therapy. Concerning TAK-779, this CCR5 and CXCR3 antagonist diminished the number of graft-infiltrating cells by suppressing the expression of their receptors in the graft. As a result, it reduced the total number of recipient T cells involved in graft rejection. As the next step, we focused on the participation of monocytes/ macrophages in this field. PQA-18 has been the focus of a novel immunosuppressant that attenuates not only the production of various cytokines, such as IL-2 & TNF-α, on T cells, but the differentiation of macrophages by inhibiting PAK2 as well. In this report, we summarize our previous studies not only regarding the above drugs, but on an anti-complement drug and a JAK inhibitor as well.

Effect of microscopy-assisted portoenterostomy (MAPE) for biliary atresia.

PURPOSE: Portoenterostomy (PE) is the standard treatment for biliary atresia (BA). However, micro-bile ducts are difficult to identify with surgical loupes and dissect systematically. We report the effects of our attempts to dissect hilar tissue using a surgical microscope. METHODS: Microscopy-assisted portoenterostomy (MAPE) was initiated in 2014. Patients born between 2000 and 2013 who underwent PE until day 70 without a surgical microscope for BA were gathered as historical control. MAPE in re-do PE cases (Re-MAPE) was evaluated in the same manner. RESULTS: Ten patients underwent MAPE for BA during the study period. 17 patients in the conventional PE group were gathered. In the MAPE group, the jaundice clearance rate was 80%, compared with 53% in the conventional PE group. Re-MAPE was performed in four patients, who had a jaundice clearance rate of 75%, essentially identical to the rate with initial MAPE. At age 4 years, the native liver survival rate was 58% in the MAPE group and 38% in the conventional PE group. The native liver survival rate in the Re-MAPE group was 75%. CONCLUSION: MAPE is useful for sharing the surgical field during open PE in patients with BA. It may improve the rate of jaundice clearance.

Prenatally diagnosed congenital pyloric atresia in consecutive three siblings: a case report.

BACKGROUND: Congenital pyloric atresia (CPA) is a rare gastrointestinal anomaly frequently associated with epidermolysis bullosa (EB). Although the complications of familial isolated CPA are minor, delays in diagnosis can increase the chances of morbidity. CASE PRESENTATION: Three female infants born to a Japanese mother presented with CPA at birth. There was no consanguinity between the parents, and the spacing between pregnancies was 2 years in each case. All 3 siblings had a prenatal diagnosis of CPA owing to polyhydramnios and a dilated stomach, without dilatation of the rest of the gastrointestinal tract. All patients underwent reconstructive surgeries for establishing bowel continuity (Case 1, pyloromyotomy; Case 2, gastroduodenostomy in a diamond fashion; and Case 3, gastroduodenostomy in a side-to-side fashion) soon after birth. Their postoperative courses were uneventful, and they grew up healthily, without any complications. CONCLUSION: Fetal ultrasonography is useful for diagnosing CPA prenatally. Successful prenatal diagnosis can lead to timely intervention after birth.

One Year of Preemptive Valganciclovir Administration in Children After Liver Transplantation.

OBJECTIVES: Valganciclovir (VGCV) is used as prophylaxis against cytomegalovirus (CMV) infection after pediatric living donor liver transplantation (LDLT). The purpose of this study was to examine the efficacy of 1 year of preemptive VGCV administration compared with a shorter administration after pediatric LDLT. METHODS: VGCV was administered to 56 children who underwent LDLT. CMV and Epstein-Barr virus (EBV) antibody status, pp65 antigenemia, and other laboratory data were assessed at 1 year after LDLT. Patients were divided into the 1-year group (n = 32) (patients who had 1 year of VGCV administration) and the <1-year group (n = 24) (patients who had less than 1 year of VGCV administration). RESULTS: Study participants consisted of 34 females and 22 males, with a mean age of 4.2 years at transplant. Regarding pretransplant donor (D)/recipient (R) CMV antibody status, 13 were D positive (+)/R negative (-), 27 were D+/R+, 8 were D-/R+, and 8 were D-/R-. For EBV, 22 were D+/R+, 32 were D+/R-, and 2 were D-/R-. In the 1-year group, only 2 patients (6.5%) developed CMV infection, whereas 8 patients (33.3%) developed CMV infection in the <1-year group. The CMV pp65 antigenemia assay was positive in 2 patients. CMV IgM was positive in 7 patients. One year of preemptive VGCV administration was associated with a lower incidence of CMV infection (P = .008), but not EBV infection. No adverse effects were observed. CONCLUSIONS: One year of preemptive VGCV administration after LDLT is safe and suppresses CMV infection. It was useful after pediatric LDLT.

Beta-D-Glucan Levels With Use of an Anti-adhesion Barrier Film in Pediatric Living Donor Liver Transplantation.

INTRODUCTION: Serum beta-D-glucan (BDG) levels may increase with anti-adhesion barrier film (ABF) use during pediatric living donor liver transplantation (LDLT). It may affect detection of fungal infections after LDLT. We evaluate BDG levels after pediatric LDLT. METHODS: Pediatric patients who received an ABF during LDLT were included. Patients who may have had fungal infections prior to LDLT were excluded. One sheet of ABF was placed in the peritoneum during abdominal closure. Serum BDG levels before transplantation and on postoperative days (PODs) 1, 4, 7, 14, 21, and 28 and peritoneal fluid BDG levels on PODs 1 and 7 were measured. RESULTS: Sixteen patients received an ABF during LDLT. Median age at transplant was 1.9 years (range, 6-11 years). Median body weight was 12.6 kg (range, 6.8-39 kg). Indications for LDLT were biliary atresia (n = 10) and other (n = 5). Prior to transplantation, the mean serum BDG level was 3.8 pg/mL. Mean Serum BDG levels were 18.1, 38.3, 5.3, 3.8, 3.3, and 3.3 pg/mL on PODs 1, 4, 7, 14, 21, and 28, respectively. Mean peritoneal fluid BDG levels were 485.9 and 240.4 pg/mL on PODs 1 and 7, respectively. No clinical fungal infections were observed. CONCLUSIONS: BDG levels were high in serum and peritoneal fluid after pediatric LDLT. Serum BDG levels normalized after POD 7. Careful interpretation of BDG levels until POD 7 is needed when an ABF has been used.

Serum Trough Concentration and Effects of Mycophenolate Mofetil Based on Pathologic Findings in Infants After Liver Transplantation.

OBJECTIVES: Mycophenolate mofetil (MMF) is mainly used in conjunction with calcineurin inhibitors as an additional immunosuppressive for renal sparing after liver transplantation. However, few reports about MMF use in infants after living donor liver transplantation (LDLT) are available. The purpose of this study was to examine the efficacy and safety of MMF in infants. METHODS: This study enrolled infants younger than 1 year of age who received LDLT at our institution. Patients received oral MMF twice daily. The initial dose was 40 to 50 mg/kg/d, which was increased to a target mycophenolic acid (MPA) trough level of 2 mg/L. Body weight, height, MMF dose, MPA trough level, acute cellular rejection (ACR) episodes, pathologic findings, and adverse effects were analyzed. Allograft fibrosis was graded using the Meta-analysis of Histological Data in Viral Hepatitis score. RESULTS: Patients received MMF for refractory ACR (n = 2), fulminant hepatitis (n = 2), and pre-existing antibodies (n = 1). Original diseases were biliary atresia (n = 3) and fulminant hepatitis (n = 2). Mean age at transplant was 8 months (range 3-10 months). The last available mean trough level was 2.7 mg/L. The mean dose was 66 mg/kg/d or 1429 mg/m2/d at the time of the last available through level. The regression line for MMF dose and MPA trough level was y = 1.8 × 10-3x. The correlation coefficient was 0.65. All allografts showed F1 to F2 fibrosis. Two patients discontinued MMF because of infection and bone marrow suppression, respectively. Two patients converted to everolimus. One patient continued on MMF. CONCLUSIONS: After LDLT, infants require a higher MMF dose than older patients based on trough levels, but allograft fibrosis can progress.

Safety and Efficacy of Everolimus Rescue Treatment After Pediatric Living Donor Liver Transplantation.

PURPOSE: Everolimus (EVR) is a derivative of sirolimus with a similar mechanism of action. The safety and efficacy of EVR after pediatric living donor liver transplantation (LDLT) are currently unknown. The purpose of this study was to examine the safety and efficacy of EVR as rescue therapy after pediatric LDLT. METHODS: This study included patients younger than 19 years of age who received EVR after LDLT at our institution. EVR was administered as rescue treatment in addition to tacrolimus. In 21 patients, EVR dose, trough level, outcomes, and adverse effects were assessed. RESULTS: Original diseases of patients consisted of biliary atresia (n = 11), Alagille syndrome (n = 3), fulminant hepatitis (n = 3), hepatoblastoma (n = 2), and other (n = 2). Mean age at transplant was 2.0 years (range 0.6-6.2 years). Mean age at initial EVR administration was 8.0 years (range 0.9-18.9 years). Indications for EVR use were graft fibrosis (n = 8), refractory acute cellular rejection (n = 5), renal sparing (n = 4), hepatoblastoma (n = 2), and chronic rejection (CR) (n = 2). Mean duration of administration was 17.1 months (range 2.1-60.4 months). Mean dose was 0.5 mg/m2 twice daily. Mean EVR trough level was 2.5 ng/mL (range 1.5-5.0 ng/mL). Liver function improved and fibrosis did not progress in all patients with CR. However, 14 patients (67%) experienced adverse effects that required EVR dose reduction or discontinuation. CONCLUSION: EVR is tolerable for pediatric patients after LDLT with dose adjustment. EVR had a certain effect to relieve progression on CR. Further follow-up is required.