The impact of rituximab in ABO‐incompatible pediatric living donor liver transplantation: The experience of a single center

Previous studies have demonstrated the safety of ABO‐incompatible pediatric LDLT using preoperative plasmapheresis and rituximab; however, no reports have described the timing and dosage of rituximab administration for pediatric LDLT. This study aimed to describe a safe and effective dosage and timing of rituximab for patients undergoing pediatric ABO‐incompatible LDLT based on the experience of our single center. A total of 192 LDLTs in 187 patients were examined. These cases included 29 ABO‐incompatible LDLTs in 28 patients. Rituximab was used beginning in January 2004 in recipients older than two yr of age (first period: 375 mg/m² in two cases; second period: 50 mg/m² in two cases; and 200 mg/m² in eight cases). Two patients who received 375 mg/m² rituximab died of Pneumocystis carinii pneumonia and hemophagocytic syndrome. One patient who received 50 mg/m² rituximab required retransplantation as a consequence of antibody‐mediated complications. All eight patients administered 200 mg/m² survived, and the mean CD20⁺ lymphocyte count was 0.1% at the time of LDLT. In the preoperative management of patients undergoing pediatric ABO‐incompatible LDLT, the administration of 200 mg/m² rituximab three wk prior to LDLT was safe and effective.     

Acute antibody‐mediated rejection in ABO‐compatible pediatric liver transplant recipients: case series and review of the literature

Acute AMR is well reported following ABO‐incompatible LTx. However, it remains uncommon in ABO‐compatible LTx. It typically presents with graft dysfunction ≤2 weeks post‐LTx and is often associated with graft loss. We report the clinical presentation, treatment regimen, and outcome of six pediatric LTx recipients diagnosed with early acute AMR based on (i) clinical signs of graft dysfunction, (ii) histopathology indicative of acute injury ± C4d staining, and (iii) presence of HLA DSA. All patients developed elevated ALT and GGT ≤ 45 days post‐LTx. All showed HLA class I (n=4) and/or II (n=6) DSA (peak MFI 6153–11 910). Four had de novo DSA, and two had preformed DSA. Five were initially diagnosed with ACR refractory to steroid therapy. Four exhibited resolution of graft dysfunction with AMR therapy. Two had refractory AMR—one was re‐transplanted; the other was treated with eculizumab and showed improvement in graft function but later died due to a tracheostomy complication. Our case series suggests that AMR following ABO‐compatible LTx may be under‐diagnosed. The presentation can be variable, and treatment should be individualized. Eculizumab may be an option for refractory AMR. Ultimately, future multicenter studies are needed to better define diagnostic criteria, characterize optimal treatment, and assess long‐term outcomes following liver AMR.     

Antibody‐mediated rejection after ABO‐incompatible pediatric living donor liver transplantation for propionic acidemia: A case report

We herein present the case of a four‐yr‐old boy with PA who developed AMR after ABO‐incompatible LDLT despite undergoing B cell desensitization using rituximab. Although the CD19+ lymphocyte count decreased to 0.1% nine days after the administration of rituximab, he developed a high fever which was accompanied by arthralgia due to a streptococcal infection 13 days after rituximab prophylaxis. After the clearance of the infection, he underwent ABO‐incompatible LDLT 36 days after the administration of rituximab. The CD19+ lymphocyte count just prior to LDLT was 1.2%. He developed AMR five days after LDLT, and the antidonor‐type IgM and IgG antibody titers increased to 1:1024 and 1:1024, respectively. He was treated by plasma exchange, IVIG, steroid pulse therapy, and rituximab re‐administration; however, his liver dysfunction continued. Despite intensive treatment, he died due to complicated abdominal hernia, acute renal failure, and ARDS. This case suggests that a streptococcal infection may induce the activation of innate immune responses; thus, additional desensitization therapy should be considered prior to ABO‐incompatible LDLT if B cell reactivation is suspected.     

Chemotherapy‐induced B‐cell depletion in hepatoblastoma patients undergoing ABO‐incompatible living donor liver transplantation

LT from ABO‐I donors requires preconditioning regimens to prevent postoperative catastrophic AMR. NAC for HBL is known to cause myelosuppression leading to a reduction in the number and function of lymphocytes. We investigated this chemotherapy‐induced myelosuppression in HBL patients listed for LT from ABO‐I donors with reference to the kinetics of B, T cells, and anti‐ABO blood type isoagglutinin titers. Between 2005 and 2015, of the 319 patients who underwent LDLT at our institute, 12 were indicated for unresectable HBL. Three patients with unresectable HBL who underwent LDLT from ABO‐I donors are included in this study. Immunosuppression consisted of a standard regime of tacrolimus and low‐dose steroids as in ABO compatible/identical LDLT. No additional preoperative therapies for B‐cell depletion were used. Absolute lymphocyte counts, lymphocyte subsets (including CD20+ B cells, CD3+CD4+ T cells and CD3+CD8+ T cells), and anti‐ABO blood type isoagglutinin titers were measured before LDLT and postoperatively. The median age at diagnosis was 19 months (range, 3–31 months). The median follow‐up was seven months (range, 6–15 months). The median interval from the last NAC to LDLT was 33 days (range, 25–52 days). The median interval from LDLT to adjuvant chemotherapy was 28 days (range, 22–36 days). The counts of CD20+ B cells before LDLT were depleted to median 5 cells/mm³ (range, 0–6 cells/mm³). There was a transient rebound in the CD20+ B cell counts on day seven (maximum of 82 cells/mm³) followed by a decline starting at 14 days after LDLT that was sustained for the duration of adjuvant chemotherapy. Anti‐ABO blood type isoagglutinin titers were lowered to between 1:1 and 1:16 before LDLT and remained low for the duration of follow‐up in this study. All of the three patients remained in good health without either acute cellular or AMR after LDLT. The B‐cell depletion that occurs after cisplatin‐based chemotherapy for HBL may help accomplish safe ABO‐I LDLT in children without the use of additional conditioning regimens for prevention of AMR.     

ABO‐incompatible pediatric liver transplantation in very small recipients: Birmingham’s experience

Gelas T, McKiernan PJ, Kelly DA, Mayer DA, Mirza DF, Sharif K. ABO‐incompatible pediatric liver transplantation in very small recipients: Birmingham’s experience.
Pediatr Transplantation 2011: 15: 706–711. © 2011 John Wiley & Sons A/S. Abstract: Liver transplantation (LT) for very small recipients is challenging but in experienced centres, good results can be achieved. Despite the risk of antibody‐mediated acute rejection, some studies have demonstrated the safety of ABO incompatible liver transplantation (ILT) in children and particularly in infants. The aim of our study was to describe the outcome of liver transplantation in infants <5 kg and the safety of using ILT in this group. All LT performed between 1991 and 2010 in children <5 kg were reviewed. Twenty‐nine patients were included, five of whom had an ILT. Acute liver failure was encountered in 20 cases. The recipient age and weight at transplantation were respectively 63 days (range: 14–268 days) and 4 kg (range: 2.4–5 kg). The graft‐to‐recipient ratio was 6.1% (range 2.3–9%). An aortic conduit and delayed abdominal closure were used respectively in 76% and 81% of the procedures. The ABO compatible liver transplantation (CLT) and ILT groups were similar regarding recipient’s demographics, graft types or technical transplantation data. The one‐ and five‐yr patient and graft survival were respectively 62%, 62% and 62%, 57.9% with a median follow‐up of 95 months. Vascular complications occurred in six cases (21.4%) and biliary complications were encountered in five patients (17%). Acute and chronic rejection developed respectively in 37% and 26% of the recipients. The five patients undergoing ILT are all alive without graft lost after a median follow‐up of 34 months (range 7–55 months). When compared with the CLT group, no significant differences were found regarding patient or graft survival, vascular or biliary complications and rejection rates. In our experience, ILT in small infants has short and long term outcomes comparable to ABO‐compatible grafts and excellent results can be achieved with a standard immunosuppressive protocol. To avoid mortality on the waiting list for neonatal recipients, ABO‐incompatible liver grafts can be used safely.     

Pediatric liver transplantation for acute liver failure at a single center: A 10‐yr experience

Heffron TG, Pillen T, Smallwood G, Rodriguez J, Sekar S, Henry S, Vos M, Casper K, Gupta NA, Fasola CG, Romero R. Pediatric liver transplantation for acute liver failure at a single center: A 10‐yr experience.
Pediatr Transplantation 2010:14:228–232. © 2009 John Wiley & Sons A/S. Abstract: Children transplanted for ALF urgently require an optimal graft and have lower post‐transplant survival compared with children transplanted for chronic liver disease. Over 10 yr, 33 consecutive children transplanted for ALF were followed. Demographics, encephalopathy, intubation, dialysis, laboratory values, graft type ABOI, XL (GRWR > 5%), DDSLT, LDLT and WLT were evaluated. Complications and survival were determined. ALF accounted for 33/201 (16.4%) of transplants during this period. Twelve of 33 received ABOI, five XL grafts, 18 DDSLT, and three LDLT. Waiting time pretransplant was 2.1 days. One‐ and three‐yr patient survival in the ALF group was 93.4% and 88.9%, and graft survivals were 86.4% and 77.7%. Median follow‐up was 1452 days. ABOI one‐ and three yr patient and graft survival in the ALF was 91.6% and 78.6%. No difference in graft or patient survival was noted in the ALF and chronic liver disease group or the ABOI and the ABO compatible group. A combination of ABO incompatible donor livers, XL grafts, DDSLT, LDLT and WLT led to a short wait time and subsequent graft and patient survival comparable to patients with non‐acute disease.     

Diaphragmatic hernias after pediatric liver transplantation: Experience of a high‐volume transplant center

Diaphragmatic hernias (DHs) are rare complications after pediatric liver transplantation (PLT). It is now widely accepted that DHs after liver transplantation (LT) is a pediatric related condition. PLTs (under of age 18) performed between January 2013 and June 2019 at Malatya Inonu University Institute of Liver Transplantation were retrospectively scanned. Study group consisting DHs and a control group were compared. Among 280 PLTs, 8 of them were complicated with DHs (%2.9). Median age of the patients with DH was 3.0 (0.8‐9.5) years. Median graft recipient weight ratio was 2.5 (0.9‐4.4). Five patients were below 5th percentiles in terms of pediatric weight growth chart at the time of LT. Also, 6 patients were below 5th percentiles in terms of pediatric height growth chart. There was no statistical difference between study and control groups. There are many risk factors mentioned in literature that may be primarily responsible for DHs after PLT. These factors are left lobe and large‐for‐size grafts, malnutrition, trauma or diathermy of diaphragmatic nerve and vessels and immunosuppressants. In our study, we could not specify any reason that differs in DHs. In our aspect, narrow diaphragma and thorax are exposed to high intra‐abdominal pressure from abdomen. Large‐for‐size grafts, which are specific to children, also may contribute to this affect. Excessive diathermy and trauma to diaphragmatic collaterals may aggravate the risk of DH. More patients are needed to make an exact conclusion, in order to evaluate with comparable study on this aspect.     

Outcomes of pediatric living donor kidney transplantation: A single‐center experience

Renal transplantation is the treatment of choice for children with ESRD offering advantages of improved survival, growth potential, cognitive development, and quality of life. The aim of our study was to compare the outcomes of LDKT vs DDKT performed in children at a single center. Retrospective chart review of pediatric patients who underwent kidney transplantation from 2005 to 2014 was performed. Ninety‐one renal transplants were accomplished, and 31 cases (38.27%) were LDKT, and in 96.7% of the cases, the graft was obtained through laparoscopy. Thirty‐four receptors weighted <25 kg. LDKT group had statistically significant lower cold ischemia times than DDKT one. Complication rate was 9.67% for LDKT and 18.33% for DDKT. eGFR was better in LDKT. Patient survival rate was 100% for LDKT and 98.3% for DDKT, and graft survival rate was 96.7% for LDKT and 88.33%‐80% for DDKT at a year and 5 years. Our program of pediatric kidney transplantation has achieved optimal patient and graft survival rates with low rate of complications. Living donor pediatric kidney transplants have higher patient and better graft survival rates than deceased donor kidney transplants.     

Plasmapheresis treatment of antibody‐mediated rejection in an A2 donor to O pediatric liver transplant recipient

Martin T, Schwartz J, Demetris A, Comstock J, Lowichik A, Book L. Plasmapheresis treatment of antibody‐mediated rejection in an A2 donor to O pediatric liver transplant recipient.
Pediatr Transplantation 2011: 15:E15–E18. © 2009 John Wiley & Sons A/S. Abstract: It is safe to transplant kidneys from blood group A2 donors into O recipients if the latter have low titers of anti‐A antibodies. However, in liver transplantation, O and B recipients of A2 donor livers are not routinely screened for anti‐blood group antibodies because of the immuno‐absorptive capacity of the liver and the low incidence of antibody‐mediated rejection. Herein, we report a rare case of combined cell and antibody‐mediated rejection in a pediatric blood group O recipient of an A2 donor liver, and rescue of the allograft using PP and IVIG.     

A case of pediatric live‐donor liver transplantation with a left lateral segment reduction by a linear stapler after reperfusion

In pediatric LDLT, graft reduction is sometimes required because of the graft size mismatch. Dividing the portal triad and hepatic veins with a linear stapler is a rapid and safe method of reduction. We herein present a case with a left lateral segment reduction achieved using a linear stapler after reperfusion in pediatric LDLT. The patient was a male who had previously undergone Kasai procedure for biliary atresia. We performed the LDLT with his father's lateral segment. According to the pre‐operative volumetry, the GV/SLV ratio was 102.5%. As the patient's PV was narrow, sclerotic and thick, we decided to put an interposition with the IMV graft of the donor between the confluence and the graft PV. The graft PV was anastomosed to the IMV graft. The warm ischemic time was 34 min, and the cold ischemic time was 82 min. The ratio of the graft size to the recipient weight (G/R ratio) was 4.2%. After reperfusion, we found that the graft had poor perfusion and decided to reduce the graft size. We noted good perfusion in the residual area after the lateral edge was clamped with an intestinal clamp. The liver tissue was sufficiently fractured with an intestinal clamp and then was divided with a linear stapler. The final G/R ratio was 3.6%. The total length of the operation was 12 h and 20 min. The amount of blood lost was 430 mL. No surgical complications, including post‐operative hemorrhage and bile leakage, were encountered. We believe that using the linear stapler decreased the duration of the operation and was an acceptable technique for reducing the graft after reperfusion.     

Central pontine myelinolysis following pediatric living donor liver transplantation: A case report and review of literature

CPM is one of the most serious neurological complications that can occur after OLT and is characterized by symmetrical demyelinization in the basis pontis. The etiology of CPM remains unclear, although the rapid correction of the serum sodium and CNI concentrations may be associated with the development of CPM. With recent advances in MRI technology, early diagnosis of CPM has become possible. Here, we present the case of a five‐yr‐old female who developed CNI‐associated CPM after undergoing LDLT. A decreased level of consciousness and dysphasia was noted one wk after LDLT, and MRI revealed findings compatible with a diagnosis of CPM. The patient fully recovered from the neurological deficits related to CPM following the switch from the CNI to sirolimus. We propose MRI to be promptly considered for patients with abnormal neurological findings, together with the substitution of CNI with an mTOR inhibitor as a management regimen for CNI‐related CPM.     

Long‐term outcomes of living‐related small intestinal transplantation in children: A single‐center experience

Pediatric patients with irreversible intestinal failure present a significant challenge to meet the nutritional needs that promote growth. From 2002 to 2013, 13 living‐related small intestinal transplantations were performed in 10 children, with a median age of 18 months. Grafts included isolated living‐related intestinal transplantation (n=7), and living‐related liver and small intestine (n=6). The immunosuppression protocol consisted of induction with thymoglobulin and maintenance therapy with tacrolimus and steroids. Seven of 10 children are currently alive with a functioning graft and good quality of life. Six of the seven children who are alive have a follow‐up longer than 10 years. The average time to initiation of oral diet was 32 days (range, 13‐202 days). The median day for ileostomy takedown was 77 (range, 18‐224 days). Seven children are on an oral diet, and one of them is on supplements at night through a g‐tube. We observed an improvement in growth during the first 3 years post‐transplant and progressive weight gain throughout the first year post‐transplantation. Growth catch‐up and weight gain plateaued after these time periods. We concluded that living donor intestinal transplantation potentially offers a feasible, alternative strategy for long‐term treatment of irreversible intestinal failure in children.     

Diaphragmatic hernia in infants following living donor liver transplantation: report of three cases and a review of the literature

DH is a rare complication following LT. This report presents three cases of right-sided DH after LT using a left-sided graft. All of the patients were younger than one yr of age, and they were critically ill owing to their original disease, characterized by biliary atresia, progressive familiar intrahepatic cholestasis, and acute liver failure. DH occurred with sudden onset within three months after LT. All of the cases were promptly diagnosed and treated. A literature review of 24 cases of DH identified four factors associated with DH: left-sided graft, right-sided DH, relatively delayed onset of DH, and age-specific chief complaint. DH following LT should be considered as a potential surgical complication when a left-sided graft is used, especially in small infants with coagulopathy and malnutrition.     

Antibody‐mediated rejection with the presence of glomerular crescents in a pediatric kidney transplant recipient: A case report

Glomerular crescents in kidney transplantation are indicative of severe glomerular injury and constitute a hallmark of RPGN. Their concurrence with ABMR has been rarely described only in adult patients. We report a case of 10‐year‐old boy with compound heterozygous Fin‐major Finnish‐type congenital nephrotic syndrome, who had received a deceased‐donor kidney transplant 5 years before onset of acute kidney injury and nephrotic range proteinuria without hematuria. Kidney allograft biopsy illustrated 6 glomeruli with global sclerosis and 6 with remarkable circumferential or segmental cellular crescents. Negative glomerular immunofluorescence for immune‐complex deposits and the absence of serum ANCA eliminated the presence of immune‐mediated and ANCA‐positive pauci‐immune crescentic glomerulonephritis. Diagnosis of ABMR was based on the high levels of HLA class II DSA and the histological evidence of glomerulitis, peritubular capillaritis, and acute tubular injury with positive linear peritubular capillary C4d staining. The patient despite plasmapheresis and enhanced immunosuppressive treatment progressed to end‐stage renal disease. We conclude that glomerular crescents may represent a finding of AMBR and possibly a marker of poor allograft prognosis in pediatric patients.     

Reduced ATG‐F dosage for induction in pediatric renal transplantation: A single‐center experience

Rabbit antithymocyte globulin (ATG‐F) is an extensively used induction agent. To our knowledge, no study to date has assessed reduced ATG‐F dosage in children undergoing renal transplantation. This was a retrospective analysis of pediatric renal recipients in the Department of Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, from May 2007 to February 2013. Thirty‐nine children underwent renal transplantation including 25 living related and 14 cardiac deceased donor transplantation. Each recipient received ATG‐F 1.5 mg/kg/d once daily for 4 days. Of the 39 recipients, five (12.8%) showed delayed graft function, including one of 25 recipients (4%) of living donor and four of 14 recipients (28.6%) of deceased donor transplantation (p < 0.05). Six of the 39 recipients (15.4%) showed acute rejection on renal biopsy. Follow‐up in these children ranged from 6 to 87 months. The one‐, three‐, and five‐yr recipients and grafts survival rates postoperation were each 94.9% and 97.3%, 97.3%, and 94.6%, respectively. The incidence of postoperative infection was 35.9% (14/39), and did not differ significantly in the living related and deceased donor groups (p > 0.05). Low‐dose ATG‐F can be safely used as an immune induction agent in pediatric renal transplantation.     

Renal transplantation in children under 3 years of age: Experience from a single‐center study

RTx remains challenging in children under 3 years of age. This single‐center study reviewed the medical records of children <3 years transplanted since 1987 (N = 32, Group 1). They were matched for donor type and RTx period with children aged 3‐13 years (N = 32, Group 2) and 13‐18 years (N = 32, Group 3). There were no between‐group significant differences regarding distributions of gender, primary renal disease, proportion of dialysis before RTx, and growth (SDS). Compared to Groups 2 and 3, Group 1 had more peritoneal dialyses (P < .001), more EBV mismatches (P = .04), and longer warm ischemia times (P < .001). The risk of graft loss was not significantly different among age groups (hazard ratio, 2.4 in Group 2 and 2.0 in Group 3 vs Group 1; P = .2). Death occurred in four patients (3 in Group 1 and 1 in Group 2) and graft loss occurred in 28 patients, mainly due to chronic allograft nephropathy. In recipients <3 years of age, the outcomes of RTx are close to those obtained in older pediatric age groups. Thus, young patients may be transplanted in experienced multidisciplinary teams without additional risks provided that particular attention is paid to donor selection and prevention/early diagnosis of comorbidities and complications.     

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.     

Long‐term outcome of pediatric kidney transplantation: A single‐center experience from Greece

Pediatric kidney Tx has critically altered the outcome in ESRD pediatric patients. The aims of this study were to determine long‐term graft and patient survival in a homogeneous ethnic population. We reviewed the medical charts of pediatric kidney Tx performed between 1990 and 2012 in Greece. Seventy‐five kidney Txs were performed from LRD and 62 from DD. The 10‐ and 20‐yr graft survival was higher in LRD Tx compared with DD Tx. Both patient and graft survival at 10 and 20 yr after Tx were similar in LRD Tx from grandparents compared with parents (92.9% vs. 93.4% 20‐yr patient survival, 71.4% vs. 78.7% and 57.1% vs. 72.1%, 10‐ and 20‐yr graft survival, respectively). However, there was a decreasing tendency in LRD Tx rates in period 2001–2012 compared with period 1990–2000 (47.1% vs. 62.7%). Risk factors for poor five‐yr graft survival were DD Tx, and induction treatment with ALG compared with basiliximab, but their effect attenuated at 10 yr after Tx. In conclusion, Tx from LRD may offer efficient survival outcomes irrespective of donor age, suggesting that even older LRD could be an excellent option for the 1st kidney Tx in children and adolescents.     

Living donor liver transplantation in children: a single North American center experience over two decades

Little data concerning hospital charges and long-term outcomes of LDLT in North American children according to transplant indications have been published. To compare outcomes of patient and graft survival and healthcare charges for LDLT for those with BA vs. other diagnoses (non-BA). A retrospective review of 52 children receiving 53 LDLT (38 BA and 14 non-BA) from 1992 to 2010 at our institution was performed. One-, five-, and 10-yr patient and graft survival data were comparable to national figures reported to UNOS. Average one-yr charges for recipients and donors were $242 849 for BA patients and $183 614 for non-BA (p = 0.074). BA patients were 1.23 ± 1.20 yr of age vs. 4.25 ± 5.02 for non-BA, p = 0.045. Examination of the total population of patients who were alive in 2010 in five chronological groupings showed that the crude five-yr survival rates were 1992-1995: 9/11 (82%); 1995-1997: 6/10 (60%); 1997-1999: 8/10 (80%); 1999-2001: 9/10 (90%); and 2001-2003: 7/7 (100%). Thus, examination of the clinical and financial data together over the entire period of the transplant program suggests that the dramatic improvement in patient survival was accomplished without a dramatic increase in indexed charges. All 53 donors survived, and only 10% had complications requiring hospitalization. LDLT in children results in excellent outcomes for patients and donors. Ways to lower costs and maximize graft outcome should be investigated.