Outcome of liver re‐transplantation in children—Impact and special analysis of early re‐transplantation

In case of graft failure, re‐LTX is the only life‐saving option but it has been associated with inferior results. This study analyzes the outcome following pediatric re‐LTX with a main focus on the timely relation between initial transplant and re‐LTX. All pediatric LTX at our institution between 2000 and 2010 divided into patients with primary LTX and patients undergoing re‐LTX early (≤30 days) or late (>30 days) after previous LTX were analyzed. Two hundred and ninety‐eight primary LTX(79%), 33 early (9%), and 46 late (12%) re‐LTX were performed. Patient/graft survival was significantly worse for children undergoing early re‐LTX compared to primary LTX and late re‐LTX (p = 0.024/0.001 and p = 0.015/0.03). One‐/five‐yr graft survival rates were 66%/49% for early re‐LTX compared to 86%/76% for late re‐LTX and 90%/74% for primary LTX. The inferior results in children undergoing early re‐LTX were due to events occurring in the first six months with similar survival thereafter. No difference in outcome was evident after adjustment of the groups for high‐urgency status. Outcome was excellent for primary LTX and late re‐LTX, supporting late re‐LTX in children. Early re‐LTX takes an elevated risk of early graft loss and patient death; however, beyond the early postoperative period, the outcome was comparable.     

Outcome of duct‐to‐duct vs. Roux‐en‐Y hepaticojejunostomy biliary anastomoses in below 15‐kg pediatric liver transplant recipients

The best type of biliary anastomosis to use in lower weight pediatric liver transplant recipients is debatable. In this study, we share a single center's experience comparing the rate of anastomotic biliary complications based on the type of biliary anastomosis performed in this population of patients. A retrospective review of pediatric liver transplants for recipients weighing <15 kg from 11/2003 till 12/2011 was performed. Patients were grouped based on the type of biliary anastomosis into two groups: duct‐to‐duct (d‐d) and Roux‐en‐Y hepaticojejunostomy (h‐j) anastomoses. A total of 24 patients (12 males, 12 females) with a mean age of 26 ± 20 months and a mean weight of 9.27 ± 2.63 kg (range = 5.3–13.9 kg) were studied. All anastomotic complications occurred in patients who received left lateral segments. No statistical differences were found in the post‐operative biliary (p = 0.86) or vascular (p = 0.99) complications between the two groups. Acknowledging the limited sample size, our data suggest that duct‐to‐duct anastomosis can be performed safely in pediatric liver transplantation recipients weighing below 15 kg.     

Liver transplantation in children using non‐heart‐beating donors (NHBD)

Gozzini S, Perera MTPR, Mayer DA, Mirza DF, Kelly DA, Muiesan P, Sharif K. Liver transplantation in children using non‐heart‐beating donors (NHBD).
Pediatr Transplantation 2010: 14:554–557. © 2010 John Wiley & Sons A/S. Abstract: Selected livers from controlled NHBD are accepted for OLT in adults. Recent evidence has shown good medium‐term outcome. The purpose of this study was to report our experience of pediatric OLT with whole and partial grafts from NHBD, analyzing complications and outcome. Retrospective review of all the recipients who underwent primary OLT between December 2005 and December 2008, using livers from NHBD. Four children (one male child) mean age was 9.5 yr (0.2–17), mean weight was 26 kg (range 2.6–48), underwent OLT using NHBD. Mean donor age was 14.2 yr, and mean WIT (systolic BP <50 mmHg to cold perfusion) 12.2 min (range 10–15). Two children received reduced grafts and two full grafts. Mean cold ischemia time was 7.18 h (range 6–8). Liver function tests one wk and nine months post‐OLT confirmed a good graft function. One child was treated for two episodes of acute rejection. Post‐transplant complications included two cases of mild ischemic cholangiopathy treated conservatively. Graft and patient survival was 100% with a mean follow‐up of 19 months (range 8.1–43.4). Short‐ to medium‐term follow‐up suggests that liver grafts from young NHBD with short warm and cold ischemia times can be safely utilized in pediatric transplantation.     

Induction regimens and post‐transplantation lymphoproliferative disorder after pediatric intestinal transplantation: Single‐center experience

Pediatric recipients of intestinal transplants have a high incidence of PTLD, but the impact of specific induction immunosuppression agents is unclear. In this single‐center retrospective review from 2000 to 2017, we describe the incidence, characteristics, and outcomes of PTLD after primary intestinal transplantation in 173 children with or without liver, after induction with rATG, alemtuzumab, or anti‐IL‐2R agents. Thirty cases of PTLD occurred among 28 children, 28 EBV+ and 2 EBV?. Although not statistically significant, the PTLD incidence was higher after isolated intestinal transplant compared with liver‐inclusive allograft (19.3% vs 13.3%, P = .393) and after induction with anti‐IL‐2R antibody and alemtuzumab compared with rATG (28.6% and 27.3% vs 13.3%, P = .076). The 30 PTLD cases included 13 monomorphic PTLD, 13 polymorphic PTLD, one spindle cell, one Burkitt lymphoma, and two cases too necrotic to classify. After reduction of immunosuppression, management was based on disease histology and extent. Resection with or without rituximab was used for polymorphic tumors and limited disease extent, whereas chemotherapy was used for diffuse disease. Of the 28 patients, 11 recovered with functioning allografts (39.3%), 10 recovered after enterectomy (35.7%), and seven patients died (25%), three due to PTLD and four due to other causes. All who died of progressive PTLD had received chemotherapy, highlighting the mortality of PTLD, toxicity of treatment and need for novel agents. Alemtuzumab is no longer used for induction at our center.     

Luminex‐based virtual crossmatching facilitates combined third‐time cardiac and de novo renal transplantation in a sensitized patient with sustained antibody‐mediated cardiac allograft rejection

Deutsch M‐André, Kauke T, Sadoni S, Kofler S, Schmauss D, Bigdeli AK, Weiss M, Reichart B, Kaczmarek I. Luminex‐based virtual crossmatching facilitates combined third‐time cardiac and de novo renal transplantation in a sensitized patient with sustained antibody‐mediated cardiac allograft rejection.
Pediatr Transplantation 2010: 14:E96–E100. © 2009 John Wiley & Sons A/S. Abstract: Allosensitization represents a major obstacle to successful re‐transplantation since circulating antibodies can elicit antibody‐mediated rejection episodes with subsequent graft failure. Since sensitization is primarily considered a contraindication to transplantation the duration for patients waiting for a suitable donor organ to become available is considerably prolonged. Herein, we report on the successful application of a Luminex‐based virtual crossmatch approach to facilitate combined third‐time cardiac and de novo renal transplantation in a sensitized patient with sustained antibody‐mediated cardiac allograft rejection.     

Association of post‐transplant donor‐specific HLA antibody with liver graft fibrosis during long‐term follow‐up after pediatric liver transplantation

The aim of this study was to evaluate the significance of post‐transplant DSA as a predictor of liver fibrosis during long‐term follow‐up after pediatric LT. We evaluated the histological findings in 18 LT recipients who underwent liver biopsy after DSA screening. Liver fibrosis was scored based on the METAVIR fibrosis staging. Patients were divided into 2 groups based on histological findings, and clinical characteristics among patients with liver fibrosis were assessed. Of 18 patients, 7 were included in the fibrosis group. No significant between‐group differences were found regarding peritransplant characteristics, including age, sex, primary disease, ABO incompatibility, and immunosuppressive regimen. Episodes of acute rejection and non‐adherence to immunosuppressive drugs were comparable between both groups. The MFI for anti‐DR DSA and positive rate were significantly higher in the fibrosis group (1655 vs 216; P = .019, 86% vs 27%; P = .012, respectively). MFI for anti‐DQ DSA was higher in the fibrosis group, but non‐significantly (2052 vs 384; P = .46). Post‐transplant anti‐DR DSA is associated with graft fibrosis during long‐term follow‐up. This finding seems useful for the implementation of valid histological examinations of liver grafts for patients with higher MFI, especially for anti‐DR DSA, after pediatric LT.     

Donor‐specific anti‐HLA antibody production following pediatric ABO‐incompatible heart transplantation

ABO‐i heart transplantation can be performed in infants with end‐stage heart failure to increase organ availability. The development of newly detected DSAs is associated with decreased cardiac graft survival, and the effect of ABO‐i transplantation on DSA production is unknown. We examined DSA production and rejection frequency in infant recipients of ABO‐i and ABO‐c heart transplants via a retrospective cohort study of infant heart transplant recipients transplanted at a single pediatric center between January 2004 and November 2014. Patients were included if they were less than 1 year of age at transplant and had a minimum of 6 months follow‐up. DSA positivity was examined under two categories, either the lowest level detectable (MFI > 500) or a level presumed to have clinical relevance in our immunogenetics laboratory (MFI > 5000). Of 52 patients, 36 received ABO‐c transplants and 16 received ABO‐i transplants. Compared to ABO‐c recipients, the ABO‐i group showed a consistent but statistically non‐significant finding of less frequent ndDSA positivity (69.4% ABO‐c vs 43.8% ABO‐i with MFI >500, P = 0.122; 41.7% ABO‐c vs 25% ABO‐i with MFI >5000, P = 0.353). Additionally, ABO‐i patients were less likely to have any form of rejection (12.5% vs 47.2%, P = 0.027) or acute cellular rejection (6.3% vs 38.9%, P = 0.021). Our data suggest that infants receiving ABO‐i heart transplants may be less likely to develop ndDSAs or have rejection compared to same age ABO‐c recipients. Larger multicenter studies are needed to confirm results from this single center study.     

Transplantation for infantile nephronophthisis with loss‐of‐function mutation in NPHP3: Lesson from a case

The choice of KT only or CLKT for infantile NPHP with mild liver fibrosis is understudied. A 5‐year‐old girl was transferred to our center for KT due to ESRD. Her primary disease was infantile NPHP with compound heterozygous NPHP3 mutations: c.458A>C(p.Q153P)/missense mutation and c.2032A>T(p. K678X)/nonsense mutation. The patient had elevated liver enzymes and biopsy‐proven liver fibrosis. As liver synthesis was acceptable, only KT was performed. However, liver fibrosis progressed at 1.5 years after transplantation, manifested with portal hypertension and hypersplenism. Common causes for portal hypertension were excluded, and the progression was attributed to NPHP. AMR attacked allograft at about 2 years post‐transplant. To solve both the liver and the kidney problems, CLKT was performed. Her liver and kidney function recovered initially, but she unfortunately died of pneumonia and subsequent intracranial hemorrhage two weeks later. Nonsense mutation in NPHP3 gene may be correlated with rapid progression of liver disease in infantile NPHP. More studies are required to determine the role of CLKT in these cases; however, combined transplantation may improve long‐term graft and patient survival.     

Graft‐versus‐host disease (GVHD) prophylaxis by using methotrexate decreases pre‐engraftment syndrome and severe acute GVHD,and accelerates engraftment after cord blood transplantation

GVHD and graft failure are serious problems in CBT. PES after CBT also occurs frequently and is associated with transplantation‐related complications such as acute GVHD. We reviewed medical records for 70 consecutive child CBT recipients between December 1997 and April 2015. Forty‐nine patients received prophylaxis against GVHD with CsA or Tac in combination with mPSL from day +7 (mPSL group), and 21 patients received CsA or Tac with MTX on day +1 and day +3 (MTX group). Neutrophil engraftment was detected in 59 patients (84.3%). Neutrophil engraftment rate in the MTX group was significantly higher than that in the mPSL group (21/21 (100%) and 38/49 (77.6%), respectively, p = 0.027). PES developed in 35 patients, and the incidence of PES in the mPSL group was significantly higher than that in the MTX group (p = 0.036). The incidence of severe acute GVHD (grade III or IV) in the MTX group was significantly lower than that in the mPSL group (p = 0.049). Although this study was a small‐scale study, the results showed that increase in the rate of engraftment and decrease in the incidence of early immune reactions such as PES and severe acute GVHD could be achieved by early commencement of immunosuppression using MTX.     

IGG3 anti‐HLA donor‐specific antibodies and graft function in pediatric kidney transplant recipients

Anti‐HLA DSAs are associated with ABMR and graft loss in KT recipients, yet the influence of DSA IgG subclass on outcomes in pediatric KT recipients is not completely understood. We performed a single‐center retrospective chart review of pediatric KT recipients with anti‐HLA DSAs, aiming to study the association between specific DSA IgG subclasses and graft outcomes, including ABMR and significant graft dysfunction (graft loss or 50% decrease in eGFR). Thirty‐six patients (mean age 15.4y) with DSAs initially detected 1 month‐14.3 years post‐transplantation were followed for a median of 2.8 years. Rates of IgG1, 2, 3, and 4 subclass detection were 92%, 33%, 58%, and 25%, respectively. Twenty‐two patients (61%) had clinical ABMR, whereas 19% had subclinical ABMR, and 13 (36%) experienced significant graft dysfunction. Patients with IgG3+ DSAs had a higher risk of graft dysfunction compared with IgG3‐ patients (52% vs 13%, P = .03). In a multiple Cox proportional regression analysis, the presence of IgG3+ DSA was independently associated with significant graft dysfunction (HR 10.45, 95% CI 1.97‐55.55, P = .006). In conclusion, IgG3 subclass DSAs are associated with graft dysfunction and may be useful for risk stratification and treatment decisions in DSA‐positive pediatric KT recipients.     

Pretransplant six‐minute walk test predicts peri‐ and post‐operative outcomes after pediatric lung transplantation

The purpose of the pretransplant assessment in lung transplantation is to determine a patient's need for transplant as well as their potential survival post‐procedure. In 2005, the UNOS introduced the LAS, a calculation based on multiple physiologic measures to determine need and likelihood for survival. Measures include NYHA class and the 6‐MWT. Some adult studies indicate a positive correlation with 6‐MWT and waiting list survival. In pediatric/adolescent patients, there are minimal data regarding the predictive value of physiologic markers in either wait list survival or post‐transplant outcome. A retrospective cohort study of 60 consecutive lung transplantations from 1990 to 2008 was performed at a pediatric tertiary care facility. Functional pretransplant assessments were abstracted from the medical record and compared with outcomes after transplantation. Results: a 6‐MWT of >1000 ft (305 m) prior to transplantation correlated with a shorter ICU stay (7 vs. 11 days, p = 0.046) and fewer days of mechanical ventilation (2 vs. 4, p = 0.04). A pretransplant 6‐MWT greater than 750 ft (229 m) correlated with shorter overall hospitalization (37 vs. 20 days, p = 0.03). Measuring pretransplant 6‐MWT tests for pediatric patients is valuable in predicting peri‐operative outcomes after lung transplantation.     

Non‐invasive biological quantification of acute gastrointestinal graft‐versus‐host disease in children by plasma citrulline

Clinical grading of GI involvement during acute GVHD remains a challenging issue, especially in children. Plasma citrulline, a non‐protein amino acid selectively produced and released by enterocytes, is a suitable surrogate endpoint for small intestinal epithelial cell mass, irrespective of the underlying cause of cell loss. Children referred for allogeneic bone marrow transplantation who were free from chronic malabsorption or constitutional disease involving the GI tract were consecutively included in this prospective study. Plasma citrulline and albumin concentration was measured every week between day 7 and day 28 of BMT until resolution of the aGVHD or occurrence of chronic GVHD. In total, 31 children were included between 2008 and 2011. After a CR, citrulline levels fell to a minimum level on day 7 and then increased to reach the initial value on day 28. After day 28, plasma citrulline but not albumin was strongly linked to the occurrence of GI GVHD, the threshold being set at 10 μmol/L. The correlation with clinical grade of GI‐aGVHD now needs to be assessed in larger populations. In pediatric patients, citrulline is valuable as a suitable non‐invasive marker of GI involvement in acute GVHD.