pLT Recipients Research Articles

Hepatic artery stenosis after pediatric liver transplantation: The potential role of conservative management

AimThis study aimed to investigate the outcomes and effectiveness of various treatment strategies in patients with hepatic artery stenosis (HAS) after pediatric liver transplantation (pLT). MethodsThis is a single center observational cohort study between January 1st, 2004 and August 1st, 2023, including pLT recipients aged <18 years. The primary outcome was graft and patient survival. The secondary outcomes included incidence of biliary complications, technical success of surgery or endovascular therapy (EVT), and changes in liver function. The cut-off for early and late HAS was 14 days after pLT. ResultsAmong a total of 327 pLT patients, 4 % (n = 13) developed HAS (n = 3 early; n = 10 late). Treatments included surgical revascularization for one early HAS, conservative management with anticoagulation for one early and four late HAS, and EVT for one early and six late HAS. Over a median follow-up of 28.2 months after the diagnosis of HAS, graft survival was 100 % and 83 % in early and late HAS groups, and patient survival reached 100 % in both groups. One graft loss occurred in the conservative group. Conversely, graft survival in the EVT group was 100 %. ConclusionThe long-term outcomes of HAS after pLT are excellent. Both EVT and conservative management exhibited high graft survival rates for late HAS, with EVT achieving high technical success.

Outcomes of adults who received liver transplant as young children.

BackgroundPatient and graft survival 20-years after pediatric liver transplantation (pLT) are excellent. In children, attainment of normal growth, education and social adaptation to be an independent adult are equally important. This is particularly relevant for children who receive liver transplant at a young age, where infantile-onset liver disease, surgery and immunosuppression can adversely affect growth and neurodevelopment. The aim of this study was to evaluate the long-term physical and psychosocial outcomes of pLT recipients with normal graft function. We coin the term ‘meaningful survival’.MethodsWe performed a cross-sectional study of pLT recipients who received transplants between 1985 and 2004. A 20-year evaluation of physical health (growth, renal function), mental wellbeing and social outcomes (substance abuse, adherence, education, employment) was performed. All patients included were considered to have normal graft function.FindingsEighty-four patients met study criteria. Median age at transplantation was 1.3 years (IQR 0·7–3·3 years), with median duration of follow-up of 20.2 years (18·0–23·5). At median of 20-years, 19 patients (23%) had chronic renal dysfunction and 3 patients (4%) had a BMI of >30 (mean 20·4). Evaluation of long-term psychosocial outcomes demonstrated 22 patients (26%) with mental health disorders. Substance abuse was lower than national average. 62 patients (74%) were in education, employment or training. Overall, only 26% of our cohort achieved a composite outcome of ‘meaningful survival’.InterpretationThis is the largest reported long-term study of biopsychosocial outcomes of pLT recipients with normal liver biochemistry, with follow-up upon completion of physical growth and senior school education. Importantly, despite normal liver function, many patients did not demonstrate ‘meaningful survival’. We must refocus our efforts towards better understanding the long-term outcomes of children. A ‘meaningful survival’ rather than mere survival should be our goal.FundingNone.

Non-standard hepatic venous reconstruction in the setting of absent inferior vena cava in partial graft pediatric liver transplantation-A matched retrospective cohort study.

Recipient cava may be unavailable for outflow reconstruction in some children undergoing liver transplantation (PLT) due to caval agenesis, tumor, or fibrotic caval occlusion. Non-standard hepatic venous reconstruction (NHVR) with a direct veno-caval anastomosis or neo-cava reconstruction is necessary in such cases. Retrospective review of all PLT needing NHVR performed in our unit from January 2010 to September 2019 was performed. Outcomes of this group were compared to a 2:1 matched control group who underwent transplantation with standard piggyback technique. Fifteen children (4.9%) of 304 PLT recipients underwent NHVR. Caval agenesis in biliary atresia (n=5, 33%) and hepatoblastoma infiltrating the cava (n=4, 27%) were the commonest indications. Ten children had neo-cava reconstruction, while 5 had direct anastomosis to the supra-hepatic caval cuff or right atrium. One child had developed neo-cava thrombosis without graft venous outflow obstruction in the post-operative period. There was no significant difference in major morbidity, need for re-operation (20% vs 16.7%; P=1.00), hospital stay (24days, vs 21days; P=.32), graft & patient survival among the study and control groups. Absent or inadequate recipient cava during PLT with a partial liver graft can be safely managed with technical modifications. Results equivalent to standard piggyback implantation can be achieved.

Outcome after pediatric liver transplantation for staged abdominal wall closure with use of biological mesh-Study with long-term follow-up.

Abdominal wall closure after pediatric liver transplantation (pLT) in infants may be hampered by graft-to-recipient size discrepancy. Herein, we describe the use of a porcine dermal collagen acellular graft (PDCG) as a biological mesh (BM) for abdominal wall closure in pLT recipients. Patients <2years of age, who underwent pLT from 2011 to 2014, were analyzed, divided into definite abdominal wall closure with and without implantation of a BM. Primary end-point was the occurrence of postoperative abdominal wall infection. Secondary end-points included 1- and 5-year patient and graft survival and the development of abdominal wall hernia. In five out of 21 pLT recipients (23.8%), direct abdominal wall closure was achieved, whereas 16 recipients (76.2%) received a BM. BM removal was necessary in one patient (6.3%) due to abdominal wall infection, whereas no abdominal wall infection occurred in the no-BM group. No significant differences between the two groups were observed for 1- and 5-year patient and graft survival. Two late abdominal wall hernias were observed in the BM group vs none in the no-BM group. Definite abdominal wall closure with a BM after pLT is feasible and safe when direct closure cannot be achieved with comparable postoperative patient and graft survival rates.

Salvage Living Donor Liver Transplantation (SLDLT) as a Treatment Modality for Recurrent Hepatocellular Carcinoma (HCC)

Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer all over the world. Salvage livingdonor liver transplantation (SLDLT) has been proposed for patients who developed HCC recurrence after primaryresection or liver deterioration in patients undergoing liver resection (LR).Aim of the work: The aim of this study is to compare and evaluate the patient survival and cancer recurrencerates between patients who underwent (SLDLT) and (PLT) in our centers between 2014 and 2018.Patients and methods: A retrospective study was conducted on total of 110 HCC patients who underwentLDLT for HCC from January 2014 till January 2018 by the same surgical team at 3 centers (Ain Shams UniversitySpecialized Hospital, Wadi-ElNile Hospital and Egypt Air Hospital). Patients were divided into two groups. Group Aincluded primary LDLT for 95 cases which were within Milan criteria and group B for SLDLT was performed in 15cases.Results: Among the 110 HCC patients, 95 (86.4%) underwent PLT, and 15 (13.6%) underwent SLT for HCCrecurrence after the primary resection. The operative time was significantly more (P value=0.001) in the SLTrecipients group, as the median operative time was (10) hours while it was (8) hours in the PLT recipients group. Forall post-operative complications, no statistical significant difference was found between the PLT and SLT recipients.Similar rates were observed as regard the overall survival between the SLT and PLT recipients. However, the 1year, 3 year and 5 year disease-free survival rates were 94.5%, 93.0%, and 92.1% in PLT recipients, compared torecurrence that occurred in 1 patient after 9 months (6.7 %) in SLT recipients which was not significantly differentstatistically.Conclusion: Our study shows that SLT is a safe and technically feasible procedure for patients who developed HCCrecurrence following primary liver resection. Also, the survival rates were similar to PLT.

Intraoperative blood loss and transfusion during primary pediatric liver transplantation: A single-center experience.

Children undergoing liver transplantation are at a significant risk for intraoperative hemorrhage and thrombotic complications, we aim to identify novel risk factors for massive intraoperative blood loss and transfusion in PLT recipients and describe its impact on graft survival and hospital LOS. We reviewed all primary PLTs performed at our institution between September 2007 and September 2016. Data are presented as n (%) or median (interquartile range). EBL was standardized by weight. Massive EBL and MT were defined as greater than the 85th percentile of the cohort. 250 transplantations were performed during the study period. 38 (15%) recipients had massive EBL, and LOS was 31.5 (15-58) days compared to 11 (7-21) days among those without massive EBL (P<0.001). MT median LOS was 34 (14-59) days compared to 11 (7-21) days among those without MT (P=0.001). Upon backward stepwise regression, technical variant graft, operative time, and transfusion of FFP, platelet, and/or cryoprecipitate were significant independent risk factors for massive EBL and MT, while admission from home was a protective factor. Recipient weight was a significant independent risk factor for MT alone. Massive EBL and MT were not statistically significant for overall graft survival. MT was, however, a significant risk factor for 30-day graft loss. PLT recipients with massive EBL or MT had significantly longer LOS and increased 30-day graft loss in patients who required MT. We identified longer operative time and technical variant graft were significant independent risk factors for massive EBL and MT, while being admitted from home was a protective factor.

Procalcitonin for infections in the first week after pediatric liver transplantation

BackgroundProcalcitonin (PCT) has become a commonly used serum inflammatory marker. Our aim was to describe the kinetics and usefulness of serial post-operative PCT measurements to detect bacterial infection in a cohort of children immediately after pediatric liver transplantation (pLT).MethodsWe performed a retrospective chart review of a cohort of pLT recipients with serial serum PCT measurements in the first week following pLT. The presence of infection was determined on clinical and biological parameters. Normal PCT was defined as < 0.5 (ng/ml).ResultsThirty-nine patients underwent 41 pLT. PCT was measured daily during the first week post pLT. Values first increased following surgery and then decreased, nearing 0.5 ng/ml at day seven. Peak PCT reached a median of 5.61 ng/ml (IQR 3.83-10.8). Seventeen patients were considered to have an infection. There was no significant difference in daily PCT or peak PCT between infected and non infected patients during the first post-operative week. AUC of ROC curve for PCT during first week was never higher than 0.6.ConclusionsWe conclude that serial PCT measurements during the first week after pLT is not useful to identify patients with bacterial infections. Rather, we propose that serum PCT may be useful after the first week post pLT.

Late cytomegalovirus infection in children: High incidence of allograft rejection and hepatitis in donor negative and seropositive liver transplant recipients.

The complications and outcome associated with late CMV infection and disease on the graft are poorly characterized in PLT recipients. We studied the overall incidence, risk factors, and outcome of late CMV infection and disease (infection 6months after transplant) in 180 PLT recipients admitted between 2008 and 2011 at the King's College Hospital. Antiviral prophylaxis of intravenous ganciclovir was given only to the D+R- group starting at day 7 post-transplant. The remaining groups (D-R+, D+R+, and D-R-) received pre-emptive therapy when they have CMV viremia above cut-off value and treatment for symptomatic CMV infection. The overall incidence of late CMV infection and disease was 9.4% (19/180) and 14.5% (19/130) in D+R-, D-R+, D+R- groups. The D-R+ group had the highest incidence of hepatitis (37.5%) and significantly increased incidence of CMV disease, and single and multiple acute rejection episodes when compared to the D+R- group, which received prophylaxis. The late CMV infection and disease in pediatric LT recipients was comparable to adult LT recipients despite variable duration of antiviral prophylaxis. Our results show that D-R+group had highest rate of hepatitis and rejection episodes, associated with high morbidity, and should be considered for antiviral prophylaxis.

Safety and Tolerance of Donor-Derived Mesenchymal Stem Cells in Pediatric Living-Donor Liver Transplantation: The MYSTEP1 Study

Background Calcineurin inhibitors (CNI) have significantly improved patient and graft survival in pediatric liver transplantation (pLT). However, CNI toxicity leads to significant morbidity. Moreover, CNIs cannot prevent long-term allograft injury. Mesenchymal stem (stromal) cells (MSC) have potent immunomodulatory properties, which may promote allograft tolerance and ameliorate toxicity of high-dose CNI. The MYSTEP1 trial aims to investigate safety and feasibility of donor-derived MSCs in pLT. Methods/Design 7 to 10 children undergoing living-donor pLT will be included in this open-label, prospective pilot trial. A dose of 1 × 106 MSCs/kg body weight will be given at two time points: first by intraportal infusion intraoperatively and second by intravenous infusion on postoperative day 2. In addition, participants will receive standard immunosuppressive treatment. Our primary objective is to assess the safety of intraportal and intravenous MSC infusion in pLT recipients. Our secondary objective is to evaluate efficacy of MSC treatment as measured by the individual need for immunosuppression and the incidence of biopsy-proven acute rejection. We will perform detailed immune monitoring to investigate immunomodulatory effects. Discussion Our study will provide information on the safety of donor-derived MSCs in pediatric living-donor liver transplantation and their effect on immunomodulation and graft survival.

Complications of indwelling central venous catheters in pediatric liver transplant recipients

In pLT recipients, the advantages of ICVCs need to be weighed against the risk of complications. This single-center retrospective study aimed to review ICVC complications in our cohort of pLT recipients. We performed chart reviews of pLT patients having undergone transplant between 01/2000 and 03/2014 and who underwent ICVC placement either before or after LT. We identified 100 ICVC in 85 patients. Overall observation time was 90 470 catheter-days. There was no difference in catheter lifespan between those inserted pre- or post-transplant; 46% of ICVC presented a complication. Most frequent complications were MD and infection. The infection rate was 0.09 per 1000 catheter-days, and MD rate was 0.36 per 1000 catheter-days. Patients having received technical variant grafts were more at risk of complications. To the best of our knowledge, this is the first study examining ICVC complications in pLT recipients. We conclude that ICVC have a high rate of MD. Children receiving technical variants may be more at risk of complications. By removing ICVC in a select number of patients at six months post-insertion, we might avoid as much as 60% of complications.

The EASTR Study: indications for transfusion and estimates of transfusion recipient numbers in hospitals supplied by the National Blood Service

This study provides data on National Blood Service (NBS) red blood cell (RBC, n = 9142), platelet (PLT, n = 4232) and fresh frozen plasma (FFP, n = 3584) recipients independently sampled by monthly quota from 29 representative hospitals over 12 months in 2001-2002. Hospitals were stratified by size according to total yearly RBC issues. Transfusion indications were chosen from diagnostic and procedural codes, and recipients grouped into Epidemiology and Survival of Transfusion Recipients Case-mix Groups (E-CMGs). The main E-CMGs were digestive [19% of RBC recipients; including 5% gastrointestinal (GI) bleeds and 3% colorectal surgery], musculoskeletal (15%; 12% hip and knee replacement), haematology (13%) and obstetrics and gynaecology (10%). Renal failure, fractured neck of femur, cardiac artery by-pass grafting (CABG) and paediatrics, each accounted for 3-4% recipients. FFP recipients: the main E-CMGs were digestive (21% of FFP recipients; including 7% GI bleeds and 3% colorectal surgery), hepatobiliary (15%; 7% liver disease and 2% liver transplant), cardiac (12%) and paediatrics (9%) The renal, paediatrics, vascular and haematology E-CMGs each had 6-7% of recipients. PLT recipients: the main E-CMGs were haematology (27% of PLT recipients; including 9% lymphoma and 8% acute leukaemia), cardiac (17%), paediatrics (13%), hepatobiliary (10%) and digestive (9%). Back-weighting gave national estimates of 433 000 RBC, 57 500 FFP and 41 500 PLT recipients/year in England and North Wales, median age 69, 64 and 59 years, respectively. Digestive and hepatobiliary indications emerged as the top reason for transfusion in RBC and FFP recipients, and was also a frequent indication in PLT recipients.

Suivi médical, vie quotidienne et vêcu de jeunes adultes après transplantation hépatique dans l’enfance

Over the last two decades liver transplantation for children (pLT) with life-threatening acute or chronic liver diseases has yielded high long-term success rates. Long-term follow-up of pLT recipients has focused mainly on somatic complications (infections, chronic rejection, biliary problems, cancer occurrence, etc.). Other studies have examined precise aspects of everyday life, and particularly health-related quality of life. In contrast, no global surveys of everyday life, including educational and vocational issues, academic performance, personal feelings and concerns and at-risk behaviors have yet been carried out among adults who received liver grafts during childhood. We conducted a global survey of these young adults' everyday lives. The study was based on a structured questionnaire administered during phone interviews. One hundred sixteen pLT patients managed in a single pediatric liver unit since 1986 were interviewed between April 2005 and July 2006 by the same pediatrician (JPD), who was not involved in their personal medical management. Mean age at interview was 21 +/- 4 (17-33) years; mean age at pLT was 7.0 +/- 4.6 (0.5-16) years; and the mean and median follow-up periods after LT were respectively 13.9 +/- 3.9 years and 15 years. Three-quarters of the patients said they were satisfied with their quality of life and 81% were satisfied with their health status. A significant difference in the age at which LT was performed was found between patients reporting "good or very good" quality of life and patients reporting "neither good nor bad" quality of life (mean age at LT 6.2 +/- 4.1 vs 9.4 +/- 1.4 years; p = 0.0002). Two-thirds of the patients were still attending school. One-third were in age-appropriate school grades, and 31%, 23% and 13% were respectively 1, 2 and 3 years behind. Twenty-five per cent of patients were in paid employment and 12% were unemployed. Reported at-risk behaviors (tobacco and cannabis use) were not more frequent than among these patients' peers, and alcohol consumption was significantly lower (p<0.0001). Strict adherence to medications was reported by only 55% of patients. Concerns about their future health were expressed by 53% of patients. Many patients were reluctant to speak openly to their peers about their LT status. The vast majority of patients wished to discuss personal problems with a physician (quality of life, vocational problems, future health, sexuality, pregnancy), and also wanted more medical information from caregivers. A large majority of young adults transplanted during childhood have good quality of life. Educational level and academic performance are lower than among these patients' peers. This study highlights personal difficulties encountered by a noteworthy proportion of young adults transplanted during childhood. This needs to be taken into account both by pediatricians and by adult medical care providers.

Permanent Survival of Fully MHC-Mismatched Islet Allografts by Targeting a Single Chemokine Receptor Pathway

Chemokine receptor blockade can diminish the recruitment of host effector cells and prolong allograft survival, but little is known of the role of chemokine receptors in promoting host sensitization. We engrafted fully allogeneic islets into streptozotocin-treated normal mice or mice with the autosomal recessive paucity of lymph node T cell (plt) mutation; the latter lack secondary lymphoid expression of the CCR7 ligands, secondary lymphoid organ chemokine (CCL21) and EBV-induced molecule-1 ligand chemokine (CCL19). plt mice showed permanent survival of islets engrafted under the kidney capsule, whereas controls rejected islet allografts in 12 days (p < 0.001), and consistent with this, plt mice had normal allogeneic T cell responses, but deficient migration of donor dendritic cell to draining lymph nodes. Peritransplant i.v. injection of donor splenocytes caused plt recipients to reject their allografts by 12 days, and sensitization at 60 days posttransplant of plt mice with well-functioning allografts restored acute rejection. Finally, islet allografts transplanted intrahepatically in plt mice were rejected approximately 12 days posttransplant, like controls, as were primarily revascularized cardiac allografts. These data show that the chemokine-directed homing of donor dendritic cell to secondary lymphoid tissues is essential for host sensitization and allograft rejection. Interruption of such homing can prevent T cell priming and islet allograft rejection despite normal T and B cell functions of the recipient, with potential clinical implications.

CXCL9 Antagonism Further Extends Prolonged Cardiac Allograft Survival in CCL19/CCL21‐Deficient Mice

CCL19/MIP-3beta and CCL21/SLC are essential for chemotactic recruitment of mature dendritic cells (DC) to T-cell areas of secondary lymphoid tissue. Paucity of lymph node T-cells (plt/plt) mice lack CCL21-serine (ser) and CCL19 expression. We tested plt/plt and wild type (wt) BALB/c (H2d) mice as recipients of heart or skin allografts from C57BL/10J (H2b) donors. Donor DC trafficking to secondary lymphoid tissue was markedly reduced in plt heart but not skin allograft recipients. Heart, but not skin grafts survived significantly longer in plt recipients. Accordingly, T cells from plt heart transplant recipients demonstrated poor anti-donor responses in ex vivo MLR, compared to wt heart or wt and plt skin recipients. Moreover, donor-reactive T cells from plt heart recipients exhibited Th2-skewing in comparison to T cells from wt heart or skin graft recipients. Anti-CXCL9/Mig was administered for 2 weeks post-transplant to determine whether impairment of activated T-cell migration could further prolong cardiac allograft survival in plt recipients. CXCL9-antagonism extended graft survival significantly only in plt mice, likely due, in part, to retention of alloactivated T cells in secondary lymphoid tissue/reduction of graft-infiltrating T cells. Thus, targeting DC and activated T-cell migration concomitantly has additive effects in prolonging heart graft survival with potential for therapeutic application.

Sphingosine 1-phosphate receptor activation: evidence for distinct chemokine compartments

Introduction: FTY720 is a sphingosine derived immunomodulator that causes T cell egress from peripheral blood and spleen to peripheral lymph nodes through a mechanism dependent on activation of the sphingosine 1-phosphate receptor and sensitization of the CCL19/CCR7 chemokine system. The purposes of this study were to determine if FTY720 enhances T cell migration to other chemokine systems and by what mechanism, and if a chemokine dependent compartmental model of FTY720 enhanced T cell migration exists. Methods: In vivo migration assays were performed with wild type or various knockout (KO) mice strains receiving FTY720 (0.3 mg/kg by gavage); thymus, peripheral blood, spleen, and peripheral lymph nodes were harvested after 18 hours; and T cell distribution was determined by flow cytometry. Control mice received water only. Adoptive transfer assays were performed with CSFE labelled wild type or KO splenocytes injected into wild type or various KO mice strains. All mice were transferred with 2.0 × 107 splenocytes; the experimental group received FTY720, the control group received water. Peripheral blood, spleen, and peripheral lymph nodes were harvested after 18 hours and T cell distribution was determined by flow cytometry. All experiments were performed 3 times with 3 mice per experimental and control groups. Standard deviations and p-values were calculated with Student’s t-test. Results: As shown in Figure 1, in wild-type but not CCR2−/−, CCL2−/−, or plt mice total T cell numbers were reduced in the thymus following FTY720 administration compared to controls. Peripheral blood total T cell numbers were significantly reduced in all mice strains but plt mice had statistically more total T cells then wild type, CCR2−/−, or CCL2−/−. Sequestration of T cells in LN occurred in wild type, plt, and CCL2−/− but not CCR2−/− mice compared to controls; T cell accumulation was significantly greater in wild type compared to plt or CCL2−/− mice. T cell splenic egress was seen in wild type, plt, CCR2−/−, and CCL2−/− strains compared to controls. As shown in Figure 2, CCR2−/− transferred T cells fail to accumulate in the LN in both wild type and plt recipients following FTY720 administration compared to controls and to B6 T cells transferred into the same strains. Conclusions: We conclude that FTY720 enhancement of thymic T cell egress is dependent on the CCR7 and CCR2 chemokine system. LN T cell sequestration is dependent on both CCR2 and CCR7 chemokine systems but also display a CCR7 and CCR2 independent method of T cell accumulation. FTY720 enhance T cell migration occurs in a compartmentalized fashion where the thymus, peripheral blood, peripheral lymph node, and spleen compartments appear to be independent of one another.