Kidney transplant in pediatric gut transplant recipients - Technical challenges and outcomes.

BACKGROUND: There is limited data in the literature about pediatric kidney transplant (KT) following gut transplant (GT). The purpose of this study is to highlight the technical challenges and outcomes of KT in pediatric gut recipients who developed kidney failure (KF). METHODS: A retrospective single-center study of pediatric GT recipients from January 2000 to December 2019 was performed. In total, 14 (7%) out of 206 pediatric GT recipients developed KF and were listed for KT. Ten patients underwent kidney after gut transplant (KAGT), three patients underwent simultaneous kidney and re-do gut transplant (SKAGT), and one patient died on the KT waitlist. RESULTS: 1-, 5-, and 10-year kidney graft survival was 100%, 91%, and 78%, respectively. 1-, 5-, and 10-year GT graft survival was 100%, 77%, and 77%, respectively. 1-, 5-, and 10-year patient survival was 100%, 91%, and 91%, respectively. CONCLUSION: Despite the technical complexity, KAGT and SKAGT for pediatric GT recipients that develop KF can be performed with favorable outcomes.

Enhanced Donor Antigen Presentation by B Cells Predicts Acute Cellular Rejection and Late Outcomes After Transplantation.

Background: Enhanced B-cell presentation of donor alloantigen relative to presentation of HLA-mismatched reference alloantigen is associated with acute cellular rejection (ACR), when expressed as a ratio called the antigen presenting index (API) in an exploratory cohort of liver and intestine transplant (LT and IT) recipients. Methods: To test clinical performance, we measured the API using the previously described 6-h assay in 84 LT and 54 IT recipients with median age 3.3 y (0.05-23.96). Recipients experiencing ACR within 60 d after testing were termed rejectors. Results: We first confirmed that B-cell uptake and presentation of alloantigen induced and thus reflected the alloresponse of T-helper cells, which were incubated without and with cytochalasin and primaquine to inhibit antigen uptake and presentation, respectively. Transplant recipients included 76 males and 62 females. Rejectors were tested at median 3.6 d before diagnosis. The API was higher among rejectors compared with nonrejectors (2.2 ±â€…0.2 versus 0.6 ±â€…0.04, P value = 1.7E-09). In logistic regression and receiver-operating-characteristic analysis, API ≥1.1 achieved sensitivity, specificity, and positive and negative predictive values for predicting ACR in 99 training set samples. Corresponding metrics ranged from 80% to 88% in 32 independent posttransplant samples, and 73% to 100% in 20 independent pretransplant samples. In time-to-event analysis, API ≥1.1 predicted higher incidence of late donor-specific anti-HLA antibodies after API measurements in LT recipients (P = 0.011) and graft loss in IT recipients (P = 0.008), compared with recipients with API <1.1, respectively. Conclusions: Enhanced donor antigen presentation by circulating B cells predicts rejection after liver or intestine transplantation as well as higher incidence of DSA and graft loss late after transplantation.

Factors associated with thrombotic and hemorrhagic complications in pediatric liver transplant: A multi-center analysis from the Starzl Network for Excellence in Pediatric Transplantation.

BACKGROUND: Survival after pediatric liver transplantation (PLT) is negatively impacted by thrombotic and hemorrhagic complications. Limited data exists regarding factors associated with these complications and utilization of anticoagulation. METHODS: Retrospective review of donor, recipient variables and outcomes from four centers participating in the Starzl Network for Excellence in Pediatric Transplantation. RESULTS: 76 PLT included 39 (51%) technical variant transplants, with mean follow-up 628 ± 193.6 days. Median age/weight at transplant were 59.3 ± 53.8 months and 19.6 ± 17.2 kg. Seven (9.2%) transplants experienced intraoperative hepatic artery thrombosis (iHAT), all successfully corrected. Four HAT recurred postoperatively on POD 1,7,8 and 616. All three portal vein thromboses (PVT) occurred on POD1. Anticoagulation protocols were initiated intraoperatively in 50 and postoperatively in 66 and were active for all thrombotic and hemorrhagic events. Two patients were re-transplanted for HAT. Two patients died without having thrombotic or hemorrhagic complications. iHAT and post-operative HAT were associated with lower hepatic arterial flows. iHAT was associated with donor variant anatomy, reduced allografts and intraoperative blood loss. Intraoperative ultrasound could not predict post-operative HAT nor PVT. Surgeon pre-operative concern regarding the native portal vein correlated with postoperative PVT. Lower hepatic arterial and portal flows, higher estimated blood losses, higher prothrombin time and use of arterial interposition grafts were associated with postoperative hemorrhagic complications. CONCLUSIONS: Thrombotic and hemorrhagic complications after pediatric liver transplant remain rare but significant events. Their occurrence can be predicted with pre-operative assessment of donor and recipient vascular anatomy and direct flow measurement but may not be predicted with ultrasound evaluation nor prevented with anticoagulation.

Center use of technical variant grafts varies widely and impacts pediatric liver transplant waitlist and recipient outcomes in the United States.

To assess the impact of technical variant grafts (TVGs) [including living donor (LD) and deceased donor split/partial grafts] on waitlist (WL) and transplant outcomes for pediatric liver transplant (LT) candidates, we performed a retrospective analysis of Organ Procurement and Transplantation Network (OPTN) data on first-time LT or liver-kidney pediatric candidates listed at centers that performed >10 LTs during the study period, 2004-2020. Center variance was plotted for LT volume, TVG usage, and survival. A composite center metric of TVG usage and WL mortality was developed to demonstrate the existing variation and potential for improvement. Sixty-four centers performed 7842 LTs; 657 children died on the WL. Proportions of WL mortality by center ranged from 0% to 31% and those of TVG usage from 0% to 76%. Higher TVG usage, from deceased donor or LD, independently or in combination, significantly correlated with lower WL mortality. In multivariable analyses, death from listing was significantly lower with increased center TVG usage (HR = 0.611, CI: 0.40-0.92) and LT volume (HR = 0.995, CI: 0.99-1.0). Recipients of LD transplants (HR = 0.637, CI: 0.51-0.79) had significantly increased survival from transplant compared with other graft types, and recipients of deceased donor TVGs (HR = 1.066, CI: 0.93-1.22) had statistically similar outcomes compared with whole graft recipients. Increased TVG utilization may decrease WL mortality in the US. Hence, policy and training to increase TVG usage, availability, and expertise are critical.

Operational tolerance after intestine re-transplantation in childhood and immunological correlates. Case report and review.

BACKGROUND: Operational tolerance after retransplantation of the intestine has never been reported. PURPOSE: To two recently described intestine transplant recipients with operational tolerance, we now add a third. METHODS: Review of case record and immunological testing to confirm donor-specific hyporesponsiveness in multiple immune cell compartments. RESULTS: Re-transplanted with a multivisceral liver- and kidney-inclusive intestine allograft at age 12 years, this recipient self-discontinued immunosuppression 14 years after the retransplant and has been rejection free for 2 years thereafter. As in the two previous reports, immunological testing demonstrated decreased donor-specific inflammatory response of T-cytotoxic memory cells and B-cells, decreased presentation of donor antigen by B-cells and monocytes, absence of donor-specific anti-HLA antibodies, circulating FOXP3 + T-helper cells, and intact cellular and humoral immunity to cytomegalovirus and Epstein-Barr virus. Additionally, our recipient demonstrated enhanced donor-activation-induced apoptosis of alloreactive T-cytotoxic memory cells. CONCLUSIONS: Despite variable paths to tolerance which include graft versus host disease in two previous cases, and rejection-related loss of the primary isolated intestinal allograft in our recipient, the three cases with operational tolerance are bound by common themes: a relatively large donor antigenic load transmitted during intestine transplantation, and donor-specific hyporesponsiveness. Cell-based assays suggest enhanced donor-induced apoptosis of recipient T-cells and circulating T-regulatory cells as mechanistic links between antigenic load and donor-specific hyporesponsiveness.

State of pediatric liver transplantation in the United States and achieving zero wait list mortality with ideal outcomes: A statement from the Starzl Network for Excellence in Pediatric Transplant Surgeon's Working Group.

BACKGROUND: Liver transplant is a life-saving therapy that can restore quality life for several pediatric liver diseases. However, it is not available to all children who need one. Expertise in medical and surgical management is heterogeneous, and allocation policies are not optimally serving children. Technical variant grafts from both living and deceased donors are underutilized. METHODS: Several national efforts in pediatric liver transplant to improve access to and outcomes from liver transplant for children have been instituted and include adjustments to allocation policies, UNOS-sponsored collaborative improvement projects, and the emergence of national learning networks to study ongoing challenges in the field the Surgical Working group of the Starzl Network for Excellence in Pediatric Transplantation (SNEPT) discusses key issues and proposes potential solutions to eliminate the persistent wait list mortality that pediatric patients face. RESULTS: A discussion of the factors impacting pediatric patients' access to liver transplant is undertaken, along with a proposal of several measures to ensure equitable access to life-saving liver transplant. CONCLUSIONS: Pediatric liver transplant wait list mortality can and should be eliminated. Several measures, including collaborative efforts among centers, could be leveraged to acheive this goal.

Impaired Cellular and Antibody immunity after COVID-19 in Chronically Immunosuppressed Transplant Recipients.

Assessment of cellular immunity to the SARS-CoV-2 coronavirus is of great interest in chronically immunosuppressed transplant recipients (Tr), who are predisposed to infections and vaccination failures. We evaluated CD154-expressing T-cells induced by spike (S) antigenic peptides in 204 subjects-103 COVID-19 patients and 101 healthy unexposed subjects. S-reactive CD154+T-cell frequencies were a) higher in 42 healthy unexposed Tr who were sampled pre-pandemic, compared with healthy NT (p=0.02), b) lower in Tr COVID-19 patients compared with healthy Tr (p<0.0001) and were accompanied by lower S-reactive B-cell frequencies (p<0.05), c) lower in Tr with severe COVID-19 (p<0.0001), or COVID-19 requiring hospitalization (p<0.05), compared with healthy Tr. Among Tr with COVID-19, cytomegalovirus co-infection occurred in 34%; further, incidence of anti-receptor-binding-domain IgG (p=0.011) was lower compared with NT COVID-19 patients. Healthy unexposed Tr exhibit pre-existing T-cell immunity to SARS-CoV-2. COVID-19 impairs anti-S T-cell and antibody and predisposes to CMV co-infection in transplant recipients.

Domino liver transplant from a donor with maple syrup urine disease into a recipient with phenylketonuria.

Classical phenylketonuria (PKU) presents a unique challenge for women of child-bearing age. In the context of pregnancy, poorly controlled hyperphenylalaninemia can result in a devastating constellation of outcomes for the baby referred to as the maternal PKU Syndrome. We present the case of a woman with classical PKU unable to maintain a restricted diet and refractory to pharmacological therapies. She elected to undergo a domino liver transplant, receiving an organ from a donor with classical branched chain ketoacid dehydrogenase deficiency (maple syrup urine disease). Plasma phenylalanine concentrations normalized within a few days after transplant and remained so on an unrestricted diet during the first year of follow-up. The patient reports subjective improvements in mood, energy level, and overall quality of life. In the appropriate clinical setting, liver transplant should be considered to provide metabolic stability for PKU patients, particularly women of childbearing age.

Factors associated with improved patient and graft survival beyond 1 year in pediatric liver transplantation.

With advances in surgical techniques, medical management, and more equitable allocation systems, children who receive a liver transplantation (LT) today can expect remarkable outcomes early after LT. However, beyond 1 year after transplant, attrition rates have not improved. We reviewed two separate eras (Era 1: January 1995-June 2004 vs. Era 2: July 2004-March 2018) of the Society of Pediatric Liver Transplantation registry to explore the evolution and associated factors contributing to late graft loss (LGL) and late mortality (LM). The fraction of long-term pediatric LT recipients surviving after 1 year with their first graft significantly improved (81.5% in Era 1 vs. 85.7% in Era 2; p < 0.0001). This improvement occurred despite significant changes in patient selection toward higher risk populations (p < 0.001) and without notable improvement in perioperative complications such as hepatic artery thrombosis (p = 0.24) and early posttransplant reoperation (p = 0.94) that have historically contributed to poor late-allograft outcomes. Improved outcomes were associated with changes in patient characteristics and perioperative practices, which subsequently impacted both early post-LT complications as well as other sequalae known to contribute to adverse events in long-term pediatric LT recipients. In conclusion, despite significant changes in patient selection toward higher risk populations, and without notable improvement in several perioperative complications known to contribute to poor late-allograft outcomes, significant improvements in LGL and a trend toward improvement in LM was seen in a more contemporary cohort of children receiving an LT.

Technical Aspects and Considerations of Meso-Rex Bypass Following Liver Transplantation With Left Lateral Segment Grafts: Case Report and Review of the Literature.

In pediatric patients with extrahepatic portal vein obstruction and complications of portal hypertension, but with normal liver function, a meso-Rex bypass (MRB) connecting the superior mesenteric vein to the intrahepatic left portal is the favored surgical management. Pediatric patients with a history of a partial liver transplant (LT), especially living donors, are at greater risk for portal vein complications. Hence, an adequate knowledge of this technique and its additional challenges in the post-LT patient setting is crucial. We provide an overview of the available literature on technical aspects for an MRB post-LT. Preoperative considerations are highlighted, along with intraoperative considerations and postoperative management. Special attention is given to the even-more-demanding aspect of performing an MRB post-liver transplantation with a left lateral segment. Surgical alternatives are also discussed. In addition, we report here a unique case in which this surgical technique was performed on a complex pediatric patient with a history of a living-donor LT with a left lateral segment graft over a decade ago.

Living Donor Liver Transplantation vs. Split Liver Transplantation Using Left Lateral Segment Grafts in Pediatric Recipients: An Analysis of the UNOS Database.

Split and LDLT in pediatric patients have the potential to decrease wait times and waitlist mortality. Using UNOS-STAR data, we compared outcomes of pediatric patients undergoing LDLT and SLT using LLS grafts. The baseline characteristics and post-operative outcomes were compared between groups. Actuarial graft and patient survival were analyzed with Kaplan-Meier curves. Between 2010 and 2019, 911 pediatric LT were included in the analysis (LD graft group, n = 508, split graft group, n = 403). LD graft recipients spent more time on the waitlist vs. the split graft group (60 (22-138) days vs. 46 (16-108) days; p = 0.007). LD recipients had a lower rate of graft failure, found in 9.8% of patients compared with 14.6% in the split graft group (p = 0.02). HAT was the most common graft failure cause, with similar rates. Graft and patient survival at 1-, 3-, and 5-years was comparable between LDLT and SLT. In subgroup analyses, patients with biliary atresia, those ≤10 kg or ≤10 years old receiving an LD graft showed improved graft survival. In conclusion, LDLT is associated with a lower rate of graft failure in pediatric patients. The use of LLS regardless of the type of donor is a safe way to facilitate access to transplantation to pediatric patients with acceptable short and long-term outcomes.

Increasing Living Donor Liver Transplantation Using Liver Paired Exchange.

BACKGROUND: Living donor liver transplantation (LDLT) continues to be the primary modality of liver transplantation in Asia, but it accounts for about 5% of all liver transplantations in the US. ABO incompatibility is the primary reason motivated donors are declined. Although kidney paired exchanges are common, liver paired exchange (LPE) is still evolving in the US. STUDY DESIGN: This is a retrospective review (between January 1, 2019, and July 31, 2021) of our initial experience with LPE. RESULTS: A total of 10 LPEs (20 LDLTs) were performed during the study period. Seven LPEs were initiated by a nondirected O donor. The other 3 pair sets involved 1 ABO compatible and 1 ABO incompatible pair. Transplantations in a pair set were completed within a mean of 4.8 (range 1-14) days of each other. All 20 donors are doing well with no major complications at 12.7 (range 1-20) months. Seventeen of 20 recipients are alive and have good allograft function. One recipient died in the early postoperative period. Two late deaths of patients with functioning allografts were due to COVID-19 (at 8 months) and peritoneal carcinomatosis and gram-negative sepsis (at 9 months). CONCLUSIONS: LPE is feasible in a high-volume LDLT center and is a useful option to increase LDLT by overcoming ABO incompatibility. Nondirected donors can be utilized to initiate an LPE.

Long-term outcomes of intestinal transplantation from donors aged under 1 year.

BACKGROUND: The aim of the study was to analyze the long-term outcomes of transplants utilizing ITx donors <1 year and to compare these results with older donors. METHODS: Between January 2007 and December 2019, the primary ITx donors in the Children's Hospital of Pittsburgh of UPMC were retrospectively reviewed. Short- and long-term outcomes of recipients receiving a deceased donor organ from donors <1 year were compared with those found in all other recipients. RESULTS: During the study period, there were 89 primary ITx donors, using 30 donors (33.7%) aged <1 year. The mean age of their recipients was 1.6 ± 0.7 (0.7-3.2) years. The 30 graft types were isolated intestine (n = 3, 10.0%), liver bowel (n = 20, 66.7%), and multivisceral (n = 7, 23.3%). Technical complications occurred in 12 (40.0%) recipients. Candidates transplanted with intestine allografts from donors <1 year of age had shorter wait times (p < .001), more liver-inclusive grafts (p < .001), and less donor-specific antibodies (DSA) (p = .014). During follow-up, the recipients had less graft loss (p = .018), and more remained alive with graft in place (p = .011). Among children transplanted with such donors, 3-year and graft survival rates were 86.7% and 82.9% compared to 62.8% and 49.9% in the cohort of donors >1 year (p = .032 and .011). CONCLUSIONS: Donor age <1 year was associated with improved graft survival. Optimal utilization of this population for toddler candidates would increase intestine availability, reduce time to transplantation, and potentially improve long-term outcome.

North American Biliary Stricture Management Strategies in Children After Liver Transplantation: A Multicenter Analysis From the Society of Pediatric Liver Transplantation (SPLIT) Registry.

Biliary strictures affect 4%-12% of pediatric liver transplantations. Biliary strictures can contribute to graft loss if left untreated; however, there remains no consensus on the best course of treatment. Study objectives included analyses of outcomes associated with biliary stricture management strategies via percutaneous transhepatic cholangiography (PTC), endoscopic retrograde cholangiopancreatography (ERCP), or surgery. We identified pediatric liver transplantation recipients (2011-2016) with biliary strictures from the Society of Pediatric Liver Transplantation (SPLIT) registry and retrieved imaging, procedural, and operative reports from individual centers. Subanalyses were performed to specifically evaluate PTC and ERCP for "optimal biliary outcome" (OBO), defined as graft survival with stricture resolution and without recurrence or surgery. A total of 113 children with a median follow-up of 3.9 years had strictures diagnosed 100 days (interquartile range, 30-290) after liver transplantation; 81% were isolated anastomotic strictures. Stricture resolution was achieved in 92% within 101 days, more frequently with isolated anastomotic strictures (96%). 20% of strictures recurred, more commonly in association with hepatic artery thrombosis (32%). Patient and graft survival at 1 and 3 years were 99% and 98% and 94% and 92%, respectively. In a subgroup analysis of 79 patients with extrahepatic strictures managed by PTC/ERCP, 59% achieved OBO following a median of 4 PTC, and 75% following a median of 3 ERCP (P < 0.001). Among patients with OBO, those with ERCP had longer time intervals between successive procedures (41, 47, 54, 62, 71 days) than for PTC (27, 31, 36, 41, 48 days; P < 0.001). Allograft salvage was successful across all interventions. Stricture resolution was achieved in 92%, with 20% risk of recurrence. Resolution without recurrence was highest in patients with isolated anastomotic strictures and without hepatic artery thrombosis.

Increased use of split liver grafts in adult recipients following implementation of a pediatric liver transplant program.

BACKGROUND: Split liver transplantation (SLT) is a strategy to address organ shortage, but is a technically more demanding procedure than whole graft liver transplantation (LT). We aimed to determine the outcomes following SLT in adult recipients as well as to highlight the impact that having a pediatric LT program has on SLT implementation. METHODS: All SLTs conducted at a single-center from 2010 to 2019 were identified. Patient data was obtained through retrospective review of the electronic medical record. Kaplan-Meier analysis assessed primary outcomes of 1-,3-, and 5-year graft and patient survival. RESULTS: We identified 37 SLTs performed at our institution from 2010 to 2019. Twenty-four donated livers resulted in 21 extended right lobes and 16 left lateral segments for adults and pediatrics recipients, respectively. Eighty-one percent (30/37) of the SLTs were performed after introduction of the combined pediatric program in 2016. 13/24 donor livers were split with both grafts allocated and used at our institution and 92% occurred after introduction of the pediatric program. Graft survival rates at 1-, 3-, and 5-years were 94% in adult recipients and 100% for all time periods in pediatric recipients. Actuarial post-transplant patient survival was 100% at 1-, 3-, and 5-years in both. CONCLUSIONS: The introduction of a pediatric liver transplantation program resulted in more than a fourfold increase in the number of SLTs performed at our center. Increase in allocation and use of both grafts at our institution was also seen.