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.

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.

Long-term liver transplant outcomes for progressive familial intrahepatic cholestasis type 1: The Pittsburgh experience.

BACKGROUND: Progressive familial intrahepatic cholestasis type 1 (PFIC1) arises from biallelic variants in the ATP8B1 gene that annul FIC1 activity, resulting in progressive liver disease. Liver transplant (LT) is indicated in refractory disease; however, post-LT complications including worsening diarrhea and steatohepatitis progressing to fibrosis with graft loss have been reported. We aim to describe long-term outcomes of PFIC1 LT recipients at our center, focusing on the histological changes of the allografts. METHODS: We assessed 7 PFIC1 patients post-LT at the Children's Hospital of Pittsburgh (CHP). All pre-transplant, explant, and sequential post-transplant pathology samples were reviewed. Continuous data are presented as the mean ± SD. We compared the pre- and post-transplant height and weight z-scores using Wilcoxon signed-rank test. RESULTS: Seven (29% male) patients with PFIC1 received a LT (n = 6) or had post-LT care (n = 1) at CHP. Six had confirmed or suspected identical genetic. At a mean follow-up of 10.9 years, both patient survival and graft survival were 100%. Diarrhea persisted (n = 3) or newly developed (n = 4) in all patients after LT contributing to ongoing growth failure, with mean z-scores -2.63 (weight) and -2.98 (height) at follow-up. Histologically, allograft steatosis was common but was not accompanied by significant inflammation, ballooning, or fibrosis. CONCLUSION: We show that extrahepatic disease persists and near-universal allograft steatosis occurs. However, at a mean follow-up period of over 10 years, no patients developed steatohepatitis or significant fibrosis, and both patient survival and graft survival are excellent.

Metabolic Control and "Ideal" Outcomes in Liver Transplantation for Maple Syrup Urine Disease.

OBJECTIVES: To assess outcomes following liver transplantation for maple syrup urine disease by determining attainment and sustainability of metabolic control and apply an "ideal" outcome composite in long-term survivors. STUDY DESIGN: A single center, retrospective review collected clinical data including branched-chain amino acid (leucine, isoleucine, and valine) levels following liver transplant and determined achievement of an ideal long-term outcome profile of a first allograft stable on immunosuppression monotherapy, normal growth, and absence of common transplant-related sequelae. RESULTS: Of 77 patients meeting inclusion criteria identified, 23 were long-term (≥10-year) survivors and were additionally assessed for ideal outcome attainment. Patient and graft survival were 100% and 99%, respectively, and all patients were on an unrestricted protein intake diet. Although significant variation was noted in mean isoleucine (P < .01) and leucine (P < .05) levels postliver transplantation, no difference was seen in valine (P = .29) and overall clinical impact was likely negligible as metabolic stability was achieved and sustained beyond 3 years postliver transplantation and no metabolic crises were identified. Of 23 long-term survivors with available data, 9 (39%) achieved all composite metrics determined to define "ideal" outcomes in pediatric postliver transplantation populations. CONCLUSIONS: Liver transplant enables long-term metabolic stability for patients with maple syrup urine disease. A combination of experience and improvement in both pre- and postliver transplantation care has enabled excellent survival and minimal comorbidities following transplant.

Pediatric intestinal transplantation.

The field of intestinal transplantation has experienced dramatic growth since the first reported cases 3 decades ago. Improvements in operative technique, donor assessment and immunosuppressive protocols have afforded children who suffer from life-threatening complications of intestinal failure a chance at long-term survival. As experience has grown, newer diseases, with more systemic manifestations have arisen as potential indications for transplant. After discussing the historical developments of intestinal transplant as a backdrop, this review focuses on the specific pre-operative indications for transplant as well as the great success that intestinal rehabilitation has witnessed over the past decade. A detailed discussion of evolution of immunosuppressive strategies is followed a general review of the common infectious complications experienced by children after intestinal transplant as well as the current long- and short-term results, including a section on new research on the quality of life in this challenging population of patients.

A Challenging Case of Severe Infantile Cholestasis in Alpha-1 Antitrypsin Deficiency.

Jaundice in the newborn period can be physiologic and is often due to benign causes. Jaundice due to conjugated hyperbilirubinemia extending beyond the second week of life may be an early sign of several cholestatic or metabolic liver diseases, and it requires logical and timely analysis so that specific treatments can be initiated. Alpha-1 antitrypsin deficiency is the most common genetic cause of pediatric liver disease and transplantation, and it must be considered when evaluating cholestatic infants. Here, we present an unusual case of alpha-1 antitrypsin deficiency with severe infantile cholestasis and rapid decompensation in the first 4 months of life, where in-depth but timely diagnosis was crucial for the appropriate intervention to take place.

Host conditioning and rejection monitoring in hepatocyte transplantation in humans.

BACKGROUND & AIMS: Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. METHODS: Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. RESULTS: Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343±48µM (normal 30-119µM) to 854±25µM (treatment goal ≤360µM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900µM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. CONCLUSIONS: Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. LAY SUMMARY: Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.

Clinical Hepatocyte Transplantation: What Is Next?

PURPOSE OF REVIEW: Significant recent scientific developments have occurred in the field of liver repopulation and regeneration. While techniques to facilitate liver repopulation with donor hepatocytes and different cell sources have been studied extensively in the laboratory, in recent years clinical hepatocyte transplantation (HT) and liver repopulation trials have demonstrated new disease indications and also immunological challenges that will require the incorporation of a fresh look and new experimental approaches. RECENT FINDINGS: Growth advantage and regenerative stimulus are necessary to allow donor hepatocytes to proliferate. Current research efforts focus on mechanisms of donor hepatocyte expansion in response to liver injury/preconditioning. Moreover, latest clinical evidence shows that important obstacles to HT include optimizing engraftment and limited duration of effectiveness, with hepatocytes being lost to immunological rejection. We will discuss alternatives for cellular rejection monitoring, as well as new modalities to follow cellular graft function and near-to-clinical cell sources. SUMMARY: HT partially corrects genetic disorders for a limited period of time and has been associated with reversal of ALF. The main identified obstacles that remain to make HT a curative approach include improving engraftment rates, and methods for monitoring cellular graft function and rejection. This review aims to discuss current state-of-the-art in clinical HT and provide insights into innovative approaches taken to overcome these obstacles.

Failure to Rescue as a Quality Improvement Approach in Transplantation: A First Effort to Evaluate This Tool in Pediatric Liver Transplantation.

BACKGROUND: Significant intercenter variation exists in mortality and death-censored graft loss (DCGL) after transplantation. Failure to rescue (FTR, death after a major complication) is an emerging tool in quality improvement and may underlie this variation. This study is the first effort to investigate the relationship between FTR and outcomes in transplantation to assess its utility in care improvement. METHODS: Using the Studies of Pediatric Liver Transplantation database, we identified 2330 children undergoing primary liver transplants at 21 centers. Centers were ranked by risk-adjusted mortality and sorted into tertiles. We then compared mortality, complications, and FTR across tertiles. RESULTS: Overall mortality was 4.9%, ranging from 1.4% to 8.1% in the low and high mortality tertiles (P < 0.01). The low mortality tertile had significantly lower rates of complications (30.9% vs 38.5% and 40.4%, P < 0.01) as well as FTR (4.6% vs 9.9% and 14.3%, P < 0.01). A similar trend was seen in the DCGL analysis. CONCLUSIONS: Our results demonstrate that although centers with higher mortality and DCGL have more frequent major complications, they exhibit 3-fold the rate of FTR. Efforts to standardize perioperative care, and thus minimize FTR, will have value to pediatric liver transplantation recipients. This preliminary study indicates that FTR may provide a useful quality improvement tool for the field of transplantation and warrants further investigation.

Long-term outcomes and predictors in pediatric liver retransplantation.

Historically, 9-29% of pediatric liver transplant recipients have required retransplantation. Although outcomes have improved over the last decade, currently published patient and graft survival remain lower after retransplant than after primary transplant. Data from liver retransplantation recipients at our institution between 1991 and 2013 were retrospectively reviewed. Kaplan-Meier estimates were used to depict patient and graft survival. Predictors of survival were analyzed using a series of Cox proportional hazards models. Predictors were analyzed separately for patients who had "early" (≤ 30 days after primary transplant) and "late" retransplants. Eighty-four patients underwent retransplant at a median time of 241 days. Sixty percent had late retransplants. At one, five, and 10 yr, actuarial patient and graft survival were 73%/71%, 66%/63%, and 58%/53%, respectively. Since 2002, patient and graft survival improved to 86%/86% at one yr and 93%/87% at five yr. While operative complications were a common cause of death after earlier retransplants, since 2002, infection has been the only cause of death. Significant morbidities at five-yr follow-up include renal dysfunction (15%), diabetes (13%), hypertension (26%), chronic rejection (7%), and PTLD (2%). Current survival after pediatric liver retransplantation has improved significantly, but long-term immunosuppressant morbidity remains an opportunity for improvement.

Retained surgical stents as a cause of biliary obstruction in pediatric liver transplants.

BACKGROUND: Small-caliber plastic stents are sometimes placed across the hepaticojejunostomy in liver transplant recipients at the time of biliary reconstruction. These stents usually pass spontaneously, but they can be retained and, rarely, this may cause biliary obstruction. OBJECTIVE: The purpose of this paper is twofold: to describe the appearance of biliary tract obstruction caused by retained surgical stents in pediatric liver transplants, and to report how these stents can be removed using interventional radiology techniques. MATERIALS AND METHODS: Three pediatric patients presenting with biochemical and imaging evidence of biliary obstruction were encountered over a 6-month period. At percutaneous cholangiography all patients were found to have retained surgical stents which appeared to be causing biliary tract obstruction. Percutaneous snaring of the stents was undertaken. RESULTS: All stents were successfully removed using interventional radiology techniques, and follow-up showed no evidence of recurrent obstruction. CONCLUSION: Surgical stents in children undergoing hepaticojejunostomy may be retained and cause biliary obstruction. Radiologists involved with imaging these patients should be aware of this potential cause of biliary obstruction. This complication is amenable to interventional radiology techniques with good long-term results. There is no easy endoscopic or surgical treatment option in these patients.

Parent perspectives on decisions to participate in a phase I hepatocyte transplant trial.

We examined factors that affect decision-making for families presented with a phase I clinical trial of hepatocyte transplant as a potential alternative to liver transplant for their children among two groups: (i) families who were actually offered enrollment in the hepatocyte trial and; (ii) families whose children had liver transplants before the trial was available. We conducted semi-structured interviews about actual and hypothetical decision-making regarding trial participation and used grounded theory analysis to identify common themes. The most common motivator for participation was decline in the child's health. The most common deterrent was lack of data from prior hepatocyte transplants, particularly when compared with data available about liver transplant. Interviewees' point of comparison for evaluating relative benefits and risks of hepatocyte transplant oscillated between the alternative of doing nothing while waiting for a liver (the relevant alternative) vs. the alternative of getting a liver. These results suggest that families' reluctance to participate may result from misconceptions about severity of the child's disease, underestimating risks of liver transplant, or confusion about the role of hepatocyte transplant in the treatment pathway. Clarification of available treatment alternatives and associated risks as part of informed consent may improve the quality of decision-making regarding trial enrollment.

New potential cell source for hepatocyte transplantation: discarded livers from metabolic disease liver transplants.

UNLABELLED: Domino liver transplantation is a method used to increase the number of liver grafts available for orthotopic liver transplantation (OLT). Reports indicate that livers from patients with metabolic liver disease can be safely transplanted into select recipients if the donor's defect and the recipient's metabolic needs are carefully considered. The liver of patients with many types of metabolic liver disease is morphologically and biochemically normal, except for the mutation that characterizes that disease. Other biochemical functions normally performed by the liver are present and presumably "normal" in these hepatocytes. Hepatocytes were isolated from the liver of 35 organ donors and 35 liver tissues taken at OLT from patients with liver disease were analyzed for 9 different measures of viability and function. The data indicate that cells isolated from some diseased livers performed as well or better than those isolated from organ donors with respect to viability, cell yield, plating efficiency and in assays of liver function, including drug metabolism, conjugation reactions and ammonia metabolism. Cells from metabolic diseased livers rapidly and efficiently repopulated a mouse liver upon transplantation. CONCLUSIONS: As with domino liver transplantation, domino cell transplantation deserves consideration as method to extend the pool of available organs and cells for transplantation.

Right diaphragmatic hernia after liver transplant in pediatrics: a case report and review of the literature.

Diaphragmatic hernias (DH) are an unusual complication after pediatric liver transplantation; however, they have been reported with increased frequency in the past few years. DHs are responsible for nearly half of the small bowel obstructions requiring surgical intervention in this patient population. It has been suggested that the use of a left lobe liver graft, surgical trauma, malnourishment, elevated intra-abdominal pressures, and mTor inhibitors may predispose to development of DH. The use of a segmental graft may increase the recognition of diaphragmatic hernia because the surgically damaged right hemi-diaphragm often remains exposed to underlying viscera, instead of being covered by the right hepatic lobe. Treatment is surgical reduction, with up to 20% of the patients requiring resection of the herniated intestine. Herein we describe a case of DH after left segmental liver transplant in a two- yr-old boy that presented one month post left lobe split liver transplant with abdominal pain, anorexia, and respiratory distress. Just like in the majority of the reported cases, an urgent laparotomy with primary repair was performed. No resection of the herniated segment of intestine was required. For pediatric patients with otherwise unexplained respiratory or gastrointestinal symptoms after a left lateral segment liver transplant, right-sided diaphragmatic hernias should always be high in the differential diagnosis.