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BACKGROUND Little is known about outcomes of pediatric patients transplanted using donor liver grafts with abnormal biopsy results. We assessed donor liver biopsy data to report characteristics and outcomes of abnormal livers transplanted in pediatric patients. MATERIAL AND METHODS We identified pediatric patients who received a liver transplant from a biopsied deceased donor between 2015 and 2022 using the national database UNOS Standard Transplant Analysis and Research files. Recipients were excluded if they received multi-organ transplants or were lost to follow-up. Livers with ≤5% macrosteatosis, no fibrosis, and no inflammation were classified as normal livers (NL). Allografts with >5% macrosteatosis, any fibrosis, or any inflammation were considered abnormal livers (AL). Donor and recipient demographic data and outcomes were examined. RESULTS Of the 3808 total pediatric liver transplants in the study period, there were 213 biopsied donor liver allografts transplanted into pediatric recipients. Of those, 114 were NL and 99 were AL. 35.4% (35/99) of the AL had >5% macrosteatosis with a mean of 7.6±11.4%, 64.6% (64/99) had any inflammation, and 18.2% (18/99) had any fibrosis. AL donors were significantly older than NL donors. AL recipients had higher PELD scores. There were no significant differences in length of stay, rejection rates and causes, or allograft survival between AL and NL. Multivariable analysis revealed that inflammation was independently associated with a significantly greater risk for graft failure. CONCLUSIONS Outcomes of abnormal livers are excellent. Inflammation was an independent risk factor for poor graft prognosis. Donor biopsies in pediatric liver transplantation can be a useful adjunct to assess outcomes.

Introduction: Organ procurement organizations (OPO) have started to employ transplant-trained surgeons dedicated to organ procurement with the aim to increase allograft utilization and enhance the use of procured organs. We investigated the effects of an OPO-employed surgeon on the procurement and utilization of organs from pediatric donors within the Southwestern Transplant Alliance OPO., Methods: OPO data were obtained for all procurements that were performed between 2014 and 2019. The analysis was performed to see if the presence of an OPO donor surgeon impacted the utilization of pediatric livers. Donor and recipient demographic data were examined between allografts procured with the presence of an OPO surgeon (OPO-Present) and those without an OPO surgeon (OPO-Absent). A p-value of <.05 was considered significant., Results: Of 149 pediatric procurements, 91 included an OPO-donor surgeon. In procurements with OPO-Present, donors were younger (8.2 vs. 11.2, p < .05) and had longer distances to travel to the recipient center (334 vs. 175 miles p < .05), but had comparable cold ischemic times. In terms of organ share type, more OPO-Present livers were shared nationally and there was no difference in discard rate between OPO-Present and OPO-Absent procurements. Finally, OPO-Present livers were more likely to be transplanted to pediatric recipients compared to OPO-Absent (47.3% vs. 24.1% p < .05)., Conclusion: The presence of an OPO surgeon has impacted organ utilization, leading to increased transplantation of pediatric livers in pediatric recipients, and has expanded the geographical share of pediatric livers., (© 2023 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Background: Pre-transplant deceased donor liver biopsy may impact decision making; however, interpretation of the results remains variable and depends on accepting center practice patterns., Methods: In this cohort study, adult recipients from 04/01/2015-12/31/2020 were identified using the UNOS STARfile data. The deceased donor liver biopsies were stratified by risk based on degree of fibrosis, macrovesicular fat content, and level of portal infiltration (low-risk: no fibrosis, no portal infiltrates, and <30% macrosteatosis; moderate-risk: some fibrosis or mild infiltrates and <30% macrosteatosis; high-risk: most fibrosis, moderate/marked infiltrates, or ≥30% macrosteatosis). Graft utilization, donor risk profile, and recipient outcomes were compared across groups., Results: Of the 51,094 donor livers available, 20,086 (39.3%) were biopsied, and 34,606 (67.7%) were transplanted. Of the transplanted livers, 14,908 (43.1%) were biopsied. The transplanted grafts had lower mean macrovesicular fat content (9.3% transplanted vs. 26.9% non-transplanted, P < 0.001) and less often had any degree of fibrosis (20.9% vs. 39.9%, P < 0.001) or portal infiltration (51.3% vs. 58.2%, P < 0.001) versus non-transplanted grafts. Post-transplant recipient LOS (14.2 days high-risk vs. 15.2 days low-risk, P = 0.170) and 1-year graft survival (90.5% vs. 91.7%, P = 0.137) did not differ significantly between high- versus low-risk groups. Kaplan-Meier survival estimates further revealed no differences in the 5-year graft survival across risk strata (P = 0.833). Of the 5178 grafts biopsied and turned down, PSM revealed 1338 (26.0%) were potentially useable based on biopsy results and donor characteristics., Conclusion: Carefully matched deceased donor livers with some fibrosis, inflammation, or steatosis ≥30% may be suitable for transplantation. Further study of this group of grafts may decrease turndowns of potentially useable organs., (© 2023 The Authors. World Journal of Surgery published by John Wiley & Sons Ltd on behalf of International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Objective: To assess how liver allografts preserved using portable normothermic machine perfusion (NMP) compare against those that underwent ischemic cold storage (ICS) in the setting of donation after brain death (DBD) and donation after circulatory death (DCD) liver transplantation (LT)., Background: Compared with conventional ICS, NMP may offer more homeostatic preservation, permit physiological assessment of organ function, and provide opportunities for graft improvement/modification. We report a single-center US experience of liver NMP., Methods: A single-center, retrospective analysis of collected data on 541 adult whole LTs from 469 DBD donors [NMP (n = 58) vs ICS (n = 411)] and 72 DCD donors [NMP (n = 52) vs ICS (n = 20)] between January 2016 and December 2022., Results: In DBD LT, male sex [odds ratio (95% CI): 1.83 (1.08-3.09)] and >10% macrosteatosis of the donor liver [1.85 (1.10-3.10)] were statistically significant independent risk factors of early allograft dysfunction (EAD). Donor age >40 years and cold ischemia time >7 hours were independent risk factors of reperfusion syndrome (RPS). One-year, 3-year, and 5-year incidences of ischemic cholangiopathy (IC) did not differ significantly in DBD cases between the NMP and ICS cohorts. In DCD LT, NMP was an independent protective factor against EAD [0.11 (0.03-0.46)] and RPS [0.04 (0.01-0.25)]. The incidence of IC in the DCD cases at 1-year and 3-year time points was significantly lower in the NMP cohort (1.9% compared with 20% in the ICS group)., Conclusions: Compared with conventional ICS, NMP can significantly reduce the incidence of EAD, RPS, and IC after DCD LT., Competing Interests: M.M. is an employee of Transmedics OCS. J.F.M. serves on the Transmedics Clinical Advisory Board. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pediatric recipients of living donor kidneys have a low rate of delayed graft function (DGF). We examined the incidence, risk factors and outcomes of DGF in pediatric patients who received a living donor allograft., Methods: The STARfile was queried to examine all pediatric patients transplanted with a living donor kidney between 2000 and 2020. Donor and recipient demographic data were examined, as were survival and outcomes. Recipients were stratified into DGF and no DGF groups. DGF was defined as the need for dialysis within the first week after transplant., Results: 6480 pediatric patients received a living donor (LD) kidney transplant during the study period. 269 (4.2%) developed DGF post-transplant. Donors were similar in age, creatinine, and cold ischemia time. Recipients of kidneys with DGF were similar in age, sensitization status and HLA mismatch. Focal segmental glomerulosclerosis (FSGS) was the most common diagnosis in recipients with DGF, and allograft thrombosis was the most common cause of graft loss in this group. Small recipients (weight < 15 kg) were found to have a significantly higher rate of DGF. Length of stay doubled in recipients with DGF, and rejection rates were higher post-transplant. Recipients of LD kidneys who developed DGF had significantly worse 1 year allograft survival (67% vs. 98%, p < .0001)., Conclusions: Pediatric living donor kidney transplant recipients who experience DGF have significantly poorer allograft survival. Optimizing the donor and recipient matching to avoid compounding risks may allow for better outcomes., (© 2022 Wiley Periodicals LLC.)

The American Society of Transplant Surgeons supports efforts to increase the number of organs that are critically needed for patients desperately awaiting transplantation. In the United States, transplantation using organs procured from donation after circulatory death (DCD) donors has continued to increase in number. Despite these increases, substantial variability in the utilization and practices of DCD transplantation still exists. To improve DCD organ utilization, it is important to create a set of best practices for DCD recovery. The following recommendations aim to provide guidance on contemporary issues surrounding DCD organ procurement in the United States. A work group was composed of members of the American Society of Transplant Surgeon Scientific Studies Committee and the Thoracic Organ Transplantation Committee. The following topics were identified by the group either as controversial or lacking standardization: prewithdrawal preparation, definition of donor warm ischemia time, DCD surgical technique, combined thoracic and abdominal procurements, and normothermic regional perfusion. The proposed recommendations were classified on the basis of the grade of available evidence and the strength of the recommendation. This information should be valuable for transplant programs as well as for organ procurement organizations and donor hospitals as they develop robust DCD donor procurement protocols., (Copyright © 2022 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

The number of children being listed for transplant continues to be greater than the number of available organs. In fact, over the past decade, rates of liver and kidney transplants in pediatric transplantation are essentially unchanged (Am J Transplant. 2020;20:193 and Am J Transplant. 2020;20:20). The use of DCD donors offers a potential solution to organ scarcity; however, the use of DCD organs in pediatric transplantation remains a rare event. Pediatric transplants done using carefully chosen DCD donor organs have shown to have outcomes similar to those seen with the use of donation after brain death (DBD) donors. Herein, we review the literature to examine the utilization of DCD livers and kidneys, outcomes of these allografts, and assess if DCD organs are a viable method to increase organ availability in pediatric transplantation., (© 2022 Wiley Periodicals LLC.)

Background: Liver transplantation has increased in volume and provides substantial survival benefit. However, there remains a need for value-based assessment of this costly procedure., Methods: Model for end stage liver disease era adult recipients were identified using United Network for Organ Sharing Standard Transplant Analysis file data (n = 75,988) and compared across time periods (period A: February 2002 to January 2007; B: February 2007 to January 2013; C: February 2013 to January 2019). Liver centers were divided into volume tertiles for each period (small, medium, large). Value for the index transplant episode was defined as percentage graft survival ≥1 year divided by mean posttransplant duration of stay., Results: All centers increased value over time due to ubiquitous improvement in 1-year graft survival. However, large centers demonstrated the most significant value change (large +17% vs small +7.0%, P < .001) due to a -8.5% reduction in large centers duration of stay from period A to C, while small centers duration of stay remained unchanged (-0.1%). Large centers delivered higher value despite more complex care: older recipients (54.8 ± 10.3 vs 53.0 ± 11.4 years P < .001), fewer model for end stage liver disease exceptions (34.0% vs 38.2%, P < .001), higher rates of candidate portal vein thrombosis (10.1% vs 8.5%, P < .001) and prior abdominal surgery (43.4% vs 37.4%, P < .001), and more marginal donor utilization (donor risk index 1.45 ± 0.38 vs 1.36 ± 0.33, P < .001). Mahalanobis metric matching demonstrated that compared with small centers, large centers progressively shortened recipient duration of stay per transplant in each period (A: -0.36 days, P = .437; B: -2.14 days, P < .001; C: -2.49 days, P < .001)., Conclusion: There is value in liver transplant volume. Adoption of value-based practices from large centers may allow optimization of health care delivery for this costly procedure., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: NMP provides a superior strategy for the assessment and preservation of marginal donor livers and has demonstrated increased utilization and enhances organ quality when used in adult liver transplantation. We aimed to evaluate the interest of incorporating the use of NMP in pediatric liver transplantation., Methods: An anonymous online survey was distributed to pediatric transplant surgeons and hepatologists across the United States. Respondent demographic information, attitudes toward NMP in pediatric liver transplantation, and barriers to utilization were examined., Results: Thirty-two providers (18 transplant surgeons and 14 hepatologists) completed the survey, yielding a response rate of 64%. Half (50%) of respondents indicated prior exposure to NMP. Overall, 96% of respondents believed there was benefit to using NMP in pediatric liver transplantation. DCD (68%) and post-cross-clamp (75%) grafts were the greatest opportunity for NMP use. A role in splitting livers ex vivo (71%) was also seen as a potential major opportunity. Cost was perceived as a barrier to implementation (36%), followed by institutional factors (32%). Cost tolerance was significantly greater in respondents residing in OPTN regions with greater than median wait times (63% vs. 11% in OPTN regions with greater vs. shorter wait times, p = .010)., Conclusions: There is significant interest within the pediatric liver transplant community for NMP to expand the donor pool. Interest appears particularly strong in regions where wait times for suitable pediatric donors are prolonged., (© 2022 Wiley Periodicals LLC.)

Successful normothermic machine perfusion of heart allografts (MPH) has led to rapid growth in transplantation of donation after circulatory death (DCD) heart allografts but has introduced complexity in the procurement process. This study examines the impact of MPH use in DCD procurements on warm ischemia time (WIT) and organ yield. DCD procurements from 2019 to 2020 were identified using the OPTN database. Procurements with and without the use of MPH were compared using propensity score matching. Observed to expected (O:E) yield ratios were calculated, where the expected values were obtained using the models developed by the Scientific Registry of Transplant Recipients. In total, 1237 DCD procurements met inclusion criteria (MPH: 109 and control: 1128). After PSM, no difference was found between groups in median total WIT (24.0 min vs. 24.0 min, p = .89), but the MPH group demonstrated shorter median operative WIT (circulatory arrest to cross-clamp; 8.7 min vs. 10.9 min, p = .003). The overall organ yield of DCD heart donors was observed to be 33% higher than expected (O:E 1.33; 95% CI: 1.22-1.45). Observed yield of non-heart organs was not significantly different from expected for liver, kidney, lung, and pancreas grafts. MPH use in DCD procurements does not lead to delays in WIT and does not negatively affect organ yield of other concurrently procured organs., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Normothermic machine perfusion of organs is growing in popularity and has been used for both abdominal and thoracic organ preservation before transplantation. The use of normothermic machine perfusion for donation after cardiac death organs can reduce cold ischemia time and help prevent ischemia-related complications. We present a successful case of a donation after cardiac death procurement with both liver and heart allografts preserved by normothermic machine perfusion. Both allografts were perfused without complications and transplanted successfully. As the technology continues to become more prevalent, the situation described will become more commonplace, and we offer a view of the future in transplantation., (© 2022 Wiley Periodicals LLC.)

Arterial injury leading to vascular occlusion is a rare complication of kidney transplantation that requires urgent intervention to salvage the kidney and prevent graft loss. Occasionally, the recipient iliac vessels may be injured, resulting in acute ischaemia of the lower extremity in addition to loss of blood flow to the kidney transplant. In the case presented here, a 58-year-old man with chronic kidney disease secondary to IgA nephropathy underwent pre-emptive deceased donor renal transplantation complicated by an external iliac artery (EIA) dissection proximal to the transplant anastomosis. However, as a result of retrograde blood flow from collateral vessels, perfusion of the kidney and right lower extremity was initially preserved and early diagnosis was made after post-transplant ultrasound. This report reviews the aetiology, clinical features and therapeutic options for arterial injuries post-transplant. This case also highlights the importance of post-transplant vigilance and the value of routine postoperative ultrasound imaging., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Although cellular transplantation remains a relatively small field compared to solid organ transplantation, the prospects for advancement in basic science and clinical care remain bountiful. In this review, notable historical events and the current landscape of the field of cellular transplantation are reviewed with an emphasis on islets (allo- and xeno-), hepatocytes (including bioartificial liver), adoptive regulatory immunotherapy, and stem cells (SCs, specifically endogenous organ-specific and mesenchymal). Also, the nascent but rapidly evolving field of three-dimensional bioprinting is highlighted, including its major processing steps and latest achievements. To reach its full potential where cellular transplants are a more viable alternative than solid organ transplants, fundamental change in how the field is regulated and advanced is needed. Greater public and private investment in the development of cellular transplantation is required. Furthermore, consistent with the call of multiple national transplant societies for allo-islet transplants, the oversight of cellular transplants should mirror that of solid organ transplants and not be classified under the unsustainable, outdated model that requires licensing as a drug with the Food and Drug Administration. Cellular transplantation has the potential to bring profound benefit through progress in bioengineering and regenerative medicine, limiting immunosuppression-related toxicity, and providing markedly reduced surgical morbidity., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: During the initial wave of the COVID-19 pandemic, organ transplantation was classified a CMS Tier 3b procedure which should not be postponed. The differential impact of the pandemic on access to liver transplantation was assessed., Summary Background Data: Disparities in organ access and transplant outcomes among vulnerable populations have served as obstacles in liver transplantation., Methods: Using UNOS STARfile data, adult waitlisted candidates were identified from March 1, 2020 to November 30, 2020 (n = 21,702 pandemic) and March 1, 2019 to November 30, 2019 (n = 22,797 pre-pandemic), and further categorized and analyzed by time periods: March to May (Period 1), June to August (Period 2), and September to November (Period 3). Comparisons between pandemic and pre-pandemic groups included: Minority status, demographics, diagnosis, MELD, insurance type, and transplant center characteristics. Liver transplant centers (n = 113) were divided into tertiles by volume (small, medium, large) for further analyses. Multivariable logistic regression was fitted to assess odds of transplant. Competing risk regression was used to predict probability of removal from the waitlist due to transplantation or death and sickness. Additional temporal analyses were performed to assess changes in outcomes over the course of the pandemic., Results: During Period 1 of the pandemic, Minorities showed greater reduction in both listing (-14% vs -12% Whites), and transplant (-15% vs -7% Whites), despite a higher median MELD at transplant (23 vs 20 Whites, P < 0.001). Of candidates with public insurance, Minorities demonstrated an 18.5% decrease in transplants during Period 1 (vs -8% Whites). Although large programs increased transplants during Period 1, accounting for 61.5% of liver transplants versus 53.4% pre-pandemic (P < 0.001), Minorities constituted significantly fewer transplants at these programs during this time period (27.7% pandemic vs 31.7% pre-pandemic, P = 0.04). Although improvements in disparities in candidate listings, removals, and transplants were observed during Periods 2 and 3, the adjusted odds ratio of transplant for Minorities was 0.89 (95% CI 0.83-0.96, P = 0.001) over the entire pandemic period., Conclusions: COVID-19's effect on access to liver transplantation has been ubiquitous. However, Minorities, especially those with public insurance, have been disproportionately affected. Importantly, despite the uncertainty and challenges, our systems have remarkable resiliency, as demonstrated by the temporal improvements observed during Periods 2 and 3. As the pandemic persists, and the aftermath ensues, health care systems must consciously strive to identify and equitably serve vulnerable populations., Competing Interests: Conflict of interest: Raymond Lynch receives research support from the Mid-America Transplant Foundation. The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Conflicts of interest None. M. MacConmara is the site PI for PROTECT and Continuous Access Protocol clinical trials using the TransMedics OCS Liver device.

Hereditary haemochromatosis results in multiorgan dysfunction secondary to iron overload. Haemojuvelin (HJV)-associated haemochromatosis, is a rapidly progressing form of haemochromatosis caused by mutation in the HJV that frequently results in heart and liver failure. Herein, we describe the successful treatment of a 39-year-old woman with decompensated heart failure and liver cirrhosis requiring extracorporeal membrane oxygenation who was successfully treated with combined heart-liver transplantation. Following her life-saving multiorgan transplantation, she was also noted to have rapid correction of her serum ferritin to normal levels. She remains healthy with excellent allograft function and normal iron and ferratin levels 4 years after the procedure. To our knowledge, this case is the first demonstration that combined heart-liver transplantation is a feasible option for patients with heart and liver failure secondary to HJV-associated haemochromatosis and indeed offers a long-standing corrective solution to treat this condition and restore physiologically normal iron metabolism., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Spontaneous survival rates in acute liver failure (ALF) are vastly improved by liver transplantation (LT). However, the value of induction agents beyond steroids continues to be debated. To understand the potential benefit of different induction regimens in the ALF population, we compared overall survival of recipients undergoing LT in the United States for ALF. Using the Scientific Registry of Transplant Recipients, we assessed the impact of induction immunosuppression (IS) in a cohort of 3754 first-time LT recipients with a diagnosis of ALF from 2002 to 2018. Induction IS therapy was grouped into steroid-only induction, use of antithymocyte globulin (ATG), or interleukin 2 receptor antibody. Other regimens were excluded from analysis. Survival analysis was estimated via Cox proportional hazards models and expressed as hazard ratios (HRs). In LT for ALF, the use of induction agents beyond steroids is increasingly frequent over the last 2 decades. The use of ATG is associated with worse overall survival, even after adjusting for donor and recipient factors, with HR of 1.24 (95% confidence interval, 1.00-1.53; P = 0.05). An elevated serum creatinine, recipient and donor age, and Black ethnicity, were all associated with reduced survival, whereas maintenance IS with calcineurin inhibitors (CNIs) was associated with improved survival. Although adjunct induction therapy has become more common, our analysis shows that compared with a steroid-only induction regimen, the addition of ATG is associated with worse overall survival after LT for ALF. CNI maintenance was highly protective, suggesting that an IS strategy focusing on corticosteroid-only induction followed by CNI maintenance may offer the best overall survival rate., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Purpose of Review: To review the role of machine perfusion in advancing the study and clinical application of liver xenotransplantation to liver transplantation., Recent Findings: Recent multicenter trial has shown the benefits of normothermic machine perfusion (NMP) in the assessment and selection of suitable allografts for liver transplantation, especially marginal liver allografts. Advances in ex-vivo therapeutic intervention with proof-of-concept studies demonstrating successful ex-vivo genetic modification of donor allografts and blockade of gene expression with siRNA., Summary: Xenotransplantation and NMP are two of the most exciting and eagerly anticipated technologies in organ transplantation. Since the emergence of clinical transplantation, clinicians and researchers have attempted to manipulate xenografts for clinical use or to develop devices that could provide physiologic support of donor organs ex vivo. The past decade has seen significant progress in NMP with recent emergence of devices suitable for use in clinical practice. Following discovery of novel gene-editing techniques, xenotransplantation has also developed rapidly with encouraging outcomes in preclinical studies. Xenotransplantation is now currently poised to advance into the clinical realm. NMP can not only assist in the development of other novel technologies by providing a unique environment to safely study organ function and assess organ suitability but may also improve outcomes following hepatic xenotransplantation. In this review, we describe the current use of NMP in xenotransplantation research and also discuss the potential roles for NMP in xenotransplantation research and future clinical practice.

Objective: Normothermic machine perfusion (NMP) enables optimized ex-vivo preservation of a donor liver in a normal physiologic state. The impact of this emerging technology on donor liver utilization has yet to be assessed., Summary Background Data: NMP of the donor liver and ex-vivo enhancement of its function has been envisioned for decades, however only with recent technological advances have devices been suitable for transition to clinical practice. The present study examines the effect NMP on liver utilization in the United States., Methods: The United Network for Organ Sharing database was queried to identify deceased donor livers procured from 2016 to 2019 (n = 30596). Donor livers were divided by preservation method: standard cold-static preservation (COLD, n = 30,368) versus NMP (n = 228). Donor and recipient risk factors, liver disposition, and discard reasons were analyzed. The primary outcome was liver discard rate between 2 groups., Results: A total of 4037 livers were discarded. The NMP group had a 3.5% discard rate versus 13.3% in the COLD group (P < 0.001), and this was despite NMP donors being older (47.7 vs 39.5 years, P < 0.0001), more frequently donation after cardiac death (DCD) (18% vs 7%, P < 0.001), and having a greater donor risk index (1.6 vs 1.5, P < 0.05). The most common reasons for liver discard in the COLD group were biopsy findings (38%), DCD warm ischemic time (11%), and prolonged preservation time (10%). Survival analysis, following propensity score matching, found no significant difference in 1-year overall survival between recipients of NMP versus COLD livers., Conclusions: NMP reduces the discard rate of procured livers despite its use in donors traditionally considered of more marginal quality. NMP maintains excellent graft and patient survival. Broader application of NMP technology holds the potential to generate a significant number of additional liver grafts for transplantation every year, thus greatly reducing the nationwide disparity between supply and demand., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Thirty to 90% of hepatocytes contain whole-genome duplications, but little is known about the fates or functions of these polyploid cells or how they affect development of liver disease. We investigated the effects of continuous proliferative pressure, observed in chronically damaged liver tissues, on polyploid cells., Methods: We studied Rosa-rtTa mice (controls) and Rosa-rtTa;TRE-short hairpin RNA mice, which have reversible knockdown of anillin, actin binding protein (ANLN). Transient administration of doxycycline increases the frequency and degree of hepatocyte polyploidy without permanently altering levels of ANLN. Mice were then given diethylnitrosamine and carbon tetrachloride (CCl 4 ) to induce mutations, chronic liver damage, and carcinogenesis. We performed partial hepatectomies to test liver regeneration and then RNA-sequencing to identify changes in gene expression. Lineage tracing was used to rule out repopulation from non-hepatocyte sources. We imaged dividing hepatocytes to estimate the frequency of mitotic errors during regeneration. We also performed whole-exome sequencing of 54 liver nodules from patients with cirrhosis to quantify aneuploidy, a possible outcome of polyploid cell divisions., Results: Liver tissues from control mice given CCl 4 had significant increases in ploidy compared with livers from uninjured mice. Mice with knockdown of ANLN had hepatocyte ploidy above physiologic levels and developed significantly fewer liver tumors after administration of diethylnitrosamine and CCl 4 compared with control mice. Increased hepatocyte polyploidy was not associated with altered regenerative capacity or tissue fitness, changes in gene expression, or more mitotic errors. Based on lineage-tracing experiments, non-hepatocytes did not contribute to liver regeneration in mice with increased polyploidy. Despite an equivalent rate of mitosis in hepatocytes of differing ploidies, we found no lagging chromosomes or micronuclei in mitotic polyploid cells. In nodules of human cirrhotic liver tissue, there was no evidence of chromosome-level copy number variations., Conclusions: Mice with increased polyploid hepatocytes develop fewer liver tumors following chronic liver damage. Remarkably, polyploid hepatocytes maintain the ability to regenerate liver tissues during chronic damage without generating mitotic errors, and aneuploidy is not commonly observed in cirrhotic livers. Strategies to increase numbers of polypoid hepatocytes might be effective in preventing liver cancer., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Despite the high number of children listed for kidney transplantation and shortage of deceased organ donors, there is reluctance to utilize DCD kidneys in pediatric recipients. We examined outcomes in pediatric kidney transplant patients who received a DCD kidney allograft. UNOS database was queried to examine outcomes in all pediatric kidney transplant recipients from 1994 to 2017. Pediatric status was defined as <18 years at the time of transplantation. Recipients were divided by DBD or DCD allograft status. Donor and recipient demographic data were examined. Patient and allograft survival was calculated, and Kaplan-Meier survival curves were generated. A P-value of <0.05 was considered to be significant. A total of 286 pediatric kidney transplant recipients received a DCD allograft. The donors in the DCD group were significantly younger than those in the DBD group (21.7 vs 23.3 years), with a higher KDPI (26.5% vs 22.9%). In the DCD group, the average age at transplant was younger (11.6 vs 12.9 years), with no difference in cold ischemia time or length of stay between the two groups. Rates of delayed graft function were higher in the DCD group, but despite this, there were no significant differences in allograft or patient survival between the groups. There is no difference in allograft survival in pediatric kidney transplant recipients who receive a DCD kidney allograft. DCD kidney allografts are suitable for transplantation in pediatric patients and can greatly expand the donor pool., (© 2019 Wiley Periodicals, Inc.)

Background: Strategies to expand numbers of deceased donor kidneys suitable for pediatric recipients are urgently needed to prevent long-term dialysis-associated morbidity and mortality. Donors designated as increased risk of disease transmission (IRD) are infrequently used in pediatric recipients. We examined outcomes of these kidneys in pediatric patients and the potential to increase the donor pool., Methods: The United Network for Organ Sharing (UNOS) database records presence of IRD in all deceased donors since 2004. All pediatric kidney transplant recipients from 2004 to 2017 were identified and stratified by IRD status, and outcomes were examined., Results: Four hundred seventy-three pediatric kidney transplant recipients received an IRD allograft. IRD donors had lower kidney donor profile index (KDPI); were more likely to be younger, male, and Caucasian; and were more likely to have used drugs. IRD kidneys were more likely to have been biopsied and placed on pulsatile perfusion. Other than an older recipient age, demographic data were not different between groups. Allograft and patient survivals were similar, as were rejection and delayed graft function rates. Compared with adult recipients and adult IRD recipients, pediatric recipients were more likely to have a younger donor, receive a kidney with a lower creatinine, and were less likely to have delayed graft function (p < 0.05). There were no recorded disease transmissions in IRD group., Conclusions: Patient and allograft survivals are similar in IRD and non-IRD kidneys. High-quality IRD organs used in adults represent a large number of donors with excellent outcomes. IRD allografts have a potential to increase transplant volume and should be considered for pediatric patients.

The number of simultaneous liver-kidney transplantations (SLKTs) and use of induction therapy for SLKT have increased recently, without much published evidence, especially in the context of maintenance immunosuppression containing tacrolimus (TAC) and mycophenolic acid (MPA). We queried the Organ Procurement and Transplant Network registry for SLKT recipients maintained on TAC/MPA at discharge in the United States for 2002-2016. The cohort was divided into 3 groups on the basis of induction type: rabbit antithymocyte globulin (r-ATG; n = 831), interleukin 2 receptor antagonist (IL2RA; n = 1558), and no induction (n = 2333). Primary outcomes were posttransplant all-cause mortality and acute rejection rates in kidney and liver allografts at 12 months. Survival rates were analyzed by the Kaplan-Meier method. A propensity score analysis was used to control potential selection bias. Multivariate inverse probability weighted Cox proportional hazard and logistic regression models were used to estimate the hazard ratios (HRs) and odds ratios. Among SLKT recipients, survival estimates at 3 years were lower for recipients receiving r-ATG (P = 0.05). Compared with no induction, the multivariate analyses showed an increased mortality risk with r-ATG (HR, 1.29; 95% confidence interval [CI], 1.10-1.52; P = 0.002) and no difference in acute liver or kidney rejection rates at 12 months across all induction categories. No difference in outcomes was noted with IL2RA induction over the no induction category. In conclusion, there appears to be no survival benefit nor reduction in rejection rates for SLKT recipients who receive induction therapy, and r-ATG appears to increase mortality risk compared with no induction., (Copyright © 2018 by the American Association for the Study of Liver Diseases.)

Introduction: There is a mismatch that exists in donor liver organ supply and demand. DCD livers represents a potential source to increase the number of liver grafts available for use in pediatric recipients; however, there has been hesitancy to use such organs. We evaluated patient and allograft outcomes in pediatric liver transplant recipients of DCD livers., Methods: The UNOS database was queried to examine outcomes in all liver transplant recipients from 1993 to 2017. Patients were then divided according to adult and pediatric status, DBD or DCD allograft status, and era of transplant. Donor and recipient demographic data were examined, and patient and allograft survival were calculated. A P-value of <0.05 was considered to be significant., Results: A total of 57 pediatric recipients received a DCD liver allograft. DCD recipients were older than DBD recipients. There was no difference in the final PELD score between the groups. There were no differences in causes of allograft failure between the DCD and DBD groups. Importantly, the overall allograft survival in the DCD and DBD groups was similar, as was allograft survival based on era., Conclusion: Pediatric liver transplant recipients of DCD allografts have comparable patient and allograft survival when compared to DBD allograft recipients. Use of DCD allografts in the pediatric liver transplant population should be strongly considered to increase the donor organ pool., (© 2018 Wiley Periodicals, Inc.)

Pediatric liver and kidney transplantation have become the standard and accepted treatment for children with end-stage renal and liver disease. Since the first successful kidney transplant in 1954 by Dr Joseph Murray and the first liver transplant by Dr Thomas Starzl, the scope of indications for visceral organ transplantation as well as the range of recipient and donor ages has expanded. The first pediatric liver and kidney transplants, simultaneous multivisceral transplants, living-donor and donation-after-cardiac-death organs have evolved rapidly into the standard of care for end-stage renal and liver failure in children., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Patients with combined liver and kidney failure may remain on dialysis for years while awaiting simultaneous liver-kidney transplantation (SLKT). The role of peritoneal dialysis (PD) in patients with advanced liver and kidney failure awaiting SLKT remains to be defined. We present our single-institution experience with PD in cirrhotics, 3 of whom went on to receive successful SLKT. Patients initiated in our PD program between 2006 and 2016 who had both liver and kidney failure were identified. Medical and dialysis records were reviewed retrospectively. Outcomes included mortality, transplantation status, hospitalizations, need for large-volume paracentesis (LVP), peritonitis rates, PD treatment longevity, and albumin level. Twelve patients with combined liver and kidney failure were treated in our PD program. No patients died and 3 patients received SLKT. Four patients remain listed for transplantation. There was no need for LVP after initiating dialysis. The rate of peritonitis was 0.2 events per patient per year, most commonly due to coagulase-negative Staphylococcus Our data illustrate that PD is a viable bridging therapy for patients with liver and kidney failure who await SLKT., (Copyright © 2018 International Society for Peritoneal Dialysis.)

Background: Pediatric patients who undergo liver transplantation are at higher risk of developing vascular complications when compared to adult liver transplant recipients. The consequences of hepatic artery thrombosis (HAT) or portal vein thrombosis (PVT) can cause significant morbidity and mortality. We examined pediatric liver transplant recipients who developed vascular thrombosis and the presence of thrombophilia., Methods: We examined outcome in all pediatric patients who underwent liver transplantation. Recipient, donor demographic data, and outcome data were examined. Categorical differences were compared using the unpaired Student t-test and nominal variables using either the chi-square or the Fischer exact test. A P value of <0.05 was considered significant., Results: Forty-six pediatric patients underwent liver transplantation. Twenty-one recipients were found to have thrombophilia, including 5 with HAT and 2 with PVT. When comparing recipients with or without any vascular thrombosis, those with thrombophilia had a significantly higher incidence of developing a vascular thrombosis (7/21 versus 0/25, P = 0.0017). Five of 42 recipients with artery-to-artery reconstruction developed HAT versus 0 of 4 with a conduit. Recipients who developed any thrombosis were significantly lower in weight than those who did not develop any thrombosis (9.0 ± 1.6 kg versus 22.2 ± 16.0 kg, P = 0.0366)., Conclusions: All pediatric liver transplant recipients who developed any vascular thrombosis were also found to have thrombophilia. Recipients who were smaller in size were at significantly higher risk of developing vascular thrombosis. Lower weight recipients with thrombophilia may benefit from arterial reconstruction with a conduit to decrease the risk of vascular thrombosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Hemolytic uremic syndrome (HUS) accounts for <1% of renal transplants in the US. There are limited data on the characteristics and outcomes of HUS in pediatric and adult kidney transplant recipients in the US., Methods: This study included all renal transplant recipients identified with HUS (N=1,233) as a cause of end-stage renal disease between 1987 and 2013 using the UNOS/OPTN database. The cohort was divided into two age groups: pediatric (N=447) and adult (N=786). Main outcomes were acute rejection rate at one-year, allograft and patient survival, and recurrence of HUS post-transplant. Both age groups were then compared with a propensity score (1:2 ratio) matched control group with an alternative primary kidney disease (non-HUS cohort: pediatric [N= 829] and adult [N=1,547])., Results: In pediatric cohort, when compared to the PS matched controls, acute rejection, death censored allograft and patient survival was similar in the HUS group. However, in the adult cohort, the graft and patient survivals were significantly worse in the HUS group. HUS was associated with allograft loss (HR=1.40, 95%CI 1.14-1.71) in adult recipients. Patients with HUS recurrence had significantly lower allograft and patient survival rates compared to the non-recurrent group in both age groups. Acute rejection was one of the major predictor of HUS recurrence in adults (OR=2.64, 95%CI 1.25-5.60). Calcineurin inhibitors (CNI) were not associated HUS recurrence in both age groups., Conclusion: Pediatric HUS-patients, unlike adult recipients, have similar outcomes compared to the PS matched controls. Recurrence of HUS is associated with poor allograft and patient survival in pediatric and adult patients. Use of CNIs seem to be safe as a part of maintenance immunosuppression post-transplantation. A comprehensive national registry is urgently needed.

Background and Objectives: Induction therapy with IL-2 receptor antagonist (IL2-RA) is recommended as a first line agent in living donor renal transplantation (LRT). However, use of IL2-RA remains controversial in LRT with tacrolimus (TAC)/mycophenolic acid (MPA) with or without steroids., Design, Setting, Participants, & Measurements: The Organ Procurement and Transplantation Network registry was studied for patients receiving LRT from 2000 to 2012 maintained on TAC/MPA at discharge (n=36,153) to compare effectiveness of IL2-RA to other induction options. The cohort was initially divided into two groups based on use of maintenance steroid at time of hospital discharge: steroid (n=25,996) versus no-steroid (n=10,157). Each group was further stratified into three categories according to commonly used antibody induction approach: IL2-RA, rabbit anti-thymocyte globulin (r-ATG), and no-induction in the steroid group versus IL2-RA, r-ATG and alemtuzumab in the no-steroid group. The main outcomes were the risk of acute rejection at 1 year and overall allograft failure (graft failure or death) post-transplantation through the end of follow-up. Propensity score-weighted regression analysis was used to minimize selection bias due to non-random assignment of induction therapies., Results: Multivariable logistic and Cox analysis adjusted for propensity score showed that outcomes in the steroid group were similar between no-induction (odds ratio [OR], 0.96; 95% confidence interval [95% CI], 0.86 to 1.08 for acute rejection; and hazard ratio [HR], 0.99; 95% CI, 0.90 to 1.08 for overall allograft failure) and IL2-RA categories. In the no-steroid group, odds of acute rejection with r-ATG (OR, 0.73; 95% CI, 0.59 to 0.90) and alemtuzumab (OR, 0.53; 95% CI, 0.42 to 0.67) were lower; however, overall allograft failure risk was higher with alemtuzumab (HR, 1.27; 95% CI, 1.03 to 1.56) but not with r-ATG (HR, 1.19; 95% CI, 0.97 to 1.45), compared with IL2-RA induction., Conclusions: Compared with no-induction therapy, IL2-RA induction was not associated with better outcomes when TAC/MPA/steroids were used in LRT recipients. r-ATG appears to be an acceptable and possibly the preferred induction alternative for IL2-RA in steroid-avoidance protocols., (Copyright © 2015 by the American Society of Nephrology.)

CD4+CD25+ regulatory T cells (Tregs) play a critical role in suppressing the development of autoimmune disease, in controlling potentially harmful inflammatory responses, and in maintaining immune homeostasis. Because severe injury triggers both excessive inflammation and suppressed adaptive immunity, we wished to test whether injury could influence Treg activity. Using a mouse burn injury model, we demonstrate that injury significantly enhances Treg function. This increase in Treg activity is apparent at 7 days after injury and is restricted to lymph node CD4+CD25+ T cells draining the injury site. Moreover, we show that this injury-induced increase in Treg activity is cell-contact dependent and is mediated in part by increased cell surface TGF-beta1 expression. To test the in vivo significance of these findings, mice were depleted of CD4+CD25+ T cells before sham or burn injury and then were immunized to follow the development of T cell-dependent Ag-specific immune reactivity. We observed that injured mice, which normally demonstrate suppressed Th1-type immunity, showed normal Th1 responses when depleted of CD4+CD25+ T cells. Taken together, these observations suggest that injury can induce or amplify CD4+CD25+ Treg function and that CD4+CD25+ T cells contribute to the development of postinjury immune suppression.

Angiogenesis is intimately related to the growth and progression of tumours and must be induced to facilitate growth beyond a minimum size. It has been implicated in the development of metastases and survival in breast carcinoma. VEGF is a cytokine that plays an important role in angiogenesis. Its expression is increased in solid tumours during induction of angiogenesis and it has been implicated as a prognostic marker in patients with node negative breast carcinoma. We studied VEGF expression, in a series of patients with node positive breast carcinoma and examined histopathological parameters of the tumour and the prognostic value of VEGF expression. Specimens from 108 cases of node positive breast cancer were stained for VEGF using an antibody suitable for use on formalin fixed tissue. VEGF staining was cytoplasmic and was scored by intensity and the percent positive cells. Patients with positive VEGF staining (n=48) were compared with patients with negative VEGF staining (n=60). Demographic criteria were similar in both groups. Only one (12%) patient with lobular carcinoma and one (14%) patient with medullary carcinoma expressed VEGF compared with 46 (49%) patients with ductal carcinoma (NOS). DCIS was present in 60 tumours. There was a strong correlation between staining in DCIS and the adjacent invasive tumours. There was no significant association between VEGF staining and T stage, tumour size or the number of positive lymph nodes. VEGF expression had no prognostic significance either for disease-free or overall survival in patients with node positive disease. This study failed to support a role for VEGF as a prognostic marker in patients with node positive breast carcinoma.

Aims: p21, an inhibitor of cyclin-dependent kinase, is involved in the p53 pathway of growth control. Its expression has been linked to cellular differentiation. It has been implicated in p53-mediated growth arrest following DNA damage and in terminally differentiated cells. This study analysed p21 and p53 expression, in a series of node-positive patients with breast carcinoma and examined histopathological parameters of the tumour and the prognostic implications of p21 and p53 expression., Methods: One hundred and five consecutive patients with node-positive disease and at least 3 years follow-up were identified. Sections were stained for p53 and p21 using monoclonal antibodies. Results were expressed as percentage positive cells, and over 20% considered positive for p53 and over 10% considered for p21., Results: p21 was overexpressed (>10% of cells positive) in 65% of patients and p53 was overexpressed (>20% of cells positive in 68%. The mean (SEM) level of p21 staining was 5.7(0.8)% and was 54.9(4.0)% for p53. There was no correlation between p21 and p53 expression (r=0.071 P=0.5). There were no significant differences in demographic criteria between patients that were p21 positive or negative and p53 positive or negative. There were no significant differences in tumour type, grade or stage between the groups. p21 expression did not have prognostic significance; however, p53 positivity was associated with a worse prognosis, which remained when controlled for stage., Conclusions: This study demonstrated p21 overexpression in 65% of patients with node-positive breast carcinoma. Levels did not correlate with p53 status and unlike p53 failed to have prognostic significance., (Copyright Harcourt Publishers Limited.)