Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease.

Normal tissues accumulate genetic changes with age, but it is unknown if somatic mutations promote clonal expansion of non-malignant cells in the setting of chronic degenerative diseases. Exome sequencing of diseased liver samples from 82 patients revealed a complex mutational landscape in cirrhosis. Additional ultra-deep sequencing identified recurrent mutations in PKD1, PPARGC1B, KMT2D, and ARID1A. The number and size of mutant clones increased as a function of fibrosis stage and tissue damage. To interrogate the functional impact of mutated genes, a pooled in vivo CRISPR screening approach was established. In agreement with sequencing results, examination of 147 genes again revealed that loss of Pkd1, Kmt2d, and Arid1a promoted clonal expansion. Conditional heterozygous deletion of these genes in mice was also hepatoprotective in injury assays. Pre-malignant somatic alterations are often viewed through the lens of cancer, but we show that mutations can promote regeneration, likely independent of carcinogenesis.

The effect of an organ procurement organization surgeon on pediatric organ utilization.

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.

A contemporary analysis of 20,086 deceased donor liver biopsies.

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.

American Society of Transplant Surgeons recommendations on best practices in donation after circulatory death organ procurement.

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.

Impact of Portable Normothermic Machine Perfusion for Liver Transplantation From Adult Deceased Donors.

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.

Use of DCD organs: Expanding the donor pool to increase pediatric transplantation.

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.

Delayed graft function in pediatric living donor kidney transplantation.

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.

Normothermic machine perfusion for older transplant recipients.

INTRODUCTION: Elderly patients (≥65 years old) are increasingly undergoing liver transplantation and are more likely to be removed from the waitlist. Normothermic machine perfusion (NMP) holds promise in expanding the number of livers available for transplant and improving outcomes for marginal donors and recipients. We aimed to determine the impact of NMP on outcomes in elderly recipients at our institution and nationally using the UNOS database. METHODS: The use of NMP on outcomes in elderly recipients was reviewed using both the UNOS/SRTR database (2016-2022) and institutional data (2018-2020). Characteristics and clinical outcomes were compared between the NMP and static cold (control) groups within both populations. RESULTS: Nationally, using the UNOS/SRTR database, we identified 165 elderly recipients from 28 centers who received a liver allograft undergoing NMP and 4270 that underwent traditional cold static storage. NMP donors were older (48.3 vs. 43.4 years, p < 0.01), had similar rates of steatosis (8.5% vs 8.5%, p = 0.58), were more likely to be from a DCD (41.8% vs 12.3%, p < 0.01), and had a higher donor risk index (DRI; 1.70 vs. 1.60, p < 0.02). NMP recipients had similar age but had a lower MELD score at transplant (17.9 vs. 20.7, p = 0.01). Despite increased marginality of the donor graft, NMP recipients had similar allograft survival and decreased length of stay, even after accounting for recipient characteristics including MELD. Institutional data showed that 10 elderly recipients underwent NMP and 68 underwent cold static storage. At our institution, NMP recipients had a similar length of stay, rates of complications, and readmissions. CONCLUSIONS: NMP may mitigate donor risk factors that are relative contraindications for transplantation in elderly liver recipients, increasing the donor pool. The application of NMP in older recipients should be considered.

The impact of machine perfusion of the heart on warm ischemia time and organ yield in donation after circulatory death.

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.

Outcomes of Simultaneous Liver-Kidney Transplantation Using Kidneys of Deceased Donors With Acute Kidney Injury.

Outcomes from simultaneous liver-kidney transplantation (SLKT) when using kidneys from donors with acute kidney injury (AKI) have not been studied. We studied 5344 SLKTs between May 1, 2007, and December 31, 2019, by using Organ Procurement and Transplantation Network registry data supplemented with United Network for Organ Sharing-DonorNet data. Designating a donor as having AKI required by definition that the following criteria were met: (1) the donor's condition aligned with the Kidney Disease: Improving Global Outcomes (KDIGO) international consensus guidelines and the terminal serum creatinine (Scr) level was ≥1.5 times the minimum Scr level for deceased donors before organ recovery and (2) the terminal Scr level was ≥1.5 mg/dL (a clinically meaningful and intuitive Scr threshold for defining AKI for transplant providers). The primary outcomes were liver transplant all-cause graft failure (ACGF; defined as graft failures and deaths) and kidney transplant death-censored graft failure (DCGF) at 1 year after transplant. The donors with AKI were young, had good organ quality, and had a short cold ischemia time. In the study cohort, 4482 donors had no AKI, whereas 862 had AKI (KDIGO AKI stages: 1, n = 521; 2, n = 202; and 3, n = 138). In the group with AKI and the group with no AKI, respectively, liver ACGF at 1 year (11.1% versus 12.9% [P = 0.13]; hazard ratio [HR], 1.20; 95% confidence interval [CI], 0.97-1.49) and kidney DCGF at 1 year (4.6% versus 5.7% [P = 0.18]; HR, 1.27; 95% CI, 0.95-1.70) did not differ in the full multivariable Cox proportional hazard models. Selected kidneys from deceased donors with AKI can be considered for SLKT.

Normothermic Machine Perfusion in pediatric liver transplantation: A survey of attitudes and barriers.

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.

Simultaneous ex vivo normothermic preservation of liver and heart grafts from a donation after circulatory death donor.

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.

Challenges, highlights, and opportunities in cellular transplantation: A white paper of the current landscape.

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.

Liver Transplantation in the Time of a Pandemic: A Widening of the Racial and Socioeconomic Health Care Gap During COVID-19.

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.

Mice With Increased Numbers of Polyploid Hepatocytes Maintain Regenerative Capacity But Develop Fewer Hepatocellular Carcinomas Following Chronic Liver Injury.

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 (CCl4) 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 CCl4 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 CCl4 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.

Comparison of Clinical Outcomes of Induction Regimens in Patients Undergoing Liver Transplantation for Acute Liver Failure.

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.

Making Every Liver Count: Increased Transplant Yield of Donor Livers Through Normothermic Machine Perfusion.

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.

Trends in utilization of deceased donor kidneys based on hepatitis C virus status and impact of public health service labeling on discard.

BACKGROUND: Kidneys from deceased donors infected with hepatitis C virus (HCV) are underutilized. Most HCV virus-infected donors are designated as Public Health Service increased donors (PHS-IR). Impact of PHS and HCV designations on discard is not well studied. METHODS: We queried the UNOS data set for all deceased donor kidneys between January 2015 and December 2018. The final study cohort donors (n = 38 702) were stratified into three groups based on HCV antibody (Ab) and NAT status: (a) Ab-/NAT- (n = 35 861); (b) Ab+/NAT- (n = 973); and (c) Ab±/NAT+ (n = 1868). We analyzed utilization/discard rates of these organs, the impact of PHS-IR and HCV designations on discard using multivariable two-level hierarchical logistic regression models, forecasted number of HCV viremic donors/kidneys by 2023. RESULTS: During the study period, (a) the number of viremic donor kidneys increased 2 folds; (b) the multilevel mixed-effects logistic regression models showed that, overall, the PHS labeling (OR 1.20, CI 95% CI 1.15-1.29) and HCV designation (OR 2.29; 95% CI 2.15-2.43) were independently associated with increased risk of discard; (c) contrary to the general perception, PHS-IR kidneys across all HCV groups, compared to PHS-IR kidneys were more likely to be discarded; (d) we forecasted that the number of kidneys from HCV viremic donor kidneys might increase from 1376 in 2019 to 2092 in 2023. CONCLUSION: Hepatitis C virus viremic kidneys might represent 10%-15% of deceased donor organ pool soon with the current rate of the opioid epidemic. PHS labeling effect on discard requires further discussion of the utility of this classification.

The role of machine perfusion in liver xenotransplantation.

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.

Lack of Benefit and Potential Harm of Induction Therapy in Simultaneous Liver-Kidney Transplants.

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.