A Decade of Liver Transplantation in the United States: Drivers of Discard and Underutilization.

Background: Organ shortage remains a major challenge for the field of transplantation. Maximizing utilization and minimizing discard of available organs is crucial to reduce waitlist times. Our aim was to investigate the landscape of liver recovery, discard over the past decade in the United States, and identify areas to reduce organ discard. Methods: This study used the Scientific Registry of Transplant Recipients United Network for Organ Sharing database to analyze the rates and associated reasons of discarded organs from 2010 to 2021. All deceased donors were evaluated, and data were analyzed by organ type, year, and region. Organ disposition was analyzed by year and region. Donor demographics and liver biopsy data were also analyzed. Results: The volume of liver transplantation increased steadily, with a 44% increase from 2010 to 2021. Donation after circulatory death transplantation increased by 239%, comprising 10.6% of transplants in 2021, yet discard rates remained high at 30% for this donor subset. For all donor types, the liver discard rate has remained stable around 10% despite a 74% increase in available donors. Seventy percent of liver discards were attributed to organ factors, with biopsy findings accounting for 40% of all discards. Of livers that were biopsied, 70% had macrosteatosis of <30%. Conclusions: Analysis of trends in transplantation and discard allow for identifying areas of underutilization. Donation after circulatory death livers have expanded the pool of transplanted livers but remain discarded at high rates. Significant differences remain in discard rates between geographic regions. We identify several areas to lower the discard rates. The expanding role of machine perfusion may allow for utilization of previously discarded organs.

Outcomes after kidney transplant alone in patients with cirrhosis-A case-control study.

BACKGROUND: Guidelines recommend kidney transplant alone (KTA) in compensated cirrhosis based on a few small studies, but this is not widely performed despite its potential benefit to patients and the organ supply. Our aim was to determine the outcomes of KTA in patients with compensated cirrhosis. STUDY DESIGN: From 1/2012 to 12/2021, outcomes in KTA recipients with compensated cirrhosis were retrospectively compared to patients with chronic liver disease (CLD) but no cirrhosis. Patients with compensated cirrhosis were also compared to a matched cohort (based on age, time on hemodialysis, sex, and ethnicity) of KTA recipients without CLD. The outcomes included patient survival, allograft failure, allograft rejection, serious infection, liver decompensation, and length of stay (LOS). RESULTS: Over 9 years, 1562 KTAs were performed, with 150 (9.6%) patients having CLD mostly due to chronic hepatitis C, and a median follow-up of 3.5 years. 32/150 (21%) had compensated cirrhosis at the time of KTA with a mean MELD-Na of 22 (1.5). Matched controls (n = 189) were identified. We found no differences in patient survival (p = .07), allograft failure (p = .6), allograft rejection (p = .43), rates of serious infection (p = .31), as well as LOS (p = .61) among patients with compensated cirrhosis compared to patients with CLD but no cirrhosis, but with higher rates of liver decompensation (p = .004). Similarly, compared to patients without CLD, patients with cirrhosis had similar rates of patient survival (p = .20), allograft failure (p = .27), allograft rejection (p = .62) and LOS (p = .19) but with higher rates of serious infections (p = .001). CONCLUSIONS: Our study supports the safety and efficacy of KTA in patients with compensated cirrhosis.

Comparison of Single-Port Robotic Donor Nephrectomy and Laparoscopic Donor Nephrectomy.

Purpose: To compare the intra- and postoperative outcomes of single-port robotic donor nephrectomies (SP RDNs) and laparoscopic donor nephrectomies (LDNs). Materials and Methods: We retrospectively reviewed our institutional database for patients who received LDN or SP RDN between September 2020 and December 2022. Donor baseline characteristics, intraoperative outcomes, postoperative outcomes, and recipient renal function were extracted and compared between LDN and SP RDN. SP RDN learning curve analysis based on operative time and graft extraction time was performed using cumulative sum analysis. Results: One hundred forty-four patients underwent LDN and 32 patients underwent SP RDN. LDN and SP RDN had similar operative times (LDN: 190.3 ± 28.0 minutes, SP RDN: 194.5 ± 35.1 minutes, p = 0.3253). SP RDN patients had significantly greater extraction times (LDN: 83.2 ± 40.3 seconds, SP RDN: 204.1 ± 52.2 seconds, p < 0.0001) and warm ischemia times (LDN: 145.1 ± 61.7 seconds, SP RDN: 275.4 ± 65.6 seconds, p < 0.0001). There were no differences in patient subjective pain scores, inpatient opioid usage, or Clavien-Dindo II+ complications. Short- and medium-term postoperative donor and recipient renal function were also similar between the groups. SP RDN graft extraction time and total operative time learning curves were achieved at case 27 and 13, respectively. Conclusion: SP RDN is a safe and feasible alternative to LDN that minimizes postoperative abdominal incisional scars and has a short learning curve. Future randomized prospective clinical trials are needed to confirm the findings of this study and to identify other potential benefits and drawbacks of SP RDNs.

Living Donor Liver Transplantation for Hepatocellular Carcinoma Within and Outside Traditional Selection Criteria: A Multicentric North American Experience.

OBJECTIVE: To evaluate long-term oncologic outcomes of patients post-living donor liver transplantation (LDLT) within and outside standard transplantation selection criteria and the added value of the incorporation of the New York-California (NYCA) score. BACKGROUND: LDLT offers an opportunity to decrease the liver transplantation waitlist, reduce waitlist mortality, and expand selection criteria for patients with hepatocellular carcinoma (HCC). METHODS: Primary adult LDLT recipients between October 1999 and August 2019 were identified from a multicenter cohort of 12 North American centers. Posttransplantation and recurrence-free survival were evaluated using the Kaplan-Meier method. RESULTS: Three hundred sixty LDLTs were identified. Patients within Milan criteria (MC) at transplantation had a 1, 5, and 10-year posttransplantation survival of 90.9%, 78.5%, and 64.1% versus outside MC 90.4%, 68.6%, and 57.7% ( P = 0.20), respectively. For patients within the University of California San Francisco (UCSF) criteria, respective posttransplantation survival was 90.6%, 77.8%, and 65.0%, versus outside UCSF 92.1%, 63.8%, and 45.8% ( P = 0.08). Fifty-three (83%) patients classified as outside MC at transplantation would have been classified as either low or acceptable risk with the NYCA score. These patients had a 5-year overall survival of 72.2%. Similarly, 28(80%) patients classified as outside UCSF at transplantation would have been classified as a low or acceptable risk with a 5-year overall survival of 65.3%. CONCLUSIONS: Long-term survival is excellent for patients with HCC undergoing LDLT within and outside selection criteria, exceeding the minimum recommended 5-year rate of 60% proposed by consensus guidelines. The NYCA categorization offers insight into identifying a substantial proportion of patients with HCC outside the MC and the UCSF criteria who still achieve similar post-LDLT outcomes as patients within the criteria.

Sustained in vivo perfusion of a re-endothelialized tissue engineered kidney graft in a human-scale animal model.

Introduction: Despite progress in whole-organ decellularization and recellularization, maintaining long-term perfusion in vivo remains a hurdle to realizing clinical translation of bioengineered kidney grafts. The objectives for the present study were to define a threshold glucose consumption rate (GCR) that could be used to predict in vivo graft hemocompatibility and utilize this threshold to assess the in vivo performance of clinically relevant decellularized porcine kidney grafts recellularized with human umbilical vein endothelial cells (HUVECs). Materials and methods: Twenty-two porcine kidneys were decellularized and 19 were re-endothelialized using HUVECs. Functional revascularization of control decellularized (n = 3) and re-endothelialized porcine kidneys (n = 16) was tested using an ex vivo porcine blood flow model to define an appropriate metabolic glucose consumption rate (GCR) threshold above which would sustain patent blood flow. Re-endothelialized grafts (n = 9) were then transplanted into immunosuppressed pigs with perfusion measured using angiography post-implant and on days 3 and 7 with 3 native kidneys used as controls. Patent recellularized kidney grafts underwent histological analysis following explant. Results: The glucose consumption rate of recellularized kidney grafts reached a peak of 39.9 ± 9.7 mg/h at 21 ± 5 days, at which point the grafts were determined to have sufficient histological vascular coverage with endothelial cells. Based on these results, a minimum glucose consumption rate threshold of 20 mg/h was set. The revascularized kidneys had a mean perfusion percentage of 87.7% ± 10.3%, 80.9% ± 33.1%, and 68.5% ± 38.6% post-reperfusion on Days 0, 3 and 7, respectively. The 3 native kidneys had a mean post-perfusion percentage of 98.4% ± 1.6%. These results were not statistically significant. Conclusion: This study is the first to demonstrate that human-scale bioengineered porcine kidney grafts developed via perfusion decellularization and subsequent re-endothelialization using HUVEC can maintain patency with consistent blood flow for up to 7 days in vivo. These results lay the foundation for future research to produce human-scale recellularized kidney grafts for transplantation.

Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: Analysis of the US Multicenter HCC Transplant Consortium.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22-1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p < 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

Outcomes in liver transplant recipients with nonalcoholic fatty liver disease-related HCC: results from the US multicenter HCC transplant consortium.

NAFLD will soon be the most common indication for liver transplantation (LT). In NAFLD, HCC may occur at earlier stages of fibrosis and present with more advanced tumor stage, raising concern for aggressive disease. Thus, adult LT recipients with HCC from 20 US centers transplanted between 2002 and 2013 were analyzed to determine whether NAFLD impacts recurrence-free post-LT survival. Five hundred and thirty-eight (10.8%) of 4981 total patients had NAFLD. Patients with NAFLD were significantly older (63 vs. 58, p<0.001), had higher body mass index (30.5 vs. 27.4, p<0.001), and were more likely to have diabetes (57.3% vs. 28.8%, p<0.001). Patients with NAFLD were less likely to receive pre-LT locoregional therapy (63.6% vs. 72.9%, p<0.001), had higher median lab MELD (15 vs. 13, p<0.001) and neutrophil-lymphocyte ratio (3.8 vs. 2.9, p<0.001), and were more likely to have their maximum pre-LT alpha fetoprotein at time of LT (44.1% vs. 36.1%, p<0.001). NAFLD patients were more likely to have an incidental HCC on explant (19.4% vs. 10.4%, p<0.001); however, explant characteristics including tumor differentiation and vascular invasion were not different between groups. Comparing NAFLD and non-NAFLD patients, the 1, 3, and 5-year cumulative incidence of recurrence (3.1%, 9.1%, 11.5% vs. 4.9%, 10.1%, 12.6%, p=0.36) and recurrence-free survival rates (87%, 76%, and 67% vs. 87%, 75%, and 67%, p=0.97) were not different. In competing risks analysis, NAFLD did not significantly impact recurrence in univariable (HR: 0.88, p=0.36) nor in adjusted analysis (HR: 0.91, p=0.49). With NAFLD among the most common causes of HCC and poised to become the leading indication for LT, a better understanding of disease-specific models to predict recurrence is needed. In this NAFLD cohort, incidental HCCs were common, raising concerns about early detection. However, despite less locoregional therapy and high neutrophil-lymphocyte ratio, explant tumor characteristics and post-transplant recurrence-free survival were not different compared to non-NAFLD patients.

Vascularized Tracheal Transplantation: A Twenty Month Follow Up.

BACKGROUND: Tracheal transplantation has been considered the ideal option for the reconstruction of long-segment circumferential tracheal defects. Our group developed a technique for vascularized single-staged tracheal transplantation. Twenty months ago, we performed the first-in-human tracheal transplantation. Herein, we report a twenty-month follow-up. METHODS: The recipient presented with a 9.0 cm airway tracheal stenosis and complete cricoid stenosis. The patient previously failed six major conventional surgical procedures. Prior to transplantation, the patient's airway was maintained with an extended tracheostomy and stent. The patient experienced repeated life-threatening airway obstruction because of mucous plugging and obstructive granulation tissue. In January 2020 the patient underwent a single-staged tracheal transplantation treated with triple-therapy immunosuppression. Organ rejection was monitored with endoscopic tracheoscopy, narrow-band imaging, free-cell DNA assessment, and histological and cytogenetic analysis of tracheal biopsies. Mucociliary function was assessed with dye motility studies. RESULTS: Twenty months following transplantation, there has been no evidence of acute or chronic rejection. Since day 60, there has been no detectable free cell DNA, a surrogate marker for immune-mediated allograft rejection. Fluorescence in situ hybridization (FISH) cytogenetics demonstrated that the donor trachea was repopulated with recipient epithelium establishing a chimeric allograft. Narrow-band imaging demonstrates a well-vascularized epithelial mucosa and bronchoscopic biopsies demonstrate normal ciliated epithelial architecture and viable epithelial lining with functional ciliated epithelium. The patient has resumed a normal life without a stent or tracheostomy and has returned to work. CONCLUSIONS: Twenty months after single-staged vascularized tracheal transplantation, the trachea is functional and the patient breathes without the need for a tracheostomy or stent. Single-staged long-segment tracheal transplantation is a viable option for tracheal defects that are not amenable to conventional reconstructive techniques. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1839-1845, 2023.

Early Liver Transplantation for Severe Alcohol-Associated Hepatitis and a History of Prior Liver Decompensation.

INTRODUCTION: In the published studies of early liver transplantation (LT) for alcohol-associated hepatitis (AH), patients with a prior liver decompensation are excluded. The appropriateness of this criteria is unknown. METHODS: Among 6 American Consortium of Early Liver Transplantation for Alcohol-Associated Hepatitis sites, we included consecutive early LT for clinically diagnosed AH between 2007 and 2020. Patients were stratified as first vs prior history of liver decompensation, with the latter defined as a diagnosis of ascites, hepatic encephalopathy, variceal bleeding, or jaundice, and evidence of alcohol use after this event. Adjusted Cox regression assessed the association of first (vs prior) decompensation with post-LT mortality and harmful (i.e., any binge and/or frequent) alcohol use. RESULTS: A total of 241 LT recipients (210 first vs 31 prior decompensation) were included: median age 43 vs 38 years ( P = 0.23), Model for End-Stage Liver Disease Sodium score of 39 vs 39 ( P = 0.98), and follow-up after LT 2.3 vs 1.7 years ( P = 0.08). Unadjusted 1- and 3-year survival among first vs prior decompensation was 93% (95% confidence interval [CI] 89%-96%) vs 86% (95% CI 66%-94%) and 85% (95% CI 79%-90%) vs 78% (95% CI 57%-89%). Prior (vs first) decompensation was associated with higher adjusted post-LT mortality (adjusted hazard ratio 2.72, 95% CI 1.61-4.59) and harmful alcohol use (adjusted hazard ratio 1.77, 95% CI 1.07-2.94). DISCUSSION: Prior liver decompensation was associated with higher risk of post-LT mortality and harmful alcohol use. These results are a preliminary safety signal and validate first decompensation as a criterion for consideration in early LT for AH patients. However, the high 3-year survival suggests a survival benefit for early LT and the need for larger studies to refine this criterion. These results suggest that prior liver decompensation is a risk factor, but not an absolute contraindication to early LT.

Outcomes of Anesthesiologist-Led Care of Patients Following Liver Transplantation During the COVID-19 Pandemic.

BACKGROUND: During the COVID-19 pandemic, anesthesiologists were redeployed as transplant ICU intensivists and a postanesthesia care unit was converted to a novel transplant ICU. This study compared the outcomes of patients undergoing liver transplantation under the new model with the prepandemic model. METHODS: Adult patients who underwent liver transplantation at an urban tertiary care center in the United States from December 28, 2015, through May 1, 2020, were identified and grouped according to date of procedure. Peri-COVID cases included transplants that were performed after March 3, 2020. Transplants performed before March 3, 2020, served as pre-COVID controls. RESULTS: A total of 523 liver transplant patients (30 study cases, 493 controls) were included. Kaplan-Meier survival analysis showed no significant difference in novel transplant ICU length of stay (N-TLOS) (median LOS 3.8 vs. 4.5 days, log-rank p = 0.60) and hospital length of stay (HLOS) (median LOS 14.2 vs. 14.5 days, log-rank p = 0.66). Cox proportional hazards regression with inverse probability of treatment weighting showed no difference in N-TLOS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.67-1.23, p = 0.55) or HLOS (HR 0.90, 95% CI 0.65-1.25, p = 0.52). In addition, there were no significant differences (pre-COVID vs. COVID) in time to extubation (median [interquartile range] 28.7 [20.6-50.7] vs. 26.8 [17.4-40.8] hours, p = 0.35), one-year patient survival (12.0% vs. 6.7%, p = 0.055), one-year graft survival (13.4% vs. 6.7%, p = 0.43), and readmission to the ICU (15.0% vs. 20.0%, p = 0.68). CONCLUSION: Care provided by non-intensivist anesthesiologists to patients undergoing orthotopic liver transplantation during a pandemic emergency resulted in outcomes similar to those of care provided by intensivists.

Ten-Year Outcomes of Liver Transplant and Downstaging for Hepatocellular Carcinoma.

Importance: National guidelines on transplant selection have adopted successful downstaging to within Milan criteria (MC) as a viable option for the treatment of hepatocellular carcinoma (HCC) before liver transplant (LT). Recurrence of HCC after LT carries a poor prognosis, and treatment modalities remain challenging. Objective: To establish the 10-year outcomes of patients with HCC after LT in a large, multicenter US study based on individual data; provide robust data on the long-term role of downstaging; and evaluate the association of treatment modalities with postrecurrence survival. Design, Setting, and Participants: In this cohort study, a retrospective, multicenter analysis of prospectively collected data was conducted for 2645 adults who had undergone LT for HCC at 5 US academic centers between January 2001 and December 2015. The analysis was performed from May 2019 through June 2021. Outcomes of 341 patients whose disease was downstaged to within MC were compared with those in 2122 patients whose disease was always within MC and 182 patients whose disease was not downstaged. The associations of tumor and treatment factors on postrecurrence survival were analyzed using Cox proportional hazards regression and multivariable logistic regression models. Main Outcomes and Measures: The primary outcome was overall survival for the whole cohort and according to downstaging status. Secondary outcomes were time to recurrence, recurrence-free survival, and recurrence after specific post-LT therapies. Results: Of the 2645 patients studied, the median age was 59.9 years (IQR, 54.7-64.7 years). The majority of the patients were men (2028 [76.7%] vs 617 [23.3%] women). The 10-year post-LT survival and recurrence rates were, respectively, 52.1% and 20.6% among those whose disease was downstaged; 61.5% and 13.3% in those always within MC; and 43.3% and 41.1% in those whose disease was not downstaged. Independent variables associated with downstaging failure were tumor size greater than 7 cm at diagnosis (OR, 2.62; 95% CI, 1.20-5.75; P = .02), more than 3 tumors at diagnosis (OR, 2.34; 95% CI, 1.22-4.50; P = .01), and α-fetoprotein response of at least 20 ng/mL with less than 50% improvement from maximum α-fetoprotein before LT (OR, 1.99; 95% CI, 1.14-3.46; P = .02). Surgically treated patients with recurrent HCC differed in clinicopathologic characteristics and had improved 5-year postrecurrence survival rates (31.6% vs 7.3%; P < .001). Conclusions and Relevance: In a large, multicenter cohort of patients with HCC successfully downstaged to within MC, 10-year post-LT outcomes were excellent, validating national downstaging policies and showing a clear utility benefit for LT prioritization decision making. Surgical management of HCC recurrence after LT was associated with improved survival in well-selected patients and should be pursued, if feasible.

Recurrent Liver Allograft Injury in Patients With Donor-Derived Malignancy Treated With Immunosuppression Cessation and Retransplantation.

OBJECTIVES: Donor-derived malignancy of the liver allograft is a rare but serious condition in the setting of necessary immunosuppression. Retransplantation after abrupt immunosuppression cessation has been performed with durable cancer-free survival. METHODS: We present 2 cases of patients with donor-derived malignancy who were treated with complete immunosuppression cessation, which induced rapidly progressive liver allograft rejection and failure, with a need for subsequent retransplantation. We reviewed all serial liver biopsies and explants from both patients and performed C4d immunostaining. RESULTS: Initial explants of both patients showed severe allograft rejection, with unusual features of sinusoidal obstruction syndrome and C4d positivity. Malignant tumors in the explants were necrotic, related to rejection of donor-derived cancer cells and tissue. Follow-up of both patients has shown long-term cancer-free survival but issues with recurrent allograft failure requiring a third transplant. The reasons for retransplantation in both cases were related to allograft failure from antibody-mediated rejection. CONCLUSIONS: Clinicians should be aware of a potentially increased risk of rejection and recurrent allograft failure when strategizing treatment of donor-derived malignancy with immunosuppression cessation and retransplantation.

Impact of Portable Normothermic Blood-Based Machine Perfusion on Outcomes of Liver Transplant: The OCS Liver PROTECT Randomized Clinical Trial.

IMPORTANCE: Ischemic cold storage (ICS) of livers for transplant is associated with serious posttransplant complications and underuse of liver allografts. OBJECTIVE: To determine whether portable normothermic machine perfusion preservation of livers obtained from deceased donors using the Organ Care System (OCS) Liver ameliorates early allograft dysfunction (EAD) and ischemic biliary complications (IBCs). DESIGN, SETTING, AND PARTICIPANTS: This multicenter randomized clinical trial (International Randomized Trial to Evaluate the Effectiveness of the Portable Organ Care System Liver for Preserving and Assessing Donor Livers for Transplantation) was conducted between November 2016 and October 2019 at 20 US liver transplant programs. The trial compared outcomes for 300 recipients of livers preserved using either OCS (n = 153) or ICS (n = 147). Participants were actively listed for liver transplant on the United Network of Organ Sharing national waiting list. INTERVENTIONS: Transplants were performed for recipients randomly assigned to receive donor livers preserved by either conventional ICS or the OCS Liver initiated at the donor hospital. MAIN OUTCOMES AND MEASURES: The primary effectiveness end point was incidence of EAD. Secondary end points included OCS Liver ex vivo assessment capability of donor allografts, extent of reperfusion syndrome, incidence of IBC at 6 and 12 months, and overall recipient survival after transplant. The primary safety end point was the number of liver graft-related severe adverse events within 30 days after transplant. RESULTS: Of 293 patients in the per-protocol population, the primary analysis population for effectiveness, 151 were in the OCS Liver group (mean [SD] age, 57.1 [10.3] years; 102 [67%] men), and 142 were in the ICS group (mean SD age, 58.6 [10.0] years; 100 [68%] men). The primary effectiveness end point was met by a significant decrease in EAD (27 of 150 [18%] vs 44 of 141 [31%]; P = .01). The OCS Liver preserved livers had significant reduction in histopathologic evidence of ischemia-reperfusion injury after reperfusion (eg, less moderate to severe lobular inflammation: 9 of 150 [6%] for OCS Liver vs 18 of 141 [13%] for ICS; P = .004). The OCS Liver resulted in significantly higher use of livers from donors after cardiac death (28 of 55 [51%] for the OCS Liver vs 13 of 51 [26%] for ICS; P = .007). The OCS Liver was also associated with significant reduction in incidence of IBC 6 months (1.3% vs 8.5%; P = .02) and 12 months (2.6% vs 9.9%; P = .02) after transplant. CONCLUSIONS AND RELEVANCE: This multicenter randomized clinical trial provides the first indication, to our knowledge, that normothermic machine perfusion preservation of deceased donor livers reduces both posttransplant EAD and IBC. Use of the OCS Liver also resulted in increased use of livers from donors after cardiac death. Together these findings indicate that OCS Liver preservation is associated with superior posttransplant outcomes and increased donor liver use. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02522871.

National Landscape of Human Immunodeficiency Virus-Positive Deceased Organ Donors in the United States.

BACKGROUND: Organ transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV-positive donors is critical for safety. METHODS: We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) test results within the HIV Organ Policy Equity (HOPE) Act in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262, NCT03500315, and NCT03734393). We compared clinical characteristics in HIV-positive versus FP donors. We measured CD4 T cells, HIV viral load (VL), drug resistance mutations (DRMs), coreceptor tropism, and serum antiretroviral therapy (ART) detection, using mass spectrometry in HIV-positive donors. RESULTS: Between March 2016 and March 2020, 92 donors (58 HIV positive, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidneys and 46 livers). Each year the number of donors increased. The prevalence of hepatitis B (16% vs 0%), syphilis (16% vs 0%), and cytomegalovirus (CMV; 91% vs 58%) was higher in HIV-positive versus FP donors; the prevalences of hepatitis C viremia were similar (2% vs 6%). Most HIV-positive donors (71%) had a known HIV diagnosis, of whom 90% were prescribed ART and 68% had a VL <400 copies/mL. The median CD4 T-cell count (interquartile range) was 194/µL (77-331/µL), and the median CD4 T-cell percentage was 27.0% (16.8%-36.1%). Major HIV DRMs were detected in 42%, including nonnucleoside reverse-transcriptase inhibitors (33%), integrase strand transfer inhibitors (4%), and multiclass (13%). Serum ART was detected in 46% and matched ART by history. CONCLUSION: The use of HIV-positive donor organs is increasing. HIV DRMs are common, yet resistance that would compromise integrase strand transfer inhibitor-based regimens is rare, which is reassuring regarding safety.

Outcomes of transplantation for HBV- vs. HCV-related HCC: impact of DAA HCV therapy in a national analysis of >20,000 patients.

BACKGROUND: The development of direct-acting antiviral (DAA) therapy has revolutionized HCV management. We present a large national study comparing post-LT outcomes for HBV-HCC vs. HCV-HCC according to DAA era. METHODS: Data were collected from OPTN/UNOS Registry. Groups included pre-DAA (January 2003-October 2013) and post-DAA (November2013-January2019) eras. Outcomes for patients with HBV(n = 2000) vs. HCV(n = 18,964) were compared in each era. RESULTS: In the pre-DAA era, there were significant differences between HBV-versus HCV, including the percentage of Caucasian race, pre-LT and maximum AFP levels <20 ng/mL, MELD-score, complete tumor necrosis, and vascular invasion. In the post-DAA-era, differences were noted in wait time>9 months, the percentage of Caucasian race, pre-LT and AFP(max) levels<20 ng/mL, and MELD-score. In the pre-DAA-era, the 5-and-10 year survival rates were 80.5% and 71% for HBV-HCC, and 69% and 54.4% for HCV-HCC (p < 0.001); in the post-DAA-era, 5-year survival was 83.4% for HBV-HCC and 78.5% for HCV-HCC(p = 0.08). Independent pre-LT predictors of lower survival included recipient and donor age>50yrs, wait-time>9months, higher MELD-score (p < 0.001), AFP level>20 ng/mL, and MC at diagnosis. HCV status did not predict outcome in the post-DAA-era after adjusting for tumor characteristics. CONCLUSION: After the introduction of effective DAA-HCV therapy, results of LT for HCV-HCC are significantly improved and are no longer statistically different from results in patients with HBV-HCC.

Single-stage long-segment tracheal transplantation.

Tracheal transplantation has been envisioned as a viable option for reconstruction of long-segment tracheal defects. We report the first human single-stage long-segment tracheal transplantation. Narrow-band imaging and bronchoscopic biopsies demonstrate allograft vascularization and viable epithelial lining. The recipient was immunosuppressed with Tacrolimus, Mycophenolate mofetil, and corticosteroids. Six months after transplantation, the trachea is both functional and the patient is breathing without the need of a tracheostomy or stent.

A subset of liver resident natural killer cells is expanded in hepatitis C-infected patients with better liver function.

Viral hepatitis leads to immune-mediated liver injury. The rate of disease progression varies between individuals. We aimed to phenotype immune cells associated with preservation of normal liver function during hepatitis C virus (HCV) infection. Clinical data and specimens were obtained from 19 HCV-infected patients undergoing liver transplantation. Liver and peripheral blood mononuclear cells were isolated and eight subsets of innate immune cells were delineated by multiparameter flow cytometry. Cytokine assays and microarrays were performed. Intrahepatic CD56Bright/CD16- natural killer (NK) cells comprised the only subset correlating with better liver function, i.e., lower bilirubin (p = 0.0002) and lower model for end stage of liver disease scores (p = 0.03). The signature of liver NK cells from HCV-infected patients included genes expressed by NK cells in normal liver and by decidual NK cells. Portal vein blood had a higher concentration of interleukin (IL)-10 than peripheral blood (p = 0.03). LMCs were less responsive to toll-like receptor (TLR) stimulation than PBMCs, with fewer pro-inflammatory gene-expression pathways up-regulated after in vitro exposure to lipopolysaccharide and a TLR-7/8 agonist. Hepatic CD56Bright/CD16- NK cells may be critical for maintaining liver homeostasis. Portal vein IL-10 may prime inhibitory pathways, attenuating TLR signaling and reducing responsiveness to pro-inflammatory stimuli.

Multicenter validation of the liver graft assessment following transplantation (L-GrAFT) score for assessment of early allograft dysfunction.

BACKGROUND & AIMS: Early allograft dysfunction (EAD) following liver transplantation (LT) negatively impacts graft and patient outcomes. Previously we reported that the liver graft assessment following transplantation (L-GrAFT7) risk score was superior to binary EAD or the model for early allograft function (MEAF) score for estimating 3-month graft failure-free survival in a single-center derivation cohort. Herein, we sought to externally validate L-GrAFT7, and compare its prognostic performance to EAD and MEAF. METHODS: Accuracies of L-GrAFT7, EAD, and MEAF were compared in a 3-center US validation cohort (n = 3,201), and a Consortium for Organ Preservation in Europe (COPE) normothermic machine perfusion (NMP) trial cohort (n = 222); characteristics were compared to assess generalizability. RESULTS: Compared to the derivation cohort, patients in the validation and NMP trial cohort had lower recipient median MELD scores; were less likely to require pretransplant hospitalization, renal replacement therapy or mechanical ventilation; and had superior 1-year overall (90% and 95% vs. 84%) and graft failure-free (88% and 93% vs. 81%) survival, with a lower incidence of 3-month graft failure (7.4% and 4.0% vs. 11.1%; p <0.001 for all comparisons). Despite significant differences in cohort characteristics, L-GrAFT7 maintained an excellent validation AUROC of 0.78, significantly superior to binary EAD (AUROC 0.68, p = 0.001) and MEAF scores (AUROC 0.72, p <0.001). In post hoc analysis of the COPE NMP trial, the highest tertile of L-GrAFT7 was significantly associated with time to liver allograft (hazard ratio [HR] 2.17, p = 0.016), Clavien ≥IIIB (HR 2.60, p = 0.034) and ≥IVa (HR 4.99, p = 0.011) complications; post-LT length of hospitalization (p = 0.002); and renal replacement therapy (odds ratio 3.62, p = 0.016). CONCLUSIONS: We have validated the L-GrAFT7 risk score as a generalizable, highly accurate, individualized risk assessment of 3-month liver allograft failure that is superior to existing scores. L-GrAFT7 may standardize grading of early hepatic allograft function and serve as a clinical endpoint in translational studies (www.lgraft.com). LAY SUMMARY: Early allograft dysfunction negatively affects outcomes following liver transplantation. In independent multicenter US and European cohorts totaling 3,423 patients undergoing liver transplantation, the liver graft assessment following transplantation (L-GrAFT) risk score is validated as a superior measure of early allograft function that accurately discriminates 3-month graft failure-free survival and post-liver transplantation complications.