The Effect of Normothermic Machine Perfusion on the Immune Profile of Donor Liver.

Background: Normothermic machine perfusion (NMP) allows viability assessment and potential resuscitation of donor livers prior to transplantation. The immunological effect of NMP on liver allografts is undetermined, with potential implications on allograft function, rejection outcomes and overall survival. In this study we define the changes in immune profile of human livers during NMP. Methods: Six human livers were placed on a NMP device. Tissue and perfusate samples were obtained during cold storage prior to perfusion and at 1, 3, and 6 hours of perfusion. Flow cytometry, immunohistochemistry, and bead-based immunoassays were used to measure leukocyte composition and cytokines in the perfusate and within the liver tissue. Mean values between baseline and time points were compared by Student's t-test. Results: Within circulating perfusate, significantly increased frequencies of CD4 T cells, B cells and eosinophils were detectable by 1 hour of NMP and continued to increase at 6 hours of perfusion. On the other hand, NK cell frequency significantly decreased by 1 hour of NMP and remained decreased for the duration of perfusion. Within the liver tissue there was significantly increased B cell frequency but decreased neutrophils detectable at 6 hours of NMP. A transient decrease in intermediate monocyte frequency was detectable in liver tissue during the middle of the perfusion run. Overall, no significant differences were detectable in tissue resident T regulatory cells during NMP. Significantly increased levels of pro-inflammatory and anti-inflammatory cytokines were seen following initiation of NMP that continued to rise throughout duration of perfusion. Conclusions: Time-dependent dynamic changes are seen in individual leukocyte cell-types within both perfusate and tissue compartments of donor livers during NMP. This suggests a potential role of NMP in altering the immunogenicity of donor livers prior to transplant. These data also provide insights for future work to recondition the intrinsic immune profile of donor livers during NMP prior to transplantation.

Relatively Poor Long-term Outcomes Following Liver Transplantation for NASH in the United States.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) continues to increase in frequency as an indication for liver transplantation (LT). Data on long-term outcomes for these patients are limited. We aimed to compare long-term patient and graft survival in patients undergoing LT for NASH in the United States to other indications. METHODS: We analyzed data from the Scientific Registry of Transplant Recipients of adult patients who underwent primary deceased-donor LT from January 1, 2005, to December 31, 2019. RESULTS: NASH has increased as an indication for LT by 4.5-fold, from 5.2% in 2005 to 23.4% in 2019. Patient (61.2%) and graft survival (59.2%) at 10 y are significantly poorer for NASH than for all other indications other than alcohol. Patients transplanted for NASH have higher body mass index (32.2 versus 27.6) and greater frequency of diabetes (13% versus 11.6%) than any other indication ( P < 0.001). Portal vein thrombosis, location in intensive care unit, dialysis, and pre-LT diabetes ( P < 0.001 for all) are independently predictive of patient death and graft loss. Body mass index is not predictive. NASH patients undergoing simultaneous liver kidney have markedly worse 10-y patient and graft survival than liver-only (52.3% versus 62.1%). Graft loss was attributed to recurrence of NASH in <1% of patients. CONCLUSIONS: LT for NASH is associated with relatively poor long-term patient and graft survival when compared with patients transplanted for other indications, NASH patients undergoing simultaneous liver kidney have the worst long-term outcomes.

Donor leukocyte trafficking during human ex vivo lung perfusion.

BACKGROUND: Ex vivo lung perfusion (EVLP) is used to assess and preserve lungs prior to transplantation. However, its inherent immunomodulatory effects are not completely understood. We examine perfusate and tissue compartments to determine the change in immune cell composition in human lungs maintained on EVLP. METHODS: Six human lungs unsuitable for transplantation underwent EVLP. Tissue and perfusate samples were obtained during cold storage and at 1-, 3- and 6-h during perfusion. Flow cytometry, immunohistochemistry, and bead-based immunoassays were used to measure leukocyte composition and cytokines. Mean values between baseline and time points were compared by Student's t test. RESULTS: During the 1st hour of perfusion, perfusate neutrophils increased (+22.2 ± 13.5%, p < 0.05), monocytes decreased (-77.5 ± 8.6%, p < 0.01) and NK cells decreased (-61.5 ± 22.6%, p < 0.01) compared to cold storage. In contrast, tissue neutrophils decreased (-22.1 ± 12.2%, p < 0.05) with no change in monocytes and NK cells. By 6 h, perfusate neutrophils, NK cells, and tissue neutrophils were similar to baseline. Perfusate monocytes remained decreased, while tissue monocytes remained unchanged. There was no significant change in B cells or T cell subsets. Pro-inflammatory cytokines (IL-1b, G-CSF, IFN-gamma, CXCL2, CXCL1 granzyme A, and granzyme B) and lymphocyte activating cytokines (IL-2, IL-4, IL-6, IL-8) increased during perfusion. CONCLUSIONS: Early mobilization of innate immune cells occurs in both perfusate and tissue compartments during EVLP, with neutrophils and NK cells returning to baseline and monocytes remaining depleted after 6 h. The immunomodulatory effect of EVLP may provide a therapeutic window to decrease the immunogenicity of lungs prior to transplantation.

Nonhepatic Cancer in the Pediatric Liver Transplant Population: Guidelines From the ILTS-SETH Consensus Conference.

The incidence and geographical distribution of cancers in children are dramatically different from the adult population. Consequent to improvements in postcancer survival, there is a progressive increase in the number of patients requiring liver transplantation (LT) who are in remission from pretransplant malignancy (PTM). Conventionally, however, PTM has been considered a relative contraindication to LT. Furthermore, with improving post-LT survival now extending beyond decades, the cumulative effect of immunosuppression and the increasing risk of de novo cancers need to be acknowledged. A working group was formed to evaluate, discuss, and retrieve all the evidence and provide guidelines with regards to best practices surrounding nonhepatic cancer in the pediatric LT (PLT) population. Further subsections of research included (a) extrahepatic solid tumors, leukemia, lymphoma, and other hematological disturbances before PLT and (b) malignancies following PLT (including posttransplant lymphoproliferative disorders). This guidance provides a collection of evidence-based expert opinions, consensus, and best practices on nonhepatic cancers in PLT.

The Impact of COVID-19 on Kidney Transplant Recipients in Pre-Vaccination and Delta Strain Era: A Systematic Review and Meta-Analysis.

Herein, we performed a meta-analysis of published clinical outcomes of corona virus disease 2019 (COVID-19) in hospitalized kidney transplant recipients. A systematic database search was conducted between December 1, 2019 and April 20, 2020. We analyzed 48 studies comprising 3137 kidney transplant recipients with COVID-19. Fever (77%), cough (65%), dyspnea (48%), and gastrointestinal symptoms (28%) were predominant on hospital admission. The most common comorbidities were hypertension (83%), diabetes mellitus (34%), and cardiac disease (23%). The pooled prevalence of acute respiratory distress syndrome and acute kidney injury were 58% and 48%, respectively. Invasive ventilation and dialysis were required in 24% and 22% patients, respectively. In-hospital mortality rate was as high as 21%, and increased to over 50% for patients in intensive care unit (ICU) or requiring invasive ventilation. Risk of mortality in patients with acute respiratory distress syndrome (ARDS), on mechanical ventilation, and ICU admission was increased: OR = 19.59, OR = 3.80, and OR = 13.39, respectively. Mortality risk in the elderly was OR = 3.90; however, no such association was observed in terms of time since transplantation and gender. Fever, cough, dyspnea, and gastrointestinal symptoms were common on admission for COVID-19 in kidney transplant patients. Mortality was as high as 20% and increased to over 50% in patients in ICU and required invasive ventilation.

Living Donor Liver Transplantation in the United States: Evolution of Frequency, Outcomes, Center Volumes, and Factors Associated With Outcomes.

Recent modifications in organ allocation policies and increases in chronic liver diseases may have resulted in important changes in living donor liver transplantation (LDLT) in the United States. We examined the trends, outcomes, and factors associated with outcomes in adult LDLT. United Network for Organ Sharing data on 2566 adult LDLT recipients who received transplants from January 1, 2010, through December 31, 2019, were analyzed. LDLT graft and patient survival rates were compared with propensity score-matched deceased donor liver transplantation recipients by the Kaplan-Meier curve estimator. The association between preceding LDLT frequency and subsequent outcomes were assessed by Cox proportional hazards mixed effects modeling. After a stable annual frequency of LDLTs from 2010 to 2014 (~200 per year), the number of LDLTs doubled to 440 in 2019. The 1-year and 5-year graft survival rates for LDLT recipients were 88.4% and 78.1%, respectively, compared with 92.5% and 80.7% in the propensity score-matched donation after brain death recipients (P = 0.005), respectively. Older donor age and recipient diabetes mellitus and life support requirement were significantly associated with graft failure among LDLT recipients (P values <0.05). Average preceding LDLT frequencies of <3 per year, 3 to 20 per year, and >20 per year resulted in 1-year graft survival rates of 82%, 88% to 89%, and 93%, respectively (P values <0.05). There were 3 living donor deaths (0.12%). The frequency of LDLTs has doubled during the past decade, with good outcomes and acceptable donor safety profiles. However, there appear to be varying threshold transplant frequencies (volume/unit time) associated with acceptable (88%-89%) and aspirational (93%) 1-year graft survival rates. These data should be reassuring and encourage LDLT practice as efforts continue to expand the donor pool.

COVID-19 in hospitalized liver transplant recipients: An early systematic review and meta-analysis.

Adverse clinical outcomes related to SARS-CoV-2 infection among liver transplant (LTx) recipients remain undefined. We performed a meta-analysis to determine the pooled prevalence of outcomes among hospitalized LTx recipients with COVID-19. A database search of literature published between December 1, 2019, and November 20, 2020, was performed per PRISMA guidelines. Twelve studies comprising 517 hospitalized LTx recipients with COVID-19 were analyzed. Common presenting symptoms were fever (71%), cough (62%), dyspnea (48%), and diarrhea (28%). Approximately 77% (95% CI, 61%-93%) of LTx recipients had a history of liver cirrhosis. The most prevalent comorbidities were hypertension (55%), diabetes (45%), and cardiac disease (21%). In-hospital mortality was 20% (95% CI, 13%-28%) and rose to 41% (95% CI, 19%-63%) (P < 0.00) with ICU admission. Additional subgroup analysis demonstrated a higher mortality risk in the elderly (>60-65 years) (OR 4.26; 95% CI, 2.14-8.49). There was no correlation in respect to sex or time since transplant. In summary, LTx recipients with COVID-19 had a high prevalence of dyspnea and gastrointestinal symptoms. In-hospital mortality was comparable to non-transplant populations with similar comorbidities but appeared to be less than what is reported elsewhere for cirrhotic patients (26%-40%). Importantly, the observed high case fatality in the elderly could be due to age-associated comorbidities.

Liver transplantation for alcoholic hepatitis in the United States: Excellent outcomes with profound temporal and geographic variation in frequency.

Medical-refractory severe alcoholic hepatitis (AH) has a high mortality. The national frequency, longer term outcomes and regional practices of AH liver transplantation (LT) in the United States are not well described, despite the increasing mortality from alcohol-associated liver disease. We analyzed the trends in frequency and outcomes of UNOS data on 39 455 adult patients who underwent LT from 2014 to 2019, including AH LT recipients. LTs for AH increased 5-fold, from 28 in 2014 to 138 in 2019, varying 8-fold between UNOS regions. Three transplant centers accounted for 50%-90% of AH LTs within each region. The number of transplant centers performing AH LTs increased from 14 in 2014 to 47 in 2019. AH patients were younger (mean = 39.4 years), had higher MELD scores (mean = 36.8), and were more often on dialysis (46.0%) and in ICU (38.4%), compared to other indications (all P < .05). One- and 5-year graft survivals for AH LT recipients were 91.7% and 81.9%, respectively. The frequency of AH LT is increasing rapidly, with excellent medium-term outcomes. An impact of AH recurrence on patient or graft survival is not apparent in this national analysis. There are marked geographic variations in practices, highlighting the lack of selection criteria standardization.

The Abdominal Transplant Surgery Workforce: Current state and future trends.

Transplant surgical workforce concerns have arisen in the last 5 years as reflected in challenges securing job opportunities for new fellows. The present survey was designed by the ASTS Membership and Workforce Committee to describe the current practice characteristics of transplant centers in order to estimate changes in the workforce. The survey questionnaire requested information about the transplant programs, the transplant surgeons involved in the program, and the estimated changes in the staffing of the program over the next 3 years. Seventy-one transplant centers responded from a total of 235 identified and queried (30.2% response rate), with median responding centers per UNOS region of 7 (IQR 4.5-8.5). The recruitment outlook for the next 3 years forecasts a positive inflow of surgeons at a 2:1 rate (incoming:leaving). The new female transplant workforce within the responding cohort has increased from 3.7% in 1980 to 18.4% in 2010. Currently, 13.1% of practicing US transplant surgeons in this survey are female which is higher than many other surgical specialties. This report represents the most up-to-date view into the abdominal transplant surgical workforce. The positive job recruitment outlook for transplant surgeons and the narrowing gender gap are new findings from this study.

Case Series of 10 Patients with Cirrhosis Undergoing Emergent Repair of Ruptured Umbilical Hernias: Natural History and Predictors of Outcomes.

OBJECTIVES: Ascites represents an important event in the natural history of cirrhosis, portending increased 1-year mortality. Umbilical herniation with rupture is an uncommon complication of large-volume ascites that is associated with significant morbidity and mortality. The aim of this study was to describe predictors of outcomes in patients undergoing emergent repair for spontaneous umbilical hernia rupture. MATERIALS AND METHODS: We report a case series of 10 patients with decompensated cirrhosis (mean age 66 ± 9 years, mean Model for End-Stage Liver Disease score of 21 ± 7) who presented with a ruptured umbilical hernia and had emergent repair. RESULTS: Thirty percent (3/10) of patients died or required liver transplant. Factors associated with death or transplant included the development of bacterial peritonitis (P = .03) and the presurgical 30-day Mayo Clinic Postoperative Mortality Risk in Patient with Cirrhosis Score (P = .03). CONCLUSIONS: Emergent repair after umbilical hernia rupture in patients with decompensated cirrhosis carries a poor prognosis with 30% of patients developing poor postsurgical outcomes.

Adverse Effect of Post-Discharge Care Fragmentation on Outcomes after Readmissions after Liver Transplantation.

BACKGROUND: Post-discharge surgical care fragmentation is defined as readmission to any hospital other than the hospital at which surgery was performed. The objective of this study was to assess the impact of fragmented readmissions within the first year after orthotopic liver transplantation (OLT). STUDY DESIGN: The Healthcare Cost and Utilization Project State Inpatient Databases for Florida and California from 2006 to 2011 were used to identify OLT patients. Post-discharge fragmentation was defined as any readmission to a non-index hospital, including readmitted patients transferred to the index hospital after 24 hours. Outcomes included adverse events, defined as 30-day mortality and 30-day readmission after a fragmented readmission. All statistical analyses considered a hierarchical data structure and were performed with multilevel, mixed-effects models. RESULTS: We analyzed 2,996 patients with 7,485 readmission encounters at 299 hospitals; 1,236 (16.5%) readmissions were fragmented. After adjustment for age, sex, readmission reason, index liver transplantation cost, readmission length of stay, number of previous readmissions, and time from transplantation, post-discharge fragmentation increased the odds of both 30-day mortality (odds ratio [OR] = 1.75; 95% CI 1.16 to 2.65) and 30-day readmission (OR = 2.14; 95% CI 1.83 to 2.49). Predictors of adverse events after a fragmented readmission included increased number of previous readmissions (OR = 1.07; 95% CI 1.01 to 1.14) and readmission within 90 days of OLT (OR = 2.19; 95% CI 1.61 to 2.98). CONCLUSIONS: Post-discharge fragmentation significantly increases the risk of both 30-day mortality and subsequent readmission after a readmission in the first year after OLT. More inpatient visits before a readmission and less time elapsed from index surgery increase the odds of an adverse event after discharge from a fragmented readmission. These parameters could guide transfer decisions for patients with post-discharge fragmentation.