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Hepatic encephalopathy represents a continuum of neuropsychiatric symptoms among patients with end-stage liver disease. When a patient with cirrhosis presents with altered mental status (AMS), routine neurologic imaging is not typically recommended, due to low diagnostic yield. Guidance from the American Association for the Study of Liver Disease states that, on initial presentation, brain imaging is not required unless there are other signs of intracranial pathology, including focal neurologic deficits. We present a case of a 61-year-old female with cirrhosis presenting with AMS without focal deficits, in whom neurological imaging revealed a meningioma and subsequent resection led to symptom improvement.

BACKGROUND Obesity, defined as a high body mass index (hBMI) of 30 kg/m or greater, is a growing epidemic worldwide and is associated with multiple comorbidities. High BMI individuals account for an increasing portion of potential liver donors. Here we evaluate trends in the utilization and outcomes of hBMI donors on a national and regional level and the potential role of liver biopsy in donor evaluation. METHODS United Network for Organ Sharing Standard Transplant Analysis and Research database was evaluated for deceased donor liver transplants between 2006 and 2016 across 11 Organ Procurement and Transplantation Network regions. High BMI donors were compared with lower BMI counterparts and evaluated for biopsy rates, utilization rates and allograft outcomes. Univariate and multivariable analyses were performed. RESULTS Seventy-seven thousand fifty potential donors were identified and 60 200 transplants were evaluated. Utilization rates for hBMI donors were 66.1% versus 78.1% for lower BMI donors (P < 0.001). Pretransplant biopsy was performed more frequently in hBMI donors (52.1% vs 33.1%, P < 0.001) and macrosteatosis of 30% or greater was identified more often (21.1% vs 12.2%, P < 0.001). Biopsy performance increased utilization rate of hBMI donors in 7 of 11 Organ Procurement and Transplantation Network regions. region 6 showed the highest rate of biopsy performance, high rate of hBMI donor utilization, and highest 5-year estimated graft survival rates of all regions. CONCLUSIONS High BMI donors have not previously been associated with worse graft survival in multivariable analyses; however, they are used much less frequently. Liver biopsy may increase the utilization rate of hBMI donors and improve donor selection. Further evaluation of regions with high rates of utilization and good outcomes is warranted.

Intraoperative extracorporeal membrane oxygenation (ECMO) support, both venoarterial and venovenous (VV), have been used sparingly and with limited success in the setting of liver transplantation. Here, we report the successful use of VV-ECMO in the resuscitation and pulmonary bridging support after severe systemic inflammatory response in a combined liver and kidney transplant recipient who suffered primary nonfunction of both allografts. Where conventional ventilator maneuvers may prove ineffective, the implementation of VV-ECMO should be considered as a therapeutic option in limited, short-lived acute pulmonary injury.

Background Liver transplantation (LT) can significantly improve mortality for severe alcoholic hepatitis (AH). However, this practice remains controversial. Our aim is to report the findings from our institution regarding outcomes for LT in severe AH and to discuss the results of a pilot program for discharging selected patients with close follow-up, in order to demonstrate sustained outpatient sobriety before listing. Methods Patient records were reviewed retrospectively from January 1, 2015 to January 17, 2018. The primary outcomes were patient and graft survival after LT. Secondary outcomes included relapse rates after LT, survival for those not transplanted, and reasons for denial among those not approved for transplant listing. Results A total of 18 patients with severe AH were considered for LT, of which 10 were transplanted and 8 were either denied transplantation or died before completing the evaluation. Patient and graft survival rates were 100% among those transplanted, and only 1 of the 10 patients (10%) returned to harmful drinking. In comparison, 6 of 8 (75%) of patients not transplanted died. Among the 10 patients transplanted, 4 were initially not approved for listing and were discharged with close follow-up, to demonstrate outpatient sobriety. All 4 of those patients demonstrated short-term abstinence and ultimately underwent transplantation, with no instances of relapse post-LT. Conclusions Liver transplantation for AH can achieve excellent outcomes with low rates of relapse. Carefully selected patients can be discharged with close monitoring to demonstrate commitment to outpatient sobriety prior to transplant listing.

Background: Mortality for patients with acute‐on‐chronic liver failure (ACLF) may be underestimated by the model for end‐stage liver disease‐sodium (MELD‐Na) score. / Aim: To assess waitlist outcomes across varying grades of ACLF among a cohort of patients listed with a MELD‐Na score ≥35, and therefore having similar priority for liver transplantation. / Methods: We analysed the United Network for Organ Sharing (UNOS) database, years 2010‐2017. Waitlist outcomes were evaluated using Fine and Gray's competing risks regression. / Results: We identified 6342 candidates at listing with a MELD‐Na score ≥35, of whom 3122 had ACLF‐3. Extra‐hepatic organ failures were present primarily in patients with four to six organ failures. Competing risks regression revealed that candidates listed with ACLF‐3 had a significantly higher risk for 90‐day waitlist mortality (Sub‐hazard ratio (SHR) = 1.41; 95% confidence interval [CI] 1.12‐1.78) relative to patients with lower ACLF grades. Subgroup analysis of ACLF‐3 revealed that both the presence of three organ failures (SHR = 1.40, 95% CI 1.20‐1.63) or four to six organ failures at listing (SHR = 3.01; 95% CI 2.54‐3.58) was associated with increased waitlist death. Candidates with four to six organ failures also had the lowest likelihood of receiving liver transplantation (SHR = 0.61, 95% CI 0.54‐0.68). The Share 35 rule was associated with reduced 90‐day waitlist mortality among the full cohort of patients listed with ACLF‐3 and MELD‐Na score ≥35 (SHR = 0.59; 95% CI 0.49‐0.70). However, Share 35 rule implementation was not associated with reduced waitlist mortality among patients with four to six organ failures (SHR = 0.76; 95% CI 0.58‐1.02). / Conclusion: The MELD‐Na score disadvantages patients with ACLF‐3, both with and without extra‐hepatic organ failures. Incorporation of organ failures into allocation policy warrants further exploration.

Background: It remains unknown to what extent hepatocellular carcinomas (HCCs) are detected very early (T1 stage; ie, unifocal Methods: Patients with HCC diagnosed from 2004 through 2014 were identified from the National Cancer Database. Logistic regression was used to identify factors associated with T1 HCC detection, and Cox proportional hazard analyses identified factors associated with overall survival among patients with T1 HCC. Results: Of 110,182 eligible patients, the proportion with T1 HCC increased from 2.6% in 2004 to 6.8% in 2014 (PConclusions: Despite increases over time

Introduction: The COVID-19 pandemic demands an urgent response from the transplant community in order to protect our vulnerable patient population We present the rare case of COVID-19 in a combined liver-kidney transplant recipient from the United States Case Report: The patient is a 77 year-old diabetic woman who presented to our transplant center with decompensated cryptogenic cirrhosis She underwent combined liver-kidney transplant Postoperatively, her liver enzymes normalized, and she no longer required dialysis She was discharged to a rehabilitation facility 12 days after transplant (POD #12) On POD #13, the patient had rehabilitation sessions with an occupational therapist who later tested positive for COVID-19 This day is presumed to be her first exposure, and subsequent days will be referred to as 'post-exposure days' (PEXD) On PEXD #9 (POD #22), the patient developed a fever of 103 degrees, accompanied by chills and nausea However, no dyspnea, cough, or respiratory complaints were present at presentation Other than an elevation in alkaline phosphatase of 168 U/L, her liver enzymes and creatinine were normal (Table 1) Chest CT only showed trace right pleural effusion with no pulmonary infiltrates, no ground-glass opacification, and no consolidation (Figure 1) Abdominal CT revealed a 20 x 15 cm fluid collection surrounding the left kidney graft Mycophenolate mofetil was discontinued, but prednisone and tacrolimus were continued Tacrolimus dosing was adjusted to achieve a target daily through level range of 6 - 10 ng/mL The following morning (PEXD #10), the patient underwent percutaneous drainage of her perinephric abscess Her fever and pain subsided following intervention On PEXD #11, the patient's COVID-19 test resulted as positive Isolation precautions were maintained Chest X ray was clear She had no dyspnea or cough, and she maintained oxygen saturation of 96-100% on room air A five-day course of treatment with oral hydroxychloroquine at 400 mg was planned, and started on PEXD #11 However, the patient had a significant elevation in liver enzymes immediately following treatment initiation The drug was discontinued on PEXD #13 The patient's liver enzymes improved following drug cessation We decided to initiate treatment with azithromycin on PEXD #15, completing a five-day treatment course The patient remained asymptomatic and did not require oxygen therapy at any point On PEXD #23 (hospital day 14, POD# 36), the patient was discharged home MMF was not restarted Tacrolimus and steroid taper were continued as scheduled Allograft function and chest imaging prior to discharge were normal Conclusions: Calcineurin inhibitors interfere with the cyclophilins and FKBP required by various coronaviridae for replication Along with steroids, they also dampen the cytokine storm The antiviral potential of calcineurin inhibitors and steroids warrants further investigation into their role as viable therapy for COVID-19

BackgroundHistorically, liver allografts with >30% macrosteatosis (MaS) on donor biopsy have been associated with early allograft dysfunction and worse graft survival; however, successful outcomes have been reported in small cohorts. This study proposes an elevated MaS threshold for organ utilization without detriment to graft survival.MethodsThe UNOS Standard Transplant Analysis and Research database was evaluated for transplants between 2006-2015. Graft survival up to 1-year was evaluated by Kaplan-Meier (KM) survival analyses, and by univariate and multivariable logistic regression analyses, including donor and recipient characteristics. Odds ratios (OR) with 95% confidence intervals (CI) for risk of graft loss are reported.ResultsThirty-day risk of graft loss was increased with MaS as low as 10-19% (OR [95% CI] 1.301 [1.055-1.605], pConclusionsIn conjunction with recipient selection, organs with MaS up to 50% may be safely used without detriment to outcomes.

Alcoholic hepatitis (AH) is a condition of acute liver inflammation in the setting of heavy alcohol use that is often managed with corticosteroids in severe cases. Among non-responders to steroids, however, prognosis is poor with up to 75% mortality within 6 months after treatment failure. Early liver transplantation (LT) can achieve an acceptable short-term survival, and initial studies have demonstrated 3-year survival rates of up to 84%. However, the practice of early LT in severe AH remains controversial with concerns over the 6-month rule of sobriety and risk of alcohol relapse post-transplant. Proponents of LT advocate for better understanding of alcohol use as a disorder rather than self-inflicted cause of illness, aim to redefine the misguided application of the 6-month rule, and point out similar relapse rates among patients with early LT and those with greater than 6 months abstinence before transplant. Opponents of LT emphasize the correlation between alcohol relapse and graft failure and mortality, public resistance and potential for distrust among donors, and arguments that transplant centers need to establish improved models to predict relapse and standardize candidate selection criteria across centers. Here we review recent literature on this controversy and provide recommendations for moving forward to consensus.

It is known that chronic kidney disease (CKD) is associated with increased postoperative morbidity and mortality in patients with peripheral artery disease who underwent lower extremity surgical revascularization; however, outcomes after peripheral vascular intervention (PVI) are less well established. This study sought to determine the impact of CKD on adverse outcomes in patients with peripheral artery disease who underwent PVI. Using data from the Veteran Affairs Clinical Assessment, Reporting, and Tracking System Program, we identified a cohort of 755 patients who underwent lower extremity PVI from June 2005 to August 2010 at 33 sites. The outcomes of interest were mortality, progression to dialysis, myocardial infarction, limb amputation, and stroke. Kaplan-Meier survival analysis and Cox proportional hazard frailty models assessed the association between CKD and adverse outcomes. Of the patients who underwent lower extremity PVI, 201 patients (27%) had CKD. The presence of CKD was associated with decreased survival (5-year survival probability of CKD compared with non-CKD: 49.9% [41.6% to 59.9%] vs 80.1% [76.2% to 84.1]), which persisted after risk adjustment (HR 1.57; 95% confidence interval 1.13 to 2.19). In addition, there was a significant association between CKD and progression to dialysis (HR 6.62; 95% confidence interval 2.25 to 19.43). In contrast, there was no association between CKD and re-hospitalization for myocardial infarction, limb amputation, or stroke. In conclusion, CKD is present in 1 of 4 patients who underwent PVI and is associated with increased risk of mortality and progression to dialysis.

ObjectivesChronic infection with hepatitis C virus (HCV) was previously the leading indication for liver transplant (LT) in the United States. However, since 2014 the use of direct-acting antivirals (DAAs) has decreased the chronic HCV burden, while the prevalence of nonalcoholic steatohepatitis (NASH) has risen substantially through the last decade. Both gender and ethnic disparities in indications for LT have been shown in the past but no data on this have been reported since the implementation of DAAs.MethodsWe assessed changes in etiologies for LT listing and in gender and ethnic differences in those listed for LT. Adult patients registered for LT in the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between January 1, 2004 and December 31, 2016 were included. Multinomial logistic regression modeling was used to test for changes in waitlist or liver transplant rates.ResultsThe study included 127,164 adult patients registered for LT. By 2016, alcoholic liver disease (ALD) was the leading etiology for waitlisting and LT; NASH was second; hepatocellular carcinoma (HCC) due to chronic HCV and chronic HCV alone were 3rd and 4th. NASH was the leading cause for LT for women and the 2nd leading cause for men (following ALD). NASH increased as the cause in all ethnic subgroups and was the leading cause in 2016 among Asian, Hispanic, and non-Hispanic white females. We also found that although the indication for liver transplant for hepatocellular carcinoma (HCC) due to HCV has increased over the years, this indication decreased for the first time between 2015 and 2016 in both males and females.ConclusionsNASH is currently the second leading cause for LT waitlist registration/liver transplantation overall, and in females, the leading cause. Given the rate of increase, NASH will likely rise to become the leading indication for LT in males as well.

Cirrhosis is a major cause of morbidity and mortality worldwide with liver transplantations as it only possible cure. In the face of a significant organ shortage many patients die waiting. A major complication of cirrhosis is the development of portal hypertension and ascites. The management of ascites has barely evolved over the last hundred years and includes only a few milestones in our treatment approach, but has overall significantly improved patient morbidity and survival. Our mainstay to ascites management includes changes in diet, diuretics, shunt procedures, and large volume paracentesis. The understanding of the pathophysiology of cirrhosis and portal hypertension has significantly improved in the last couple of decades but the changes in ascites management have not seemed to mirror this newer knowledge. We herein review the history of ascites management and discuss some its current limitations.

Objectives The purpose of this study was to examine the temporal trends in demographics, clinical characteristics, management strategies, and in-hospital outcomes in patients with acute myocardial infarction complicated by cardiogenic shock (CS-AMI) who underwent percutaneous coronary intervention (PCI) from the Cath-PCI Registry (2005 to 2013). Background The authors examined contemporary use and outcomes of PCI in patients with CS-AMI. Methods The authors used the Cath-PCI Registry to evaluate 56,497 patients (January 2005 to December 2013) undergoing PCI for CS-AMI. Temporal trends in clinical variables and outcomes were assessed. Results Compared with cases performed from 2005 to 2006, CS-AMI patients receiving PCI from 2011 to 2013 were more likely to have diabetes, hypertension, dyslipidemia, previous PCI, dialysis, but less likely to have chronic lung disease, peripheral vascular disease, or heart failure within 2 weeks (p Conclusions Our study shows that despite the evolution of medical technology and use of contemporary therapeutic measures, in-hospital mortality in CS-AMI patients who are managed invasively continues to rise. Additional research and targeted efforts are indicated to improve outcomes in this high-risk cohort.

Expression of genes associated with inflammation was analyzed during differentiation of human pluripotent stem cells (PSCs) to hepatic cells. Messenger RNA transcript profiles of differentiated endoderm (day 5), hepatoblast (day 15) and hepatocyte-like cells (day 21) were obtained by RNA sequencing analysis. When compared to endoderm cells an immature cell type, the hepatic cells (days 15 and 21) had significantly higher expression of acute phase protein genes including complement factors, coagulation factors, serum amyloid A and serpins. Furthermore, hepatic phase of cells expressed proinflammatory cytokines IL18 and IL32 as well as cytokine receptors IL18R1, IL1R1, IL1RAP, IL2RG, IL6R, IL6ST and IL10RB. These cells also produced CCL14, CCL15, and CXCL- 1, 2, 3, 16 and 17 chemokines. Endoderm cells had higher levels of chemokine receptors, CXCR4 and CXCR7, than that of hepatic cells. Sirtuin family of genes involved in aging, inflammation and metabolism were differentially regulated in endoderm and hepatic phase cells. Ligands and receptors of the tumor necrosis factor (TNF) family as well as downstream signaling factors TRAF2, TRAF4, FADD, NFKB1 and NFKBIB were differentially expressed during hepatic differentiation.

Background Changing opinions on the alcohol abstinence requirement have led to increased liver transplantation (LT) for alcoholic hepatitis (AH). We aimed to determine the trend in LT for AH in the United States and overall and graft survival rates. Methods Adult liver-alone and liver-kidney registrations added to the Organ Procurement and Transplantation Network waiting list between 2004 and 2018 were divided into 3 periods (2004-2009, 2010-2013, 2014-2018). Kaplan-Meier survival models illustrated patient and graft survival. Results Between 2004 and 2018, 529 AH patients were registered for and 254 received LT. By periods, 116, 73, and 340 patients were registered for and 49, 17, and 188 patients received LT, respectively, indicating a increase in LT for AH from 2014 to 2018. Yearly registrants from 2014 to 2018 were 32, 47, 51, 70, and 140, and recipients were 16, 24, 24, 38, and 88, respectively, indicating increases of 338% and 450% in registrants and recipients, respectively, since 2014. AH patients had the highest 1- and 3-year posttransplant survival (93.2% and 87.3%, respectively) and graft survival (90.4% and 84.8%, respectively) comparing to other LT recipients. Conclusions LT for AH in the United States is at an all-time high with an increased overall patient and graft survival.

Summary Background Infection is the most common cause of mortality in end-stage liver disease (ESLD). The impact of obesity on infection risk in ESLD is not established. Aim To characterise the impact of obesity on infection risk in ESLD. Methods We evaluated the association between infection and obesity in patients with ESLD. Patients grouped as non-obese, obesity class I–II and obesity class III were studied using the Nationwide Inpatient Sample. Validated diagnostic code based algorithms were utilised to determine weight category and infections, including bacteraemia, skin/soft tissue infection, urinary tract infection (UTI), pneumonia/respiratory infection, Clostridium difficile infection (CDI) and spontaneous bacterial peritonitis (SBP). Risk factors for infection and mortality were assessed using multivariable logistic regression analysis. Results Of 115 465 patients identified, 100 957 (87.5%) were non-obese and 14 508 (12.5%) were obese, with 9489 (8.2%) as obesity class I–II and 5019 (4.3%) as obesity class III. 37 117 patients (32.1%) had an infection diagnosis. Infection was most prevalent among obesity class III (44.0%), followed by obesity class I–II (38.9%) and then non-obese (31.9%). In multivariable modelling, class III obesity (OR = 1.41; 95% CI 1.32–1.51; P < 0.001), and class I–II obesity (OR = 1.08; 95% CI 1.01–1.15; P = 0.026) were associated with infection. Compared to non-obese patients, obese individuals had greater prevalence of bacteraemia, UTI, and skin/soft tissue infection as compared to non-obese patients. Conclusions Obesity is newly identified to be independently associated with infection in end-stage liver disease. The distribution of infection sites varies based on weight category.

Complete control of the hepatic vasculature is routine during liver transplantation and sometimes required in general surgical cases. Knowledge of approach and management to hepatic vasculature control can be lifesaving. This article offers our systematic approach to controlling hepatic vasculature, where these techniques can be applied in trauma, general surgical, and transplant settings.

Primary sclerosing cholangitis (PSC) patients suffer from comorbidities unaccounted for by the model for end-stage liver disease scoring system and may benefit from the increased donor organ pool provided by donation after cardiac death (DCD) liver transplantation. However, the impact of DCD transplantation on PSC graft outcomes is unknown.We studied 41,018 patients using the United Network for Organ Sharing database from 2002 through 2012. Kaplan-Meier analysis and Cox regression were used to evaluate graft survival and risk factors for graft failure, respectively.The PSC patients receiving DCD livers (n=75) showed greater overall graft failure (37.3% vs. 20.4%, P = 0.001), graft failure from biliary complications (47.4% vs. 13.9%, P = 0.002), and shorter graft survival time (P = 0.003), compared to PSC patients receiving donation after brain death organs (n=1592). Among DCD transplants (n=1943), PSC and non-PSC patients showed similar prevalence of graft failure and graft survival time, though a trend existed toward increased biliary-induced graft failure among PSC patients (47.4 vs. 26.4%, P = 0.063). Cox modeling demonstrated that PSC patients have a positive graft survival advantage compared to non-PSC patients (hazard ratio [HR]=0.72, P0.001), whereas DCD transplantation increased risk of graft failure (HR = 1.28, P0.001). Furthermore, the interaction between DCD transplant and PSC was significant (HR = 1.76, P = 0.015), indicating that use of DCD organs impacts graft survival more in PSC than non-PSC patients.Donation after cardiac death liver transplantation leads to significantly worse outcomes in PSC. We recommend cautious use of DCD transplantation in this population.

Deep venous thrombosis (DVT) occurs in 0.1% of persons per year, affecting 15%-40% of general surgical procedures without prophylaxis. Thromboembolic prophylaxis is not commonly used after orthotopic liver transplantation (LT) owing to the risks of bleeding and coagulopathy. Cirrhosis and the association with the coagulation cascade, before and after transplantation, are not well understood. The purpose of this study was to determine the incidence of DVT and its risk factors after LT.We retrospectively reviewed LTs performed at our center from 2005 to 2012. We identified patients with Doppler examinations showing DVT after LT, platelet count, and international normalized ratio (INR) at time of DVT, associated symptoms, DVT prophylaxis, and perioperative risk factors. We determined the incidence of DVT, the odds ratio of each preoperative risk factor, the difference in platelet count and INR between those with and without a DVT, and the weighted risk of each factor in the development of DVT with the use of logistic regression modeling.Of 314 patients, the incidence of DVT was 8.6% (27/314). Between those with and without DVT there was no significant difference in age, sex, platelet count, INR, infection, hepatocellular cancer, use of venous bypass, and prior surgery. There was a significant difference in mobility, 67% vs 20% (P .0001), and the use of factor VII, 11% vs 2% (P .05). The estimated risk for of developing DVT for patients with neither of these factors was 4%; with factor VII the risk rose to 17%; with mobility difficulty the risk rose to 23%; and with both the risk was 62%. In our entire population, there were no cases of pulmonary embolism.The risk of developing a DVT after LT is ≥9% even with mechanical DVT prophylaxis. Consideration should be given to using both mechanical and chemical prophylaxis after LT.

Background Ibrutinib is a Bruton's tyrosine Kinase (BTK) antagonist that inhibits B cell receptor (BCR) signaling. Complete BTK deficiency is associated with absence of B-cells. Ibrutinb is currently approved by FDA for treatment of B-cell malignancies, including Waldenstrom macroglobulinaemia. We recently carried out studies to determine if ibrutinib could modify alloantibody responses. Materials and methods A mouse model of allogenic sensitization using a C57BL/6 mouse as the recipient of a skin allograft from an HLA-A2 transgenic mouse was utilized to examine the effects of ibrutinib on alloantibody responses and B cell effector functions. Donor-specific antibody (DSA) levels were measured in a flow-cytometric antibody binding assay. Splenic T and B cell subsets and plasma cells were analyzed in flow cytometry. Results Control mice developed peak levels of DSA IgM at day 14 PTx while the ibrutinib treated mice had significantly lower levels of DSA IgM ( p = 0.0047). Control mice developed HLA.A2-specific IgG antibodies at day 14 (230 ± 60 MFI) and reached peak levels at day 21 (426 ± 61 MFI). In contrast, mice in the treatment group had low levels of HLA.A2-specific IgG at day 14 (109 ± 59 MFI, p = 0.004) and day 21 (241 ± 86 MFI, p = 0.003). FACS analysis found a reduction of B220 + or CD19 + B cell population ( p p + CD138 + plasma cells ( p Conclusions Ibrutinib is effective in suppressing alloantibody responses through blocking BTK-mediated BCR signaling, leading to reduction of B cells and short-lived plasma cells in the spleens. Use of ibrutinib may provide benefits to HLA-sensitized transplant patients for alloantibody suppression.

The Braden Scale is a standardized tool to assess pressure ulcer risk that is reported for all hospitalized patients in the United States per requirements of the Center for Medicare and Medicaid Services. Previous data have shown the Braden Scale can predict both frailty and mortality risk in patients with decompensated cirrhosis. Our aim was to evaluate the association of the Braden Scale score with short-term outcomes after liver transplantation (LT). We performed a retrospective cohort study of deceased donor LT recipients at 2 centers and categorized them according to the Braden Scale at hospital admission as low (>18), moderate (16-18), or high risk (

Background Preformed donor-specific human leukocyte antigen antibodies (DSAs) in patients undergoing simultaneous liver and kidney transplantation (SLKT) are an independent risk factor for poorer patient and renal allograft survival. The outcomes of patients highly sensitized (HS) against HLA antigens undergoing SLKT and select HS SLKT recipients undergoing desensitization at a high-volume desensitization center were investigated. Methods Seventy-five patients undergoing SLKT at a high-volume desensitization center between January 1, 2001, and December 31, 2015, were retrospectively reviewed. HS patients were defined by panel-reactive antibody (PRA) >30% (n = 17 patients), 11 of whom received pre- or perioperative desensitization with high-dose intravenous immunoglobulin (IVIG) ± rituximab. Results HS patients had significantly higher class I and class II PRA (class I = 41.3% ± 40.0% vs 2.5% ± 6.3%; class II = 45.7% ± 36.4% vs 1.0% ± 2.9%; P P = .05), and more likely to have had a prior transplant ( P = .03). HS patients demonstrated greater susceptibility to renal cell-mediated rejection (CMR) (23.5% vs 5.2%, P = .02) compared to nonsensitized patients. Higher renal antibody-mediated rejection (ABMR) was also observed in HS patients, 11.8% vs 3.4%, but did not reach significance ( P = .18). Desensitization in select HS SLKT patients was well tolerated but did not improve patient and allograft survival or significantly curtail rejection. Conclusion HS SLKT recipients demonstrated increased allograft rejection, particularly CMR, but patient and graft survival were not impacted in the first year post-transplant. Select HS SLKT patients tolerated desensitization with high-dose IVIG ± rituximab and may have received additional immunoprotection against ABMR but survival was not affected.

Background & Aims Liver transplantation for patients with acute-on-chronic liver failure (ACLF) with 3 or more failing organs (ACLF-3) is controversial. We compared liver waitlist mortality or removal according to model for end-stage liver disease (MELD) score vs ACLF category. We also studied factors associated with reduced odds of survival for 1 year after liver transplantation in patients with ACLF-3. Methods We analyzed data from the United Network for Organ Sharing (UNOS) from 2005 through 2016. We identified patients who were on the waitlist (100,594) and those who received liver transplants (50,552). Patients with ACLF were identified based on the European Association for the Study of the Liver-chronic liver failure criteria. Outcomes were evaluated with competing risks regression, Kaplan-Meier analysis, and Cox proportional hazards regression. Results Patients with ACLF-3 were more likely to die or be removed from the waitlist, regardless of MELD-sodium (MELD-Na) score, compared with the other ACLF groups; the proportion was greatest for patients with an ACLF-3 score and MELD-Na score below 25 (43.8% at 28 days). Mechanical ventilation at liver transplantation (hazard ratio [HR] 1.49; 95% confidence interval [CI] 1.22–1.84), donor risk index above 1.7 (HR 1.22; 95% CI 1.09–1.35), and liver transplantation within 30 days of listing (HR 0.89; 95% CI 0.81–0.98) were independently associated with survival for 1 year after liver transplantation Conclusions In an analysis of data from the UNOS registry, we found high mortality among patients with ACLF-3 on the liver transplant waitlist, even among those with lower MELD-Na scores. So, certain patients with ACLF-3 have poor outcomes regardless of MELD-Na score. Liver transplantation increases odds of survival for these patients, particularly if performed within 30 days of placement on the waitlist. Mechanical ventilation at liver transplantation and use of marginal organs were associated with increased risk of death.

The Share 35 policy for liver allocation prioritizes patients with Model for End-Stage Liver Disease (MELD) scores ≥ 35 for regional sharing of liver allografts. To better assess donor-recipient interactions and inform expectations, this study identified factors affecting graft survival independent of MELD score and derived a risk index for transplantation in the MELD ≥ 35 population.The United Network for Organ Sharing (UNOS) STAR database was evaluated for deceased donor liver transplants with recipients' MELD ≥ 35, between January 2006 and June 2016. Data were randomly split into test and validate cohorts. Four individual models of graft survival spanning 90 days to 5 years were evaluated with univariate and multivariate Cox proportional hazards analyses against donor- and recipient-specific characteristics. Significant factors were compiled to generate the Liver Transplant Survival Index (LTSI-35), and survival analyses were performed.Five risk groups (very low, low, moderate, high, and severe) were identified, with 1-year graft survival rates of 90.8% ± 0.2%, 89.3% ± 0.3%, 85.0% ± 0.3%, 79.8% ± 0.3%, and 70.3% ± 0.4% (p0.001 across groups), respectively. The greatest risk of graft loss was associated with donation after circulatory death (DCD) donors (1-year hazard ratio [HR] = 1.61 [95% CI 1.26 to 2.05], p = 0.001), recipients' requiring ventilator support (HR 1.32 [95% CI 1.17 to 1.51], p0.001), and recipient portal vein thrombosis (HR 1.21 [95% CI 1.03 to 1.42], p = 0.003). Subgroup analysis revealed increased risk of graft loss with graft macrosteatosis ≥ 30% on pre-donation biopsy at 90 days (HR 1.64 [1.33 to 1.99], p0.001).The LTSI-35 identifies risk factors for graft loss in a high-MELD population which, when combined, may portend worse outcomes. The LTSI-35 may be used to influence donor selection, organ allocation, and to inform expectations for allograft survival.

Purpose BCMA, a member of the tumor necrosis factor receptor superfamily (TNFRSF17), is selectively expressed during plasma cell differentiation while being nearly absent on naive and memory B cells. Therefore, BCMA appears as a highly selective antigen for mature B-cell targeting. The current study investigated BCMA expression by peripheral B cells and plasma cells during the development of de novo alloantibody responses. Methods A mouse model of allo-sensitization induced by skin allograft was used to study BCMA expression by B cell subsets and plasma cells. Blood samples were collected weekly for measurement of anti-HLA.A2 IgM and IgG titers. PBMCs and splenic lymphocytes were analyzed in FACS for identification of B cell subsets expressing surface BCMA. Splenic B-cells were isolated using EasySep B-cell isolation kit. mRNA expression of TNFRSF17 was studied in quantitative PCR. Results qPCR demonstrated a significant increase in TNFRSF17 mRNA expression by splenic B-cells isolated from HLA.A2 sensitized mice (p=0.004 vs. naive control). Multi-perimeter FACS analysis of splenic lymphocytic cells showed that cell surface BCMA (CD269) was expressed by the majority of CD38+CD138+ plasma cells (60-80%), and by members of CD19+CD23+sIgD+ mature B-cells. CD269 was scarcely expression by early transitional B-cells (CD93+/CD19+/CD23-). Following skin grafting BCMA was increasingly expressed on mature B cells and plasma cells at Days 14 (p=0.03 vs. naive control mice), 21(p=0.004) and 28(p=0.0001) PTx. Increase in BCMA expression by B cells was associated with high DSA IgG titers in the blood, indicating plasmablast differentiation. Conclusion Our data demonstrate that BCMA are increasingly expressed by B/plasma cells during the development of de novo alloantibody responses. Thus, targeting BCMA may serve as a new treatment strategy for desensitization in HLA highly sensitized transplant patients.

BackgroundCritically ill cirrhotics require liver transplantation urgently, but are at high risk for perioperative mortality. The Model for End-stage Liver Disease (MELD) score, recently updated to incorporate serum sodium, estimates survival probability in patients with cirrhosis, but needs additional evaluation in the critically ill. The purpose of this study was to evaluate the predictive power of ICU admission MELD scores and identify clinical risk factors associated with increased mortality.Study designThis was a retrospective review of cirrhotic patients admitted to the ICU between January 2011 and December 2014. Patients who were discharged or underwent transplantation (survivors) were compared with those who died (nonsurvivors). Demographic characteristics, admission MELD scores, and clinical risk factors were recorded. Multivariate regression was used to identify independent predictors of mortality, and measures of model performance were assessed to determine predictive accuracy.ResultsOf 276 patients who met inclusion criteria, 153 were considered survivors and 123 were nonsurvivors. Survivor and nonsurvivor cohorts had similar demographic characteristics. Nonsurvivors had increased MELD, gastrointestinal bleeding, infection, mechanical ventilation, encephalopathy, vasopressors, dialysis, renal replacement therapy, requirement of blood products, and ICU length of stay. The MELD demonstrated low predictive power (c-statistic 0.73). Multivariate analysis identified MELD score (adjusted odds ratio [AOR]= 1.05), mechanical ventilation (AOR= 4.55), vasopressors (AOR= 3.87), and continuous renal replacement therapy (AOR= 2.43) as independent predictors of mortality, with stronger predictive accuracy (c-statistic 0.87).ConclusionsThe MELD demonstrated relatively poor predictive accuracy in critically ill patients with cirrhosis and might not be the best indicator for prognosis in the ICU population. Prognostic accuracy is significantly improved when variables indicating organ support (mechanical ventilation, vasopressors, and continuous renal replacement therapy) are included in the model.

Antibodies targeting T cells and B cells are increasingly used for immunosuppression in clinical transplantation. However, the impact of T-cell depletion by antibodies on B-cell homeostasis is poorly understood. Using a mouse model of allosensitization with skin allograft, we investigated whether targeting T cells by anti-CD3ε alters peripheral B-cell homeostasis and alloantibody responses following B-cell depletion by anti-CD20. We found that anti-CD3ε induced a discrete B220(lo), but not a conventional B220(hi) subset, in the spleens of the allosensitized mice 14 days after anti-CD20 treatment. The splenic B220(lo) cells were refractory to anti-CD20 depletion. Flow cytometry revealed that the splenic B220(lo) cells were phenotypically similar to the B220(lo) AA4.1(+) CD23(-) sIgM(lo) sIgD(-) developing B cells (pre-B to immature B) normally presented in the bone marrow. Despite the presence of the splenic B220(lo) cells, mice treated with combined anti-CD3ε/CD20 produced limited alloantibodies in response to the primary skin allografts. Alloantibody production increased significantly in the mice following re-immunization by donor-specific splenocytes. We conclude that anti-CD3ε can induce an expansion of B220(lo) B cells in the spleens after B-cell depletion by anti-CD20. These B cells are not producing alloantibodies, but re-immunization of the mice with alloantigen leads to risk of alloantibody response.

BackgroundRecurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is rarely curable. However, in view of the advent of new treatments, it is critical that patients at high risk for recurrence are identified.MethodsPatients undergoing LT for HCC at a single centre between 2002 and 2010 were reviewed and data on clinical parameters and explant pathology were analysed to determine factors associated with HCC recurrence. All necrotic and viable tumour nodules were included in explant staging. All patients underwent LT according to the United Network for Organ Sharing (UNOS) Model for End-stage Liver Disease (MELD) tumour exception policies.ResultsLiver transplantation was performed in 122 patients with HCC during this period. Rates of recurrence-free survival in the entire cohort at 1 year and 3 years were 95% and 89%, respectively. Thirteen patients developed HCC recurrence at a median of 14 months post-LT. In univariate analysis the factors associated with HCC recurrence were bilobar tumours, vascular invasion, and stage exceeding either Milan or University of California San Francisco (UCSF) Criteria. Multivariate analysis showed pathology outside UCSF Criteria was the major predictor of recurrence; when pathology outside UCSF Criteria was found in combination with vascular invasion, the predicted 3-year recurrence-free survival was only 26%.ConclusionsExplant pathology can be used to predict the risk for recurrent HCC after LT, which may allow for improved adjuvant and management strategies.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the occurrence of HCC has more than doubled in the United States in the past decade. Early detection is considered key to reducing the mortality of HCC. Methods: Using two-dimensional gel electrophoresis and high-performance liquid chromatography we have analyzed the glycosylation of Apo-J from healthy controls, patients with liver cirrhosis, or those with HCC. Results: Apo-J in the serum from patients with HCC had decreased levels of (β-1,4) triantennary N-linked glycan compared with the healthy controls or patients with liver cirrhosis. We analyzed this change in an independent cohort of 76 patients with HCC, 32 with cirrhosis, and 43 infected with hepatitis C virus using the Datura stramonium lectin (DSL), which binds to (β-1,4) triantennary N-linked glycan. The level of DSL-reactive Apo-J allowed us to differentiate HCC from cirrhosis with an area under the receiver operating characteristic curve (AUROC) of 0.852. When Apo-J was combined with other serum biomarkers such as α-fetoprotein (AFP) and fucosylated kininogen by using a multivariate logistic regression model, the AUROC increased to 0.944, a value much greater than that observed with AFP alone (AUROC of 0.765). Conclusions: The glycosylation of Apo-J is a useful marker when used alone or in combination with outer makers for the early detection of HCC. Impact: The potential use of a combination of AFP, DSL-reactive Apo-J, and fucosylated kininogen as a biomarker of HCC would have great value in the management of patients with liver disease. Cancer Epidemiol Biomarkers Prev; 20(6); 1222–9. ©2011 AACR.

Biliary epithelia express high levels of CD44 in hepatobiliary diseases. The role of CD44-hyaluronic acid interaction in biliary pathology, however, is unclear. A rat model of hepatic cholestasis induced by bile duct ligation was employed for characterization of hepatic CD44 expression and extracellular hyaluronan distribution. Cell culture experiments were employed to determine whether hyaluronan can regulate cholangiocyte growth through interacting with adhesion molecule CD44. Biliary epithelial cells were found to express the highest level of CD44 mRNA among four major types of nonparenchymal liver cells, including Kupffer, hepatic stellate, and liver sinusoidal endothelial cells isolated from cholestatic livers. CD44-positive biliary epithelia lining the intrahepatic bile ducts were geographically associated with extracellular hyaluronan accumulated in the portal tracts of the livers, suggesting a role for CD44 and hyaluronan in the development of biliary proliferation. Cellular proliferation assays demonstrated that cholangiocyte propagation was accelerated by hyaluronan treatment and antagonized by small interfering RNA CD44 or anti-CD44 antibody. The study provides compelling evidence to suggest that proliferative biliary epithelia lining the intrahepatic bile ducts are a prime source of hepatic CD44. CD44-hyaluronan interaction, by enhancing biliary proliferation, may play a pathogenic role in the development of cholestatic liver diseases.

Background B cell depletion by anti-CD20 antibody is used in desensitization protocols and for treatment of antibody-mediated rejection (AMR). However, little is known about the efficacy and the mechanism(s) of action. Methods A mouse model of HLA sensitization was used to study the effectiveness of anti-CD20 treatment on B cell depletion and anti-HLA antibody suppression. Results Immunization of C57BL/6 mice with skin grafts from a transgenic C57BL.Tg/HLA-A2.1 mouse resulted in robust production of anti-HLA IgM and IgG antibodies, and accelerated rejection of a secondary skin allograft (within 3 days) featured by intragraft IgG and C4d deposition. Both IgM and IgG alloantibodies are specific to HLA-A2 as well as to a panel of class I HLA, including A1, A3, A25, A26, A29, and A30. These alloantibodies were complement-dependently cytotoxic (CDC) against HLA-A2 expressing target cells. Administration of 2 doses of a mouse–anti-mouse CD20 monoclonal antibody significantly reduced the levels of anti-HLA IgG2a antibodies, suppressed serum CDC, and prolonged survival of the secondary skin allografts. Suppression of anti-HLA IgG antibodies was associated with significant depletion of B220 + /CD5 − B cells from the blood, the spleen and the bone marrow of the treated animals. Conclusion Anti-CD20 treatment effectively depletes B220 + /CD5 − B cells, resulting in potent suppression of anti-HLA IgG and prolongation of skin graft survival. The data are in support for the use of anti-CD20 antibodies in highly-HLA sensitized patients undergoing desensitization and for the treatment of AMR.

Liver transplantation in patients infected with the human immunodeficiency virus (HIV) has been increasingly performed with reasonable outcomes; however, medical management of both immunosuppression and antiretroviral therapy can be challenging owing to drug toxicities and interactions. Nucleoside reverse transcriptase inhibitors (NRTIs), a common backbone of highly active antiretroviral therapy (HAART), were the first class of effective antiretroviral drugs developed. NRTIs are commonly used for posttransplant HAART therapy and have a rare but fatal complication of mitochondrial toxicity, manifesting as severe lactic acidosis, hepatic steatosis, and lipoatrophy. Herein, we have reported on the first known successful treatment of severe mitochondrial toxicity secondary to NRTIs in an HIV-infected transplant recipient.

Background More than 10,000 patients are awaiting liver transplantation, and more than 1300 die waiting yearly. The Share 35 policy was implanted 1 year ago with expectations to decrease waitlist mortality. The purpose of our study was to look at waitlist outcomes and organ usage. Methods We compared data from the United Network of Organ Sharing before and after the initiation of Share 35, looking at waitlist mortality, organs shared with Model for End-Stage Liver Disease (MELD) score ≥35, organ discards, travel distance, cold ischemia time, MELD score at transplantation, donor characteristics, and waitlist times. The χ 2 test was used to compare the data from two time periods. Results Comparing the 1-year periods, we found no change in waitlist mortality rate; transplants in MELD score ≥35 increased from 19% to 27% and decreased in MELD score15 to 34 from 74% to 67%; high-risk donors increased from 13% to 17%; and a 40% decrease in time on the waitlist before removal because of death from 58 to 35 days. Conclusions One year since Share 35, there has been no change in waitlist mortality rate. Unfortunately, it will take several years to know the impact of Share 35 on changes in patient life-years saved.