Outcome Of Orthotopic Liver Transplantation Research Articles

Clinical outcomes of liver transplantation in human immunodeficiency virus/hepatitis B virus coinfected patients in China

BackgroundHighly active antiretroviral therapy (HAART) has been able to improve the immune system function and survival of human immunodeficiency virus (HIV) patients. However, Patients coinfected with HIV and hepatitis B virus (HBV) are more likely to develop end-stage liver disease (ESLD) than those infected with HBV alone. Consequently, liver transplantation is often required for these patients. This study evaluates the outcomes of orthotopic liver transplantation (OLT) of HIV-HBV coinfected patients in China.MethodsWe conducted a retrospective analysis on all HIV-HBV coinfected patients that underwent OLT from April 1, 2019 to December 31, 2021 and their outcomes were compared to all HBV monoinfected patients undergoing OLT during the same period. Patient outcomes were determined, including cumulative survival, viral load, CD4 T-cell count and postoperative complications.ResultsThe median follow-up of HIV recipients was 36 months after OLT (interquartile range 12–39 months). Almost all patients had stable CD4 T-cell count (> 200 copies/ul), undetectable HBV DNA levels, and undetectable HIV RNA load during follow-up. The 1-, 2-, and 3-year posttransplant survival rates were 85.7% for the HIV group (unchanged from 1 to 3 years) versus 82.2%, 81.2%, and 78.8% for the non-HIV group. Cumulative survival among HIV-HBV coinfected recipients was not significantly different from the HBV monoinfected recipients (log-rank test P = 0.692). The percentage of deaths attributed to infection was comparable between the HIV and non-HIV groups (14.3% vs. 9.32%, P = 0.665). Post OLT, there was no significant difference in acute rejection, cytomegalovirus infection, bacteremia, pulmonary infection, acute kidney injury, de novo tumor and vascular and biliary complications.ConclusionsLiver transplantation in patients with HIV-HBV coinfection yields excellent outcomes in terms of intermediate- or long-term survival rate and low incidence of postoperative complications in China. These findings suggest that OLT is safe and feasible for HIV-HBV coinfected patients with ESLD.Trial registrationChinese Clinical Trial Registry (ChiCTR2300067631), registered 11 January 2023.

Cold stress-induced ferroptosis in liver sinusoidal endothelial cells determines liver transplant injury and outcomes.

Although cold preservation remains the gold standard in organ transplantation, cold stress-induced cellular injury is a significant problem in clinical orthotopic liver transplantation (OLT). Because a recent study showed that cold stress activates ferroptosis, a form of regulated cell death, we investigated whether and how ferroptosis determines OLT outcomes in mice and humans. Treatment with ferroptosis inhibitor (ferrostatin-1) during cold preservation reduced lipid peroxidation (malondialdehyde; MDA), primarily in liver sinusoidal endothelial cells (LSECs), and alleviated ischemia/reperfusion injury in mouse OLT. Similarly, ferrostatin-1 reduced cell death in cold-stressed LSEC cultures. LSECs deficient in nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of ferroptosis, were susceptible to cold stress-induced cell death, concomitant with enhanced endoplasmic reticulum (ER) stress and expression of mitochondrial Ca2+ uptake regulator (MICU1). Indeed, supplementing MICU1 inhibitor reduced ER stress, MDA expression, and cell death in NRF2-deficient but not WT LSECs, suggesting NRF2 is a critical regulator of MICU1-mediated ferroptosis. Consistent with murine data, enhanced liver NRF2 expression reduced MDA levels, hepatocellular damage, and incidence of early allograft dysfunction in human OLT recipients. This translational study provides a clinically applicable strategy in which inhibition of ferroptosis during liver cold preservation mitigates OLT injury by protecting LSECs from peritransplant stress via an NRF2-regulatory mechanism.

Liver transplantation for severe hepatic trauma: A multicenter analysis from the UNOS data set.

Orthotopic liver transplantation (OLT) is rarely indicated after hepatic trauma but it can be the only therapeutic option in some patients. There are scarce data analyzing the surgical outcomes of OLT after trauma. We used the UNOS data set to identify patients who underwent OLT for trauma from 1987 to 2022 and compared them to a cohort of patients transplanted for other indications. Cox proportional hazard and multivariable logistic regression analyses were performed to assess predictors of graft and patient survival. Seventy-two patients underwent OLT for trauma during the study period. Patients with trauma were more frequently on mechanical ventilation at the time of transplantation (26.4% vs. 7.6%, p < 0.001) and had a greater incidence of pretransplant portal vein thrombosis (12.5% vs. 4%, p = 0.002). Our 4:1 matched analysis showed that trauma patients had significantly shorter wait times, higher incidence of pretransplant portal vein thrombosis and prolonged length of stay. Trauma was associated with decreased overall graft survival (hazards ratio, 1.42; 95% confidence interval, 1.01-1.98), and increased length of stay ( p = 0.048). There were no significant differences in long-term patient survival. Unique physiological and vascular challenges after severe hepatic trauma might be associated with decreased graft survival in patients requiring liver transplantation. Prognostic and Epidemiological; Level III.

Dysfunctional Cori and Krebs cycle and inhibition of lactate transporters constitute a mechanism of primary nonfunction of fatty liver allografts

Orthotopic liver transplantation (OLT) is a lifesaving procedure. However, grafts may fail due to primary nonfunction (PNF). In the past, we demonstrated PNFs to be mainly associated with fatty allografts, and given its unpredictable nature, the development of a disease model is urgently needed. In an effort to investigate mechanism of fatty allograft-associated PNFs, we induced fatty liver disease in donor animals by feeding rats a diet deficient in methionine and choline (MCD). We performed OLT with allografts of different grades of hepatic steatosis and compared the results to healthy ones. We assessed liver function by considering serum biochemistries, and investigated genome wide responses following OLT of healthy and fatty allograft-associated PNFs. Furthermore, we performed immunohistochemistry to evaluate markers of oxidative stress and reperfusion injury, inflammation, glycolysis and gluconeogenesis, lactate transport, and its utilization as part of the Cori cycle. Strikingly, PNFs are strictly lipid content dependent. Nonetheless, a fat content of ≤17% and an increase in the size of hepatocytes of ≤11% (ballooning) greatly improved outcome of OLTs and the hepatic microcirculation. Mechanistically, PNFs arise from a dysfunctional Cori cycle with complete ablation of the lactate transporter SLC16A1. Thus, lipid-laden hepatocytes fail to perform gluconeogenesis via lactate reutilization, and the resultant hyperlactatemia and lactic acidosis causes cardiac arrhythmogenicity and death. Furthermore, the genomic and immunohistochemistry investigations underscore a dysfunctional Krebs cycle with impaired energy metabolism in lipid-burdened mitochondria. Together, we show fatty allografts to be highly vulnerable towards ischemia/reperfusion-injury, and stabilizing the Cori cycle is of critical importance to avert PNFs.

T Cell CEACAM1–TIM-3 Crosstalk Alleviates Liver Transplant Injury in Mice and Humans

Carcinoembryonic antigen-related cell adhesion molecule 1 (CC1) acts through homophilic and heterophilic interactions with T cell immunoglobulin domain and mucin domain-containing protein 3 (TIM-3), which regulates innate immune activation in orthotopic liver transplantation (OLT). We investigated whether cluster of differentiation (CD) 4+ T cell-dependent CC1-TIM-3 crosstalk may affect OLT outcomes in mice and humans. Wild-type (WT) and CC1-deficient (CC1 knock-out [KO]) mouse livers were transplanted into WT, CC1KO, or T-cell TIM-3 transgenic (TIM-3Tg)/CC1KO double-mutant recipients. CD4+ T cells were adoptively transferred into T/B cell-deficient recombination activating gene 2 protein (Rag2) KO recipients, followed by OLT. The perioperative liver-associated CC1 increase was analyzed in 50 OLT patients. OLT injury in WT livers deteriorated in CC1KO compared with CC1-proficient (WT) recipients. The frequency of TIM-3+CD4+ T cells was higher in WT than CC1KO hosts. Reconstitution of Rag2KO mice with CC1KO-T cells increased nuclear factor (NF)-κB phosphorylation and OLT damage compared with recipients repopulated with WT T cells. T-cell TIM-3 enhancement in CC1KO recipients (WT→ TIM3Tg/CC1KO) suppressed NF-κB phosphorylation in Kupffer cells and mitigated OLT injury. However, TIM-3-mediated protection was lost by pharmacologic TIM-3 blockade or an absence of CC1 in the donor liver (CC1KO→ TIM-3Tg/CC1KO). The perioperative CC1 increase in human OLT reduced hepatocellular injury, early allograft dysfunction, and the cumulative rejection rate. This translational study identifies T cell-specific CC1 signaling as a therapeutic means to alleviate OLT injury by promoting T cell-intrinsic TIM-3, which in turn interacts with liver-associated CC1 to suppress NF-κB in Kupffer cells. By suppressing peritransplant liver damage, promoting T-cell homeostasis, and improving OLT outcomes, recipient CC1 signaling serves as a novel cytoprotective sentinel.

A narrative review and expert recommendations on the assessment of the clinical manifestations, follow-up, and management of post-OLT patients with ATTRv amyloidosis.

Orthotopic liver transplantation (OLT) was the first treatment able to modify the natural course of hereditary transthyretin (ATTRv) amyloidosis, which is a rare and fatal disorder caused by the accumulation of misfolded transthyretin (TTR) variants in different organs and tissues and which leads to a progressive and multisystem dysfunction. Because the liver is the main source of TTR, OLT dramatically reduces the production of the pathogenic TTR variant, which should prevent amyloid formation and halt disease progression. However, amyloidosis progression may occur after OLT due to wild-type TTR deposition, especially in the nerves and heart. In this review, we discuss the disease features influencing OLT outcomes and the clinical manifestations of ATTRv amyloidosis progression post-OLT to improve our understanding of disease worsening after OLT and optimize the follow-up and clinical management of these patients. By conducting a literature review on the PubMed database, we identified patient characteristics that have been associated with worse post-OLT outcomes, including late-onset V50M and non-V50M variants, age >40 years, long disease duration, advanced neuropathy and autonomic dysfunction, and malnutrition. Regarding post-OLT mortality, deaths occurring within the first year after OLT were mainly associated with fatal graft complications and infectious diseases, whereas cardiovascular-related deaths usually occurred later. Considering the diverse clinical manifestations of ATTRv amyloidosis progression post-OLT, including worsening neuropathy and/or cardiomyopathy, autonomic dysfunction, and oculoleptomeningeal involvement, we present advice on the most relevant tests for assessing disease progression post-OLT. Finally, we discuss the use of new therapies based on TTR stabilizers and TTR mRNA silencers for the treatment of ATTRv amyloidosis patients post-OLT.

Outcomes of Liver Transplantation in Patients With Preexisting Coronary Artery Disease.

Advances in surgical and medical technology over the years has made liver transplantation possible for older and higher risk patients. Despite rigorous preoperative cardiac testing, cardiovascular events remain a major cause of death after orthotopic liver transplantation (OLT). However, there are little data on the outcomes of OLT in patients with preexisting coronary artery disease (CAD). This study aimed to compare all-cause and cardiovascular mortality of patients with and without history of CAD undergoing OLT. Six hundred ninety-three adult patients with cirrhosis underwent liver transplantation between July 2013 and December 2018 (female n = 243, male n = 450; median age 59). During the study period of 5 y (median follow-up, 24.1 mo), 92 of 693 patients (13.3%) died. All-cause mortality in the CAD group was significantly higher than in the non-CAD group (26.7% versus 9.6%; P <0.01). Cardiovascular events accounted for 52.5% of deaths (n = 21) in patients with CAD compared with 36.5% (n = 19) in non-CAD patients. At 6 mo, patients with combined nonalcoholic steatohepatitis (NASH)/CAD had significantly worse survival than those with CAD or NASH alone ( P <0.01). After 6 mo, patients with CAD alone had similar survival to those with combined NASH/CAD. Patients with preexisting CAD before liver transplantation are at higher risk of death from any cause, specifically cardiovascular-related death. This risk increases with coexisting NASH. The presence of NASH and CAD at the time of liver transplant should prompt the initiation of aggressive risk factor modification for patients with CAD.

Intraoperative and postoperative impact of pretransplantation transjugular intrahepatic portosystemic shunts in orthotopic liver transplantations: A systematic review and meta-analysis.

Orthotopic liver transplantation (OLT) remains the definitive treatment for patients afflicted with end-stage liver disease (ESLD). Transjugular intrahepatic portosystemic shunts (TIPS) have been adapted as a bridge to transplantation, allowing partial normalization of portal pressure and associated symptom improvement. Conflicting evidence exists on TIPS' impact on operative procedures. This study aimed to analyze available evidence on patients who underwent OLT with prior TIPS compared to OLT alone with the intent to determine TIPS' impact on surgical outcomes. Following PRISMA guidelines, a systematic review was conducted, identifying studies comparing TIPS + OLT versus OLT alone in patients with ESLD. Data were analyzed using Review Manager 5.3. Thirteen studies were included. Operative time, packed red blood cells transfusions, intensive care unit admission, length of stay, dialysis, serum creatinine levels, ascites, vascular complications, bleeding revisions, reintervention, and other complications rates were similar between both groups. Fresh frozen plasma transfusion -2.88 units (-5.42, -0.35; p= 0.03), was lower in the TIPS + OLT group. Our study found TIPS can be safely employed without having detrimental impacts on OLT outcomes, furthermore, these findings also suggest TIPS does not increase bleeding or complications.

Liver Transplantation in the Elderly: An Updated Review of 55,267 Patients in the United States

Introduction: Liver transplantation in the elderly is regarded with caution due to increased morbidity. This study assesses the postoperative outcomes of orthotopic liver transplantation (OLT) in elderly patients.

Liver Transplantation for Neuroendocrine Metastases

Neuroendocrine tumor (NET) metastasis localized to the liver is an accepted indication for liver transplantation as such tumors have a low biological aggressiveness in terms of malignancy and are slow growing. Moreover, the long-term results are comparable with and in some cases even better than those of transplantations performed for primary liver cancer. However, compared with nonmalignant conditions, neuroendocrine liver metastasis (NELM) may result in an inferior outcome of transplantation. In the face of the scarcity of donated organs and recent improved results of non-surgical treatment for NELM, controversy over patient selection and timing for liver transplantation continues. In this review, we provide an overview of the diagnostic workup and selection criteria of patients with NELM being considered for liver transplantation. Thereafter, we provide a critical analysis of the reported outcomes of orthotopic liver transplantation.

Long-term Outcome of Orthotopic Liver Transplantation in Patients With Hemochromatosis: A Summary of a 30-year Transplant Program.

Background.Hemochromatosis (HC) is an autosomal recessive disease characterized by impaired iron metabolism and a rare indication for orthotopic liver transplantation (LT). Data about iron reaccumulation and remodeling of the liver graft after LT are limited. Therefore, we performed an evaluation of the histopathologic changes during long-term follow-up in patients with HC.Methods.A retrospective analysis of patients undergoing LT at our center between 1990 and 2016 identified 29 patients with HC. End points were the evaluation of post-LT iron reaccumulation and the stage of fibrosis as well as the degree of inflammation of the liver graft. Secondary end points were patient survival and postoperative complications.Results.The median age was 52.7 y, and there were more male (82.8%) than female patients (17.2%). Post-LT serum ferritin values (>1000 μg/L) were only temporarily elevated in 2 patients. The median estimated survival after LT was 45.5 mo (0.1–285.9 mo). Twenty patients (69%) died during follow-up of 10 y. The survival of patients with HC was significantly worse (P = 0.001) when compared with the overall cohort of patients undergoing LT because of to other causes.Conclusions.There was no significant iron overload detected in patients with HC after LT, and only minimal iron deposits were described in liver biopsies. Nevertheless, patients suffering from HC show a lower post-LT survival when compared with patients without iron storage disease but mostly because of extrahepatic causes.

Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury.

Although CEACAM1 (CC1) glycoprotein resides at the interface of immune liver injury and metabolic homeostasis, its role in orthotopic liver transplantation (OLT) remains elusive. We aimed to determine whether/how CEACAM1 signaling may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. In the mouse, donor liver CC1 null mutation augmented IRI-OLT (CC1-KO→WT) by enhancing ROS expression and HMGB1 translocation during cold storage, data supported by in vitro studies where hepatic flush from CC1-deficient livers enhanced macrophage activation in bone marrow-derived macrophage cultures. Although hepatic CC1 deficiency augmented cold stress-triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI and improved OLT survival by suppressing p-p38 upregulation, ROS induction, and HMGB1 translocation (CC1-KO→WT), whereas ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in 60 human donor liver biopsies correlated negatively with activation of the ASK1/p-p38 axis, whereas low CC1 levels associated with increased ROS and HMGB1 translocation, enhanced innate and adaptive immune responses, and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of the independent predictors for early allograft dysfunction (EAD) in human OLT patients. Thus, as a checkpoint regulator of IR stress and sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.

Impact of Hepatic Artery Variations and Reconstructions on the Outcome of Orthotopic Liver Transplantation

BackgroundDonor variational arteries often require complex reconstruction.MethodsWe analysed the incidence of different variations, types of arterial reconstructions and their impact on post-operative results from 409 patients undergoing liver transplantation at Karolinska Institute between 2007 and 2015.ResultsA total of 292 (71.4%) liver grafts had a standard hepatic artery (SHA), and 117 (28.6%) showed hepatic artery variants (HAV). 58% of HAV needed reconstruction. The main variations were variant left hepatic artery (45.3%) from the gastric artery; variant right hepatic artery (38.5%); and a triple combination of variant right and left hepatic artery and the proper hepatic artery from the common hepatic artery (12.8%); other 3.4%. Patients/graft survival and arterial complications were not different between SHA and HAV. Incidence of biliary stricture was numerically higher in left hepatic artery variants (p = 0.058) and in variants where no arterial reconstruction was performed (p = 0.001). Operation and arterial warm ischaemia time were longer in the HAV group. The need for intraoperative re-reconstruction was higher in the HAV group (p = 0.04). Intraoperative bleeding was larger after back-table reconstruction than with intraoperative reconstruction (p = 0.04).ConclusionNo overall differences were found between the HAV and the SHA groups. Occurrence of a variant left hepatic artery and HAV with no reconstruction seems to increase the risk of biliary strictures.

The Viability Of Liver Transplantation In Patients Age 70 And Older: An Updated Review

Presenter: Krishnaraj Mahendraraj MD | Cedars-Sinai Medical Center Background: Liver transplantation in the elderly has been regarded with caution due to lower survival and increased morbidity. In this study, postoperative outcomes of orthotopic liver transplantation (OLT) in patients age 70 and older are compared to younger cohorts to assess its safety and efficacy. Methods: Data on 55,267 OLT recipients were abstracted from the Scientific Registry of Transplant Recipients (SRTR) over a 10 year period (2007-2017). Three age-based subgroups were created: elderly (age 70 and over), middle-age (age 50-69), and young (age 18-49). Pediatric recipients (age < 18) were excluded. Standard statistical analysis was performed using donor and recipient data to compare indications, mortality and graft survival. Results: There were 1,622 elderly OLT patients (2.9%), compared to 40,271 middle-age patients (72.9%) and 13,374 young patients (24.2%). Significantly fewer elderly patients had a BMI>30 compared to other groups (26.6% vs. 37.2% and 33.4%, p<0.01). The median MELD-Na score of elderly patients was significantly lower (18.4 vs. 21.6 and 27.2, p<0.01), with 63.8% elderly patients being MELD < 20. Most elderly patients received OLT for hepatocellular carcinoma (HCC)-exception status (665 patients; 41%). Fewer elderly patients were Status 1. They had a significantly lower pretransplant INR and bilirubin, and higher albumin. Elderly patients spend a significantly longer time on the waitlist, and tended to receive organs from older age donors. Elderly patients received organs from donors with higher rates of diabetes, hypertension, history of malignancy and macrosteatosis. Elderly patients also received a higher proportion of DCD and ECD organs. Elderly patients had lower overall survival (66.15% vs. 71.4% and 71.7%) and lower graft survival (68.4% vs. 73.9% and 75.7%), p<0.01. There were more graft complications observed in the elderly including hepatic artery thrombosis, infection, primary non-function, primary graft failure and vascular thrombosis, but these were not statistically significant. Elderly patients had a significantly lower 6-month (6.9%) and 1-year (8.7%) rejection rate compared to other groups (12% and 14%, respectively). Kaplan-Meier survival analysis of 5-year graft survival was 3.98 years in the elderly compared to 4.03 years in middle-age and 4.76 years in young recipients, p<0.001. There was no significant difference between survival estimates of elderly patients with HCC vs. non-HCC. Conclusion: Elderly OLT recipients tended to be in a better state of health at the time of transplant, and tended to wait longer for donor organs with more marginal characteristics. Despite having a significantly lower overall and graft survival rate, this difference (less than 5%) was not clinically significant. These Results suggest that OLT is a safe and viable treatment for the elderly, even when using marginal donor organs.

Antibiotic pretreatment alleviates liver transplant damage in mice and humans.

Although modifications of gut microbiota with antibiotics (Abx) influence mouse skin and cardiac allografts, its role in orthotopic liver transplantation (OLT) remains unknown. We aimed to determine whether and how recipient Abx pretreatment may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. Mice (C57BL/6) with or without Abx treatment (10 days) were transplanted with allogeneic (BALB/c) cold-stored (18 hours) livers, followed by liver and blood sampling (6 hours). We divided 264 human OLT recipients on the basis of duration of pre-OLT Abx treatment into control (Abx-free/Abx <10 days; n = 108) and Abx treatment (Abx ≥10days; n = 156) groups; OLT biopsy (Bx) samples were collected 2 hours after OLT (n = 52). Abx in mice mitigated IRI-stressed OLT (IRI-OLT), decreased CCAAT/enhancer-binding protein homologous protein (CHOP) (endoplasmic reticulum [ER] stress), enhanced LC3B (autophagy), and inhibited inflammation, whereas it increased serum prostaglandin E2 (PGE2) and hepatic PGE2 receptor 4 (EP4) expression. PGE2 increased EP4, suppressed CHOP, and induced autophagosome formation in hepatocyte cultures in an EP4-dependent manner. An EP4 antagonist restored CHOP, suppressed LC3B, and recreated IRI-OLT. Remarkably, human recipients of Abx treatment plus OLT (Abx-OLT), despite severe pretransplantation clinical acuity, had higher EP4 and LC3B levels but lower CHOP levels, which coincided with improved hepatocellular function (serum aspartate aminotransferase/serum aspartate aminotransferase [sALT/sAST]) and a decreased incidence of early allograft dysfunction (EAD). Multivariate analysis identified "Abx-free/Abx <10 days" as a predictive factor of EAD. This study documents the benefits of Abx pretreatment in liver transplant recipients, identifies ER stress and autophagy regulation by the PGE2/EP4 axis as a homeostatic underpinning, and points to the microbiome as a therapeutic target in OLT.

Potential value and limitations of different clinical scoring systems in the assessment of short- and long-term outcome following orthotopic liver transplantation.

BackgroundIn an attempt to further improve liver allograft utilization and outcome in orthotopic liver transplantation (OLT), a variety of clinical scoring systems have been developed. Here we aimed to comparatively investigate the association of the Balance-of-Risk (BAR), Survival-Outcomes-Following-Liver-Transplant (SOFT), Preallocation-Survival-Outcomes-Following-Liver-Transplant (pSOFT), Donor-Risk-Index (DRI), and the Eurotransplant-Donor-Risk-Index (ET-DRI) scores with short- and long-term outcome following OLT.MethodsWe included 338 consecutive patients, who underwent OLT in our institution between May 2010 and November 2017. For each prognostic model, the optimal cutoff values were determined with the help of the Youden-index and their diagnostic accuracy for 90-day post OLT-mortality and major postoperative complications was measured by the area under the receiver operating characteristic curve (AUROC). Patient- and graft survival were analyzed using the Kaplan-Meier method and the log-rank test. Morbidity was assessed using the Clavien-Dindo classification and the Comprehensive-Complication-Index.ResultsBAR, SOFT, and pSOFT performed well above the conventional AUROC-threshold of 0.70 with good prediction of early mortality. Only BAR showed AUC>0.70 for both mortality and major morbidity. With the cutoffs of 14, 31, and 22 respectively for BAR, SOFT, and pSOFT, subgroup analysis showed significant differences (p<0.001) in morbidity and mortality, length of intensive care- and hospital-stay and early allograft dysfunction rates. Five-years patient survival was inferior in the high BAR, pSOFT, and SOFT groups.ConclusionsOut of all scores tested, the BAR-score had the best value in predicting both 90-day morbidity and mortality after OLT showing the highest AUCs. The pSOFT and SOFT scores demonstrated an acceptable accuracy in predicting 90-day morbidity and mortality. The used BAR, SOFT, and pSOFT cutoffs allowed the identification of patients at risk in terms of five-year patient survival. The DRI and ET-DRI scores have failed to predict recipient outcomes in the present setting.

Blockade targeting Cd47 reduces iri and improves survival in liver transplantation model

Introduction: Orthotopic liver transplantation (OLT) is currently the elective treatment for advanced liver cirrhosis and acute liver failure. Ischemia/reperfusion (IRI) injury may jeopardize graft function during the postoperative period. Treatment with anti-CD47 antibodies(CD47mAbs) has demonstrated cytoprotective properties in different experimental models of ischemia and liver injury, however, there is no evidence to demonstrate its potential use in the prevention of the ischemia/reperfusioninjury that occurs during OLT. The present study is the first report to show that the administration of CD47mAbs to donors and recipients provide benefits OLT outcomes. Method: We tested the cytoprotective effect of a CD47mAb 400, administered to the donor prior to OLT or to both the donor and to recipient during OLT in ansyngeneic experimental model in the Lewis rat. Serum transaminase levels,histopathological changes, proinflammatory cytokines,cell death parameters, oxidative and nitrosative stress, and animal survival were Hepatic histology, serum transaminase levels, pro-inflammatory cytokines,celldeath parameters, oxidative and nitrosative stress, and animal survival were analyzed. Result: Our data showed that CD47mAb antibody administration to donors reduced the level of transaminases and to both the donor and recipient not only reduced the level of transaminases, but also increased animal survival,and reduced hepatocellular injury, as well as oxidative and nitrosative stress. These beneficial effects, related to reduced caspase-3 activity and diminished IL-1b, IL-6 and TNF-a expression in vivo together with IL-6 upregulation in vivo. Conclusion: The administration of a CD47mAb to donors or to both the donor and to recipien in an experimental rat model of OLT reduced indices of ischemia/reperfusion injury. Treatment of both the donor organ and the recipient provided better protection that treating the donor organ alone and also improved survival following transsplantation.

Emerging Innovations in Liver Preservation and Resuscitation

The availability of marginal liver grafts represents a potential resource of orthotopic liver transplantation (OLT) in the era of organ shortage. However, an increased susceptibility to ischemia-reperfusion injury results in the increased risk for primary nonfunction and biliary complications. Novel methods of organ preservation and resuscitation are under investigation to improve outcomes of OLT with the use of marginal grafts. Machine perfusion (MP) in OLT is categorized based on the temperature setting. Hypothermic MP minimizes oxygen demand and uses single- or dual-vessel infusion with or without oxygenation. Normothermic MP increases the metabolic rate to the physiologic level, and requires dual-vessel infusion with a higher blood flow rate with oxygenation typically by blood as an oxygen carrier. Midthermic or subnormothermic MP uses medium temperature settings to allow metabolic activity to maintain cellular integrity as well as decrease oxygen demand. Since 2010, a total of 9 clinical trials have investigated the safety and feasibility of hypothermic and normothermic MP. The results suggest that the incidence of primary nonfunction was minimal even when marginal grafts were used. Organ preservation time could be reasonably increased. MP offers an opportunity to assess the viability and time to apply therapeutic interventions. This review highlights the history of MP, mechanisms of different temperature settings in MP, and recent large animal studies and clinical trials in OLT.

Liver Transplantation in Patients With Hepatocellular Carcinoma Outside the Milan Criteria After Downstaging: Is It Worth It?

BackgroundThe outcome of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) is excellent if it is performed within the Milan criteria (ie, single tumor less than 5 cm or 3 tumors less than 3 cm each one and no macrovascular invasion). However, after a few studies, it has become possible to have a similar survival expanding those criteria. The aim of this study is to evaluate the survival of patients with advanced HCC who, after downstaging, did not met the Milan criteria although they were within the “up to seven” benchmark, and were transplanted at our center in the last 5 years. Patients and MethodsThis is a retrospective study of patients who underwent OLT for HCC in the last 5 years in our center exceeding Milan criteria despite remaining within the “up to seven” benchmark. An observational study of associated factors with overall survival based on patient characteristics after OLT was performed. For the statistical study, the statistical program SPSS v. 17.0 (Chicago, Illinois, United States) was used. ResultsWe studied 95 patients who had been transplanted for HCC in this period, 11 of whom met the study requirements. There were 10 (91%) males and 1 female. The mean age of the patients was 54.73 ± 8.75 years, with an average waiting list time of 279 days. Nine patients had a Child A status, with a mean Model for End-stage Liver Disease score of 9.64 (range, 6 to 16). The most frequent etiology of cirrhosis was hepatitis C virus infection in 6 patients (50%) followed by hepatitis B virus infection and ethanolic and cryptogenic cirrhosis. Ten patients (91%) had at least one pretransplantation transarterial chemoembolization. The survival of patients after 1 year was 75%, whereas after 4 years that rate decreases to 25%. At this time, we do not have any patients with a 5-year survival rate. The longest survival rate is 55 months. ConclusionsAlthough the expanded indication of transplantation in HCC raises controversies, especially after downstaging, it is possible to provide acceptable survival rates for patients within the expanded criteria of “up to seven” after locoregional therapies. The performance of a liver transplant in the patient profile shown in this article should also be evaluated from the perspective of the relative lack of organs for transplantation.

Diagnosis of morbid obesity may not impact healthcare utilization for orthotopic liver transplantation: A propensity matched study.

AIMTo study mortality, length of stay, and total charges in morbidly obese adults during index hospitalization for orthotopic liver transplantation.METHODSThe Nationwide Inpatient Sample was queried to obtain demographics, healthcare utilization, post orthotopic liver transplantation (OLT) complications, and short term outcomes of OLT performed from 2003 to 2011 (n = 46509). We divided patients into those with [body mass index (BMI) ≥ 40] and without (BMI < 40) morbid obesity. Multivariable logistic regression analysis was performed to characterize differences in in-hospital mortality, length of stay (LOS), and charges for OLT between patients with and without morbid obesity after adjusting for significant confounders. Additionally, propensity matching was performed to further validate the results.RESULTSOf the 46509 patients who underwent OLT during the study period, 818 (1.8%) were morbidly obese. Morbidly obese recipients were more likely to be female (46.8% vs 33.4%, P = 0.002), Caucasian (75.2% vs 67.8%, P = 0.002), in the low national income quartile (32.3% vs 22.5%, P = 0.04), and have ≥ 3 comorbidities (modified Elixhauser index; 83.9% vs 45.0%, P < 0.001). Morbidly obese patient also had an increase in procedure related hemorrhage (P = 0.028) and respiratory complications (P = 0.043). Multivariate and propensity matched analysis showed no difference in mortality (OR: 0.70; 95%CI: 0.27-1.84, P = 0.47), LOS (β: -4.44; 95%CI: -9.93, 1.05, P = 0.11) and charges for transplantation (β: $15693; 95%CI: -51622-83008, P = 0.64) between the two groups. Morbidly obese patients were more likely to have transplants on weekdays (81.7%) as compared to those without morbid obesity (75.4%, P = 0.029).CONCLUSIONMorbid obesity may not impact in-hospital mortality and health care utilization in OLT recipients. However, morbidly obese patients may be selected after careful assessment of co-morbidities.