Detrimental impact of immunosuppressive burden on clinical course in patients with Cytomegalovirus infection after liver transplantation.

INTRODUCTION: Cytomegalovirus (CMV)-infection and reactivation remain a relevant complication after liver transplantation (LT). The recipient and donor serum CMV-IgG-status has been established for risk stratification when choosing various pharmaceutical regimens for CMV-prophylaxis in the last two decades. However, factors influencing course of CMV-infection in LT remain largely unknown. In this study, the impact of immunosuppressive regimen was examined in a large cohort of patients. METHODS: All patients that underwent primary LT between 2006 and 2018 at the Charité-Universitaetsmedizin, Berlin, were included. Clinical course as well as histological and laboratory findings of patients were analyzed our prospectively maintained database. Univariate and multivariate regression analysis for impact of variables on CMV-occurrence was conducted, and survival was examined using Kaplan-Meier analysis. RESULTS: Overall, 867 patients were included in the final analysis. CMV-infection was diagnosed in 325 (37.5%) patients after transplantation. Significantly improved overall survival was observed in these patients (Log rank = 0.03). As shown by correlation and regression tree classification and regression tree analysis, the recipient/donor CMV-IgG-status with either positivity had the largest influence on CMV-occurrence. Analysis of immunosuppressive burden did not reveal statistical impact on CMV-infection, but statistically significant inverse correlation of cumulative tacrolimus trough levels and survival was found (Log rank < .001). Multivariate analysis confirmed these findings (p = .02). DISCUSSION: CMV-infection remains of clinical importance after LT. Undergone CMV-infection of either recipient or donor requires prophylactic treatment. Additionally, we found a highly significant, dosage-dependent impact of immunosuppression (IS) on long-term outcomes for these patients, underlying the importance of minimization of IS in liver transplant recipients.

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

BACKGROUND: Pre-transplant deceased donor liver biopsy may impact decision making; however, interpretation of the results remains variable and depends on accepting center practice patterns. METHODS: In this cohort study, adult recipients from 04/01/2015-12/31/2020 were identified using the UNOS STARfile data. The deceased donor liver biopsies were stratified by risk based on degree of fibrosis, macrovesicular fat content, and level of portal infiltration (low-risk: no fibrosis, no portal infiltrates, and <30% macrosteatosis; moderate-risk: some fibrosis or mild infiltrates and <30% macrosteatosis; high-risk: most fibrosis, moderate/marked infiltrates, or ≥30% macrosteatosis). Graft utilization, donor risk profile, and recipient outcomes were compared across groups. RESULTS: Of the 51,094 donor livers available, 20,086 (39.3%) were biopsied, and 34,606 (67.7%) were transplanted. Of the transplanted livers, 14,908 (43.1%) were biopsied. The transplanted grafts had lower mean macrovesicular fat content (9.3% transplanted vs. 26.9% non-transplanted, P < 0.001) and less often had any degree of fibrosis (20.9% vs. 39.9%, P < 0.001) or portal infiltration (51.3% vs. 58.2%, P < 0.001) versus non-transplanted grafts. Post-transplant recipient LOS (14.2 days high-risk vs. 15.2 days low-risk, P = 0.170) and 1-year graft survival (90.5% vs. 91.7%, P = 0.137) did not differ significantly between high- versus low-risk groups. Kaplan-Meier survival estimates further revealed no differences in the 5-year graft survival across risk strata (P = 0.833). Of the 5178 grafts biopsied and turned down, PSM revealed 1338 (26.0%) were potentially useable based on biopsy results and donor characteristics. CONCLUSION: Carefully matched deceased donor livers with some fibrosis, inflammation, or steatosis ≥30% may be suitable for transplantation. Further study of this group of grafts may decrease turndowns of potentially useable organs.

From morbidity reduction to cost-effectiveness: Enhanced recovery after surgery (ERAS) society recommendations in minimal invasive liver surgery.

PURPOSE: Minimal-invasive liver surgery (MILS) reduces surgical trauma and is associated with fewer postoperative complications. To amplify these benefits, perioperative multimodal concepts like Enhanced Recovery after Surgery (ERAS), can play a crucial role. We aimed to evaluate the cost-effectiveness for MILS in an ERAS program, considering the necessary additional workforce and associated expenses. METHODS: A prospective observational study comparing surgical approach in patients within an ERAS program compared to standard care from 2018-2022 at the Charité - Universitätsmedizin Berlin. Cost data were provided by the medical controlling office. ERAS items were applied according to the ERAS society recommendations. RESULTS: 537 patients underwent liver surgery (46% laparoscopic, 26% robotic assisted, 28% open surgery) and 487 were managed by the ERAS protocol. Implementation of ERAS reduced overall postoperative complications in the MILS group (18% vs. 32%, p = 0.048). Complications greater than Clavien-Dindo grade II incurred the highest costs (€ 31,093) compared to minor (€ 17,510) and no complications (€13,893; p < 0.001). In the event of major complications, profit margins were reduced by a median of € 6,640. CONCLUSIONS: Embracing the ERAS society recommendations in liver surgery leads to a significant reduction of complications. This outcome justifies the higher cost associated with a well-structured ERAS protocol, as it effectively offsets the expenses of complications.

Simplifying minimally invasive right hepatectomy.

BACKGROUND: Extrahepatic transection of the right hepatic artery and right portal vein before parenchymal dissection is a widely used standard for minimal invasive right hepatectomy. Hereby, hilar dissection represents a technical difficulty. We report our results of a simplified approach in which the hilar dissection is omitted and the line of dissection is defined with ultrasound. METHODS: Patients undergoing minimally invasive right hepatectomy were included. Ultrasound-guided hepatectomy (UGH) was defined by the following main steps: (1) ultrasound-guided definition of the transection line, (2) dissection of the liver parenchyma according to the caudal approach, (3) intraparenchymal transection of the right pedicle and (4) of the right liver vein, respectively. Intra- and postoperative outcomes of UGH were compared to the standard technique. Propensity score matching was performed to adjust for parameters of perioperative risk. RESULTS: Median operative time was 310 min in the UGH group compared to 338 min in the control group (p = 0.013). No differences were observed for Pringle maneuver duration (35 min vs. 25 min; p = ns) nor postoperative transaminases levels (p = ns). There was a trend toward a lower major complication rate in the UGH group (13 vs. 25%) and a shorter median hospital stay (8 days vs. 10 days); however, both being short of statistical significance (p = ns). Bile leak was observed in zero cases of UGH compared to 9 out of 32 cases (28%) for the control group (p = 0.020). CONCLUSIONS: UGH appears to be at least comparable to the standard technique in terms of intraoperative and postoperative outcomes. Accordingly, transection of the right hepatic artery and right portal vein prior to the transection phase can be omitted, at least in selected cases. These results need to be confirmed in a prospective and randomized trial.

Normothermic machine perfusion for older transplant recipients.

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

FIRE-9 - PORT / AIO-KRK-0418: a prospective, randomized, open, multicenter Phase III trial to investigate the efficacy of adjuvant/additive chemotherapy in patients with definitely-treated metastatic colorectal cancer.

BACKGROUND: Additive/adjuvant chemotherapy as concept after local treatment of colorectal metastases has not been proven to be successful by phase III trials. Accordingly, a standard of care to improve relapse rates and long-term survival is not established and adjuvant chemotherapy cannot be recommended as a standard therapy due to limited evidence in literature. The PORT trial aims to generate evidence that post-resection/ablation/radiation chemotherapy improves the survival in patients with metastatic colorectal cancer. METHODS: Patients to be included into this trial must have synchronous or metachronous metastases of colorectal cancer-either resected (R0 or R1) and/or effectively treated by ablation or radiation within 3-10 weeks before randomization-and have the primary tumor resected, without radiographic evidence of active metastatic disease at study entry. The primary endpoint of the trial is progression-free survival after 24 months, secondary endpoints include overall survival, safety, quality of life, treatments (including efficacy) beyond study participation, translational endpoints, and others. One arm of the study comprising 2/3 of the population will be treated for 6 months with modified FOLFOXIRI or modified FOLFOX6 (investigator´s choice, depending on the performance status of the patients but determined before randomization), while the other arm (1/3 of the population) will be observed and undergo scheduled follow-up computed tomography scans according to the interventional arm. DISCUSSION: Optimal oncological management after removal of colorectal metastases is unclear. The PORT trial aims to generate evidence that additive/adjuvant chemotherapy after definitive treatment of colorectal metastases improves progression free and overall survival in patients with colorectal cancer. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov ( NCT05008809 ) and EudraCT (2020-006,144-18).

Hypothermic oxygenated machine perfusion for extended criteria donor allografts: Preliminary experience with extended organ preservation times in the setting of organ reallocation.

BACKGROUND: In times of critical organ shortage, poor organ pool utilization and increased use of extended-criteria donor (ECD) allografts remain a major problem. Hypothermic oxygenated machine perfusion (HOPE) has emerged as a promising and feasible strategy in ECD liver transplantation (LT). However, potential safety limits regarding the duration of perfusion are yet to be explored. Besides marginal allograft quality (steatosis), prolonged cold ischemia time remains the most important factor for a high number of liver allografts being declined for transplantation. PATIENTS AND METHODS: Two ECD-allografts were each allocated to two recipients, who proved to be unsuitable to receive the assigned allograft upon arrival at the transplant center. The organs were reallocated by Eurotransplant and accepted by our center for two different backup patients. During that time, HOPE was commenced and continued until the recipient hepatectomy was completed. Postoperative allograft function was assessed by serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and International Normalized Ratio. Incidence of early allograft dysfunction (EAD), postoperative complications, and length of hospital stay were analyzed. RESULTS: HOPE was applied for 4 h 35 min and 4 h 20 min, resulting in a total cold preservation time of 17 h 29 min and 15 h 20 min, respectively. Both recipients displayed decreasing serum transaminases and bilirubin levels postoperatively. No EAD or major postoperative complications occurred in either patient. Serum ALT and AST levels were within the normal range at discharge. CONCLUSIONS: Extended HOPE enables the safe extension of preservation time for up to 18 h in human LT. End-ischemic HOPE may significantly improve organ pool utilization, while simultaneously facilitating operating room logistics and preventing organ injury.

The influence of the COVID-19 pandemic on surgical therapy and care: a cross-sectional study.

BACKGROUND: Due to the COVID-19 pandemic, an extensive reorganisation of healthcare resources was necessary-with a particular impact on surgical care across all disciplines. However, the direct and indirect consequences of this redistribution of resources on surgical therapy and care are largely unknown. METHODS: We analysed our prospectively collected standardised digital quality management document for all surgical cases in 2020 and compared them to the years 2018 and 2019. Periods with high COVID-19 burdens were compared with the reference periods in 2018 and 2019. RESULTS: From 2018 to 2020, 10,723 patients underwent surgical treatment at our centres. We observed a decrease in treated patients and a change in the overall patient health status. Patient age and length of hospital stay increased during the COVID-19 pandemic (p = 0.004 and p = 0.002). Furthermore, the distribution of indications for surgical treatment changed in favour of oncological cases and less elective cases such as hernia repairs (p < 0.001). Postoperative thromboembolic and pulmonary complications increased slightly during the COVID-19 pandemic. There were slight differences for postoperative overall complications according to Clavien-Dindo, with a significant increase of postoperative mortality (p = 0.01). CONCLUSION: During the COVID-19 pandemic we did not see an increase in the occurrence, or the severity of postoperative complications. Despite a slightly higher rate of mortality and specific complications being more prevalent, the biggest change was in indication for surgery, resulting in a higher proportion of older and sicker patients with corresponding comorbidities. Further research is warranted to analyse how this changed demographic will influence long-term patient care.

[Differentiated Strategies for the Therapy of Liver Metastases in Gastro-entero-pancreatic Neuroendocrine Neoplasia]. / Differenzierte Therapiestrategie bei Lebermetastasen gastro-entero-pankreatischer Neuroendokriner Neoplasien.

Neuroendocrine neoplasias comprise a heterogenous group of malignant tumours, mostly arising from the gastro-entero-pancreatic system (GEP). Most of these tumours develop from the small intestine and pancreas and the liver is the predominant site for distant metastases. Patients may be asymptomatic for a long time and liver metastases are frequently diagnosed by chance or during operations for bowel obstruction, for example, during emergency surgery. The only curative therapy consists in complete removal of primary and metastases. In case of metastatic disease, various treatment modalities need to be discussed in interdisciplinary tumour boards comprised of specialists from gastroenterology, (liver-)surgery, radiology, nuclear medicine, radiotherapy, pathology and endocrinology. By combining different therapies, even patients with progressive disease may reach long-term overall survival with good quality of life. The most important factors for decisions on therapy are individual factors like tumour grading, hormonal functionality, type of metastases and evolution of the disease. Adequate treatment of liver metastases comprises various surgical strategies as well as locally ablative radiological interventions and nuclear medical therapies, in complement to systemic treatments.

Trends in indications and outcomes of liver transplantation in Canada: A multicenter retrospective study.

The liver transplantation (LT) landscape is continuously evolving. We sought to evaluate trends in indications for LT in Canada and the impact of primary liver disease on post-LT outcomes using a national transplant registry. Adult patients who underwent a primary LT between 2000 and 2018 were retrospectively identified in the Canadian Organ Replacement Registry. Outcomes included post-LT patient and graft survival. A total of 5,722 LTs were identified. The number of LT per year increased from 251 in 2000 to 349 in 2018. The proportion of patients transplanted for HCV decreased from 31.5% in 2000 to 3.4% in 2018. In contrast, the percentage of transplants for HCC increased from 2.3% in 2000 to 32.4% in 2018, and those performed for NASH increased from 0.4% in 2005 to 12.6% in 2018. Year of transplant (per 1 year) was protective for both patient (HR:0.96,95%CI:0.94-0.97; P < 0.001) and graft survival (HR:0.97, 95%CI: 0.96-0.99; P = 0.001). Post-LT outcomes have improved over time in this nationwide analysis spanning 18 years. Moreover, trends in the indications for LT have changed, with HCC becoming the leading etiology. The decrease in the proportion of HCV patients and increase in those with NASH has implications on the evolving management of LT patients.

Transplantation programs facing lack of empirical evidence on SARS-CoV-2 vaccination: A society recommendation consensus update.

BACKGROUND: Since phase III trials for the most prominent vaccines excluded immunocompromised or immunosuppressed patients, data on safety and efficacy of SARS-CoV-2 vaccines for recipients of solid organ transplantations are scarce. AIMS: Our study offers a synthesis of expert opinions aligned with available data addressing key questions of the clinical management of SARS-CoV-2 vaccinations for transplant patients. METHOD: An online research was performed retrieving available recommendations by national and international transplantation organizations and state institutions on SARS-CoV2 vaccination management for transplant recipients. RESULTS: Eleven key statements were identified from recommendations by 18 national and international societies, and consensus for the individual statements was evaluated by means of the Society Recommendation Consensus score. The highest consensus level (SRC A) was found for prioritized access to vaccination for transplant patients despite anticipation of a weakened immune response. All currently authorized vaccines can be considered safe for transplant patients (SRC A). The handling of immunosuppressive medication, the timely management of vaccines, and other aspects were aligned with available expert opinions. CONCLUSION: Expert consensus can be determined for crucial aspects of the implementation of SARS-CoV-2 vaccination programs. We hereby offer a tool for immediate decision-making until empirical data becomes available.

Ex vivo machine perfusion: current applications and future directions in liver transplantation.

BACKGROUND: Liver transplantation is the only curative treatment option for end-stage liver disease; however, its use remains limited due to a shortage of suitable organs. In recent years, ex vivo liver machine perfusion has been introduced to liver transplantation, as a means to expand the donor organ pool. PURPOSE: To present a systematic review of prospective clinical studies on ex vivo liver machine perfusion, in order to assess current applications and highlight future directions. METHODS: A systematic literature search of both PubMed and ISI web of science databases as well as the ClinicalTrials.gov registry was performed. RESULTS: Twenty-one articles on prospective clinical trials on ex vivo liver machine perfusion were identified. Out of these, eight reported on hypothermic, eleven on normothermic, and two on sequential perfusion. These trials have demonstrated the safety and feasibility of ex vivo liver machine perfusion in both standard and expanded criteria donors. Currently, there are twelve studies enrolled in the clinicaltrials.gov  registry, and these focus on use of ex vivo perfusion in extended criteria donors and declined organs. CONCLUSION: Ex vivo liver machine perfusion seems to be a suitable strategy to expand the donor pool for liver transplantation and holds promise as a platform for reconditioning diseased organs.

The ILLS Laparoscopic Liver Surgery Fellow Skills Curriculum.

INTRODUCTION: Laparoscopy is becoming the standard approach in liver surgery. As the degree of difficulty varies greatly from core skills to advanced procedures, strategies for teaching young surgeons need to be reconsidered. We here aimed to design a skills curriculum for LLR. METHODS: Using the nominal group technique, 22 substeps of LLR were identified by 61 hepatobiliary surgeons. The raters were asked to rate (1) the difficulty of substeps and (2) the minimum number of times that the substep must be performed for mastery of the technique. According to the frequency of defined substeps, being estimated on the basis of high volume center experiences (n = 222 LLR; 1/2017-12/2018), the center's training capacity and defined goals for a 2-year fellowship were calculated. RESULTS: Ten surgical substeps (45%) are routinely performed and can thus be taught sufficiently at centers carrying out ≥50 LLR in 2 years. As the mobilization of the right liver lobe and the dissection of the hepatic artery or portal vein is performed in only 27% and 28% of all LLR, respectively, sufficient training can only be provided at centers with ≥100 LLRs in 2 years. Mastery of complex parenchymal dissection (19%) and hilar lymphadenectomy (8%) can only be achieved in center performing ≥200 LLR in 2 years. CONCLUSION: We here suggest a stepwise approach for training of hepatobiliary fellows in LLR. Based on the estimated complexity of the substeps and the size of the center, not every substep can be learned within 2 years.

Hospitalization Before Liver Transplantation Predicts Posttransplant Patient Survival: A Propensity Score-Matched Analysis.

In contrast to donor factors predicting outcomes of liver transplantation (LT), few suitable recipient parameters have been identified. To this end, we performed an in-depth analysis of hospitalization status and duration prior to LT as a potential risk factor for posttransplant outcome. The pretransplant hospitalization status of all patients undergoing LT between 2005 and 2016 at the Charité-Universitätsmedizin Berlin was analyzed retrospectively using propensity score matching. At the time of organ acceptance, 226 of 1134 (19.9%) recipients were hospitalized in an intensive care unit (ICU), 146 (12.9%) in a regular ward (RW) and 762 patients (67.2%) were at home. Hospitalized patients (RW and ICU) compared with patients from home showed a dramatically shorter 3-month survival (78.7% versus 94.4%), 1-year survival (66.3% versus 87.3%), and 3-year survival (61.7% versus 81.7%; all P < 0.001), whereas no significant difference was detected for 3-year survival between ICU and RW patients (61.5% versus 62.3%; P = 0.60). These results remained significant after propensity score matching. Furthermore, in ICU patients, but not in RW patients, survival correlated with days spent in the ICU before LT (1-year survival: 1-6 versus 7-14 days: 73.7% versus 60.5%, P = 0.04; 7-14 days versus >14 days, 60.5% versus 51.0%, P = 0.006). In conclusion, hospitalization status before transplantation is a valuable predictor of patient survival following LT.

Tissue-based miRNA mapping in alcoholic liver cirrhosis: different profiles in cirrhosis with or without hepatocellular carcinoma.

Context: Alcoholic liver cirrhosis is a significant risk factor for the development of hepatocellular carcinoma (HCC). The importance of tumour-associated cirrhosis in the development or progression of HCC is not understood. MiRNAs are important regulators for HCC development, but their role in HCC due to alcoholic liver cirrhosis is unclear.Objective: The aim of this study is the detection of miRNA expression in alcoholic liver cirrhosis, tumour-associated cirrhosis, and HCC.Materials and methods: We analysed the differences in the miRNA profiles of HCC, tumour-associated cirrhosis, and cirrhosis without HCC samples from 30 patients who underwent liver transplantation because of alcoholic liver disease.Results: Microarray analyses revealed 40 significantly differentially expressed miRNAs between HCC tissue and tumour-associated cirrhosis tissue. Furthermore, the microarray analysis discovered 56 differentially expressed miRNAs in tumour-associated cirrhosis and cirrhosis without HCC.Discussion: The differences of miRNA profile in alcoholic liver cirrhosis with and without HCC could improve understanding of HCC development, as well as lead to a new diagnostic tool in HCC screening.Conclusion: We were able to show for the first time, the differences of miRNA profile as promising biomarker in HCC, tumour-associated cirrhosis, and cirrhosis without HCC in context of alcoholic liver disease.

[Declined Liver Grafts - Analysis of the German Donor Population from 2010 to 2018]. / Nicht transplantierte Spenderorgane ­ eine bundesweite Auswertung aller Organangebote für die Lebertransplantation von 2010 bis 2018.

BACKGROUND: The lack of suitable allografts limits the availability of liver transplantation in Germany. The quality of potentially available German donor livers has to date not been analyzed. METHODS: Analysis of all donors for potential liver transplantations reported to the Eurotransplant by the German Organ Transplantation Foundation from 2010 to 2018. Categorization of transplanted and discarded organs utilizing available histopathological reports and predefined extended criteria for organ donation. RESULTS: A total of 8594 livers were offered for transplantation, of which 15.2 % were discarded. During the analysis period the proportion of donor livers from extended criteria donors increased from 65 % to 70 % (p = 0.005). In 2018, 21.3 % of offered donor livers were discarded, more than half (56.4 %) of these organs came from donors meeting multiple extended criteria. Livers were significantly more likely to be not transplanted, when from donors of older age (> 65 years; 41 vs. 28 %), BMI > 30 kg/m2 (29 vs. 14 %) or elevated transaminase levels (all p < 0,001). CONCLUSION: Despite the consistent organ scarcity in Germany, a relevant amount of livers cannot be transplanted due to a multitude of organ quality limitations. This should stimulate the search for concepts such as normothermic ex vivo machine perfusion to evaluate, protect and potentially improve organ quality.

Improvement of Normothermic Ex Vivo Machine Perfusion of Rat Liver Grafts by Dialysis and Kupffer Cell Inhibition With Glycine.

Normothermic ex vivo liver machine perfusion might be a superior preservation strategy for liver grafts from extended criteria donors. However, standardized small animal models are not available for basic research on machine perfusion of liver grafts. A laboratory-scaled perfusion system was developed consisting of a custom-made perfusion chamber, a pressure-controlled roller pump, and an oxygenator. Male Wistar rat livers were perfused via the portal vein for 6 hours using oxygenated culture medium supplemented with rat erythrocytes. A separate circuit was connected via a dialysis membrane to the main circuit for plasma volume expansion. Glycine was added to the flush solution, the perfusate, and the perfusion circuit. Portal pressure and transaminase release were stable over the perfusion period. Dialysis significantly decreased the potassium concentration of the perfusate and led to significantly higher bile and total urea production. Hematoxylin-eosin staining and immunostaining for single-stranded DNA and activated caspase 3 showed less sinusoidal dilatation and tissue damage in livers treated with dialysis and glycine. Although Kupffer cells were preserved, tumor necrosis factor α messenger RNA levels were significantly decreased by both treatments. For proof of concept, the optimized perfusion protocol was tested with donation after circulatory death (DCD) grafts, resulting in significantly lower transaminase release into the perfusate and preserved liver architecture compared with baseline perfusion. In conclusion, our laboratory-scaled normothermic portovenous ex vivo liver perfusion system enables rat liver preservation for 6 hours. Both dialysis and glycine treatment were shown to be synergistic for preservation of the integrity of normal and DCD liver grafts.

The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism.

Reduced expression of the Indy ("I am Not Dead, Yet") gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane-associated citrate transporter expressed highly in the liver, protects mice from high-fat diet-induced and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We studied a possible role of mIndy in human hepatic fat metabolism. In obese, insulin-resistant patients with nonalcoholic fatty liver disease, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In nonhuman primates, a 2-year high-fat, high-sucrose diet increased hepatic mIndy expression. Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin-6 (IL-6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL-6 markedly induced mIndy transcription through the IL-6 receptor and activation of the transcription factor signal transducer and activator of transcription 3, and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-signal transducer and activator of transcription 3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx, and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL-6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and nonhuman primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 through mINDY. CONCLUSION: Targeting human mINDY may have therapeutic potential in obese patients with nonalcoholic fatty liver disease. German Clinical Trials Register: DRKS00005450. (Hepatology 2017;66:616-630).

The value of microparticles in detecting acute rejection episodes after liver transplantation.

CONTEXT: Non-invasive markers for diagnosis of acute rejection (AR) following liver transplantation have not been developed, yet. OBJECTIVE: We analyzed the correlation of plasma microparticle levels (MP) with AR. MATERIALS AND METHODS: MP (CD4, CD8, CD25, CD31, MHC) of 11 AR patients and 11 controls were analyzed within the first week after transplantation. RESULTS: CD4, CD8 and CD31 positive MP were higher in the AR, whereas overall MP count, CD25 and MHCI positive MP proportions did not differ between both groups. DISCUSSION AND CONCLUSION: MP dynamics within the first period of transplantation could help to clarify on-going mechanisms of immunomodulation.