Mitsugumin 53 mitigation of ischemia-reperfusion injury in a mouse model.

OBJECTIVE: Primary graft dysfunction is often attributed to ischemia-reperfusion injury, and prevention would be a therapeutic approach to mitigate injury. Mitsugumin 53, a myokine, is a component of the endogenous cell membrane repair machinery. Previously, exogenous administration of recombinant human (recombinant human mitsugumin 53) protein has been shown to mitigate acute lung injury. In this study, we aimed to quantify a therapeutic benefit of recombinant human mitsugumin 53 to mitigate a transplant-relevant model of ischemia-reperfusion injury. METHODS: C57BL/6J mice were subjected to 1 hour of ischemia (via left lung hilar clamp), followed by 24 hours of reperfusion. mg53-/- mice were administered exogenous recombinant human mitsugumin 53 or saline before reperfusion. Tissue, bronchoalveolar lavage, and blood samples were collected at death and used to quantify the extent of lung injury via histology and biochemical assays. RESULTS: Administration of recombinant human mitsugumin 53 showed a significant decrease in an established biometric profile of lung injury as measured by lactate dehydrogenase and endothelin-1 in the bronchoalveolar lavage and plasma. Biochemical markers of apoptosis and pyroptosis (interleukin-1ß and tumor necrosis factor-α) were also significantly mitigated, overall demonstrating recombinant human mitsugumin 53's ability to decrease the inflammatory response of ischemia-reperfusion injury. Exogenous recombinant human mitsugumin 53 administration showed a trend toward decreasing overall cellular infiltrate and neutrophil response. Fluorescent colocalization imaging revealed recombinant human mitsugumin 53 was effectively delivered to the endothelium. CONCLUSIONS: These data demonstrate that recombinant human mitsugumin 53 has the potential to prevent or reverse ischemia-reperfusion injury-mediated lung damage. Although additional studies are needed in wild-type mice to demonstrate efficacy, this work serves as proof-of-concept to indicate the potential therapeutic benefit of mitsugumin 53 administration to mitigate ischemia-reperfusion injury.

MG53 mitigates warm ischemic lung injury in a murine model of transplantation.

OBJECTIVES: Lung transplant warm ischemia-reperfusion injury (IRI) results in cellular injury, inflammation, and poor graft function. Mitsugumin 53 (MG53) is an endogenous protein with cell membrane repair properties and the ability to modulate the inflammasome. We hypothesize that the absence of circulating MG53 protein in the recipient increases IRI, and higher levels of circulating MG53 protein mitigate IRI associated with lung transplantation. METHODS: To demonstrate protection, wild-type (wt) lung donor allografts were transplanted into a wt background, a MG53 knockout (mg53-/-), or a constitutively overexpressed MG53 (tissue plasminogen activator-MG53) recipient mouse after 1 hour of warm ischemic injury. Mice survived for 5 days after transplantation. Bronchioalveolar lavage, serum, and tissue were collected at sacrifice. Bronchioalveolar lavage, serum, and tissue markers of apoptosis and a biometric profile of lung health were analyzed. RESULTS: mg53-/- mice had significantly greater levels of markers of overall cell lysis and endothelial cell injury. Overexpression of MG53 resulted in a signature similar to that of wt controls. At the time of explant, tissue plasminogen activator-MG53 recipient tissue expressed significantly greater levels of MG53, measured by immunohistochemistry, compared with mg53-/-, demonstrating uptake of endogenous overexpressed MG53 into donor tissue. CONCLUSIONS: In a warm IRI model of lung transplantation, the absence of MG53 resulted in increased cell injury and inflammation. Endogenous overexpression of MG53 in the recipient results in protection in the wt donor. Together, these data suggest that MG53 is a potential therapeutic agent for use in lung transplantation to mitigate IRI.

Biometric Profiling to Quantify Lung Injury Through Ex Vivo Lung Perfusion Following Warm Ischemia.

Standard physiologic assessment parameters of donor lung grafts may not accurately reflect lung injury or quality. A biometric profile of ischemic injury could be identified as a means to assess the quality of the donor allograft. We sought to identify a biometric profile of lung ischemic injury assessed during ex vivo lung perfusion (EVLP). A rat model of lung donation after circulatory death (DCD) warm ischemic injury with subsequent EVLP evaluation was utilized. We did not observe a significant correlation between the classical physiological assessment parameters and the duration of the ischemic. In the perfusate, solubilized lactate dehydrogenase (LDH) as well as hyaluronic acid (HA) significantly correlated with duration of ischemic injury and length of perfusion ( p < 0.05). Similarly, in perfusates, the endothelin-1 (ET-1) and Big ET-1 correlated ischemic injury ( p < 0.05) and demonstrated a measure of endothelial cell injury. In tissue protein expression, heme oxygenase-1 (HO-1), angiopoietin 1 (Ang-1), and angiopoietin 2 (Ang-2) levels were correlated with the duration of ischemic injury ( p < 0.05). Cleaved caspase-3 levels were significantly elevated at 90 and 120 minutes ( p < 0.05) demonstrating increased apoptosis. A biometric profile of solubilized and tissue protein markers correlated with cell injury is a critical tool to aid in the evaluation of lung transplantation, as accurate evaluation of lung quality is imperative and improved quality leads to better results. http://links.lww.com/ASAIO/B49.

Is a Preservation Solution for Living Donor Liver Transplantation Needed? Adding a New Chapter in LDLT!

Preservation solutions are required for organ viability in deceased donor liver transplantation (LT). However, their role in live donor LT (LDLT) has not been standardized. Methods: Eighty adult recipients who underwent right lobe LDLT at the Department of Liver Transplantation Surgery, Gambat, Pakistan, were studied. Based on shorter cold ischemia time and no back table reconstruction work, recipients were assigned to receive "no preservation solution" (cases/non-histidine-tryptophan-ketoglutarate group; n = 40) or "HTK group" (controls; n = 40). Early allograft dysfunction (bilirubin, transaminases, and international normalized ratio), postoperative complications (biliary and vascular), hospital stay, and 1-y survival were reported. The direct cost was also reported. Results: Demographics and clinical characteristics were comparable in the 2 groups. Comparing cases versus controls, mean bilirubin, alanine aminotransferase, aspartate aminotransferase, and international normalized ratio on postoperative day 7 were similar in the 2 groups. Five (12.5%) cases and 4 (10%) controls developed early allograft dysfunction (P = 0.72). Post-LT complications (biliary leak 2.5% in cases versus 0 in control), strictures (15% in cases versus 17.5% in controls), hepatic artery thrombosis (2.5% versus 00%)' and portal vein thrombosis (0 versus 2.5%) were comparable. Mean hospital stay (10.80 + 2.36 and 11.78 + 2.91 d) and 30 d mortality (2.5% versus 5%) were also comparable. Finally, 1-y survival based on Kaplan-Meier analysis was comparable in both groups (ie, 92.5%; non-HTK group versus 90%; HTK group) (P = 0.71). The direct cost of using a non-HTK-based approach was less than the HTK solution. Conclusion: In a selected cohort of right lobe LDLT recipients, preservation solutions can be avoided safely with comparable outcomes.

Safely Expanding the Liver Donor Pool by Utilization of Organs from Donation after Circulatory Death with Comparable Results to Donation After Brain Death, a Large Single-Center Experience.

BACKGROUND: Use of livers donated after circulatory death (DCD) is one way to expand the donor pool. Our center has aggressively incorporated use of DCD liver grafts into practice. We examined our center and national outcomes as well as national DCD liver utilization. METHODS: Liver transplants performed at our center and nationally from 11/2016 through 9/2020 were compared. Primary outcomes were patient and graft survival, and national DCD liver utilization. RESULTS: For our center, DCD and donation after brain death (DBD) donors were similar except DCD donors were younger (37 vs 40 years; p < 0.05). Recipient Na-MELD (20 vs 24; p < 0.0001) and cold ischemia time (4.63 vs 5.18 h; p < 0.05) were lower in DCD recipients. There were no significant differences in 1-year patient and graft survival between DCD and DBD liver recipients locally. Nationally, there was a difference in 1-year graft survival year (89.4% vs 92.4%, p < 0.0001) but patient survival was similar between groups. The proportion of DCD livers recovered and transplanted widely varied among organ procurement organizations (OPOs) and transplant centers. CONCLUSIONS: Similar outcomes for DCD and DBD liver recipients should encourage centers and OPOs nationwide to expand utilization of DCD livers.

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

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

Electrical Impedance as a Noninvasive Metric of Quality in Allografts Undergoing Normothermic Ex Vivo Lung Perfusion.

Ex vivo lung perfusion (EVLP) increases the pool of suitable organs for transplant by facilitating assessment and repair at normothermia, thereby improving identification of quality of marginal organs. However, there exists no current objective approach for assessing total organ edema. We sought to evaluate the use of electrical impedance as a metric to assess total organ edema in lungs undergoing EVLP. Adult porcine lungs (40 kg) underwent normothermic EVLP for 4 hours. To induce varying degrees of lung injury, the allografts were perfused with either Steen, a modified cell culture media, or 0.9% normal saline. Physiologic parameters (peak airway pressure and compliance), pulmonary artery and left atrial blood gases, and extravascular lung water measurements were evaluated over time. Wet-to-dry ratios were evaluated postperfusion. Modified Murray scoring was used to calculate lung injury. Impedance values were associated with lung injury scores ( p = 0.007). Peak airway pressure ( p = 0.01) and PaO 2 /FiO 2 ratios ( p = 0.005) were both significantly associated with reduced impedance. Compliance was not associated with impedance ( p = 0.07). Wet/dry ratios were significantly associated with impedance and Murray Scoring within perfusion groups of Steen, Saline, and Modified Cell Culture ( p = 0.0186, 0.0142, 0.0002, respectively). Electrical impedance offers a noninvasive modality for measuring lung quality as assessed by tissue edema in a porcine model of normothermic EVLP. Further studies evaluating the use of impedance to assess organ edema as a quality marker in human clinical models and abdominal organs undergoing ex vivo perfusion warrant investigation.

Hepatic Resection and Transplant in Glycogen Storage Diseases.

Patients with glycogen storage diseases pose unique management challenges to clinicians.These challenges are exacerbated wheneverthey undergo surgery as the basic anomaly in their glycogen storage pathways make them susceptible to organic acidosis, which may in turn complicate their preoperative, intraoperative, and postoperative course. Because of the rarity of these diseases, clinicians may not be aware of the specific management concerns. In the case reported here, a 37-year-old patient with glycogen storage disease type 1 underwentleft hepatectomy for hepatic adenomatosis, which was complicated by intraoperative severe lactic acidosis that was successfully treated. After successful hepatectomy, the patient underwent liver transplant without major lactic acidosis or hemodynamic instability. Early recognition and aggressive management of blood sugar and lactic acidosis in patients with glycogen storage diseases can allow for successful outcomes even when complex surgical procedures are required.

Liver Transplant for Management of Hepatic Complications of Dyskeratosis Congenita: A Case Report.

Dyskeratosis congenita, a rare genetic disorder typified by progressive bone marrow failure, is classically characterized by the triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia; however, it is a multisystem disease. Although hepatic involvement occurs in about 7% of patients with dyskeratosis congenita, end-stage liver disease is rare. Treatment of dyskeratosis congenita generally involves hematopoietic stem cell transplant. For patients with hepatic failure, liver transplant can be an option. Here, we describe a case of a patient with dyskeratosis congenita who presented with liver failure and pulmonary failure, precluding him from hematopoietic stem cell transplant. After liver transplant, the patient had significant improvements in pulmonary function and transfusion requirements, allowing the patient to qualify for hematopoietic stem cell transplant. Although hematopoietic stem cell transplant is typically the first step in the management of dyskeratosis congenita, for patients with severe hepatic manifestations of the disease, a liver transplant first approach may result in better disease management.

Apprising the choice of bariatric surgery in patients with compensated cirrhosis with morbid obesity: results of a national analysis.

Bariatric surgery (BS) was proved safe in carefully selected patients with compensated cirrhosis (CC). However, limited data exist on differential impact of bariatric surgery type on clinical outcomes and health care utilization. This retrospective study utilizes the 2010-2014 Nationwide Readmissions Database. We included obese adults with CC who underwent the two most commonly used BS, Roux-en-Y (RYGB) and laparoscopic sleeve gastrectomy (LSG). Those with decompensation within 6 months of BS were excluded. Rates of hepatic decompensation (new-onset ascites, variceal bleed, encephalopathy, spontaneous bacterial peritonitis, and/or hepatorenal syndrome), surgical complications, health care utilization, and mortality were compared between RYGB and LSG. Multivariable analysis was performed to fit various models. A total of 3032 patients with CC underwent BS, including 1864 (61.5%) RYGB and 1168 (38.5%) LSG. The majority (56%) of BS were performed at large, metropolitan teaching hospitals. There were no significant differences in various decompensations and surgical complications comparing RYGB to LSG. Healthcare utilization including index length of stay (RYGB: 3.4 days vs LSG: 3.0 days), 30-day readmission rate (RYGB: 9.5% vs LSG: 3.7%), and cost of admission (RYGB: $14,006 vs LSG: $12,523) were higher in RYGB (p values < 0.001). Index admission and calendar year mortality could not be analyzed due to the few number of events. Two types of bariatric surgeries in obese patients with compensated cirrhosis have similar rates of decompensated cirrhosis events and surgical complications. However, RYGB procedure incurred increased healthcare utilization. Therefore, LSG may be the preferred BS for patients with CC. Prospective, randomized studies comparing the types of BS are needed to confirm our observations.

Pegylated-Catalase Is Protective in Lung Ischemic Injury and Oxidative Stress.

BACKGROUND: Lung transplant ischemia-reperfusion injury is typified by toxic metabolites and oxygen free radicals leading to worse graft function. Catalase is an enzyme involved in oxidative-stress detoxification. We hypothesize that direct delivery of highly concentrated polyethylene glycol-catalase (PEG-CAT) during normothermic ex vivo lung perfusion (EVLP) significantly reduces ischemia-reperfusion injury. METHODS: To demonstrate protection, primary culture porcine endothelial cells were treated with PEG-CAT (0 to 1250 U/mL) in a model of oxidative stress (400 µM H2o2). In vivo, rat lungs were subjected to 0 hours or 1 hour of warm ischemic injury and 2 hours of EVLP with or without PEG-CAT. Perfusate was collected throughout the perfusion duration and tissue was collected at the end. Tissue and perfusate underwent analysis for markers of apoptosis and a biometric signature of lung health. RESULTS: Uptake of PEG-CAT into primary endothelial cells was demonstrated with Alexa Fluor 488-labeled PEG-CAT. Oxidatively stressed cells pretreated with PEG-CAT had significantly decreased cytotoxicity and caspase 3/7 activity and increased cell viability and cell membrane integrity. In a rat model of warm ischemia with EVLP, PEG-CAT improved allograft viability as measured by indications of cell membrane integrity (lactate dehydrogenase and hyaluronic acid), presence of vasoconstrictive peptides (endothelin-1 and big endothelin-1) released from endothelial cells, and reduced apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling). CONCLUSIONS: In vitro and ex vivo, PEG-CAT protects against oxidative stress-induced cytotoxicity, maintains cellular metabolism, and mitigates lung ischemia-reperfusion in an experimental model. Together, these data suggest that PEG-CAT is a potential therapeutic target for donor organs at risk for ischemia-reperfusion injury.

Thirty-day readmission rates, trends and its impact on liver transplantation recipients: a national analysis.

Reduction of early hospital readmissions is a declared goal in the United States economic and quality improvement agenda. A retrospective study was performed using the Nationwide Readmissions Database from 2010 to 2014. Our primary aim was to study the rate of early readmissions and its predictors in liver transplant recipients (LTRs). Our secondary aims were to determine the trends of LT, reasons for readmission, costs and predictors of calendar year mortality. Multivariable logistic regression and Cox proportional hazards models were utilized. The 30-day readmission rate was 30.6% among a total of 25,054 LTRs. Trends of LT were observed to be increased in patients > 65 years (11.7-17.8%, p < 0.001) and decreased in 40-64 years (78.0-73.5%, p = 0.001) during study period. The majority of 30-day readmissions were due to post transplant complications, with packed red blood cell transfusions being the most common intervention during readmission. Medicaid or Medicare insurance, surgery at low and medium volume centers, infections, hemodialysis, liver biopsy, and length of stay > 10 days were the predictors of 30-day readmission. Moreover, number of early readmission, age > 64 years, non-alcoholic cirrhosis, and length of stay > 10 days were significant predictor of calendar year mortality in LTRs. Approximately one third of patients require early admission after LT. Early readmission not only increases burden on healthcare, but is also associated with calendar year mortality. Strategies should be implemented to reduce readmission in patients with high risk of readmission identified in our study.

Bariatric Surgery in Patients with Cirrhosis: Careful Patient and Surgery-Type Selection Is Key to Improving Outcomes.

PURPOSE: Previous reports suggest an increased mortality in cirrhotic patients undergoing bariatric surgery (BS). With advancements in management of BS, we aim to study the trends, outcomes, and their predictors in patients with cirrhosis undergoing BS. MATERIALS AND METHODS: A retrospective study was performed using the National Database from 2008 to 2013. Outcomes of BS in patients with cirrhosis were studied. In-hospital mortality, length of stay, and cost of care were compared between patients with no cirrhosis (NC), compensated cirrhosis (CC), and decompensated cirrhosis (DC). Multivariable logistic regression analysis was performed to study the predictors of mortality. RESULTS: Of the 558,017 admissions of patients who underwent BS during the study period, 3086 (0.55%) had CC and 103 (0.02%) had DC. An upward trend of vertical sleeve gastrectomy (VSG) utilization was seen during the study period. On multivariate analysis, mortality in CC was comparable with those in NC (aOR 1.88; CI 0.65-5.46); however, it was higher in DC (aOR 83.8; CI 19.3-363.8). Other predictors of mortality were older age (aOR 1.06; CI 1.04-1.08), male (aOR 2.59; CI 1.76-3.81), Medicare insurance (aOR 1.93; CI 1.24-3.01), lower income (aORs 0.44 to 0.55 for 2nd to 4th income quartile vs. 1st quartile), > 3 Elixhauser Comorbidity Index (aOR 5.30; CI 3.45-8.15), undergoing Roux-en-Y gastric bypass as opposed to VSG (aOR 3.90; CI 1.79-8.48), and centers performing < 50 BS per year (aOR 5.25; CI 3.38-8.15). Length of stay and hospital cost were also significantly higher in patients with cirrhosis as compared with those with NC. CONCLUSION: Patients with compensated cirrhosis can be considered for bariatric surgery. However, careful selection of patients, procedure type, and volume of surgical center is integral in improving outcomes and healthcare utilization in patients with cirrhosis undergoing BS.

Neoadjuvant and adjuvant treatment strategies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common liver malignancy worldwide and a major cause of cancer-related mortality for which liver resection is an important curative-intent treatment option. However, many patients present with advanced disease and with underlying chronic liver disease and/or cirrhosis, limiting the proportion of patients who are surgical candidates. In addition, the development of recurrent or de novo cancers following surgical resection is common. These issues have led investigators to evaluate the benefit of neoadjuvant and adjuvant treatment strategies aimed at improving resectability rates and decreasing recurrence rates. While high-level evidence to guide treatment decision making is lacking, recent advances in locoregional and systemic therapies, including antiviral treatment and immunotherapy, raise the prospect of novel approaches that may improve the outcomes of patients with HCC. In this review, we evaluate the evidence for various neoadjuvant and adjuvant therapies and discuss opportunities for future clinical and translational research.

[D-Ala2, D-Leu5] Enkephalin Improves Liver Preservation During Normothermic Ex Vivo Perfusion.

BACKGROUND: Meeting the metabolic demands of donor livers using normothermic ex vivo liver perfusion (NEVLP) preservation technology is challenging. The delta opioid agonist [D-Ala2, D-Leu5] enkephalin (DADLE) has been reported to decrease the metabolic demand in models of ischemia and cold preservation. We evaluated the therapeutic potential of DADLE by investigating its ability to protect against oxidative stress and hepatic injury during normothermic perfusion. MATERIALS AND METHODS: Primary rat hepatocytes were used in an in vitro model of oxidative stress to determine the minimum dose of DADLE needed to induce protection and the mechanisms associated with protection. NEVLP was then used to induce injury in rat livers and determine the effectiveness of DADLE in preventing liver injury. RESULTS: In hepatocytes, DADLE was protective against oxidative stress and led to a decrease in phosphorylation of JNK and p38. Naltrindole, a δ-opioid receptor antagonist, blocked this effect. DADLE also activated the PI3K/Akt signaling pathway, and PI3K/Akt inhibition decreased the protective effects of DADLE treatment. In addition, DADLE treatment during NEVLP resulted in lower perfusate alanine aminotransferase and tissue malondialdehyde and better tissue adenosine triphosphate and glutathione. Furthermore, perfusion with DADLE compared with perfusate alone preserved tissue architecture. CONCLUSIONS: DADLE confers protection against oxidative stress in hepatocytes and during NEVLP. These data suggest that the mechanism of protection involved the prevention of mitochondrial dysfunction by opioid receptor signaling and subsequent increased expression of prosurvival/antiapoptotic signaling pathways. Altogether, data suggest that opioid receptor agonism may serve as therapeutic target for improved liver protection during NEVLP.

Intrahepatic Delivery of Pegylated Catalase Is Protective in a Rat Ischemia/Reperfusion Injury Model.

BACKGROUND: Ischemia/reperfusion injury (IRI) can occur during liver surgery. Endogenous catalase is important to cellular antioxidant defenses and is critical to IRI prevention. Pegylation of catalase (PEG-CAT) improves its therapeutic potential by extending plasma half-life, but systemic administration of exogenous PEG-CAT has been only mildly therapeutic for hepatic IRI. Here, we investigated the protective effects of direct intrahepatic delivery of PEG-CAT during IRI using a rat hilar clamp model. MATERIALS AND METHODS: PEG-CAT was tested in vitro and in vivo. In vitro, enriched rat liver cell populations were subjected to oxidative stress injury (H2O2), and measures of cell health and viability were assessed. In vivo, rats underwent segmental (70%) hepatic warm ischemia for 1 h, followed by 6 h of reperfusion, and plasma alanine aminotransferase and aspartate aminotransferase, tissue malondialdehyde, adenosine triphosphate, and GSH, and histology were assessed. RESULTS: In vitro, PEG-CAT pretreatment of liver cells showed substantial uptake and protection against oxidative stress injury. In vivo, direct intrahepatic, but not systemic, delivery of PEG-CAT during IRI significantly reduced alanine aminotransferase and aspartate aminotransferase in a time-dependent manner (P < 0.01, P < 0.0001, respectively, for all time points) compared to control. Similarly, tissue malondialdehyde (P = 0.0048), adenosine triphosphate (P = 0.019), and GSH (P = 0.0015), and the degree of centrilobular necrosis, were improved by intrahepatic compared to systemic PEG-CAT delivery. CONCLUSIONS: Direct intrahepatic administration of PEG-CAT achieved significant protection against IRI by reducing the volume distribution and taking advantage of the substantial hepatic first-pass uptake of this molecule. The mode of delivery was an important factor for protection against hepatic IRI by PEG-CAT.

Validation of Risk Score in Predicting Early Readmissions in Decompensated Cirrhotic Patients: A Model Based on the Administrative Database.

Early readmission in patients with decompensated liver cirrhosis leads to an enormous burden on health care use. A retrospective cohort study using the 2013 and 2014 Nationwide Readmission Database (NRD) was conducted. Patients with a diagnoses of cirrhosis and at least one feature of decompensation were included. The primary outcome was to develop a validated risk model for early readmission. Secondary outcomes were to study the 30-day all-cause readmission rate and the most common reasons for readmission. A multivariable logistic regression model was fit to identify predictors of readmissions. Finally, a risk model, the Mumtaz readmission risk score, was developed for prediction of 30-day readmission based on the 2013 NRD and validated on the 2014 NRD. A total of 123,011 patients were included. The 30-day readmission rate was 27%, with 79.6% of patients readmitted with liver-related diagnoses. Age <65 years; Medicare or Medicaid insurance; nonalcoholic etiology of cirrhosis; ≥3 Elixhauser score; presence of hepatic encephalopathy, ascites, variceal bleeding, hepatocellular carcinoma, paracentesis, or hemodialysis; and discharge against medical advice were independent predictors of 30-day readmission. This validated model enabled patients with decompensated cirrhosis to be stratified into groups with low (<20%), medium, (20%-30%), and high (>30%) risk of 30-day readmissions. Conclusion: One third of patients with decompensated cirrhosis are readmitted within 30 days of discharge. The use of a simple risk scoring model with high generalizability, based on demographics, clinical features, and interventions, can bring refinement to the prediction of 30-day readmission in high-risk patients; the Mumtaz readmission risk score highlights the need for targeted interventions in order to decrease rates of readmission within this population.

En bloc liver-kidney transplantation with renal artery variation using donor splenic artery and left gastric artery as inflow to the kidney: Case report.

INTRODUCTION: En bloc liver-kidney transplantation can be difficult with renal artery variations for which the risk of multiple anastomoses can outweigh the benefits. PRESENTATION OF CASE: This report is the first to describe an en bloc liver-kidney transplantation using a donor kidney with double renal arteries. The indication for a combined liver-kidney transplant was non-alcoholic steatohepatitis (NASH) cirrhosis with chronic kidney disease secondary to hypertension and diabetes compounded by hepato-renal syndrome. The explant pathology was consistent with steatohepatitis, but did have PAS/D-positive intracytoplastic globules which suggest an additional component of alpha-1-antitrypsin deficiency. DISCUSSION: Diminished arterial inflow to the inferior renal pole was noted intraoperatively, requiring re-anastomosis of the inferior renal polar artery to the donor left gastric artery. The post-operative course was uncomplicated with patient discharge on post-operative day six. CONCLUSION: With increasing numbers of simultaneous liver-kidney transplants being performed, kidneys with multiple renal arteries can successfully be transplanted en-bloc without compromising ischemia time.

Total Pancreatectomy and Islet Autotransplantation Following Treated Hepatitis C Infection.

Hepatic parenchymal disease, including chronic viral hepatitis, has traditionally been considered a relative contraindication to islet transplantation as the islets are infused into the recipient's liver. We present a case study of a patient with treated chronic hepatitis C infection (HCV) who safely received an autologous islet transplant following total pancreatectomy with excellent clinical outcomes. The patient was a 60-year-old woman diagnosed with debilitating abdominal pain secondary to chronic pancreatitis and with preserved islet function. She had previously been treated >10 years prior to surgical evaluation with interferon monotherapy for 1 year that led to sustained virologic response, including at the time of surgical evaluation for total pancreatectomy and islet autotransplantation (TPIAT). She underwent comprehensive preoperative evaluation of the liver, including liver biopsy, which showed no significant portal inflammation or fibrosis. Following a multidisciplinary meeting and discussion of the potential risks for the patient, the decision was made to proceed with TPIAT. The patient underwent a standard total pancreatectomy, and an autologous islet dose of 6638 islet equivalents/kg body weight was infused into the liver via the portal vein. Portal vein pressure was monitored throughout the infusion with a transient peak pressure of 27 cm H2O (basal pressure of 14 cm H2O) and final pressure of 23 cm H20 at 10 min post-infusion. Aside from a transient transaminitis, liver enzymes were normal at the time of hospital discharge. At greater than 1 year of follow-up, the patient has improved quality of life, with reduction in narcotic analgesia, remains insulin independent (with normal islet function), and has normal liver function. This case illustrates that islet autotransplant into the liver can be safely performed and suggests that carefully selected patients with liver disease may be eligible for TPIAT.