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Purpose: Our study hypothesis was that once daily dosing of extended‐release tacrolimus (XRT) would be a safe and effective immunosuppression (IS) with the potential to decrease adverse events (AEs) associated with immediate release tacrolimus (IRT) after liver transplantation (LT). Methods: All patients receiving LT at our center received rabbit anti‐thymocyte globulin (RATG) induction therapy. Eligible patients were randomized in a 1:1 fashion to receive either XRT or IRT. Antimicrobial prophylaxis was the same between arms, and both groups received an antimetabolite for the first 6 months following LT. Patients were then followed at pre‐determined study intervals for the following year after LT. We administered the RAND‐36SF survey to assess patient's health‐related quality of life at pre‐determined intervals. All analysis was performed with an intention to treat basis. Results: We screened 194 consecutive patients and enrolled 110. Our control and study arms were well matched. Transplant characteristics were similar between groups. At all timepoints, both arms had similar serum creatinine and estimated glomerular filtration rate (eGFR), calculated by MDRD6 equation, with post‐transplant GFRs between 60 and 70 mL/min/1.73 m2. Tacrolimus trough levels were similar between arms. The XRT arm had fewer AEs (166) and fewer serious AEs (70) compared to IRT (201 and 99, respectively). AEs most commonly were renal, infectious, or gastrointestinal in nature. While not statistically significant, XRT was held temporarily (25 vs. 35 cases) or discontinued (3 vs. 11 cases) less frequently than IRT and had fewer instances of rejection (7 vs. 12 cases). Conclusion: This analysis showed that XRT is safe and effective as de novo maintenance IS in a steroid‐free protocol with RATG. [ABSTRACT FROM AUTHOR]

Background: The virologic and histologic outcomes of a hepatitis C virus (HCV)–infected liver graft into an HCV‐negative recipient are not well understood. We aimed to evaluate the sustained virologic response (SVR) rate and the liver histology at 1 year post‐Orthotopic liver transplantation (OLT) with an HCV‐infected graft. Methods: A total of 33 patients received the HCV antibody (Ab)+/nucleic acid amplification test (NAT)+ graft. Of these patients, 23 were HCV‐negative recipients and 10 were HCV‐positive recipients. The 1‐year biopsy data were available for 24 patients: 15 patients in HCV‐negative group who received an HCV Ab+/NAT+graft and 9 patients in HCV‐positive group who received an HCV Ab+/NAT+ graft. Patients with (+) HCV ribonucleic acid (RNA) were started on direct‐acting antiviral (DAA) treatment approximately 107 days after OLT using either a Glecaprevir‐Pibrentasvir or Sofosbuvir‐Velpatasvir or Sofosbuvir‐Ledipasvir. Results: All patients (n = 33) were treated with DAA and achieved SVR. The 1‐year post‐OLT liver biopsies were available in 24 patients: 9 patients had F1 and F2 fibrosis and 17 patients had minimal to moderate inflammation. There was no statistical difference in fibrosis and inflammation between the HCV‐negative vs. HCV‐positive recipients. All patients who received the NAT+ graft developed viremia and subsequently achieved SVR with treatment. Conclusion: At 1 year protocol liver biopsy, patients had inflammation consistent with viral hepatitis despite the successful eradication of HCV. [ABSTRACT FROM AUTHOR]

De novo Donor Specific Antibodies (DSA) are considered as a risk factor for the kidney allograft outcomes in recipients after simultaneous liver–kidney transplantation (SLKT). We hypothesized that length of hospital stay (LOS) might be associated with de novo DSA development of due to the increased likelihood of receiving blood transfusions with reduced immunosuppressive regimens. This study is a single-center, retrospective cohort study consisting of 85 recipients who underwent SLKT from 2009 to 2018 in our hospital. We divided the patients into two groups according to LOS [long hospital stay (L) group (LOS >14 days) and short hospital stay (S) group (LOS ≤14 days)]. Propensity score (PS) has been created using logistic regression to predict LOS greater than median of 14 days. The association between the presence of de novo DSA and LOS was assessed by logistic regression models adjusted for PS. The mean age at transplantation of the entire cohort was 55.5 ± 10.1 years. Sixty percent of the recipients were male and Caucasian. Median LOS in (L) group was three-fold longer than (S) group [L: median 30 days (IQR: 21–52), S: median 8.5 days (IQR: 7–11)]. Eight patients developed de novo DSA after SLKT (9.4%), all of them were in (L) group. Longer LOS was significantly associated with higher risk of development of de novo DSA in unadjusted (OR+ each 5 days: 1.09, 95% CI:1.02–1.16) and PS adjusted (OR+ each 5 days: 1.11, 95% CI:1.02–1.21) analysis. Longer hospitalization is significantly associated with the development of de novo DSA in SLKT. [ABSTRACT FROM AUTHOR]

Background: The utility of ex vivo Magnetic resonance imaging proton density fat fraction (MRI-PDFF) in donor liver fat quantification is unknown. Purpose: To evaluate the diagnostic accuracy and utility in predicting early allograft dysfunction (EAD) of ex vivo MRI-PDFF measurement of fat in deceased donor livers using histology as the gold standard. Methods: We performed Ex vivo, 1.5 Tesla MRI-PDFF on 33 human deceased donor livers before implantation, enroute to the operating room. After the exclusion of 4 images (technical errors), 29 MRI images were evaluable. Histology was evaluable in 27 of 29 patients. EAD was defined as a peak value of aminotransferase >2000 IU/mL during the first week or an INR of ≥1.6 or bilirubin ≥10 mg/dL at day 7. Results: MRI-PDFF values showed a strong positive correlation (Pearson's correlation coefficient) when histology (macro-steatosis) was included (r = 0.78, 95% confidence interval 0.57‐0.89, p<0.0001). The correlation appeared much stronger when macro plus micro-steatosis were included (r = 0.87, 95% confidence interval 0.72‐0.94, p<0.0001). EAD was noted in 7(25%) subjects. AUC (Area Under the Curve) for macro steatosis (histology) predicted EAD in 73% (95% CI: 48–99), micro plus macro steatosis in 76% (95% CI: 49–100). AUC for PDFF values predicted EAD in 67(35–98). Comparison of the ROC curves in a multivariate model revealed, adding MRI PDFF values to macro steatosis increased the ability of the model in predicting EAD (AUC: 79%, 95% CI: 59–99), and addition of macro plus micro steatosis based on histology predicted EAD even better (AUC: 90%: 79–100, P = 0.054). Conclusion: In this pilot study, MRI-PDFF imaging showed potential utility in quantifying hepatic steatosis ex-vivo donor liver evaluation and the ability to predict EAD related to severe allograft steatosis in the recipient. [ABSTRACT FROM AUTHOR]

Summary: There is a dearth of published data regarding the presence of post‐transplant donor‐specific antibodies (DSA), especially C1q‐binding DSA (C1q+DSA), and patient and kidney allograft outcomes in simultaneous liver–kidney transplant (SLKT) recipients. We conducted a retrospective cohort study consisted of 85 consecutive SLKT patients between 2009 and 2018 in our center. Associations between presence of post‐transplant DSA, including persistent and/or newly developed DSA and C1q+DSA, and all‐cause mortality and the composite outcome of mortality, allograft kidney loss, and antibody‐mediated rejection were examined using unadjusted and age and sex‐adjusted Cox proportional hazards and time‐dependent regression models. The mean age at SLKT was 56 years and 60% of the patients were male. Twelve patients (14%) had post‐transplant DSA and seven patients (8%) had C1q+DSA. The presence of post‐transplant DSA was significantly associated with increased risk of mortality (unadjusted model: Hazard Ratio (HR) = 2.72, 95% confidence interval (CI): 1.06–6.98 and adjusted model: HR = 3.20, 95% CI: 1.11–9.22) and the composite outcome (unadjusted model: HR = 3.18, 95% CI: 1.31–7.68 and adjusted model: HR = 3.93, 95% CI: 1.39–11.10). There was also higher risk for outcomes in recipients with C1q+DSA compared the ones without C1q+DSA. Post‐transplant DSA is significantly associated with worse patient and kidney allograft outcomes in SLKT. Further prospective and large cohort studies are warranted to better assess these associations. [ABSTRACT FROM AUTHOR]

Abstract: Background: Sorafenib has shown survival benefits in patients with advanced HCC; however, limited data are available on its role in OLT recipients with advanced HCC in the explant. Aim: Evaluate the role of preemptive sorafenib therapy on HCC recurrence and survival after OLT with advanced HCC on explant pathology. Methods: We retrospectively reviewed the outcome after OLT of all HCC recipients with advanced HCC in the explant pathology from 04/2006 to 12/2012 based on preemptive treatment with sorafenib. Results: During the observation period, 217 HCC recipients underwent OLT; 50 explants revealed advanced HCC. After exclusion of 5 patients who were lost to follow‐up, 45 LT recipients were finally included for analysis. Recipients were grouped as sorafenib Gr (N = 25) and nonsorafenib Gr (N = 20). Both recurrence‐free survival (RFS) (P = .67) and overall survival were similar between groups (P = .53) on Kaplan‐Meier analysis. Additionally, sorafenib use was neither associated with HCC recurrence‐free survival (HR 0.74, 95% CI [0.32‐1.70]; P = .48) nor overall survival (HR 0.92, 95% CI [0.39‐2.15], P = .84) on multivariate Cox proportional hazard model with sorafenib use as time‐varying covariates. Conclusion: Preemptive treatment with sorafenib in OLT recipients with high‐risk features in explant does not improve HCC recurrence‐free or overall survival. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) is a common posttransplant infection, most commonly seen in settings of excessive immunosuppression. Before the advent of CMV specific antiviral therapies, the standard treatment approaches for CMV disease were immunosuppression reductions to let the transplant recipient mount an immunologic response against CMV. Additionally, CMV is rarely identified as causing stricturing enteritis and has not previously been reported as causing stricturing enteritis in an adult transplant recipient. All identified reports of stricturing CMV enteritis have been reported in either pediatric patient populations or those with severe immunosuppression from human immunodeficiency virus and acquired immune deficiency syndrome. Our report presents the unusual case of an adult liver transplant recipient many years after transplant and on minimal immunosuppression with mycophenolate alone who developed stricturing CMV enteritis. [ABSTRACT FROM AUTHOR]

Hemobilia, or hemorrhage into the biliary system, is an unusual cause of gastrointestinal bleeding most commonly seen in accidental or iatrogenic trauma. We present the rare case of a 43-year-old gentleman who presents with an intrahepatic pseudoaneurysm caused by cholecystitis. The management of the hemobilia was technically challenging requiring multiple interventional procedures. We review the pathophysiology and treatment strategies for this rare case of gastrointestinal hemorrhage. [ABSTRACT FROM AUTHOR]

Introduction and Objective: The impact of pretransplant donor-specific antibodies (DSAs), especially class II DSAs, on kidney allograft outcomes remains unclear in simultaneous liver-kidney transplantation (SLKT) recipients., Methods: We examined 85 recipients who consecutively underwent SLKT between 2009 and 2018 in our center. Associations between pretransplant DSA and worsening kidney function (WKF), kidney allograft loss, composite kidney outcome (WKF and/or antibody-mediated rejection and/or death-censored kidney allograft loss), death with functioning graft, and overall mortality were examined in survival analysis. WKF was defined as an eGFR decrease of 30% or greater from baseline, or 2 or more episodes of proteinuria, at least 90 days apart from each other., Results: The mean age at SLKT was 56 ± 10 years, and 62% of the recipients were male. More than one quarter (26%) of our recipients were African American. The 2 major causes of end-stage liver disease were hepatitis C (28%) and alcoholic hepatitis (26%). Nineteen recipients (22%) had pretransplant DSAs at the time of SLKT. The DSA(+) group and DSA(-) group had similar risk of WKF (unadjusted model: hazard ratio [HR] = 0.77, 95% confidence interval [CI]: 0.29-2.05 and adjusted model: HR = 0.36, 95% CI: 0.12-1.08); similar risk of composite kidney outcome (unadjusted model: HR = 1.04, 95% CI: 0.45-2.43 and adjusted model: HR = 0.53, 95% CI: 0.20-1.39); and similar risk of overall death (unadjusted model: HR = 1.23, 95% CI: 0.45-3.36 and adjusted model: HR = 1.28, 95% CI: 0.42-3.87). We found similar results when comparing different DSA subclasses (class I and II DSAs) with recipients without DSAs., Conclusions: The presence of pretransplant DSAs was not associated with worse kidney allograft outcomes from our single-center experience. Further prospective larger studies are strongly warranted., (© 2020 S. Karger AG, Basel.)

Background: Despite substantial evidence demonstrating clear benefit, rates of preemptive kidney transplantation (PreKTx) remain low in the United States. Our goal was to identify barriers to PreKTx., Methods: Using a telephone-administered questionnaire including questions about barriers, timing of referral, timing of education, we retrospectively studied first living donor kidney transplant recipients (2006-2010) at Mayo Clinic, Rochester, MN. Of 235 patients, 145 (62%) responded to the questionnaire (74 PreKTx and 71 non-PreKTx). We compared categorical data with Fisher exact test and median times with Wilcoxon rank sum test., Results: Polycystic kidney disease (PCKD), longer median time between diagnosis and transplant, and time between education about transplant and transplant correlated with PreKTx ( P < 0.01). The presence of at least 1 patient-identified barrier (lack of referral, financial barriers, medical barriers, no identified living donor and donor evaluation delays) was associated with non-PreKTx (0.034) though no single barrier predominated. Age, education level, insurance status and source of referral (primary care, nephrology, and nonphysician referral) were not associated with the rate of PreKTx. Univariate logistic regression identified white race, PCKD, and increased time from diagnosis as factors favoring PreKTx; PCKD and increased time remained significant factors after multivariate analysis., Conclusions: Even among a patient population that is primarily white, educated, and has a spouse or first-degree relative donor, PreKTx rates remain concerningly low. Increased time between diagnosis or education and transplant are predictors of PreKTx. Greater emphasis on transplant education earlier in the stages of chronic kidney disease and community outreach from transplant centers may help to increase the rate of PreKTx., Competing Interests: The authors declare no funding or conflicts of interest.

Background: Hepatitis C virus (HCV) infection is thought to be associated with immune dysfunction. We hypothesized that HCV status would be associated with increased infectious complications in the surgical intensive care unit (SICU)., Methods: All patients admitted to our SICU between 2008 and 2012 were included. We evaluated 90-day mortality and infectious complications in the SICU. Multivariate logistic regression was performed to identify predictors of infectious complications and 90-day mortality., Results: A total of 1,941 patients were included. The HCV-positive group had a higher overall incidence of infectious complications (25% vs 18%), particularly ventilator-associated pneumonia (VAP) and bacteremia. The increased incidences of VAP and bacteremia persisted when cirrhotic patients were excluded. Prolonged intubation (Odds Ratio [OR] = 2.1), abdominal surgery (OR = 1.6), and model for end-stage liver disease ≥ 15 (OR = 1.4) were independent predictors of SICU infectious complications., Conclusions: The HCV-positive group had an increased incidence of infectious complications in the SICU, particularly VAP and bacteremia. This effect persisted when cirrhotic patients were excluded., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Flavohemoglobins metabolize nitric oxide (NO) to nitrate and protect bacteria and fungi from NO-mediated damage, growth inhibition, and killing by NO-releasing immune cells. Antimicrobial imidazoles were tested for their ability to coordinate flavohemoglobin and inhibit its NO dioxygenase (NOD) function. Miconazole, econazole, clotrimazole, and ketoconazole inhibited the NOD activity of Escherichia coli flavohemoglobin with apparent K(i) values of 80, 550, 1,300, and 5,000 nM, respectively. Saccharomyces cerevisiae, Candida albicans, and Alcaligenes eutrophus enzymes exhibited similar sensitivities to imidazoles. Imidazoles coordinated the heme iron atom, impaired ferric heme reduction, produced uncompetitive inhibition with respect to O(2) and NO, and inhibited NO metabolism by yeasts and bacteria. Nevertheless, these imidazoles were not sufficiently selective to fully mimic the NO-dependent growth stasis seen with NOD-deficient mutants. The results demonstrate a mechanism for NOD inhibition by imidazoles and suggest a target for imidazole engineering.

Nitric oxide (NO) is a poison, and organisms employ diverse systems to protect against its harmful effects. In Escherichia coli, ygaA encodes a transcription regulator (b2709) controlling anaerobic NO reduction and detoxification. Adjacent to ygaA and oppositely transcribed are ygaK (encoding a flavorubredoxin (flavoRb) (b2710) with a NO-binding non-heme diiron center) and ygbD (encoding a NADH:(flavo)Rb oxidoreductase (b2711)), which function in NO reduction and detoxification. Mutation of either ygaA or ygaK eliminated inducible anaerobic NO metabolism, whereas ygbD disruption partly impaired the activity. NO-sensitive [4Fe-4S] (de)hydratases, including the Krebs cycle aconitase and the Entner-Doudoroff pathway 6-phosphogluconate dehydratase, were more susceptible to inactivation in ygaK or ygaA mutants than in the parental strain, and these metabolic poisonings were associated with conditional growth inhibitions. flavoRb (NO reductase) and flavohemoglobin (NO dioxygenase) maximally metabolized and detoxified NO in anaerobic and aerobic E. coli, respectively, whereas both enzymes scavenged NO under microaerobic conditions. We suggest designation of the ygaA-ygaK-ygbD gene cluster as the norRVW modulon for NO reduction and detoxification.