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Introduction: Renal dysfunction in liver transplant recipients is associated with an increased risk of morbidity and mortality, with an even higher risk among patients requiring renal replacement therapy. There is limited data evaluating rejection outcomes in patients requiring renal replacement therapy after liver transplant. Program evaluation aims: To evaluate the incidence of biopsy-proven acute rejection, recipient and graft survival, infection, renal dysfunction, and immunosuppression practices. Design: This was a single-center, retrospective, cohort study. To be eligible, patients were deceased donor liver transplant recipients ≥18 year of age transplanted between January 2017 and August 2019 who received steroid-only induction and tacrolimus as part of their initial immunosuppression regimen. Results: Recipients that required renal replacement therapy (N  =  86) were compared to those who received no renal replacement therapy (N  =  158). Biopsy-proven acute rejection at 1-year posttransplant was significantly higher among those requiring renal replacement therapy (36% vs 13%, P  < .001). Patient survival at 12 months was 77% for those requiring renal replacement therapy and 94% for those not requiring renal replacement therapy ( P  < .001). Infection (HR 3.8, 95% CI 1.6-8.8; P  < .001), but not rejection (HR 0.7, 95% CI 0.3-1.7; P   =  .5) was an independent predictor of mortality. The use of renal replacement therapy after liver transplant necessitated careful titration of immunosuppression to balance the detrimental risks of infection versus rejection in this high-risk population., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: In the United States, over half of pediatric candidates receive exceptions and status upgrades that increase their allocation model of end-stage liver disease/pediatric end-stage liver disease (MELD/PELD) score above their laboratory MELD/PELD score. We determined whether these "nonstandardized" MELD/PELD exceptions accurately depict true pretransplant mortality risk., Methods: Using data from the Scientific Registry of Transplant Recipients, we identified pediatric candidates (<18 y of age) with chronic liver failure added to the waitlist between June 2016 and September 2021 and estimated all-cause pretransplant mortality with mixed-effects Cox proportional hazards models that treated allocation MELD/PELD and exception status as time-dependent covariates. We also estimated concordance statistics comparing the performance of laboratory MELD/PELD with allocation MELD/PELD. We then compared the proportion of candidates with exceptions before and after the establishment of the National Liver Review Board., Results: Out of 2026 pediatric candidates listed during our study period, 403 (19.9%) received an exception within a week of listing and 1182 (58.3%) received an exception before delisting. Candidates prioritized by their laboratory MELD/PELD scores had an almost 9 times greater risk of pretransplant mortality compared with candidates who received the same allocation score from an exception (hazard ratio 8.69; 95% confidence interval, 4.71-16.03; P < 0.001). The laboratory MELD/PELD score without exceptions was more accurate than the allocation MELD/PELD score with exceptions (Harrell's c-index 0.843 versus 0.763). The proportion of patients with an active exception at the time of transplant decreased significantly after the National Liver Review Board was implemented (67.4% versus 43.4%, P < 0.001)., Conclusions: Nonstandardized exceptions undermine the rank ordering of pediatric candidates with chronic liver failure., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Direct-acting antivirals for the treatment of hepatitis C virus (HCV) have improved outcomes in liver transplant recipients (LTRs). However, the timing of HCV treatment and approach to treating rejection have not been well described. Additionally, pharmacists' roles in these comprehensive areas have not been investigated. Methods: This single-center, retrospective, cohort review compared 1-year graft and patient survival between HCV-positive and HCV-negative LTRs. Secondary endpoints included 1-year rejection rates, HCV sustained virologic response and time to HCV treatment. Results: Ninety-two HCV Nucleic Acid Amplification Test (NAT)-positive LTRs were matched 1:1 to HCV-seronegative LTRs. One-year graft and patient survival were similar between groups. HCV-positive LTRs were more likely to experience biopsy-proven acute rejection (BPAR), and despite treatment with pulse steroids, there was no impact on graft survival or occurrence of fibrosing cholestatic hepatitis (FCH). Time to HCV treatment was 5.4-6.4 months post-transplant, with no treatment failures or impact on graft or patient survival. Conclusions: No difference was seen in graft survival at 1 year between HCV-positive and HCV-seronegative LTRs. Delayed time to treatment of HCV and treatment of rejections in the HCV-positive cohort did not impact outcomes. However, pharmacist-driven protocols could ensure more efficient initiation of HCV treatment in the future.

Steatotic livers represent a potentially underutilized resource to increase the donor graft pool; however, 1 barrier to the increased utilization of such grafts is the heterogeneity in the definition and the measurement of macrovesicular steatosis (MaS). Digital imaging software (DIS) may better standardize definitions to study posttransplant outcomes. Using HALO, a DIS, we analyzed 63 liver biopsies, from 3 transplant centers, transplanted between 2016 and 2018, and compared macrovesicular steatosis percentage (%MaS) as estimated by transplant center, donor hospital, and DIS. We also quantified the relationship between DIS characteristics and posttransplant outcomes using log-linear regression for peak aspartate aminotransferase, peak alanine aminotransferase, and total bilirubin on postoperative day 7, as well as logistic regression for early allograft dysfunction. Transplant centers and donor hospitals overestimated %MaS compared with DIS, with better agreement at lower %MaS and less agreement for higher %MaS. No DIS analyzed liver biopsies were calculated to be >20% %MaS; however, 40% of liver biopsies read by transplant center pathologists were read to be >30%. Percent MaS read by HALO was positively associated with peak aspartate aminotransferase (regression coefficient= 1.04 1.08 1.12 , p <0.001), peak alanine aminotransferase (regression coefficient = 1.04 1.08 1.12 , p <0.001), and early allograft dysfunction (OR= 1.10 1.40 1.78 , p =0.006). There was no association between HALO %MaS and total bilirubin on postoperative day 7 (regression coefficient = 0.99 1.01 1.04 , p =0.3). DIS provides reproducible quantification of steatosis that could standardize MaS definitions and identify phenotypes associated with good clinical outcomes to increase the utilization of steatite livers., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: It has long been debated whether cava anastomosis should be performed with the piggyback technique or cava replacement, with or without veno-venous bypass (VVB), with or without temporary portocaval shunt (PCS) in the setting of liver transplantation., Objectives: To identify whether different cava anastomotic techniques and other maneuvers benefit the recipient regarding short-term outcomes and to provide international expert panel recommendations., Data Sources: Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central., Methods: A systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel (CRD42021240979)., Results: Of 3205 records screened, 307 publications underwent full-text assessment for eligibility and 47 were included in qualitative synthesis. Four studies were randomized control trials. Eighteen studies were comparative. The remaining 25 were single-center retrospective noncomparative studies., Conclusion: Based on existing data and expert opinion, the panel cannot recommend one cava reconstruction technique over another, rather the surgical approach should be based on surgeon preference and center dependent, with special consideration toward patient circumstances (Quality of evidence: Low | Grade of Recommendation: Strong). The panel recommends against routine use of vevo-venous bypass (Quality of evidence: Very Low | Grade of Recommendation: Strong) and against the routine use of temporary porto-caval shunt (Quality of evidence: Very Low | Grade of Recommendation: Strong)., (© 2022 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Background: Normothermic machine perfusion (NMP) allows viability assessment and potential resuscitation of donor livers prior to transplantation. The immunological effect of NMP on liver allografts is undetermined, with potential implications on allograft function, rejection outcomes and overall survival. In this study we define the changes in immune profile of human livers during NMP., Methods: Six human livers were placed on a NMP device. Tissue and perfusate samples were obtained during cold storage prior to perfusion and at 1, 3, and 6 hours of perfusion. Flow cytometry, immunohistochemistry, and bead-based immunoassays were used to measure leukocyte composition and cytokines in the perfusate and within the liver tissue. Mean values between baseline and time points were compared by Student's t-test., Results: Within circulating perfusate, significantly increased frequencies of CD4 T cells, B cells and eosinophils were detectable by 1 hour of NMP and continued to increase at 6 hours of perfusion. On the other hand, NK cell frequency significantly decreased by 1 hour of NMP and remained decreased for the duration of perfusion. Within the liver tissue there was significantly increased B cell frequency but decreased neutrophils detectable at 6 hours of NMP. A transient decrease in intermediate monocyte frequency was detectable in liver tissue during the middle of the perfusion run. Overall, no significant differences were detectable in tissue resident T regulatory cells during NMP. Significantly increased levels of pro-inflammatory and anti-inflammatory cytokines were seen following initiation of NMP that continued to rise throughout duration of perfusion., Conclusions: Time-dependent dynamic changes are seen in individual leukocyte cell-types within both perfusate and tissue compartments of donor livers during NMP. This suggests a potential role of NMP in altering the immunogenicity of donor livers prior to transplant. These data also provide insights for future work to recondition the intrinsic immune profile of donor livers during NMP prior to transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Edobor, Lysandrou, Mirle, Sadek, Johnston, Piech, Rose, Hart, Amundsen, Jendrisak, Millis, Donington, Madariaga, Barth, di Sabato, Shanmugarajah and Fung.)

Adverse clinical outcomes related to SARS-CoV-2 infection among liver transplant (LTx) recipients remain undefined. We performed a meta-analysis to determine the pooled prevalence of outcomes among hospitalized LTx recipients with COVID-19. A database search of literature published between December 1, 2019, and November 20, 2020, was performed per PRISMA guidelines. Twelve studies comprising 517 hospitalized LTx recipients with COVID-19 were analyzed. Common presenting symptoms were fever (71%), cough (62%), dyspnea (48%), and diarrhea (28%). Approximately 77% (95% CI, 61%-93%) of LTx recipients had a history of liver cirrhosis. The most prevalent comorbidities were hypertension (55%), diabetes (45%), and cardiac disease (21%). In-hospital mortality was 20% (95% CI, 13%-28%) and rose to 41% (95% CI, 19%-63%) (P < 0.00) with ICU admission. Additional subgroup analysis demonstrated a higher mortality risk in the elderly (>60-65 years) (OR 4.26; 95% CI, 2.14-8.49). There was no correlation in respect to sex or time since transplant. In summary, LTx recipients with COVID-19 had a high prevalence of dyspnea and gastrointestinal symptoms. In-hospital mortality was comparable to non-transplant populations with similar comorbidities but appeared to be less than what is reported elsewhere for cirrhotic patients (26%-40%). Importantly, the observed high case fatality in the elderly could be due to age-associated comorbidities., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Postoperative severe cardiopulmonary failure carries a high rate of mortality. Extracorporeal membrane oxygenation (ECMO) can be used as a salvage therapy when conventional therapies fail., Methods: We retrospectively reviewed our experience with ECMO support in the early postoperative period after liver transplant between September 2011 and May 2016., Results: Out of 537 liver transplants performed at our institution, seven patients required ECMO support with a median age of 52 and a median MELD score of 28. Veno-venous ECMO was used in four patients with severe respiratory failure while the rest required veno-arterial ECMO for circulatory failure. The median time from transplant to cannulation was 3 days with a median duration of ECMO support of 7 days. All patients except one were successfully decannulated. The median hospital length of stay was 58 days with an in-hospital mortality of 28.6%., Conclusion: Extracorporeal membrane oxygenation can be considered a viable rescue therapy in the setting of severe postoperative cardiopulmonary failure. Extracorporeal membrane oxygenation therapy was successful in saving patients who were otherwise unsalvageable., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Despite the frequency of liver transplantation in alcoholic recipients, the burden of co-occurring psychosocial comorbidities remains poorly defined., Methods: A survey study was conducted to examine demographic, substance use, mental health, and social support variables among liver transplant (LT) recipients with alcoholic liver disease (ALD) (LT-ALD: n  =  67). Survey completers (n  =  67) were compared to a sample of liver transplant recipients without ALD (LT: n  =  134)., Results: Survey participants (n  =  67) were predominately male, in their mid-fifties, and were retired or on disability. Alcohol consumption during the 6 months prior to transplant was reported by more than a third of participants. Alcohol consumption post-transplant was reported by 21.2% of respondents, with 4.5% of participants reporting "at-risk" levels of post-transplant alcohol use. Illicit drug use prior to transplant was reported by nearly half of participants (47.8%), and 16.4% reported illicit drug use post-transplant. Approximately half of the sample reported a history of cigarette smoking, and one-third of respondents (29.2%) reported current cigarette smoking. Participants frequently endorsed mental health symptoms consistent with moderate to severe depression (22.4%) and anxiety (17.9%)., Conclusions: Despite relatively low rates of problematic alcohol use post-transplant, there is a significant burden of disability, substance use, and psychiatric symptomatology in this population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose of Review: This review highlights advances in liver xenotransplantation, focusing on immunologic barriers and mechanisms underlying graft failure and recipient demise, and discussion of recent in-vivo results., Recent Findings: Pig to primate models of liver xenotransplantation have been plagued by thrombocytopenia, anemia, and coagulopathy. It is now known that platelet sequestration is mediated by liver sinusoidal endothelial cells and Kupffer cells in part by asialoglycoprotein receptor 1-driven mechanisms. Xenoantigens, specifically N-glycolylneuraminic acid, play a role in graft injury as well as red blood cell consumption. Finally incompatibilities between coagulation cascade molecules contribute to lethal coagulopathy, but can be counteracted with genetic modifications and coagulation factor supplementation. Survival has markedly increased with this strategy., Summary: An increased understanding of the cellular mechanisms responsible for failure of in-vivo pig to primate liver xenotransplant models has led to improved outcomes, and this recent success supports initial clinical application.

Background: Exertional heatstroke is an extremely rare cause of fulminant hepatic failure. Maximal supportive care has failed to provide adequate survival in earlier studies. This is particularly true in cases accompanied by multiorgan failure., Methods and Materials: Our prospectively collected transplant database was retrospectively reviewed to identify patients undergoing liver transplantation for heatstroke between January 1, 2012, and December 31, 2016. We report 3 consecutive cases of male patients with fulminant hepatic failure from exertional heatstroke., Results: All patients developed multiorgan failure and required intubation, vasopressor support, and renal replacement therapy. All patients were listed urgently for liver transplantation and were supported with the molecular adsorbent recirculating system while awaiting transplantation. All patients underwent liver transplantation alone and are alive and well, with recovered renal function, normal liver allograft function, and no chronic sequelae of their multiorgan failure at more than one year., Conclusion: Extreme heatstroke leading to whole-body organ dysfunction and fulminant liver failure is a complex entity that may benefit from therapy using the Molecular Adsorbent Recirculating System while waiting for liver transplantation as a component of a multidisciplinary, multiorgan system approach., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Transplant surgeons conventionally select against livers displaying high degrees (>30%) of macrosteatosis (MaS), out of concern for primary non-function or severe graft dysfunction. As such, there is relatively limited experience with such livers, and the natural history remains incompletely characterized. We present our experience of transplanted livers with high degrees of MaS and microsteatosis (MiS), with a focus on the histopathologic and clinical outcomes., Methods: Twenty-nine cases were identified with liver biopsies available from both the donor and the corresponding liver transplant recipient. Donor liver biopsies displayed either MaS or MiS ≥15%, while all recipients received postoperative liver biopsies for cause., Results: The mean donor MaS and MiS were 15.6% (range 0%-60%) and 41.3% (7.5%-97.5%), respectively. MaS decreased significantly from donor (M=15.6%) to recipient postoperative biopsies (M=0.86%), P<.001. Similarly, MiS decreased significantly from donor biopsies (M=41.3%) to recipient postoperative biopsies (M=1.8%), P<.001. At a median of 68 days postoperatively (range 4-384), full resolution of MaS and MiS was observed in 27 of 29 recipients., Conclusions: High degrees of MaS and MiS in donor livers resolve in recipients following liver transplantation. Further insight into the mechanisms responsible for treating fatty liver diseases could translate into therapeutic targets., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Lecithin cholesterol acyl transferase (LCAT) deficiency is a rare autosomal recessive disorder of lipoprotein metabolism that results in end-stage renal disease (ESRD) necessitating transplantation. As LCAT is produced in the liver, combined kidney and liver transplantation was proposed to cure the clinical syndrome of LCAT deficiency., Methods: A 29-year-old male with ESRD secondary to LCAT deficiency underwent a sequential kidney-liver transplantation from the same living donor (LD). One year following the kidney transplant, auxiliary partial orthotopic liver transplant (APOLT) of a left lateral segment from the same donor was performed., Results: At 5 years follow-up, there have been no major complications, readmissions, or rejection episodes. Serum lipid abnormalities recurred within the first year, but liver and kidney allograft function remains intact., Conclusion: Few cases of sequential transplantation from the same LD have been performed in adults. This is the first APOLT and multi-organ transplant performed for LCAT deficiency. Sequential organ transplant from the same LD for ESRD secondary to a metabolic disorder of the liver is feasible in adults and should be further investigated., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Although transplantation of genetically modified porcine livers into baboons has yielded recipient survival for up to 7 days, survival is limited by profound thrombocytopenia, which becomes manifest almost immediately after revascularization, and by subsequent coagulopathy. Porcine von Willebrand's factor (VWF), a glycoprotein that adheres to activated platelets to initiate thrombus formation, has been shown to constitutively activate human platelets via their glycoprotein Ib (GPIb) receptors. Here, we report our pig-to-primate liver xenoperfusion model and evaluate whether targeting the GPIb-VWF axis prevents platelet sequestration., Methods: Twelve baboons underwent cross-circulation with the following extracorporeal livers: one allogeneic control with a baboon liver, 4 xenogeneic controls with a GalTKO.hCD46 pig liver, 3 GalTKO.hCD46 pig livers in recipients treated with αGPIb antibody during perfusion, and 4 GalTKO.hCD46 pig livers pre-treated with D-arginine vasopressin (DDAVP) in recipients treated with αGPIb antibody during perfusion., Results: All perfused livers appeared grossly and macroscopically normal and produced bile. Xenograft liver perfusion experiments treated with αGPIb antibody may show less platelet sequestration during the initial 2 h of perfusion. Portal venous resistance remained constant in all perfusion experiments. Platelet activation studies demonstrated platelet activation in all xenoperfusions, but not in the allogeneic perfusion., Conclusion: These observations suggest that primate platelet sequestration by porcine liver and the associated thrombocytopenia are multifactorial and perhaps partially mediated by a constitutive interaction between porcine VWF and the primate GPIb receptor. Control of platelet sequestration and consumptive coagulopathy in liver xenotransplantation will likely require a multifaceted approach in our clinically relevant perfusion model., (© 2014 John Wiley & Sons A/S.)

Background: Perioperative renal dysfunction in liver transplant recipients complicates maintenance immunosuppressive therapy, particularly in patients with hepatitis C. Calcineurin inhibitors exacerbate renal dysfunction and mammalian target-of-rapamycin inhibitors are generally avoided because of perceived perioperative risks. The authors' experience with seven liver transplant patients who received belatacept and mycophenolic acid maintenance immunosuppression is reported., Methods: A retrospective review of adult liver transplant recipients with hepatitis C receiving belatacept was conducted under Institutional Review Board approval. All patients were Epstein-Barr virus IgG seropositive. The primary endpoint was patient and graft survival, with secondary endpoints including the incidence of acute rejection, degree of renal function recovery, and occurrence of major side effects., Results: Between December 19, 2011 and January 25, 2013, seven liver transplant recipients with hepatitis C received belatacept immunosuppression in the perioperative period. The primary indication for belatacept was perioperative renal dysfunction. Belatacept was initiated between 2 and 90 days posttransplant and the duration of belatacept therapy ranged from 19 to 89 days. Patients were transitioned onto calcineurin inhibitor therapy when they reached chronic kidney disease stage 2 or better. Six-month patient and graft survival was 86%. There was one episode of graft rejection on belatacept therapy in a patient who had also had early rejection before initiation of belatacept., Conclusions: The results in this initial group of patients suggest that belatacept with mycophenolic acid may be a safe maintenance immunosuppression regimen in hepatitis C-positive liver transplant recipients with renal dysfunction, and that this regimen can serve as an effective bridge to calcineurin inhibitor therapy.

Background: Although the LigaSure device is widely used, its use in liver transplantation, where compounding factors of portal hypertension, coagulopathy, and thrombocytopenia exist, is poorly described., Methods: From October 1, 2011, to December 31, 2011, 6 patients underwent liver transplantation with recipient hepatectomy utilizing the LigaSure device. Outcomes using the device were compared with 6 contemporaneous patients in whom the device was not used., Results: Patient demographics, preoperative laboratory values, and Model for End-Stage Liver Disease scores were not different. Recipient hepatectomy was performed, on average, 43 minutes faster using the LigaSure device (P = .02). Although total operative time and intraoperative blood product usage were lower when the LigaSure was used, these differences did not attain statistical significance. Duration of stay and recipient readmission rates were similar., Conclusions: LigaSure vessel sealing is an efficient method for recipient hepatectomy in liver transplantation. Vessel sealing of caval, portal, and other structures can be safely performed in the setting of end-stage liver disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: Cytomegalovirus (CMV) infection is responsible for significant morbidity and mortality among solid organ transplant recipients. Prophylaxis using valganciclovir (VGCV) in orthotopic liver transplant (OLT) recipients is not approved by the Food and Drug Administration and its use is controversial. This study aimed to evaluate the effectiveness of VGCV in CMV prophylaxis in OLT recipients., Methods: We carried out a retrospective, single-centre study including all OLT procedures performed during 2005-2008. Patients with early death (at ≤ 30 days), without CMV serology or prophylaxis, or with follow-up of <1 year were excluded., Results: The overall incidence of CMV disease was 6% (n= 9). The ganciclovir (GCV) and VGCV groups had similar incidences of CMV disease (4.6% vs. 7.0%; P= 0.4) and similar distributions of disease presentation (CMV syndrome vs. tissue-invasive CMV; P= 0.4). Incidences of CMV infection, as well as disease presentation, were similar between the high-risk (CMV D+/R-) and non-high-risk groups (P= 0.16). Although acute cellular rejection occurred more frequently in patients who developed CMV disease (P= 0.005), overall survival in these patients did not differ from that in patients who did not develop CMV infection (P= 0.5)., Conclusions: Valganciclovir is an effective antiviral for the prevention of CMV disease in liver transplant recipients. Our data support its use in high-risk OLT patients.

Liver transplantation is performed based on ABO blood type compatibility without dependence on crossmatch results. Combined liver-kidney transplantation (CLKT) is similarly performed without dependence of crossmatch results as the liver is thought to confer protection to the renal allograft against alloantibody. We report a case of CLKT in a sensitized patient with antibody-mediated rejection (AMR) of the renal allograft. AMR was confirmed with C4d staining and serial monitoring of donor-specific antibody (DSA). Despite intensive therapy directed against AMR and the presence of the liver allograft, the patient demonstrated increasing titers of alloantibody, never demonstrated adequate renal function, and ultimately expired after two months. This result demonstrates the potential for AMR of the renal allograft in sensitized recipients of CLKT., (© 2009 John Wiley & Sons A/S.)