Setting Of Liver Transplantation Research Articles

Liver Transplantation from Elderly Donors (≥85 Years Old).

Despite the ongoing trend of increasing donor ages in liver transplantation (LT) setting, a notable gap persists in the availability of comprehensive guidelines for the utilization of organs from elderly donors. This study aimed to evaluate the viability of livers grafts from donors aged ≥85 years and report the post-LT outcomes compared with those from "ideal" donors under 40 years old. Conducted retrospectively at a single center from 2005 to 2023, this study compared outcomes of LTs from donors aged ≥85 y/o and ≤40 y/o, with the propensity score matching to the recipient's gender, age, BMI, MELD score, redo-LT, LT indication, and cause of donor death. A total of 76 patients received grafts from donors ≥85 y/o and were compared to 349 liver grafts from donors ≤40 y/o. Prior to PSM, the 5-year overall survival was 63% for the elderly group and 77% for the young group (p = 0.002). After PSM, the 5-year overall survival was 63% and 73% (p = 0.1). A nomogram, developed at the time of graft acceptance and including HCC features, predicted 10-year survival after LT using a graft from a donor aged ≥85. In the context of organ scarcity, elderly donors emerge as a partial solution. Nonetheless, without proper selection, LT using very elderly donors yields inferior long-term outcomes compared to transplantation from very young donors ≤40 y/o. The resulting nomogram based on pre-transplant criteria allows for the optimization of elderly donor/recipient matching to achieve satisfactory long-term results, in addition to traditional matching methods.

NLRP3 Inflammasome in Acute and Chronic Liver Diseases.

NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is an intracellular complex that upon external stimuli or contact with specific ligands, recruits other components, forming the NLRP3 inflammasome. The NLRP3 inflammasome mainly mediates pyroptosis, a highly inflammatory mode of regulated cell death, as well as IL-18 and IL-1β production. Acute and chronic liver diseases are characterized by a massive influx of pro-inflammatory stimuli enriched in reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs) that promote the assemblage and activation of the NLRP3 inflammasome. As the major cause of inflammatory cytokine storm, the NLRP3 inflammasome exacerbates liver diseases, even though it might exert protective effects in regards to hepatitis C and B virus infection (HCV and HBV). Here, we summarize the current knowledge concerning NLRP3 inflammasome function in both acute and chronic liver disease and in the post liver transplant setting, focusing on the molecular mechanisms involved in NLRP3 activity.

Recovery of cardiac electrophysiological alterations by heart rate complexity based on multiscale entropy following liver transplantation

Autonomic nervous dysfunction is a known cardiac sequalae in patients with end-stage liver disease and is associated with a poor prognosis. Heart rate analysis using nonlinear models such as multiscale entropy (MSE) or complexity may identify marked changes in these patients where conventional heart rate variability (HRV) measurements do not. To investigate the application of heart rate complexity (HRC) based on MSE in liver transplantation settings. Thirty adult recipients of elective living donor liver transplantation were enrolled. HRV parameters using conventional HRV analysis and HRC analysis were obtained at the following time points: (1) 1 day before surgery, (2) postoperative day (POD) 7, (3) POD 14, (4) POD 90, and (5) POD 180. Preoperatively, patients with MELD score ≥ 25 had significantly lower HRC compared to patients with lower MELD scores. This difference in HRC disappeared by POD 7 following liver transplantation and subsequent analyses at POD 90 and 180 continued to show no significant difference. Our results indicated a significant negative correlation between HRC based on MSE analysis and liver disease severity preoperatively, which may be more sensitive than conventional linear HRV analysis. HRC in patients with MELD score ≧ 25 improved over time and became comparable to those with MELD < 25 as early as in 7 days.

Intraoperative indocyanine green fluorescence imaging to predict early hepatic arterial complications after liver transplantation.

In liver transplantation (LT) setting, to propose an innovative intraoperative criterion to judge arterial flow abnormality that may lead to early hepatic arterial occlusion, i.e. thrombosis or stenosis, when left untreated and to carry out re-anastomosis. After liver graft implantation, and after ensuring that there is no abnormality on the Doppler ultrasound (qualitative and quantitative assessment), we intraoperatively injected indocyanine green dye (ICG, 0.01mg/Kg) and we quantified the fluorescence signal at the graft pedicle using ImageJ software. From the obtained images of 89 adult patients transplanted in our center between September 2017 and April 2019, we constructed fluorescence intensity curves of the hepatic arterial signal, and examined their relationship with the occurrence of early hepatic arterial occlusion (thrombosis or stenosis). Early hepatic arterial occlusion occurred in seven patients (7.8%), including three thrombosis and four stenosis. Among various parameters of the flow intensity curve analyzed, the ratio of peak to plateau (RPP) fluorescence intensity and the jagged wave pattern at the plateau phase were closely associated with this dreaded event. By combining RPP at 0.275 and a jagged wave, we best predicted the occurrence of early hepatic arterial occlusion and thrombosis, with sensitivity/specificity of 0.86/0.98 and 1.00/0.94, respectively. Through a simple composite parameter, indocyanine green fluorescence imaging system is an additional and promising intraoperative modality for identifying transplant recipients at high risk of developing early hepatic arterial occlusion. This tool could assist the surgeon in the decision to redo the anastomosis despite normal Doppler ultrasonography.

Does the Use of Viscoelastic Hemostatic Assays for Periprocedural Hemostasis Management in Liver Disease Improve Clinical Outcomes?

Routine hemostasis parameters such as prothrombin time and fibrinogen are frequently abnormal in patients with chronic liver disease and have been demonstrated to be poor predictors for periprocedural bleeding. Alterations in procoagulant and anticoagulant factors in this population result in a state of rebalanced hemostasis, which is not reflected by routine hemostatic measures. Viscoelastic hemostatic assays (VHA) present a point of care measure of global hemostasis with an emerging role in guiding transfusion in the liver transplant setting. The potential role for VHA in guiding periprocedural transfusion is unknown. Here we critically appraise the available limited evidence on the use of VHA to guide prophylactic treatment in patients with cirrhosis undergoing procedures. We assess whether the impact of a VHA-guided approach improves clinical outcomes. Suggested areas for future research with a focus on clinically relevant outcomes, particularly periprocedural bleeding, are highlighted.

Rejection in the setting of combined Heart and Liver Transplantation

IntroductionEach year the number of combined heart-liver transplants (HLT) increases, with two distinct patient populations proceeding down this pathway. The first are patients with congenital heart disease (CHD), most commonly single ventricle patients palliated with Fontan. The second group are those with long standing congestive hepatopathy, amyloidosis, hemochromatosis, or alcohol induced myopathies and liver disease.One argument for HLT has been the low rate of rejection even among sensitized patients, with reported rejection rates ranging from 0% to 31%. Historically, those with CHD have been highly sensitized which in some cases may prevent or at least delay transplantation. As such, a recent consensus statement by Emamaulee et al. suggest that “there may be an immunological benefit to proceed with HLT with significantly fewer acute cellular and humoral rejection episodes”. The aim of this study is to demonstrate that HLT patients remain at risk for rejection and have required treatment for it. ResultsThere were 15 patients who underwent HLT from January 2017 to February 2022. Of the four patients who did not have CHD, none were considered sensitized, and all underwent induction with basiliximab per our institutional protocol. One of these had rejection. Rejection episodes were identified in four of the 11 CHD patients (36%) patients. ConclusionsIn our study of 15 HLT, including 11 CHD patients (73% denied transplant at ≥ 1 center) demonstrated a higher rate of rejection than previously reported. While theoretically, HLT may mitigate the likelihood of rejection, the risk still exists, and patients benefit from close monitoring commensurate with single organ transplant.

New Antibiotics Against Multidrug-Resistant Gram-Negative Bacteria in Liver Transplantation: Clinical Perspectives, Toxicity, and PK/PD Properties.

Antimicrobial resistance is a growing global health problem, and it is especially relevant among liver transplant recipients where infections, particularly when caused by microorganisms with a difficult-to-treat profile, are a significant cause of morbidity and mortality. We provide here a complete dissection of the antibiotics active against multidrug-resistant Gram-negative bacteria approved over the last years, focusing on their activity spectrum, toxicity profile and PK/PD properties, including therapeutic drug monitoring, in the setting of liver transplantation. Specifically, the following drugs are presented: ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam, cefiderocol, and eravacycline. Overall, studies on the safety and optimal employment of these drugs in liver transplant recipients are limited and especially needed. Nevertheless, these pharmaceuticals have undeniably enhanced therapeutic options for infected liver transplant recipients.

P427 Inflammatory bowel disease after liver transplantation: a retrospective cohort study from Latin America

Abstract Background The management of inflammatory bowel disease (IBD) in the setting of liver transplantation (LT) is a significant challenge. Previous data have described conflicting results on the incidence of relapses, risk of colectomy and post-transplant prognosis. In addition, there is no guidelines to recommend specific immunosuppressive regimens in this scenario. Our aim is to describe the IBD course in a cohort of liver transplanted patients in Latin America. Methods Medical records from two quaternary centers were reviewed using informatics tools to identify patients with Crohn’s Disease (CD) and Ulcerative Colitis (UC), associated with LT, from January 2010 and July 2023. Data on demographics, IBD phenotype, immunosuppressive therapy and infections were extracted. Results Among 1,683 patients that underwent LT, 45 had concomitant IBD diagnosis. Most for them (55%) were diagnosed with IBD prior to the LT. The median age at IBD diagnosis was 45 years and 57% were male. The majority had UC (80%). The causes of LT were primary sclerosing cholangitis in 24 (53.3%) patients, overlapping with autoimmune hepatitis (AIH) in 15 (33.3%), isolated AIH in 9 (20%), AIH with or without primary biliary cholangitis (PBC) in 4 (8.8%), viral hepatitis in 3 (6,6%) and other causes in 2 (4.4%) patients. Regarding immunosuppression, 19 (42.2%) patients were treated with tacrolimus, 10 (22.2%) with tacrolimus and mycophenolate mofetil, 8 (17.7%) with tacrolimus and azathioprine, 3 (6.6%) tacrolimus and everolimus, 3 (6.6%) with mycophenolate mofetil and cyclosporine, 2 (4.4%) patients with cyclosporine monotherapy. Before LT, 13 (28.8%) patients were treated with aminosalicylates and/or thiopurines, while 2 (4.4%) of them were on biologics. After LT, 20 (44.4%) patients required biological therapy, 11 (24.4%) were treated with anti-TNF (infliximab and adalimumab), 5 (11.1%) with vedolizumab, 3 (6.6%) with ustekinumab and 1 with tofacitinib. Seven (15.5%) patients required total colectomy for refractory disease, 75% after LT. Sixteen (35.5%) patients developed serious infections and the most frequent were cholangitis and cytomegalovirus (68.7%). Two patients developed adverse events, such as infliximab-induced autoimmune hepatitis and thrombocytopenic purpura related to the tacrolimus. Eight (17.7%) patients had malignancies, 3 of them related to the baseline conditions such as hepatocellular, gallbladder carcinoma, colorectal cancer, while 4 patients died during the follow-up. Conclusion In our experience, IBD patients undergoing LT exhibited an aggressive disease course and required concomitant biological therapy, despite the ongoing immunosuppressive regimens.

Role of Transjugular Intrahepatic Portosystemic Shunt in the Liver Transplant Setting.

Liver transplantation is currently the only curative therapy for patients with liver cirrhosis. Not all patients in the natural course of the disease will undergo transplantation, but the majority of them will experience portal hypertension and its complications. In addition to medical and endoscopic therapy, a key role in managing these complications is played by the placement of a transjugular intrahepatic portosystemic shunt (TIPS). Some indications for TIPS placement are well-established, and they are expanding and broadening over time. This review aims to describe the role of TIPS in managing patients with liver cirrhosis, in light of liver transplantation. As far as it is known, TIPS placement seems not to affect the surgical aspects of liver transplantation, in terms of intraoperative bleeding rates, postoperative complications, or length of stay in the Intensive Care Unit. However, the placement of a TIPS "towards transplant" can offer advantages in terms of ameliorating a patient's clinical condition at the time of transplantation and improving patient survival. Additionally, the TIPS procedure can help preserve the technical feasibility of the transplant itself. In this context, indications for TIPS placement at an earlier stage are drawing particular attention. However, TIPS insertion in decompensated patients can also lead to serious adverse events. For these reasons, further studies are needed to make reliable recommendations for TIPS in the pre-transplant setting.

Hypothermic oxygenated perfusion in liver transplantation: a meta-analysis of randomized controlled trials and matched studies.

Hypothermic oxygenated machine perfusion (HOPE) is a novel organ-preservation technology designed to optimize organ quality. However, the effects of HOPE on morbidity and mortality after liver transplantation remain unclear. This meta-analysis evaluated the potential benefits of HOPE in liver transplantation. The Embase, Web of Science, PubMed, Cochrane Library, and Scopus databases were searched for articles published up to 15 June 2023 (updated on 12 August 2023). Mean differences (MDs), risk ratios (RRs), and 95% confidence intervals were calculated. Eleven studies encompassing five randomized controlled trials and six matched studies were included, with a total of 1000 patients. HOPE did not reduce the incidence of major postoperative complications (RR 0.80), primary non-function (PNF) (RR 0.54), reperfusion syndrome (RR 0.92), hepatic artery thrombosis (RR 0.92), renal replacement therapy (RR 0.98), length of hospital stay (MD, -1.38 days), 1-year recipient death (RR 0.67), or intensive care unit stay (MD, 0.19 days) after liver transplantation. HOPE reduced the incidence of biliary complications (RR 0.74), non-anastomotic biliary strictures (NAS) (RR 0.34), early allograft dysfunction (EAD) (RR 0.54), and acute rejection (RR 0.54). In addition, HOPE improved the retransplantation (RR 0.42) and 1-year graft loss rates (RR 0.38). Compared with static cold storage (SCS), HOPE can reduce the incidence of biliary complications, NAS, EAD, and acute rejection and retransplantation rate after liver transplantation and improve the 1-year graft loss rate. These findings suggest that HOPE, when compared to SCS, can contribute to minimizing complications and enhancing graft survival in liver transplantation. Further research is needed to investigate long-term outcomes and confirm the promising advantages of HOPE in liver transplantation settings.

Myeloid spatial and transcriptional molecular signature of ischemia-reperfusion injury in human liver transplantation.

Ischemia-reperfusion injury (IRI) is a significant clinical concern in liver transplantation, with a key influence on short-term and long-term allograft and patient survival. Myeloid cells trigger and sustain tissue inflammation and damage associated with IRI, but the mechanisms regulating these activities are unknown. To address this, we investigated the molecular characteristics of intragraft myeloid cells present in biopsy-proven IRI- and IRI+ liver transplants. RNA-sequencing was performed on 80 pre-reperfusion and post-reperfusion biopsies from 40 human recipients of liver transplantation (23 IRI+, 17 IRI-). We used transcriptional profiling and computational approaches to identify specific gene coexpression network modules correlated with functional subsets of MPO+, lysozyme+, and CD68+ myeloid cells quantified by immunohistochemistry on sequential sections from the same patient biopsies. A global molecular map showed gene signatures related to myeloid activation in all patients regardless of IRI status; however, myeloid cell subsets differed dramatically in their spatial morphology and associated gene signatures. IRI- recipients were found to have a natural corticosteroid production and response profile from pre-reperfusion to post-reperfusion, particularly among monocytes/macrophages. The pre-reperfusion signature of IRI+ recipients included acute inflammatory responses in neutrophils and increased translation of adaptive immune-related genes in monocytes/macrophages coupled with decreased glucocorticoid responses. Subsequent lymphocyte activation at post-reperfusion identified transcriptional programs associated with the transition to adaptive immunity found only among IRI+ recipients. Myeloid subset-specific genes and related signaling pathways provide targets for the development of therapeutic strategies aimed at limiting IRI in the clinical setting of liver transplantation.

The Role of Normothermic Machine Perfusion in Extended Criteria Donor Grafts: A New Direction in Liver Graft Assessment and Preservation

Despite improvements in short-term and long-term outcomes of liver transplant patients, the discrepancy between the number of available livers and transplant candidates continues to increase. The use of expanded criteria donors is one strategy that can be used to address donor shortages. In recent years, preservation strategies such as normothermic machine perfusion (NMP) have been explored to improve the preservation of organs and test their viability before transplantation. We reviewed the recent literature and trials assessing the use of NMP in the setting of liver transplantation. Multiple feasibility trials have demonstrated the clinical prospect of NMP and proved its numerous advantages compared to conventional static cold storage. These advantages include preservation and viability assessment of high-risk donor allografts and grafts that would have otherwise been discarded. This review aims to address the topic of liver NMP in the setting of current and future applications in the setting of extended criteria donor grafts.

Sterile inflammation in liver transplantation.

Sterile inflammation is the immune response to damage-associated molecular patterns (DAMPs) released during cell death in the absence of foreign pathogens. In the setting of solid organ transplantation, ischemia-reperfusion injury results in mitochondria-mediated production of reactive oxygen and nitrogen species that are a major cause of uncontrolled cell death and release of various DAMPs from the graft tissue. When properly regulated, the immune response initiated by DAMP-sensing serves as means of damage control and is necessary for initiation of recovery pathways and re-establishment of homeostasis. In contrast, a dysregulated or overt sterile inflammatory response can inadvertently lead to further injury through recruitment of immune cells, innate immune cell activation, and sensitization of the adaptive immune system. In liver transplantation, sterile inflammation may manifest as early graft dysfunction, acute graft failure, or increased risk of immunosuppression-resistant rejection. Understanding the mechanisms of the development of sterile inflammation in the setting of liver transplantation is crucial for finding reliable biomarkers that predict graft function, and for development of therapeutic approaches to improve long-term transplant outcomes. Here, we discuss the recent advances that have been made to elucidate the early signs of sterile inflammation and extent of damage from it. We also discuss new therapeutics that may be effective in quelling the detrimental effects of sterile inflammation.

Liver Interventions in Children

AbstractThis review provides a comprehensive summary of the role of the interventional radiologist in managing liver disorders in children. Interventions are discussed with focus on indications for procedure, technical aspects, and patient management. Recommendations are supported by the most recent evidence and practice experience of the authors in the four subtopics, such as interventions in the post–liver transplant setting, for portal hypertension, for liver tumors, and for vascular anomalies of the liver, with emphasis on congenital portosystemic shunts.

Waiting time dictates impact of frailty: A Spanish multicenter prospective study

Frailty is prevalent in liver transplant (LT) candidates. It is considered an independent predictor of adverse outcomes pre- and post-transplant according to data obtained in the United States. We aimed to externally validate the liver frailty index (LFI) in a multicenter cohort of LT candidates. Outpatients with cirrhosis were prospectively recruited from five Spanish centers (2018-2020). Patients were defined as "frail" by an optimal cut-off of LFI ≥4.5. Patients were followed for at least 6 months to study associations of pre-LT frailty with pre- and post-transplant mortality, length of hospital and intensive care unit (ICU) stays, risk of early (<30 days) and late (30-90 days) post-transplant complications, retransplantation and cardiovascular events. Of 212 patients included, 45 patients (21%) were frail pre-LT, and the median LFI was 3.9 (IQR 3.5-4.4). After a median waiting time of 78 days, 2% died or were delisted for clinical worsening. The LFI at baseline was not predictive of mortality/delisting in LT candidates in univariable or multivariable analyses after adjusting for age and MELD-Na score (hazard ratio 1.48; p= 0.586). In contrast, compared to non-frail patients, frail LT candidates had a significantly higher length of hospital stay (9 vs. 13 days; p= 0.001) and rate of early (<30 days) post-transplant complications (55% vs. 100%; p= 0.021). In the context of a short LT waiting time, frailty does not impact pretransplant mortality and/or delisting. In contrast, LT frailty is predictive of higher post-transplant complication rates and length of hospital stay. Whether strategies aimed at pre- and/or re-habilitation are beneficial in settings with short waiting times needs to be confirmed in prospective studies. Literature is scarce on the actual impact of physical frailty on adverse outcomes in the liver transplant scenario outside North America. Evidence-based justification to extend the use of objective frailty tools in the decision-making processes in other liver transplant settings is needed. This study is the first to evaluate the predictive value of the liver frailty index in outpatients in the European liver transplant setting, showing that in a low MELD, high access system, frailty does not impact pretransplant mortality and/or delisting but is predictive of higher complication rates and longer post-transplant length of stay. In practical ways, physicians should consider physical frailty as a vital sign to be measured systematically and routinely during clinic visits; researchers are encouraged to initiate prospective studies to evaluate the benefit of applying strategies aimed at pre- and or re-habilitation in liver transplant settings with short waiting times.

Liver Transplantation for Porto-sinusoidal Vascular Liver Disorder: Unmet Questions.

We read with great interest a recent international multicenter study by Marta Magaz et al,1 analyzing post-deceased donor liver transplantation outcomes in 50 of 587 porto-sinusoidal vascular disorder (PSVD) patients registered at 28 participating centers from 1990 to 2020. Additionally, 4 of the 28 centers, performing 4322 LTs, reclassified 29 patients as PSVD after reviewing explant histology registries. We have specific essential points to note. First, the risk of progression of PSVD to advanced liver disease is highly variable, but the specific risk factors and the pathogenic mechanisms leading to these complications should have been researched. Given that the diagnosis of PSVD primarily relied on the recognition of “specific” histologic features on good-quality liver biopsies before liver transplantation (LT),2 the histological changes in the 50 explant livers should have been studied and compared with pre-LT liver biopsies to grade the severity of lesions. Theoretically, it makes sense that the degree of histological changes corresponds to the degree of portal hypertension (PHT) and decompensation. Currently, the individual histologic lesions of PSVD are evaluated using a 2-tiered system for the lesion’s absence (score 0) or presence (score 1). In the presence of similar histological lesions, it is imperative to know why some patients with PSVD developed portal hypertension and decompensation, and others did not. Vice versa, does the grading of histological lesions differ for PSVD patients who develop severe PHT and decompensation compared with those who do not? Maybe the authors can study the 50 explants with this perspective and pick up the other subtle differences between decompensated PSVD versus cirrhosis patients. Second, with PSVD being a presinusoidal disorder, probably a higher portal pressure may be required to produce a similar level of ascites than in patients with cirrhosis. Also, PSVD patients commonly have sinusoidal dilation as a finding in liver samples. Hence, it is important to know if the hepatic venous pressure gradient measurement has been done in these 50 decompensated PSVD patients to identify the presence of sinusoidal PHT.3,4 Third, LT was indicated for 2 of 79 PSVD patients with hepatocellular carcinoma. One had a history of previous hepatitis B with negative HBsAg and undetectable DNA before LT. The other patient had type 2 diabetes and showed obliterative portal venopathy and incomplete septal fibrosis. In patients with hepatocellular carcinoma (HCC), it is imperative to consider the possibility of a coexisting second potential trigger of HCC as PSVD is infrequently associated with HCC,5 and the exact etiopathogenesis of HCC in the setting of PSVD is unclear. Also, incomplete septal cirrhosis may represent regressed cirrhosis and may be unrelated to the risk factors of PSVD.6 In this case, let us assume an overlap of PSVD and parenchymal liver disease, but how to determine the respective contribution of each in the development of HCC is unclear. Hence, these 2 HCC patients may not have been included in the study. Fourth, 21 PSVD patients with severe associated conditions had suboptimal 1-y (85.2 versus 74.3%) and 5-y survival (74.8 versus 45.3%). In the deceased donor liver transplantation setting, the principle of nonfutility is also as important as the principle of utility.7 Hence, organ allocation to these patients should be critically appraised.

The interplay between sarcopenia and portal hypertension predicts ascites and mortality in cirrhosis.

The role of sarcopenia in predicting decompensation other than hepatic encephalopathy is unclear. We aimed to evaluate the prognostic role of sarcopenia, assessed by computed tomography (CT), in the development of ascites and mortality in patients with advanced chronic liver disease (ACLD) outside the liver transplantation (LT) setting. We retrospectively evaluated ACLD patients with liver stiffness measurement (LSM) >10kPa and an available CT scan within 6 months. Sarcopenia was defined as skeletal muscle index (SMI) <50 and <39 cm2/m2, respectively, in men and women. Competing risk regression models were used to assess the variables associated with the main outcomes. 209 patients were included in the final analysis and sarcopenia was present in 134 (64.1%). During a median follow-up of 37 (20-63) months, 52 patients developed ascites, 24 underwent LT, and 30 died. Sarcopenia was found a predictive factor of decompensation with ascites (SHR 2.083, 95%-CI: 1.091-3.978), independently from the features of clinically significant portal hypertension (LSM≥21kPa or portosystemic shunts). Sarcopenia (SHR: 2.744, 95%-CI: 1.105-6.816) and LSM≥21kPa (SHR: 3.973, 95%-CI: 1.548-10.197) were independent risk factors for increased mortality. Sarcopenia and portal hypertension are two major and independent risk factors for decompensation with ascites and mortality in cirrhotic patients outside the LT context.

The Role of Antiviral Prophylaxis in Preventing HBV and HDV Recurrence in the Setting of Liver Transplantation.

Hepatitis B virus (HBV) is a prevalent underlying disease, leading to liver transplantation (LT) for both decompensated cirrhosis and hepatocellular carcinoma (HCC). The hepatitis delta virus (HDV) affects approximately 5-10% of HBsAg carriers, accelerating the progression of liver injury and HCC. The initial introduction of HBV immunoglobulins (HBIG), and then of nucleos(t)ide analogues (NUCs), considerably improved the survival of HBV/HDV patients post-transplantation, as they helped prevent re-infection of the graft and recurrence of liver disease. Combination therapy with HBIG and NUCs is the primary post-transplant prophylaxis strategy in patients transplanted for HBV- and HDV-related liver disease. However, monotherapy with high-barrier NUCs, such as entecavir and tenofovir, is safe and also effective in some individuals who are at low risk of HBV reactivation. To address the problems of organ shortage, last-generation NUCs have facilitated the use of anti-HBc and HBsAg-positive grafts to meet the ever-increasing demand for grafts.

Renoprotective effects of zinc sulfate against transient liver ischemia/reperfusion injury in rats

ObjectivesLiver ischemia/reperfusion damage frequently occurs in setting of hepatic resection and liver transplantation. It leads to disturbance in remote organs such as heart, lung and kidneys. This study explored the consequences of hepatic ischemia/reperfusion on the oxidative stress parameters, biochemical factors, and histopathological alterations in the kidney's rats, as well as evaluated the role of zinc sulfate on above-mentioned parameters. Materials and methodsTwenty-eight male Wistar rats were accidently assigned into four groups (n = 7). They were Sham, ischemia/reperfusion, zinc sulfate pretreatment, and zinc sulfate pretreatment + ischemia/reperfusion groups. Sham group: obtained normal saline (2 ml/day, seven consecutive days), intraperitoneally, zinc sulfate pretreatment group: obtained zinc sulfate (5 mg/kg, seven consecutive days, intraperitoneally). Ischemia/reperfusion group: obtained normal saline as mentioned previous, then rats experienced the partial ischemia (%70) for 45 min followed by 60 min reperfusion. Zinc sulfate pretreatment group: obtained zinc sulfate as mentioned previous, then rats experience the partial ischemia/reperfusion as presented earlier. At the end of investigation, blood was withdrawn, liver and renal tissues were removed. Then, biochemical and oxidative stress parameters, and histological changes were evaluated in the mentioned tissues. ResultsThe findings of this experiment indicated that zinc sulfate markedly reduced the serum levels of liver and kidney function tests in relative to ischemia/reperfusion group. Also, antioxidant enzymes activity, ferric reducing antioxidant power, and nitric oxide significantly increased, while malondialdehyde level declined in the renal tissue of zinc sulfate + ischemia/reperfusion group compared to ischemia/reperfusion rats. Furthermore, zinc sulfate alleviated the liver and kidneys histopathological alterations following ischemia/reperfusion. ConclusionZinc sulfate ameliorated liver and kidney function, and improved oxidant-antioxidant balance in favor of antioxidants. It is suggested that zinc sulfate may be beneficial effects on hepato-renal injury after ischemia/reperfusion.

N-acetylcysteine and Reduction of Ischemia-reperfusion Injury in Liver Transplantation.

In the current issue of Transplantation, Jia et al perform a systemic review and meta-analysis looking at the utilization of N-acetylcysteine (NAC) in the donor and recipient in liver transplantation.1,2 It has been suggested that NAC may have a role in mitigating ischemia-reperfusion injury that occurs during the various stages of organ donation. The pathophysiology of ischemia-reperfusion injury is mainly due to the oxidative stress and cytotoxicity arising from the imbalance between oxidants and antioxidants. NAC is a rich source of sulfhydryl groups, which are important for replenishing glutathione (GSH) stores. GSH acts as a free radical scavenger to decrease damage caused by the toxic free radicals. GSH is the main endogenous antioxidant, and the liver is the main organ producing GSH under normal conditions.2 The present meta-analysis demonstrates a lower incidence of primary nonfunction, a reduction in posttransplant peak aspartate transaminase and alanine transaminase, and reduced postoperative complications in the NAC treatment groups compared with the control groups. As a long-time proponent of the use of NAC in the transplant setting, the overall results of this meta-analysis are encouraging. At Mayo Clinic Florida, we routinely use a NAC infusion for donation after circulatory death (DCD) liver transplant recipients. Our protocol involves a bolus of 150 mg/kg given over 1 h before reperfusion followed by an infusion of 150 mg/kg given for 72 h. Our current rate of ischemic cholangiopathy is <4%; however, whether NAC provides any direct benefit in the reduction of ischemic cholangiopathy remains unproven.3 More recently, we have also started using NAC in the perfusate when performing abdominal normothermic regional perfusion in DCD donors ([6 g/30 mL] × 3 vials). Negative effects of NAC administration are minimal. Although the meta-analysis demonstrated a slightly increased need for packed red blood cells and cryoprecipitate in NAC treatment groups, the magnitude of difference was <1 unit. This may imply that although a statistically significant difference was seen, such a small difference may not be clinically significant. There are some limitations to the present study that should be mentioned. One of the challenges with combining the data from the different studies in the present analysis is that some of the studies gave NAC to the donors at the time of donor procurement, some gave NAC to the recipients at the time of transplant, and others gave NAC to both the donor and recipient. Dosing and timing of dosing was also very heterogeneous between the different studies. Given this heterogeneity, developing a comprehensive protocol utilizing NAC is problematic. In the subanalysis, the authors did suggest that NAC administration to the recipient appeared to produce better clinical effects than administration to the donor. Another unanswered question based on the present analysis is how the benefits of NAC may vary by donor type? Some of the studies looked at living donors while others looked at donation after brain death donors and others looked at DCD donors. Could there be a more significant effect in marginal liver grafts with a suspected higher degree of ischemia-reperfusion injury or should NAC be utilized in all cases? Finally postoperative complications were treated as a binary variable (yes/no) for the analysis. Given the vastly different implications of complications based on their severity, using a classification system such as Clavien-Dindo would be more meaningful when comparing study groups. Despite the limitations of the present meta-analysis, the results are encouraging and suggest that NAC does have some potentially beneficial effects in reducing ischemia-reperfusion injury when used in the setting of liver transplantation. The adequate safety of NAC, in addition to its low costs, makes it an appealing intervention. Further studies are needed before evidence is strong enough to recommend a specific protocol describing both optimal timing and dosage for administration. Moreover, the donor type that may achieve the greatest benefit remains unknown.