Injury In Liver Transplantation Research Articles

Ferroptosis Inhibition: A Key Opportunity for the Treatment of Ischemia/Reperfusion Injury in Liver Transplantation.

The outcome after liver transplantation has improved in recent years, which can be attributed to superior storage and transportation conditions of the organs, as well as better peri- and postoperative management and advancements in surgical techniques. Nevertheless, there is an increasing discrepancy between the need for organs and their availability. Consequently, the mortality rate on the waiting list is high and continues to rise. One way of counteracting this trend is to increase the use of "expanded criteria donors." This means that more and more donors will be included, especially those who are older and having additional comorbidities (eg, steatosis). A major complication of any transplantation is the occurrence of ischemia/reperfusion injury (IRI), which often leads to liver dysfunction and failure. However, there have been various promising approaches to minimize IRI in recent years, but an effective and clinically applicable method to achieve a better outcome for patients after liver transplantation is still missing. Thereby, the so-called marginal organs are predominantly affected by IRI; thus, it is crucial to develop suitable and effective treatment options for patients. Recently, regulated cell death mechanisms, particularly ferroptosis, have been implicated to play a major role in IRI, including the liver. Therefore, inhibiting this kind of cell death modality presents a promising therapeutic approach for the management of this yet untreatable condition. Thus, this review provides an overview of the role of ferroptosis in liver IRI and transplantation and discusses possible therapeutic solutions based on ferroptosis inhibition to restrain IRI in marginal organs (especially steatosis and donation after circulatory death organs).

Systematic review and meta-analysis of the effect of N-acetylcysteine on outcomes after liver resection.

N-Acetylcysteine (NAC) is a recognized antioxidative agent that facilitates the conjugation of toxic metabolites. In recent years, NAC has been routinely used to limit ischaemia-reperfusion injury in liver transplantation. There remains, however, contradictory evidence on its effectiveness in liver resection. This meta-analysis examines the effectiveness of NAC in improving outcomes following hepatectomy. A comprehensive search of the MEDLINE, EMBASE, and Cochrane databases was performed to identify relevant randomized controlled trials (RCTs) published since database inception until November 2023. The outcomes of Day 1 biochemical markers (lactate, ALT, bilirubin, and INR), length of stay, transfusion rates, and morbidity were extracted. Quantitative pooling of data was based on a random-effects model. The study protocol was registered on PROSPERO (Registration no: CRD42023442429). Five RCTs reporting on 388 patients undergoing hepatectomy were included in the analysis. There were no significant differences in patient demographics between groups. Post-operative lactate was lower in patients receiving NAC (WMD -0.61, 95% CI -1.19 to -0.04, I2 = 67%). There were, however, no differences in the post-operative INR (WMD -0.04, 95% CI -0.19 to 0.12, I2 = 96%) and ALT (WMD -94.94, 95% CI -228.46 to 40.38; I2 = 67%). More importantly, there were no statistically significant differences in length of stay, transfusion rates, and morbidity between the two groups. The administration of NAC in liver resection did not alter important biochemical parameters suggesting any real effectiveness in reducing hepatic dysfunction. There were no improvements in the clinical outcomes of length of stay, transfusion rates, and overall morbidity.

Understudied targets of the ischemia-reperfusion injury pathogenesis in liver transplantation

Background. Liver transplantation is currently the most effective method to treat diseases with end-stage liver failure. Complications are most often associated with the initially severe patient condition, imperfect organ preservation methods, the surgical management per se, and immune system incompetence. The most common complications of transplantation include ischemic reperfusion injury, which occurs to some or another extent in each transplanted organ and worsens the course of the postoperative period. The process is based on complex pathophysiological mechanisms of cell damage due to ischemia and inflammation caused by reperfusion.Objective. To summarize current data on the mechanisms of the ischemic reperfusion injury development in liver transplantation and to find the ways to reduce adverse effects.Material and methods. The analysis of data from foreign and homeland experimental and clinical studies on the pathogenesis of ischemic reperfusion injury in liver transplantation has been performed. The search for literature data was carried out in international databases (PubMed/MedLine, ResearchGate, as well as in the scientific electronic library of Russia (eLibrary.RU) for the period from 2020-2024.Conclusion. The analyzed publications have provided various algorithms for the preservation of donor organs, including those using machine perfusion.

Comparative Study of Acute Kidney Injury in Liver Transplantation: Donation after Circulatory Death versus Brain Death.

BACKGROUND Acute kidney injury (AKI) after orthotopic liver transplantation (OLT) contributes to morbidity and mortality. Donation after circulatory death (DCD) has been established to increase the pool of organs. While surgical complications are reported to be comparable in DCD and donation after brain death (DBD) OLT, there is a knowledge gap concerning adverse kidney events in these 2 groups. MATERIAL AND METHODS In this retrospective cohort study, 154 patients received a DBD and 68 received a DCD organ (2016-2020). The primary outcome was a major adverse kidney event within 30 days (MAKE-30). The secondary outcome was dynamics of AKI and kidney replacement therapy (KRT) during the first postoperative week and on postoperative day 30. Incidence and resolution from AKI and KRT and patient survival (PS) 30 days after OLT were compared between the DCD and DBD recipients. RESULTS MAKE-30 incidence after OLT was comparable in DCD (n=27, 40%) vs DBD (n=41, 27%) recipients (risk ratio 1.49 [95% CI 1.01, 2.21], p=0.073). AKI incidence was comparable in DCD (n=58, 94%) vs DBD (n=95, 82%) recipients (risk ratio 1.14 [95% CI: 1.03, 1.27], P=0.057). Overall, 40% (n=88) of patients required KRT, with no difference between DCD (n=27, 40%) vs DBD (n=61, 40%) recipients (risk ratio 1.00 [95% CI 0.71, 1.43], P>0.999). Resolution of AKI by day 30 was lower in DCD (n=29, 50%) than in DBD (n=66, 69%) recipients (risk ratio 0.71 [95% CI: 0.53, 0.95], P=0.032). Survival after 30 days (DCD: n=64, 94% vs DBD: n=146, 95%, risk ratio 0.99 [95% CI 0.93, 1.06], P>0.999) was also comparable. CONCLUSIONS MAKE-30, short-term renal outcome, and survival did not significantly differ between DBD and DCD-OLT. Resolution of AKI by day 30 was lower in DCD than in DBD recipients.

Human umbilical cord mesenchymal stem cells alleviate fatty liver ischemia-reperfusion injury by activating autophagy through upregulation of IFNγ.

Liver ischemia-reperfusion injury (IRI) is an important factor affecting the prognosis of liver transplantation, and extended criteria donors (e.g., steatosis donor livers) are considered to be more sensitive to ischemia-reperfusion injury in liver transplantation. Currently, the application of human umbilical cord mesenchymal stem cells (hMSCs) has great promise in the treatment of various injuries in the liver. This study aimed to investigate the therapeutic role and mechanism of hMSCs in fatty liver IRI. After more than 8 weeks of high-fat chow feeding, we constructed a fatty liver mouse model and established ischemic injury of about 70% of the liver. Six hours after IRI, liver injury was significantly alleviated in hMSCs-treated mice, and the expression levels of liver enzyme, inflammatory factor TNF-α, and apoptotic proteins were significantly lower than those of the control group, which were also significant in pathological sections. Transcriptomics analysis showed that IFNγ was significantly upregulated in the hMSCs group. Mechanistically, IFNγ, which activates the MAPK pathway, is a potent agonist that promotes the occurrence of autophagy in hepatocytes to exert a protective function, which was confirmed by in vitro experiments. In summary, hMSCs treatment could slow down IRI in fatty liver by activating autophagy through upregulation of IFNγ, and this effect was partly direct.

Machine perfusion organ preservation: Highlights from the American Transplant Congress 2023.

The American Transplant Congress (ATC) 2023, held in San Diego, California, emerged as a pivotal platform showcasing the latest advancements in organ machine perfusion, a key area in solid organ and tissue transplantation. This year's congress, attended by over 4500 participants, including leading experts, emphasized innovations in machine perfusion technologies across various organ types, including liver, kidney, heart, and lung. A total of 85 abstracts on organ machine perfusion were identified. Noteworthy advancements included the use of normothermic machine perfusion in mitigating ex-situ reperfusion injury in liver transplantation, the potential of biomarkers in assessing organ quality, and the impact of machine perfusion on graft survival and ischemic cholangiopathy incidence. Kidney transplantation saw promising developments in novel preservation methods, such as subzero storage and pulsatile perfusion. Heart and lung sessions revealed significant progress in preservation techniques, including metabolic alterations to extend organ preservation time. The conference also highlighted the growing interest in machine perfusion applications in pediatric transplantation, multi-visceral organ recovery, Vascularized Composite Allotransplantation, and discussions on novel technologies for monitoring and optimizing perfusion protocols. Additionally, ATC 2023 included critical discussions on ethical concerns, legal implications, and the evolving definition of death in the era of machine preservation, illustrating the complex landscape of transplantation science. Overall, ATC 2023 showcased significant strides in machine perfusion and continued its tradition of fostering global knowledge exchange, further cementing machine perfusion's role as a transformative force in improving transplant outcomes and expanding the donor pool.

Bone marrow-derived mesenchymal stem cells reactive oxygen species-responsively secreting hepatocyte growth factor for effective treatment of ischemia-reperfusion injury in liver transplantation

Bone marrow-derived mesenchymal stem cells reactive oxygen species-responsively secreting hepatocyte growth factor for effective treatment of ischemia-reperfusion injury in liver transplantation

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.

α-Connexin Carboxyl Terminal Peptide 1 Attenuates Ischemia-Reperfusion Injury in Liver Transplantation With Extended Cold Preservation by Stabilizing Cell Junctions in Mice

• ⚫Peptide α-connexin carboxyl terminal peptide (ACT1) protects graft livers during cold storage by steadying cell junctions. • ⚫ACT1 reduces hepatic ischemia-reperfusion injury following transplantation. • ⚫ACT1 inhibits acute and chronic inflammation after transplantation. • ⚫The effect of ACT1 on cell junctions is long term. Ischemia-reperfusion injury is an inevitable process that the liver must go through after liver transplantation. Because of the worldwide shortage of grafts, reliable intervention strategies should be explored to protect grafts. α-Connexin carboxyl terminal peptide (ACT1), which is a synthetic peptide containing 25 amino acids, has the effect of stabilizing cell junctions. The purpose of this study was to investigate the role of ACT1 on ischemia-reperfusion injury after liver transplantation in mice. Experimental results showed that injury to livers that underwent extended cold preservation was reduced by ACT1. After 6 hours of reperfusion, ACT1-treated livers showed less necrosis and acute inflammation and the cell junctions were strengthened. Moreover, after 28 days of reperfusion, the application of ACT1 distinctly alleviated hepatic damage and later cholangiopathy as well as conspicuously consolidated the cell junctions. This study indicated that ACT1 produced affirmative effects in suppressing hepatic ischemia-reperfusion injury in liver transplantation with extended cold preservation in mice by protecting cell junctions and may be a potential strategy to extend the cold preservation time of grafts for liver transplantation.

Cerium oxide nanoparticles administration during machine perfusion of discarded human livers: A pilot study.

The combined approach of ex situ normothermic machine perfusion (NMP) and nanotechnology represents a strategy to mitigate ischemia/reperfusion injury in liver transplantation (LT). We evaluated the uptake, distribution, and efficacy of antioxidant cerium oxide nanoparticles (nanoceria) during normothermic perfusion of discarded human livers. A total of 9 discarded human liver grafts were randomized in 2 groups and underwent 4 h of NMP: 5 grafts were treated with nanoceria conjugated with albumin (Alb-NC; 50µg/ml) and compared with 4 untreated grafts. The intracellular uptake of nanoceria was analyzed by electron microscopy (EM) and inductively coupled plasma-mass spectrometry (ICP-MS). The antioxidant activity of Alb-NC was assayed in liver biopsies by glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) assay, telomere length, and 4977-bp common mitochondrial DNA deletion (mtDNA4977 deletion). The cytokine profile was evaluated in perfusate samples. EM and ICP-MS confirmed Alb-NC internalization, rescue of mitochondrial phenotype, decrease of lipid droplet peroxidation, and lipofuscin granules in the treated grafts. Alb-NC exerted an antioxidant activity by increasing GSH levels (percentage change: +94%±25%; p=0.01), SOD (+17%±4%; p=0.02), and CAT activity (51%±23%; p=0.03), reducing the occurrence of mtDNA4977 deletion (-67.2%±11%; p=0.03), but did not affect cytokine release. Alb-NC during ex situ perfusion decreased oxidative stress, upregulating graft antioxidant defense. They could be a tool to improve quality grafts during NMP and represent an antioxidant strategy aimed at protecting the graft against reperfusion injury during LT.

Perioperative kidney injury in liver transplantation: a prospective study with renal histology and measured glomerular filtration rates

Background Acute kidney injury (AKI) is frequent after liver transplantation (LT), with impact on graft function, morbidity and mortality. Although multifactorial, the pathophysiology of perioperative kidney injury remains unclear. Our aims were to analyze the frequency, evolution and risk factors for kidney impairment during the peri- and early post-operative period. Methods In a prospective, single-center study of 27 adult patients undergoing first single-organ LT, we analyzed measured glomerular filtration rate (mGFR) pre-transplant, at post-operative day (POD) 10, and at 1, 3, 12 and 36 months. Kidney and liver graft biopsies were performed during LT. Results A median mGFR decline of 45% was detected from pre-transplant to POD 10, correlating strongly with the mGFR evolution from baseline to 12 months (rs = 0.80, p<.001) and baseline to 36 months (rs = 0.82, p<.001). AKI occurred in 59% of recipients within 48 h of LT, notably before the introduction of calcineurin inhibitors on POD 3. AKI was strongly associated with mGFR at 12 and 36 months. Kidney and liver graft biopsies showed only minor histological changes. Donor and recipient body mass index, recipient age, model of end-stage liver disease score, diagnosis of hepatitis C, donor cause of death, as well as bleeding, transfusions and duration of the anhepatic phase correlated with early kidney dysfunction. Conclusion The greatest decline in mGFR was evident within 10 days and AKI within hours of LT, irrespective of baseline mGFR and before introduction of calcineurin inhibitors. Very early post-LT kidney injury has substantial consequences for long-term kidney function.

Liver Injury in Liver Transplant Recipients With Coronavirus Disease 2019 (COVID-19): U.S. Multicenter Experience.

Background and AimsCoronavirus disease 2019 (COVID‐19) is associated with liver injury, but the prevalence and patterns of liver injury in liver transplantation (LT) recipients with COVID‐19 are open for study.Approach and ResultsWe conducted a multicenter study in the United States of 112 adult LT recipients with COVID‐19. Median age was 61 years (interquartile range, 20), 54.5% (n = 61) were male, and 39.3% (n = 44) Hispanic. Mortality rate was 22.3% (n = 25); 72.3% (n = 81) were hospitalized and 26.8% (n = 30) admitted to the intensive care unit (ICU). Analysis of peak values of alanine aminotransferase (ALT) during COVID‐19 showed moderate liver injury (ALT 2‐5× upper limit of normal [ULN]) in 22.2% (n = 18) and severe liver injury (ALT > 5× ULN) in 12.3% (n = 10). Compared to age‐ and sex‐matched nontransplant patients with chronic liver disease and COVID‐19 (n = 375), incidence of acute liver injury was lower in LT recipients (47.5% vs. 34.6%; P = 0.037). Variables associated with liver injury in LT recipients were younger age (P = 0.009; odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20‐3.54), Hispanic ethnicity (P = 0.011; OR, 6.01; 95% CI, 1.51‐23.9), metabolic syndrome (P = 0.016; OR, 5.87; 95% CI, 1.38‐24.99), vasopressor use (P = 0.018; OR, 7.34; 95% CI, 1.39‐38.52), and antibiotic use (P = 0.046; OR, 6.93; 95% CI, 1.04‐46.26). Reduction in immunosuppression (49.4%) was not associated with liver injury (P = 0.156) or mortality (P = 0.084). Liver injury during COVID‐19 was significantly associated with mortality (P = 0.007; OR, 6.91; 95% CI, 1.68‐28.48) and ICU admission (P = 0.007; OR, 7.93; 95% CI, 1.75‐35.69) in LT recipients.ConclusionsLiver injury is associated with higher mortality and ICU admission in LT recipients with COVID‐19. Hence, monitoring liver enzymes closely can help in early identification of patients at risk for adverse outcomes. Reduction of immunosuppression during COVID‐19 did not increase risk for mortality or graft failure.

Glycocalyx as a Useful Marker of Endothelial Injury in Liver Transplantation: The Role of Preservation Solution.

The reported investigations from Schiefer et al,1 on the role of glycocalyx (GC) in orthotopic liver transplantation, propose GC as a relevant injury marker to be used in this field. GC is a complex sugar monolayer, which covers the endothelium and is thus exposed and susceptible to alteration as a consequence of liver ischemia-reperfusion (IR) injury associated with orthotopic liver transplantation. The authors have used histidine-tryptophan-ketoglutarate (HTK) solution in their study. However, other preservation solutions (PSs) with different compositions (such as University of Wisconsin [UW], Celsior, and IGL-1 PS) are commercially available and should be tested. Extension of the study with use of these alternative PS could provide important insights into organ PS. The presence of an oncotic agent (such as hydroxyethyl starch in the UW solution or polyethylene glycol 35 [PEG35] in IGL-1 solution) differentiates UW and IGL-1 from HTK and Celsior solutions, which do not contain oncotic agents. This difference is relevant because oncotic pressure, controlled by the oncotic agent, minimizes interstitial edema, which could directly affect GC. However, the oncotic agent increases viscosity, which may in turn affect the protective performance of the PS. Balancing the limitation of edema against viscosity during organ preservation is critical to GC integrity and graft status. In this context, our group reported that PEG35 used in a rinsing solution reduces liver graft damage after cold static preservation.2 The comparison of 2 PS, HTK, and IGL-1, in a rat liver cold preservation model, showed that the presence of PEG35 in the IGL-1 PS was the determinant of GC protection.3 These data support the concept that PEG35 reduces IR injury effects on the narrowing and the integrity of the GC. GC protection is linked to the mechanical properties that PEG35 confers on PS because of its viscosity, such as shear stress and PEG35 interacting with the cells causing remodeling of the cell’s actin cytoskeleton.4 It is acknowledged that IR injury is maximized in fatty livers partly because of sinusoidal narrowing and is accentuated by both normothermic and hypothermic machine perfusion.5 In addition, nitric oxide, a potent physiological vasodilator, is promoted by PEG35 through endothelial nitric oxide synthase activation.2,3 Therefore, PEG35 should be considered as an important component in any dynamic preservation strategy, such as hypothermic oxygenated perfusion, to preserve GC integrity and improve liver preservation, especially when fatty liver grafts are used.5 Thus, we support the relevance of the investigations reported by Schieffer et al, which point firmly, for the first time, to the utility of GC as a suitable marker of graft damage and preservation in orthotopic liver transplantation. Further investigation will be important to compare GC as an injury marker using different PS.

Effects of intraoperative hemodynamic management on postoperative acute kidney injury in liver transplantation: An observational cohort study.

Intraoperative restrictive fluid management strategies might improve postoperative outcomes in liver transplantation. Effects of vasopressors within any hemodynamic management strategy are unclear. We conducted an observational cohort study on adult liver transplant recipients between July 2008 and December 2017. We measured the effect of vasopressors infused at admission in the intensive care unit (ICU) and total intraoperative fluid balance. Our primary outcome was 48-hour acute kidney injury (AKI) and our secondary outcomes were 7-day AKI, need for postoperative renal replacement therapy (RRT), time to extubation in the ICU, time to ICU discharge and survival up to 1 year. We fitted models adjusted for confounders using generalized estimating equations or survival models using robust standard errors. We reported results with 95% confidence intervals. We included 532 patients. Vasopressors use was not associated with 48-hour or 7-day AKI but modified the effects of fluid balance on RRT and mortality. A higher fluid balance was associated with a higher need for RRT (OR = 1.52 [1.15, 2.01], p<0.001 for interaction) and lower survival (HR = 1.71 [1.26, 2.34], p<0.01 for interaction) only among patients without vasopressors. In patients with vasopressors, higher doses of vasopressors were associated with a higher mortality (HR = 1.29 [1.13, 1.49] per 10 μg/min of norepinephrine). The presence of any vasopressor at the end of surgery was not associated with AKI or RRT. The use of vasopressors might modify the harmful association between fluid balance and other postoperative outcomes. The liberal use of vasopressors to implement a restrictive fluid management strategy deserves further investigation.

Pre‐operative anaemia and postoperative acute kidney injury in liver transplantation: valuable but there are still some unanswered questions

Pre‐operative anaemia and postoperative acute kidney injury in liver transplantation: valuable but there are still some unanswered questions

Pretransplant left ventricular hypertrophy in association with postoperative myocardial injury in liver transplantation

Pretransplant left ventricular hypertrophy (LVH) is a common finding during preoperative cardiac evaluation. We hypothesized that patients with pretransplant LVH were associated with a higher risk of postoperative myocardial injury (PMI) in adult patients undergoing liver transplantation (LT). A retrospective cohort analysis was performed by reviewing the medical records of adult patients who underwent LT between January 2006 and October 2013. Of 893 patients, the incidences of mild, moderate, and severe LVH were 7.8%, 5.6%, and 2.5%, respectively. Propensity match was used to eliminate the pretransplant imbalance between the LVH and non-LVH groups. In after-match patients, 23.5% of LVH patients developed PMI compared to 11.8% in the control group (P=.011). The incidence of PMI in patients with moderate-severe degrees of LVH was significantly higher compared with that in patients with mild LVH (27.9% vs 19.1%, P=.016). When controlling intraoperative variables, patients with LVH had 4.5 higher odds of developing PMI (95% CI1.18-17.19, P=.028). Patients experiencing PMI had significantly higher 1-year mortality (37.5% vs 15.7%, log-rank test P<.001). Our results suggest that patients with pretransplant LVH were at a high risk of developing PMI and should be monitored closely in the perioperative period. More studies are warranted.

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis.

Hepatic ischemia-reperfusion (I/R) injury is a major problem in liver transplantation (LT). Although hepatocyte cell death is the initial event in hepatic I/R injury, the underlying mechanism remains unclear. In the present study, we retrospectively analyzed the clinical data of 202 pediatric living donor LT and found that a high serum ferritin level, a marker of iron overload, of the donor is an independent risk factor for liver damage after LT. Since ferroptosis has been recently discovered as an iron-dependent cell death that is triggered by a loss of cellular redox homeostasis, we investigated the role of ferroptosis in a murine model of hepatic I/R injury, and found that liver damage, lipid peroxidation, and upregulation of the ferroptosis marker Ptgs2 were induced by I/R, and all of these manifestations were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or α-tocopherol. Fer-1 also inhibited hepatic I/R-induced inflammatory responses. Furthermore, hepatic I/R injury was attenuated by iron chelation by deferoxamine and exacerbated by iron overload with a high iron diet. These findings demonstrate that iron overload is a novel risk factor for hepatic I/R injury in LT, and ferroptosis contributes to the pathogenesis of hepatic I/R injury.

Impact of Rifaximin Therapy on Ischemia/Reperfusion Injury in Liver Transplantation: A Propensity Score–Matched Analysis

Intestinal microbiota is thought to play an important role in hepatic ischemia/reperfusion injury (IRI) after liver transplantation (LT). Rifaximin, a nonabsorbable antibiotic used to treat encephalopathy, exhibits antibacterial activity within the gut. We report the first study examining the impact of pre-LT rifaximin use on reducing hepatic IRI and inflammatory cell infiltration after LT. This retrospective single-center study included adult LT recipients from January 2013 through June 2016. Patients were divided into 2 groups based on duration of rifaximin use before LT: rifaximin group (≥28 days) and control group (none or <28 days). Patients receiving other antibiotics within 28 days of LT and re-LTs were excluded. Outcomes and messenger RNA (mRNA) expression in the graft were compared by 1:1 propensity score-matching and multivariate analyses. On 1:1 matching (n = 39/group), rifaximin patients had lower postoperative serum transaminase levels and lower early allograft dysfunction (EAD; 10.3% versus 33.3%; P = 0.014). Of the matched patients, 8 patients (n = 4/group) had postreperfusion liver biopsies (approximately 2 hours after reperfusion) available for mRNA analysis. Hepatic expression of CD86 (macrophage marker) and cathepsin G (neutrophil marker) was significantly lower in rifaximin patients than controls (P < 0.05). The multivariate analysis included 458 patients. Rifaximin treatment <28 days was identified as an independent risk factor EAD in all patients and those with high Model for End-Stage Liver Disease (MELD) score (MELD ≥35; n = 230). In conclusion, the propensity score-matched and multivariate analyses suggest a therapeutic role of rifaximin in reducing EAD. Pre-LT rifaximin administration exerted a protective function against early liver injury, potentially by suppressing inflammatory cell activation in the graft.

Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms.

Liver disease causing end organ failure is a growing cause of mortality. In most cases, the only therapy is liver transplantation. However, liver transplantation is a complex undertaking and its success is dependent on a number of factors. In particular, liver transplantation is subject to the risks of ischaemia-reperfusion injury (IRI). Liver IRI has significant effects on the function of a liver after transplantation. The cellular and molecular mechanisms governing IRI in liver transplantation are numerous. They involve multiple cells types such as liver sinusoidal endothelial cells, hepatocytes, Kupffer cells, neutrophils and platelets acting via an interconnected network of molecular pathways such as activation of toll-like receptor signalling, alterations in micro-RNA expression, production of ROS, regulation of autophagy and activation of hypoxia-inducible factors. Interestingly, the cellular and molecular events in liver IRI can be correlated with clinical risk factors for IRI in liver transplantation such as donor organ steatosis, ischaemic times, donor age, and donor and recipient coagulopathy. Thus, understanding the relationship of the clinical risk factors for liver IRI to the cellular and molecular mechanisms that govern it is critical to higher levels of success after liver transplantation. This in turn will help in the discovery of therapeutics for IRI in liver transplantation - a process that will lead to improved outcomes for patients suffering from end-stage liver disease.

Comprehensive and combined omics analysis reveals factors of ischemia-reperfusion injury in liver transplantation.

To explore molecular mechanisms underlying liver ischemia-reperfusion injury (IRI). Four Gene Expression Omnibus datasets comprising liver transplantation data were collected for a comprehensive analysis. A proteomic analysis was performed and used for correlations analysis with transcriptomic. Ten differentially expressed genes were co-upregulated in four Gene Expression Omnibus datasets, including ATF3, CCL4, DNAJB1, DUSP5, JUND, KLF6, NFKBIA, PLAUR, PPP1R15A and TNFAIP3. The combined analysis demonstrated ten coregulated genes/proteins, including HBB, HBG2, CA1, SLC4A1, PLIN2, JUNB, HBA1, MMP9, SLC2A1 and PADI4. The coregulated differentially expressed genes and coregulated genes/proteins formed a tight interaction network and could serve as the core factors underlying IRI. Comprehensive and combined omics analyses revealed key factors underlying liver IRI, and thus having potential clinical significance.