• Humans
• Liver Transplantation/adverse effects
• Reperfusion Injury/prevention & control
• Reperfusion Injury/pathology
• Reperfusion Injury/etiology
• Reperfusion Injury/metabolism
• Ferroptosis/drug effects
• Animals
• Liver/pathology
• Liver/drug effects
• Liver/metabolism
• Liver/blood supply
• Treatment Outcome

• PR 1752/3-1 DFG
• EG 319/5-1 DFG

• Aquaporin 9
• Ischemia reperfusion
• Liver transplantation
• Normothermic machine perfusion
• Organ preservation solution

• Animals
• Rats
• Betaine/pharmacology
• Liver/pathology
• Liver/drug effects
• Liver/metabolism
• Organ Preservation Solutions
• Cold Ischemia
• Male
• Organ Preservation/methods
• Adenosine/pharmacology
• Raffinose/pharmacology
• Vacuoles/drug effects
• Vacuoles/metabolism
• Apoptosis/drug effects
• Hydrogen Peroxide/metabolism
• Allopurinol/pharmacology
• Rats, Sprague-Dawley
• Insulin/metabolism
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Hepatocytes/pathology
• Glutathione/metabolism
• Liver Transplantation
• Humans

• HTK
• IGL-2
• UW
• ischemic injury
• oxidative stress
• preservation solutions
• static cold storage
• steatotic liver
• sterile inflammation

• Animals
• Organ Preservation Solutions/pharmacology
• Rats
• Raffinose/pharmacology
• Rats, Zucker
• Insulin/metabolism
• Adenosine/metabolism
• Adenosine/pharmacology
• Fatty Liver/metabolism
• Fatty Liver/drug therapy
• Fatty Liver/pathology
• Reperfusion Injury/metabolism
• Reperfusion Injury/drug therapy
• Reperfusion Injury/prevention & control
• Antioxidants/pharmacology
• Antioxidants/metabolism
• Liver/metabolism
• Liver/drug effects
• Liver/pathology
• Allopurinol/pharmacology
• Male
• Procaine/pharmacology
• Inflammation/metabolism
• Inflammation/pathology
• Inflammation/drug therapy
• Glucose/metabolism
• Oxidative Stress/drug effects
• Glutathione/metabolism
• Lipid Peroxidation/drug effects
• Mannitol/pharmacology
• Cold Ischemia/adverse effects
• Potassium Chloride/pharmacology
• Organ Preservation/methods
• Liver Transplantation/methods

• 722619 (FOIE GRAS). This research was funded by the European Union's Horizon 2020 Research and InnovationPro-gramme under the Marie Skłodowska-Curie

• Ergothioneine
• application
• biosynthetic pathway
• fermentation
• metabolic engineering
• physiological function

• Antioxidants/metabolism
• Antioxidants/pharmacology
• Ergothioneine/biosynthesis
• Ergothioneine/metabolism
• Ergothioneine/pharmacology
• Fermented Foods
• Food Industry/methods
• Food Industry/trends
• Genetic Engineering/methods
• Metabolic Engineering/methods
• Cosmetics/chemistry
• Fungi/genetics
• Fungi/metabolism
• Bacteria/genetics
• Bacteria/metabolism

• Pringle maneuver
• immune response
• inflammatory response
• ischemia–reperfusion injury
• liver transplantation
• living liver donors
• recipients

• Humans
• Reperfusion Injury/etiology
• Living Donors
• Male
• Hepatectomy/methods
• Hepatectomy/adverse effects
• Female
• Middle Aged
• Liver Transplantation/methods
• Liver Transplantation/adverse effects
• Adult
• Double-Blind Method
• Liver/blood supply
• Liver/injuries
• Liver/surgery

• TSA-2021-2390 Inonu University

• cell therapy
• complication
• immune system
• ischemia–reperfusion injury
• liver transplantation

• National Key Research and Development Program of China

• graft preservation
• liver viability
• machine perfusion
• organ preservation
• transplantation

• Animal physiology
• Biological sciences
• Physiology

• cellular respiration
• hypothermia
• hypoxia
• ischemia reperfusion injury
• organ transplant
• reductive stress

• Adenosine
• Adult
• Allopurinol
• Brain Death
• Glucose
• Glutathione
• Humans
• Insulin
• Liver Transplantation
• Organ Preservation
• Organ Preservation Solutions
• Potassium Chloride
• Raffinose
• United States/epidemiology

• T32 DK007074 NIDDK NIH HHS
• National Institutes of Health

The machine perfusion (MP) preservation including hypothermic MP (HMP) and midthermic MP (MMP) has been considered as a promising strategy to preserve the functions of liver donated after cardiac death. The importance of understanding liver sinusoidal endothelial cells (LSEC) damage in regulating liver injury during MP has been emphasized. However, the ultrastructural changes in the LSEC and sinusoids around them after MP are unclear.

To investigate the ultrastructural changes in the LSEC and sinusoids around them after MP.

Porcine liver grafts undergo a warm ischemia time of 60 minutes perfused for 4 h with modified University of Wisconsin gluconate solution. Group A grafts were preserved with HMP at 8 °C constantly for 4 h. Group B grafts were preserved with a rewarming solution at 22 °C by MMP for 4 h. Then the ultrastructural changes in the LSEC and sinusoids in Group A and B were comparatively analyzed by using osmium-maceration scanning electron microscopy with complementary transmission electron microscopy methods.

An analysis of the LSEC after warm ischemia revealed that mitochondria with condensed-shaped cristae, abnormal vesicles, reduction of ribosomes and the endoplasmic reticulum (ER) surround the mitochondria appeared. The MP subsequent after warm ischemia alleviate the abnormal vesicles and reduction of ribosomes in LSEC, which indicated the reduction of the ER damage. However, MMP could restore the tubular mitochondrial cristae, while after HMP the condensed and narrow mitochondrial cristae remained. In addition, the volume of the sinusoidal space in the liver grafts after MMP were restored, which indicated a lower risk of pressure injury than HMP.

MMP alleviates the ER damage of LSEC by warm ischemia, additionally restore the metabolism of LSEC via the normalization of mitochondria and prevent the share stress damage of liver grafts.

• Liver
• Sinusoidal endothelial cells
• Warm ischemia
• Machine perfusion preservation
• Transplantation
• Ultrastructure

• Animals
• Humans
• Death
• Endothelial Cells
• Liver/metabolism
• Organ Preservation/methods
• Organ Preservation Solutions/pharmacology
• Perfusion/methods
• Swine

A high model of end-stage liver disease (MELD) score (>30) adversely affects outcomes even if patients receive prompt liver transplantation (LT). Therefore, balanced allocation of donor grafts is indispensable to avoid random combinations of donor and recipient risk factors, which often lead to graft or recipient loss. Predictive models aimed at avoiding donor risk factors in high-MELD score recipients are urgently required to obtain satisfactory outcomes.

Data of patients with MELD score >30 who underwent LT at three transplantation institutes between 2015 and 2018 were retrospectively reviewed. Early allograft dysfunction (EAD), length of intensive care unit (ICU) stay, and graft loss were recorded. Corresponding independent risk factors were analyzed using stepwise multivariable regression analysis. A prediction model of graft loss was developed, and discrimination and calibration were measured.

After applying the exclusion criteria, 778 patients were enrolled. The incidence of EAD was 34.8% (271/778). Donor graft macrovesicular steatosis, graft-to-recipient weight ratio (GRWR), warm ischemia time (WIT), cold ischemia time (CIT), and ABO blood incompatibility, together with donor serum albumins, were independent predictors of EAD. The incidence of ICU stay over 10 days was 64.7% (503/778). Donor age, recipient's MELD score, Child score, and CIT were independent predictors of ICU stay. The 3-year graft survival rates (GSRs) in the training and validation cohorts were 64.2 and 59.3%, respectively. The independent predictors of graft loss were recipient's Child score, ABO blood type incompatibility, donor serum total bilirubin over 17.1 μmol/L, and cold CIT. A nomogram based on these variables was internally and externally validated and showed good performance (area under the receiver operating characteristic curve = 70.8 and 66.0%, respectively). For a recipient with a high MELD score, the avoidance of ABO blood type incompatibility and CIT ≥6 h would achieve a 3-year GSR of up to 78.4%, whereas the presence of the aforementioned risk factors would decrease the GSR to 35.4%.

The long-term prognosis of recipients with MELD scores >30 could be greatly improved by avoiding ABO blood type incompatibility and CIT ≥6 h.

• ABO blood type incompatibility
• cold ischemia time
• graft survival
• liver transplantation
• model for end-stage liver disease score

• graft preservation
• liver viability
• machine perfusion
• organ preservation
• transplantation

Although machine perfusion (MP) is being increasingly adopted in liver transplantation, indications, timing, and modality are debated. To investigate current indications for MP a web‐based Google Forms survey was launched in January 2021 and addressed to 127 experts in the field, identified among first and corresponding Authors of MP literature in the last 10 years. The survey presented 10 real‐life cases of donor–recipient matching, asking whether the liver would be accepted (Q1), whether MP would be used in that particular setting (Q2) and, if so, by which MP modality (Q3) and at what timing during preservation (Q4). Respondents could also comment on each case. The agreement was evaluated using Krippendorff's alpha coefficient. Answers from 39 (30.1%) participants disclosed significant heterogeneity in graft acceptance, MP indications, technique, and timing. Agreement between respondents was generally poor (Q1, α = 0.11; Q2, α = 0.14; Q3, α = 0.12, Q4, α = 0.11). Overall, respondents preferred hypothermic MP and an end‐ischemic approach in 56.3% and 81.1% of cases, respectively. A total of 18 (46.2%) participants considered only one MP approach, whereas 17 (43.6%) and 3 (7.7%) considered using alternatively 2 or 3 different techniques. Of 38 comments, 17 (44.7%) were about the use of MP for graft viability assessment before implantation. This survey shows considerable variability in MP indications, emphasizing the need to identify scenarios of optimal utilization for each technique. Viability assessment emerges as a fundamental need of transplant professionals when considering the use of MP.

• ex situ organ perfusion
• machine perfusion
• normothermic regional perfusion
• organ preservation
• viability assessment

• animal studies
• graft preservation
• liver transplantation
• meta-analysis
• mitochondrial functions

• Animals
• Delayed Graft Function/metabolism
• Delayed Graft Function/pathology
• Delayed Graft Function/prevention & control
• Humans
• Liver Transplantation
• Mitochondria, Liver/metabolism
• Mitochondria, Liver/pathology
• Organ Preservation
• Warm Ischemia

• NKFI K120232 National Research, Development and Innovation Office
• GINOP-2.3.2-15-2016-00015 Economic Development and Innovation Operative Program
• NKFIH-1279-2/2020 TKP2020 Thematic Excellence Programme 2020

• Baseline monitoring
• Brain death
• Donor criteria
• Donor identification
• Organ conservation

A 63-year-old man with protein C deficiency underwent thoracoscopic esophagectomy and digestive reconstruction using a gastric tube for thoracic esophageal cancer. On postoperative day 3, the gastric tube was removed because of anastomotic leakage and gastric tube necrosis. Digestive reconstruction using a free jejunal graft was attempted 140 days after the first surgery. However, thrombus formation in the artery and vein of the jejunal graft resulted in a failed reconstruction. Ten days after this surgery, digestive reconstruction using the colon was performed with intraoperative heparin administered for anticoagulation control. The surgery was successful, with no thrombus formation afterward. When performing digestive reconstruction in patients with conditions predisposing to thrombus formation, perioperative management should be completed with careful attention toward preventing thrombus formation. In particular, appropriate anticoagulation control, such as the administration of intraoperative heparin, is recommended in patients with protein C deficiency because necrosis of the reconstructed organ is likely.

• esophagectomy
• perioperative management
• protein C deficiency
• thrombus formation

There is a need to improve the quality of donor liver from donation after circulatory death (DCD). The purpose of this study was to investigate the effects and mechanism of normothermic machine perfusion (NMP) combined with bone marrow mesenchymal stem cells (BMMSCs) on the oxidative stress and mitochondrial function in DCD livers. DCD livers were obtained, a rat NMP system was established, and BMMSCs were extracted and identified. The DCD livers were grouped by their preservation method: Normal, static cold storage (SCS), NMP (P), and NMP combined with BMMSCs (PB), and the preservation time was up to 8 h. An IAR20 cell oxidative stress injury model was established in vitro by simulating DCD oxidative stress injury and coculturing with BMMSCs for 6 h. Compared with SCS group, after 6 h in vitro, the PB and P groups had significantly improved liver function and liver histological damage, reduced hepatocyte apoptosis and oxidative stress, improved hepatocyte mitochondrial damage, and increased mitochondrial membrane potential. These indicators were significantly better in the PB group than in the P group. BMMSCs significantly inhibited reactive oxygen species release from the IAR20 cell oxidative stress model in vitro, ameliorated mitochondrial damage, and increased mitochondrial membrane potential level. BMMSCs also downregulated the JUN N-terminal kinase-nuclear factor kappa B (JNK-NF-κB) signaling pathway significantly in the IAR20 cell oxidative stress model and promoted AMP-activated protein kinase (AMPK) activation. We verified that NMP combined with BMMSCs also played the same role in the PB group. NMP combined with BMMSCs could improve liver quality by relieving oxidative stress injury and improving mitochondrial function in rat DCD livers. The mechanism of protective role might involve inhibiting the JNK-NF-κB pathway to reduce oxidative stress and promote AMPK activation, thereby reducing mitochondrial damage and increase mitochondrial function.

• AMP-activated protein kinase
• JNK-NF-κB signaling pathway
• bone marrow mesenchymal stem cells
• mitochondria
• normothermic machine perfusion

Donation after circulatory death (DCD) can expand the donor pool effectively. A gap remains in outcome between DCD livers and living donor livers, warranting improved DCD liver quality and urgent resolution. Bone marrow mesenchymal stem cells (BMMSCs) can regulate immunity, participate in the anti-inflammatory response, and secrete cytokines. We investigated the effect of BMMSCs combined with normothermic machine perfusion (NMP) on DCD liver quality, and the role of microcirculation therein. Rat thoracic aortas were clipped to obtain DCD livers, and a rat NMP system was established. The DCD livers were grouped by preservation method: normal, static cold storage (SCS), NMP (P), and BMMSCs plus NMP (BP); storage time was up to 8 h. Liver function in outflow perfusate was detected by biochemical methods; liver tissue histopathology was observed by hematoxylin–eosin staining; hepatocyte ultrastructure was observed by transmission electron microscopy; hepatocyte apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling; liver microcirculation–related indicators were detected by immunofluorescence, immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assay. Compared with SCS, P and BP significantly improved liver function and liver histological damage, reduced hepatocyte apoptosis, and repaired hepatocyte mitochondrial damage after 6 h in vitro. BP also significantly inhibited intrahepatic macrophage activation and intercellular adhesion, improved endothelial damage, and significantly improved endothelin 1–nitric oxide balance and microcirculation perfusion. In conclusion, BP can improve DCD liver microcirculation and quality. The mechanism may be the improvement of improve hepatic sinusoidal endothelial injury and microcirculation perfusion by inhibiting macrophage activation and intercellular adhesion.

• Bone marrow mesenchymal stem cells
• Donation after circulatory death
• Ischemia–reperfusion injury
• Microcirculation
• Normothermic machine perfusion

Hypothermic oxygenated machine perfusion (HOPE) was introduced in liver transplantation (LT) to mitigate ischemia-reperfusion injury. Available clinical data mainly concern LT with donors after circulatory-determined death, whereas data on brain-dead donors (DBD) are scarce. To assess the impact of end-ischemic HOPE in DBD LT, data on primary adult LTs performed between March 2016 and June 2018 were analyzed. HOPE was used in selected cases of donor age >80 years, apparent severe graft steatosis, or ischemia time ≥10 hours. Outcomes of HOPE-treated cases were compared with those after static cold storage. Propensity score matching (1:2) and Bayesian model averaging were used to overcome selection bias. During the study period, 25 (8.5%) out of 294 grafts were treated with HOPE. After matching, HOPE was associated with a lower severe post-reperfusion syndrome (PRS) rate (4% versus 20%, p = 0.13) and stage 2–3 acute kidney injury (AKI) (16% versus 42%, p = 0.046). Furthermore, Bayesian model averaging showed lower transaminases peak and a lower early allograft dysfunction (EAD) rate after HOPE. A steeper decline in arterial graft resistance throughout perfusion was associated with lower EAD rate. HOPE determines a significant reduction of ischemia reperfusion injury in DBD LT.

• Organ preservation
• Organ preservation solutions
• Transplantation