Ischemia-free liver transplantation improves the prognosis of recipients using Functioned Marginal Liver grafts.

Background & Aims: The shortage of donor livers hinders the development of liver transplantations. This study aimed to clarify the poor outcomes of functioned marginal liver grafts (FMLs) and provide evidence for the improvement of ischemia-free liver transplantation (IFLT) on transplantation with FMLs. Methods: Propensity score matching was used to control for confounding factors. The outcomes of the control group and FMLs were compared to demonstrate the negative impact of FMLs in liver transplantation patients. We compared the clinical improvements of the different surgical types. To elucidate the underlying mechanism, we conducted bioinformatic analysis based on transcriptome and single-cell profiles. Results: FMLs showed a significantly higher Hazard Ratio (HR: 1.969, P = 0.018) than other marginal livers. A worse 90-days survival (12.3% vs. 5.0%, P = 0.007) was observed in patients who underwent FMLs. Patients receiving FMLs had a significant overall survival benefit after IFLT (10.4% vs. 31.3%, P = 0.006). Pyroptosis and inflammation are inhibited in patients who undergo IFLT. The infiltration of Natural Killer cells was lower in liver grafts from these patients. A positive relationship was observed between IL32 and Caspase 1 (R = 0.73, P = 0.01) and Gasdermin D (R = 0.84, P = 0.0012) in the bulk transcriptome profiles. Conclusion: FMLs function as a more important negative prognostic parameter than other marginal livers do. IFLT might ameliorate liver injury in FMLs by inhibiting the infiltration of NK cells, consequently leading to the abortion of IL-32, which drives pyroptosis in monocytes and macrophages.

Activation of farnesoid X receptor enhances the efficacy of normothermic machine perfusion in ameliorating liver ischemia-reperfusion injury.

The shortage of transplant organs remains a severe global issue. Normothermic machine perfusion (NMP) has the potential to increase organ availability, yet its efficacy is hampered by the inflammatory response during machine perfusion. Mouse liver ischemia-reperfusion injury (IRI) models, discarded human liver models, and porcine marginal liver transplantation models were utilized to investigate whether farnesoid X receptor (FXR) activation could mitigate inflammation-induced liver damage. FXR expression levels before and after reperfusion were measured. Gene editing and coimmunoprecipitation techniques were employed to explore the regulatory mechanism of FXR in inflammation inhibition. The expression of FXR correlates with the extent of liver damage after reperfusion. Activation of FXR significantly suppressed the inflammatory response triggered by IRI, diminished the release of proinflammatory cytokines, and improved liver function recovery during NMP, assisting discarded human livers to reach transplant standards. Mechanistically, FXR disrupts the interaction between p65 and p300, thus inhibiting modulating the nuclear factor kappa-B signaling pathway, a key instigator of inflammation. Our research across multiple species confirms that activating FXR can optimize NMP by attenuating IRI-related liver damage, thereby improving the utilization of marginal livers for transplantation.

The establishment of diseased human whole organ model by normothermic machine perfusion technique: Principle of concept.

BACKGROUND: The global incidence of liver diseases is rising, yet there remains a dearth of precise research models to mimic these diseases. The use of normothermic machine perfusion (NMP) to study diseased livers recovered from liver transplantation (LT) recipients presents a promising avenue. Accordingly, we have developed a machine perfusion system tailored specifically for the human whole diseased livers and present our experience from the NMP of diseased livers. METHODS: Six diseased livers recovered from LT recipients with different diagnoses were collected. The diseased livers were connected to the machine perfusion system that circulated tailored perfusate, providing oxygen and nutrients. The pressure and flow of the system were recorded, and blood gas analysis and laboratory tests of perfusate and bile were examined to analyze the function of the diseased livers. Liver tissues before and after NMP were collected for histological analysis. RESULTS: Experiments showed that the system maintained the diseased livers in a physiological state, ensuring stable hemodynamics and a suitable partial pressure of oxygen and carbon dioxide. The results of blood gas analysis and laboratory tests demonstrated a restoration and sustenance of metabolism with minimal damage. Notably, a majority of the diseased livers exhibited bile production continuously, signifying their vivid functional integrity. The pathological characteristics remained stable before and after NMP. CONCLUSION: We successfully established the machine perfusion system tailored specifically for diseased human whole livers. Through the application of this system, we have developed a novel in vitro model that faithfully recapitulates the main features of human liver disease. This model holds immense promise as an advanced disease modeling platform, offering profound insights into liver diseases and potential implications for research and therapeutic development.

Novel ceRNA network construction associated with programmed cell death in acute rejection of heart allograft in mice.

Background: T cell-mediated acute rejection(AR) after heart transplantation(HT) ultimately results in graft failure and is a common indication for secondary transplantation. It's a serious threat to heart transplant recipients. This study aimed to explore the novel lncRNA-miRNA-mRNA networks that contributed to AR in a mouse heart transplantation model. Methods: The donor heart from Babl/C mice was transplanted to C57BL/6 mice with heterotopic implantation to the abdominal cavity. The control group was syngeneic heart transplantation with the same kind of mice donor. The whole-transcriptome sequencing was performed to obtain differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs) and lncRNAs (DElncRNAs) in mouse heart allograft. The biological functions of ceRNA networks was analyzed by GO and KEGG enrichment. Differentially expressed ceRNA involved in programmed cell death were further verified with qRT-PCR testing. Results: Lots of DEmRNAs, DEmiRNAs and DElncRNAs were identified in acute rejection and control after heart transplantation, including up-regulated 4754 DEmRNAs, 1634 DElncRNAs, 182 DEmiRNAs, and down-regulated 4365 DEmRNAs, 1761 DElncRNAs, 132 DEmiRNAs. Based on the ceRNA theory, lncRNA-miRNA-mRNA regulatory networks were constructed in allograft acute rejection response. The functional enrichment analysis indicate that the down-regulated mRNAs are mainly involved in cardiac muscle cell contraction, potassium channel activity, etc. and the up-regulated mRNAs are mainly involved in T cell differentiation and mononuclear cell migration, etc. The KEGG pathway enrichment analysis showed that the down-regulated DEmRNAs were mainly enriched in adrenergic signaling, axon guidance, calcium signaling pathway, etc. The up-regulated DEmRNAs were enriched in the adhesion function, chemokine signaling pathway, apoptosis, etc. Four lncRNA-mediated ceRNA regulatory pathways, Pvt1/miR-30c-5p/Pdgfc, 1700071M16Rik/miR-145a-3p/Pdgfc, 1700071M16Rik/miR-145a-3p/Tox, 1700071M16Rik/miR-145a-3p/Themis2, were finally validated. In addition, increased expression of PVT1, 1700071M16Rik, Tox and Themis2 may be considered as potential diagnostic gene biomarkers in AR. Conclusion: We speculated that Pvt1/miR-30c-5p/Pdgfc, 1700071M16Rik/miR-145a-3p/Pdgfc, 1700071M16Rik/miR-145a-3p/Tox and 1700071M16Rik/miR-145a-3p/Themis2 interaction pairs may serve as potential biomarkers in AR after HT.

Utilization of hepatitis B surface antigen-positive donors in liver transplantation for recipients with hepatocellular carcinoma: a retrospective and propensity score matching analysis.

Introduction: The use of extended criteria donor (ECD) grafts such as donor with infection of hepatitis B virus (HBV) is a potential solution for organ shortage. In this study, we aimed to evaluate the safety and long-term survival of utilization of hepatitis B surface antigen-positive (HBsAg+) donor livers in HCC patients using propensity score matching (PSM) analysis. Methods: Forty-eight donors with HBsAg-positive and 279 donors with HBsAg-negative were transplanted and enrolled in this study. PSM analysis were used to eliminate selection bias. Perioperative data and survival were collected and analyzed. Results: PSM generated 44 patient pairs. When comparing intra- and post-operative data, no significant difference was found between groups (P > 0.05). Patients with a HBsAg-positive donor had significantly worse progression-free survival (1-year: 65.9% vs. 90.9%; 3-year: 18.1% vs. 70.4%, P = 0.0060) and overall survival (1-year: 84.1% and 95.4%; 3-year: 27.2% vs. 79.5%, P = 0.0039). In multivariate analysis, donor HBsAg-positivity was an independent risk factor for survival and occurrence (P = 0.005 and 0.025, respectively). Conclusion: In conclusion, with adequate antiviral prophylaxis and treatment, utilization of HBsAg positive liver grafts did not increase the incidence of early-stage complications. However, patient with an HBsAg-positive graft had poorer progression-free survival and overall survival.

A randomized-controlled trial of ischemia-free liver transplantation for end-stage liver disease.

BACKGROUND & AIMS: Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ availability. Ischemia-free organ transplantation is a novel approach designed to avoid IRI, with the potential to improve outcomes. METHODS: In this randomized-controlled clinical trial, recipients of livers from donors after brain death were randomly assigned to receive either an ischemia-free or a 'conventional' transplant. The primary endpoint was the incidence of early allograft dysfunction. Secondary endpoints included complications related to graft IRI. RESULTS: Out of 68 randomized patients, 65 underwent transplants and were included in the analysis. 32 patients received ischemia-free liver transplantation (IFLT), and 33 received conventional liver transplantation (CLT). Early allograft dysfunction occurred in two recipients (6%) randomized to IFLT and in eight (24%) randomized to CLT (difference -18%; 95% CI -35% to -1%; p = 0.044). Post-reperfusion syndrome occurred in three recipients (9%) randomized to IFLT and in 21 (64%) randomized to CLT (difference -54%; 95% CI -74% to -35%; p <0.001). Non-anastomotic biliary strictures diagnosed with protocol magnetic resonance cholangiopancreatography at 12 months were observed in two recipients (8%) randomized to IFLT and in nine (36%) randomized to CLT (difference, -28%; 95% CI -50% to -7%; p = 0.014). The comprehensive complication index at 1 year after transplantation was 30.48 (95% CI 23.25-37.71) in the IFLT group vs. 42.14 (95% CI 35.01-49.26) in the CLT group (difference -11.66; 95% CI -21.81 to -1.51; p = 0.025). CONCLUSIONS: Among patients with end-stage liver disease, IFLT significantly reduced complications related to IRI compared to a conventional approach. CLINICAL TRIAL REGISTRATION: chictr.org. ChiCTR1900021158. IMPACT AND IMPLICATIONS: Ischemia-reperfusion injury has thus far been considered as an inevitable event in organ transplantation, compromising outcomes and limiting organ availability. Ischemia-free liver transplantation is a novel approach of transplanting donor livers without interruption of blood supply. We showed that in patients with end-stage liver disease, ischemia-free liver transplantation, compared with a conventional approach, led to reduced complications related to ischemia-reperfusion injury in this randomized trial. This new approach is expected to change the current practice in organ transplantation, improving transplant outcomes, increasing organ utilization, while providing a clinical model to delineate the impact of organ injury on alloimmunity.

Neoadjuvant programmed cell death 1 inhibitor before liver transplantation for HCC is not associated with increased graft loss.

Immune checkpoint inhibitors (ICIs) may lead to rejection and even graft loss of solid organ transplant recipients, making them not widely used in transplant patients. There is insufficient clinical experience in using ICIs as a bridging or downstaging therapy before transplantation. We performed a retrospective review of patients receiving programmed cell death 1 inhibitor (PD1) before liver transplantation for HCC in our center and analyzed the data of these patients with the purpose of investigating the safety and feasibility of preoperative PD1 inhibitor among liver transplant recipients and exploring the preoperative correlation ICIs and the postoperative risk of rejection and immune-related graft loss. A total of 16 patients enrolled in this study. Acute rejection occurred in 9 patients, with an incidence of 56.3%. The median time of rejection was 7 days after surgery. The median FK506 concentration at the time of rejection was 7.1 µg/L. All rejection reactions were reversed after adjusting the immunosuppression regimen. The interval between the last PD1 inhibitor and transplantation in the rejection group was shorter than that in the nonrejection group, and there was a statistical difference [21.0 (15.5-27.5) days vs. 60.0 (34.0-167.0) days, p =0.01]. In conclusion, PD1 inhibitor is a safe and feasible method for bridging or downstaging treatment before liver transplantation. Although preoperative PD1 inhibitor may increase the incidence of postoperative rejection, it is not associated with increased immune-related graft loss and patient death.

Association between nonalcoholic fatty liver disease and increased glucose-to-albumin ratio in adults without diabetes.

Background: Nonalcoholic fatty liver disease (NAFLD) affects approximately 30% of individuals globally. Both serum glucose and albumin were demonstrated to be potential markers for the development of NAFLD. We hypothesized that the risk of NAFLD may be proportional to the glucose-to-albumin ratio (GAR). Methods: Based on information from the National Health and Nutrition Examination Survey (NHANES) 1999-2018, it was determined that GAR was associated with an increased risk of NAFLD and liver fibrosis utilizing weighted multivariable logistic regression. Participants with a fatty liver index (FLI) over 60 were identified with NAFLD, and those with an NAFLD fibrosis score (NFS) >0.676 with evidence of NAFLD were labeled with advanced hepatic fibrosis (AHF). The liver biopsy was utilized to verify the relationship between GAR and FLD in our center cohort. Mendelian randomization analysis investigated the genetic relationship between GAR and NAFLD. Results: Of 15,534 eligible participants, 36.4% of participants were identified as NAFLD without AHF. GAR was positively correlated with the probability of NAFLD following full adjustment for possible variables (OR = 1.53, 95% CI: 1.39-1.67). It was confirmed that patients with NAFLD and AHF had an inferior prognosis. The relationship between GAR and NFS was favorable (R = 0.46, P< 0.0001), and NAFLD patients with a higher GAR tended to develop poor survival. In our center cohort, the association between GAR and NAFLD was verified. Conclusion: Among participants without diabetes, greater GAR was linked to higher risks of NAFLD. In addition, NAFLD patients with higher GAR tended to develop liver fibrosis and adverse outcomes.

Abrogation of graft ischemia-reperfusion injury in ischemia-free liver transplantation.

BACKGROUND: Ischemia-reperfusion injury (IRI) is considered an inherent component of organ transplantation that compromises transplant outcomes and organ availability. The ischemia-free liver transplantation (IFLT) procedure has been developed to avoid interruption of blood supply to liver grafts. It is unknown how IFLT might change the characteristics of graft IRI. METHODS: Serum and liver biopsy samples were collected from IFLT and conventional liver transplantation (CLT) recipients. Pathological, metabolomics, transcriptomics, and proteomics analyses were performed to identify the characteristic changes in graft IRI in IFLT. RESULTS: Peak aspartate aminotransferase (539.59 ± 661.76 U/L versus 2622.28 ± 3291.57 U/L) and alanine aminotransferase (297.64 ± 549.50 U/L versus 1184.16 ± 1502.76 U/L) levels within the first 7 days and total bilirubin levels by day 7 (3.27 ± 2.82 mg/dl versus 8.33 ± 8.76 mg/dl) were lower in the IFLT versus CLT group (all p values < 0.001). The pathological characteristics of IRI were more obvious in CLT grafts. The antioxidant pentose phosphate pathway remained active throughout the procedure in IFLT grafts and was suppressed during preservation and overactivated postrevascularization in CLT grafts. Gene transcriptional reprogramming was almost absent during IFLT but was profound during CLT. Proteomics analysis showed that "metabolism of RNA" was the major differentially expressed process between the two groups. Several proinflammatory pathways were not activated post-IFLT as they were post-CLT. The activities of natural killer cells, macrophages, and neutrophils were lower in IFLT grafts than in CLT grafts. The serum levels of 14 cytokines were increased in CLT versus IFLT recipients. CONCLUSIONS: IFLT can largely avoid the biological consequences of graft IRI, thus has the potential to improve transplant outcome while increasing organ utilization.

Combined Liver, Pancreas-Duodenum, and Kidney Transplantation for Patients with Hepatitis B Cirrhosis, Uremia, and Insulin-Dependent Diabetes.

BACKGROUND Abdominal organ cluster transplantation for the treatment of upper abdominal end-stage diseases is a serious conundrum for surgeons. CASE REPORT We performed clinical assessment of quadruple organ transplantation (liver, pancreas, duodenum, and kidney) for a patient with end-stage liver disease, post-chronic hepatitis B cirrhosis, uremia, and insulin-dependent diabetes mellitus, and explored the optimal surgical procedure. Simultaneous classic orthotopic liver, pancreas-duodenum, and heterotopic renal transplantation was performed on a 46-year-old man. The process was an improvement of surgery implemented with a single vascular anastomosis (Y graft of the superior mesenteric artery and the celiac artery open together in the common iliac artery). The pancreatic secretions and bile were drained through a modified uncut jejunal loop anastomosis, and the donor's kidneys were placed in the right iliac fossa. The patient was prescribed basiliximab, glucocorticoid, tacrolimus, and mycophenolate mofetil for immunosuppression. The hepatic function recovered satisfactorily on postoperative day (POD) 3, and pancreatic function recovered satisfactorily in postoperative month (POM) 1. Hydronephrosis occurred in the transplanted kidney, with elevated creatinine on POD 15. Consequently, renal pelvic puncture and drainage were performed. His creatinine dropped to a normal level on POD 42. No allograft rejections or other complications, like pancreatic leakage, thrombosis, or localized infections, occurred. The patient had normal liver, renal, and pancreas functions with insulin-independent after POD 365. CONCLUSIONS Simultaneous classic orthotopic liver, pancreas-duodenum, and heterotopic renal transplantation is a promising therapeutic option for patients with insulin-dependent diabetes combined with end-stage hepatic and renal disease, and our center's experience can provide a reference for clinical multiorgan transplantation.

Ultrastructural changes of donor livers in liver transplantation indicate hepatocytes injury.

The use of electron microscopy (EM) can provide details about cells and tissue down to the nanometer level. We aim to observe ultrastructural changes in the donor liver by EM and analyze the relationship with prognosis. Data from 89 liver transplant recipients were collected and analyzed for recovery of graft function. The results revealed significantly higher organelle injury scores in the primary liver graft nonfunction (PNF) group. High-score group had higher peak alanine aminotransferases, peak aspartate aminotransferases, and peak international normalized ratio (p = .041, .006 and .036, respectively). Warm ischemia time, score of rough endoplasmic reticulum and nucleus was larger in low-score group (p = .007, .006, and .025, respectively). Patients in high-score group had a significantly short survival time (60.0% vs. 92.9%, p = .0039). No significant difference was found in the analysis of 3-year survival rate (60% vs. 84.5%, p = .07). EM is one of feasible and effective strategy for evaluating the quality of donor liver and the patient's prognosis. Ultrastructural changes under EM indicate hepatocytes injury and a high score indicates a worse outcome in early period but does not affect long-term survival. RESEARCH HIGHLIGHTS: We showed that ultrastructural changes in the donor liver by electron microscopy indicate hepatocytes injury and could be a reference for prognosis. A high score indicates a worse outcome in early period but does not affect long-term survival. It is rare in the current researches.

Transplantation of Extended Criteria Donor Livers Following Continuous Normothermic Machine Perfusion Without Recooling.

BACKGROUND: Traditional liver transplant strategies with cold preservation usually result in ischemia-reperfusion injury (IRI) to the donor liver. Regular normothermic machine perfusion (NMP) donor livers suffer IRI twice. Here, we aimed to introduce a novel technique called continuous NMP without recooling to avoid a second IRI and its application in livers from extended criteria donors. METHODS: Seven donor livers transplanted following continuous NMP without recooling, 7 donor livers transplanted following standard NMP, and 14 livers under static cold storage (SCS) were included in this study. Perioperative outcomes were recorded and analyzed between groups. RESULTS: During the NMP without a recooling procedure, all livers cleared lactate quickly to normal levels in a median time of 100 min (interquartile range, 60-180) and remained stable until the end of perfusion. In the NMP without recooling and standard NMP groups, posttransplant peak aspartate aminotransferase and alanine aminotransferase levels were both significantly lower than those in the SCS group (P = 0.0015 and 0.016, respectively). The occurrence rate of early allograft dysfunction was significantly lower in the NMP without recooling group than in the SCS group (P = 0.022), whereas there was no difference in the NMP group with or without recooling (P = 0.462). CONCLUSIONS: Our pilot study revealed a novel technique designed to avoid secondary IRI. This novel technique is shown to have at least a comparable effect on the standard NMP, although more data are needed to show its superiority in the future.

Ischemic-Free Liver Transplantation Reduces the Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Ischemia reperfusion injury (IRI) is an adverse factor for hepatocellular carcinoma (HCC) recurrence after liver transplantation. Ischemic-free liver transplantation (IFLT) is a novel transplant procedure that can largely reduce or even prevent IRI, but the clinical relevance of IFLT and the recurrence of HCC after liver transplantation are still unknown. This retrospective study compared survival outcomes, HCC recurrence, perioperative data and IRI severity following liver transplantation (LT). 30 patients received IFLT and 196 patients received conventional liver transplantation (CLT) were chosen for the entire cohort between June 2017 and August 2020. A 1:3 propensity score matching was performed, 30 IFLT recipients and 85 matched CLT patients were enrolled in propensity-matched cohorts. An univariate and multivariate Cox regression analysis was performed, and showed surgical procedure (CLT vs IFLT) was an independent prognostic factor (HR 3.728, 95% CI 1.172-11.861, P=0.026) for recurrence free survival (RFS) in HCC patients following liver transplantation. In the Kaplan-Meier analysis, the RFS rates at 1 and 3 years after LT in recipients with HCC in the IFLT group were significantly higher than those in the CLT group both in the entire cohort and propensity-matched cohort (P=0.006 and P=0.048, respectively). In addition, patients in the IFLT group had a lower serum lactate level, lower serum ALT level and serum AST level on postoperative Day 1. LT recipients with HCC in the IFLT group had a lower incidence of early allograft dysfunction than LT recipients with HCC in the CLT group. Histological analysis showed no obvious hepatocyte necrosis or apoptosis in IFLT group. In conclusion, IFLT can significantly reduce IRI damage and has the potential to be a useful strategy to reduce HCC recurrence after liver transplantation.

Application of various surgical techniques in liver transplantation: a retrospective study.

BACKGROUND: Surgical techniques of liver transplantation have continually evolved and have been modified. We retrospectively analyzed a single-center case series and compared the advantages and disadvantages of each method. METHODS: Six-hundred and seventy-four recipients' perioperative data were assessed and analyzed stratified by different surgical technics [modified classic (MC), modified piggyback (MPB) and classic piggyback (CPB)]. RESULTS: MELD score and Child-Pugh scores was significantly higher in CPB groups (P=0.008 and 0.003, respectively). Anhepatic time in MPB group was longer than those in CPB group (P<0.05). The operation duration in MPB group was significantly longer than those in MC group and CPB group (P=0.003). Three patients had outflow obstruction (P=0.035). The overall survival in MPB group were better than those in MC group and CPB group in general comparison (P<0.001). In patients with preoperative creatine >120 µmol/L, the overall survival in MC group was worst (P<0.001). In patients with a high MELD score (>24), the overall survival in MPB group tended to be the best (P<0.001). CONCLUSIONS: The advantages and disadvantages are different for these three surgical techniques. A reasonable operation technique should be adopted considering the patient's unique condition to ensure the stability of hemodynamics.

Circulating Tumor Cell Is a Clinical Indicator of Pretransplant Radiofrequency Ablation for Patients with Hepatocellular Carcinoma.

INTRODUCTION: It is of great significance to confirm reliable indicators for the guidance of pretransplant radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). In this study, we aim to investigate whether circulating tumor cell (CTC) status is a clinical indicator for RFA before liver transplantation (LT) in HCC patients. METHOD: CTC analyses were measured in 79 HCC patients. Clinical outcomes including progression-free (PFS) and overall survival (OS) were compared and analyzed between patients with and without pretransplant RFA. RESULT: Forty-two patients were detected as CTC-positive and 18 patients received pretransplant RFA. Recurrence was correlated with CTC count (P=0.024), tumor number (P=0.035), liver cirrhosis (P=0.001), Milan criteria (P=0.003), and University of California San Francisco (UCSF) criteria (P=0.001). Kaplan-Meier analysis revealed that patients with CTC-positive had a lower PFS rate (P=0.0257). For CTC-positive patients, the PFS rate of the pretransplant RFA group was significantly higher than the non-pretransplant RFA group (100% vs. 46.7%, P=0.0236). For CTC-negative patients, both PFS rate and OS rate were similar and without significant differences. In multivariate analysis, pretransplant RFA was the independent factor for PFS (P=0.025). CONCLUSION: Pretransplant CTC status can guide the administration of pretransplant RFA in HCC patients which can improve PFS in CTC-positive HCC patients.

Ischaemia-free liver transplantation in humans: a first-in-human trial.

Background Ischaemia-reperfusion injury is considered an inevitable component of organ transplantation, compromising organ quality and outcomes. Although several treatments have been proposed, none has avoided graft ischaemia and its detrimental consequences. Methods Ischaemia-free liver transplantation (IFLT) comprises surgical techniques enabling continuous oxygenated blood supply to the liver of brain-dead donor during procurement, preservation, and implantation using normothermic machine perfusion technology. In this non-randomised study, 38 donor livers were transplanted using IFLT and compared to 130 conventional liver transplants (CLT). Findings Two recipients (5•3%) in the IFLT group experienced early allograft dysfunction, compared to 50•0% in patients receiving conventional transplants (absolute risk difference, 44•8%; 95% confidence interval, 33•6-55•9%). Recipients of IFLT had significantly reduced median (IQR) peak aspartate aminotransferase levels within the first week compared to CLT recipients (365, 238-697 vs 1445, 791-3244 U/L, p<0•001); likewise, median total bilirubin levels on day 7 were significantly lower (2•34, 1•39-4•09 mg/dL) in the IFLT group than in the CLT group (5•10, 1•90-11•65 mg/dL) (p<0•001). Moreover, IFLT recipients had a shorter median intensive care unit stay (1•48, 0•75-2•00 vs 1•81, 1•00-4•58 days, p=0•006). Both one-month recipient (97•4% vs 90•8%, p=0•302) and graft survival (97.4% vs 90•0%, p=0•195) were better for IFLT than CLT, albeit differences were not statistically significant. Subgroup analysis showed that the extended criteria donor livers transplanted using the IFLT technique yielded faster post-transplant recovery than did the standard criteria donor livers transplanted using the conventional approach. Interpretation IFLT provides a novel approach that may improve outcomes, and allow the successful utilisation of extended criteria livers. Funding This study was funded by National Natural Science Foundation of China, Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology, and Guangdong Provincial international Cooperation Base of Science and Technology. Panel: Research in context.

Prediction of post-transplant graft survival by different definitions of early allograft dysfunction.

BACKGROUND: The efficacy of early allograft dysfunction (EAD) definitions in predicting post-transplant graft survival in a Chinese population is still unclear. METHODS: A total of 607 orthotopic liver transplants (OLT) have been included in the current study. Model accuracy was evaluated using receiver operating characteristic (ROC) analysis. Risk factors for EAD was evaluated using univariable analysis and multivariable logistic regression model. RESULTS: The 3-, 6-, and 12-month patient/graft survival were 91.6%/91.4%, 91.1%/90%, and 87.5%/87.3%, respectively. MELDPOD5 had a superior discrimination of 3-month graft survival (C statistic, 0.83), compared with MEAF (C statistic, 0.77) and Olthoff criteria (C statistic, 0.72). Multivariate analysis of risk factors for EAD defined by MELDPOD5, showed that donor body mass index (P=0.001), donor risk index (P=0.006), intraoperative use of packed red blood cells (P=0.001), hypertension of recipient (P=0.004), and preoperative total bilirubin (P<0.001) were independent risk factors. CONCLUSIONS: The results suggest that MLEDPOD5 is a better criterion of EAD for the Chinese population, which might serve as a surrogate end-point for graft survival in clinical study.

Prognosis after liver transplantation in patients treated with anti-PD-1 immunotherapy for advanced hepatocellular carcinoma: case series.

BACKGROUND: Programmed death protein-1 (PD-1) inhibitors and liver transplantation (LT) are alternative treatments for hepatocellular carcinoma (HCC) patients. The application of PD-1 inhibitors for HCC therapy increases T cell immune activity, while immunosuppression is required for patients receiving transplantation. More clinical investigation is required to determine methods to balance these treatment effects. In this article, we are the first to describe the clinical characteristics, imaging findings, and outcomes of 5 LT patients who had a history of HCC and received anti-PD-1 therapy. METHODS: Data from 5 patients who were diagnosed with HCC and received LT after PD-1 inhibition were analyzed. The doses and courses of PD-1 and preoperative and postoperative characteristics were compared and analyzed. RESULTS: The mean interval between PD-1 inhibition and LT was 63.80±18.26 days. One patient experienced recurrence in the liver, vertebrae and lungs after 7 months, and 1 patient experienced recurrence in the lungs after 3 months. All patients displayed normal liver function at the latest follow-up visit. No acute allograft rejections occurred in any patient. CONCLUSIONS: PD-1 inhibitors may be safe for the treatment of HCC before LT when the interval between the two treatments is sufficient. Further investigations are needed for to validate these findings.

En bloc procurement of porcine abdominal multiple organ block for ex situ normothermic machine perfusion: a technique for avoiding initial cold preservation.

BACKGROUND: Normothermic machine perfusion (NMP) is a technique that maintains organs ex situ with normal metabolism, and organ function can be better preserved. The study of multiple-organ NMP is rarely reported. Multiple organ block (MOB) is a self-perfusing system for maintaining multiple organs ex situ, and porcine MOBs have been successfully preserved for 18 to 37 h. Due to the above context, we conceived to maintain abdominal multiple organ block (AMOB) ex situ utilizing NMP technology. METHODS: AMOBs were procured from Ba-Ma miniature pigs through en bloc procurement surgery. The process of cold preservation was eliminated between the procurement and machine perfusion, and a few minutes of warm ischemia emerged. Autologous whole blood was collected during procurement surgery as a perfusate component in the beginning. RESULTS: The median time of procurement surgery was approximately 220 min, and the median time of warm ischemia was 300 sec. Cases 1 and 2 suffered from repeated hypotension during the procurement surgery, and case 2 exhibited hemorrhage. After improved and optimized procurement processes, the vital signs of cases 3 to 5 remained stable during procurement. In the NMP phase, the flow increased slowly in cases 1 and 2 and did not remain stable even after continuous infusion of a high-dose vasodilator. The lactic acid level rapidly increased, and the levels of ALT and AST were obviously higher than those in cases 3 to 5. In contrast, the flow rate increased smoothly in cases 3 to 5. The lactic acid level remained stable during the first 10 h of perfusion. CONCLUSIONS: AMOB procurement from heart-beating pigs for NMP without initial cold preservation is technically feasible.