RESUMO

BACKGROUND: Circulating cytokine levels not only correlate with the progression of liver disease but also serve as indicators for the infection status of the body. Growing evidence points to the connection between donor cytokines and graft function following transplantation. This study set out to explore the clinical significance of donor cytokines in predicting liver transplantation prognosis. METHODS: Data from 172 deceased donor liver transplantations conducted between 2017 and 2022, with available donor serum cytokine information, were collected. The subjects were randomly divided into estimation (n = 120) and validation (n = 52) groups to establish and validate the model. The newly developed SA10 score was compared against established models EAD, MEAF, L-GrAFT7, and L-GrAFT10. RESULTS: Donor IL-10, along with donor age and recipient AST peak value within the first 7 days post-operation, was identified as an independent factor associated with recipient survival and was incorporated into the SA10 score. SA10 exhibited robust predictive capability, particularly for 1-month survival (AUC = 0.90, 95% CI = 0.84-0.96), outperforming EAD (AUC = 0.75, 95% CI = 0.60-0.90, p = 0.04) and L-GrAFT7 (AUC = 0.65, 95% CI = 0.49-0.81, p < 0.01). Comparable performance was observed between SA10, MEAF, and L-GrAFT10. CONCLUSION: Donor IL-10 independently influences recipient survival, with the SA10 score demonstrating comparable and even superior predictive ability compared to existing models.

Assuntos

Transplante de Fígado , Doadores de Tecidos , Humanos , Transplante de Fígado/mortalidade , Transplante de Fígado/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Doadores de Tecidos/estatística & dados numéricos , Interleucina-10/sangue , Sobrevivência de Enxerto , Prognóstico , Citocinas/sangue , Transplantados/estatística & dados numéricos

RESUMO

Brain injury is the leading cause of mortality among patients who survive cardiac arrest (CA). Clinical studies have shown that the presence of post-CA hypoxic hepatitis or pre-CA liver disease is associated with increased mortality and inferior neurological recovery. In our in vivo global cerebral ischemia model, we observed a larger infarct area, elevated tissue injury scores, and increased intravascular CD45+ cell adhesion in reperfused brains with simultaneous hepatic ischemia than in those without it. In the ex vivo brain normothermic machine perfusion (NMP) model, we demonstrated that addition of a functioning liver to the brain NMP circuit significantly reduced post-CA brain injury, increased neuronal viability, and improved electrocortical activity. Furthermore, significant alterations were observed in both the transcriptome and metabolome in the presence or absence of hepatic ischemia. Our study highlights the crucial role of the liver in the pathogenesis of post-CA brain injury.

RESUMO

OBJECTIVE: Evaluating the safety and efficacy of implanting a liver with islet grafts into patients with end-stage liver disease and diabetes mellitus (DM). BACKGROUND: DM and end-stage liver diseases are significant health concern worldwide, often coexisting and mutually influencing each other. Addressing both diseases simultaneously is paramount. METHODS: We utilized the islet transplantation combined ischemia-free liver transplantation (ITIFLT) technique to treat a patient with hepatocellular carcinoma (HCC) and type 2 diabetes mellitus (T2DM). The liver was procured and preserved using the ischemia-free liver transplantation (IFLT) technique, and during normothermic machine perfusion (NMP), isolated and purified islet grafts were transplanted into the liver through the portal vein. Finally, the liver, incorporating with the transplant islet grafts, was implanted into the recipient without interruption of blood supply. RESULTS: The patient received both liver and islet graft from the same donor. The patient achieved insulin-independence by post-transplant day (PTD) 9, and both liver and islet function remained robust. The patient was discharged on PTD 18 and experienced no surgical or transplantation-related complications during the follow-up period. Furthermore, islet grafts presence was observed in liver biopsies after islet transplantation. CONCLUSIONS: This landmark case marks the inaugural application of ITIFLT in humans, signifying its potential as a promising treatment modality for end-stage liver disease with DM.

RESUMO

Immune checkpoint inhibitors (ICIs) as a downstaging or bridging therapy for liver transplantation (LT) in hepatocellular carcinoma patients are rapidly increasing. However, the evidence about the feasibility and safety of pre-LT ICI therapy is limited and controversial. To this end, a multicenter, retrospective cohort study was conducted in 11 Chinese centers. The results showed that 83 recipients received pre-LT ICI therapy during the study period. The median post-LT follow-up was 8.1 (interquartile range 3.3-14.6) months. During the short follow-up, 23 (27.7%) recipients developed allograft rejection, and 7 of them (30.4%) were diagnosed by liver biopsy. Multivariate logistics regression analysis showed that the time interval between the last administration of ICI therapy and LT (TLAT) ≥ 30 days was an independent protective factor for allograft rejection (odds ratio = 0.096, 95% confidence interval 0.026-0.357; P < .001). Multivariate Cox analysis showed that allograft rejection was an independent risk factor for overall survival (hazard ratio = 9.960, 95% confidence interval 1.006-98.610; P = .043). We conclude that patients who receive a pre-LT ICI therapy with a TLAT shorter than 30 days have a much higher risk of allograft rejection than those with a TLAT longer than 30 days. The presence of rejection episodes might be associated with higher post-LT mortality.

Assuntos

Carcinoma Hepatocelular , Rejeição de Enxerto , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Estudos Retrospectivos , Masculino , Feminino , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Inibidores de Checkpoint Imunológico/uso terapêutico , Pessoa de Meia-Idade , Rejeição de Enxerto/etiologia , Seguimentos , Prognóstico , Sobrevivência de Enxerto/efeitos dos fármacos , Taxa de Sobrevida , Fatores de Risco

RESUMO

Background: In organ transplantation, ischemia, and reperfusion injury (IRI) is considered as an inevitable event and the major contributor to graft failure. Ischemia-free liver transplantation (IFLT) is a novel transplant procedure that can prevent IRI and provide better transplant outcomes. However, a large animal model of IFLT has not been reported. Therefore, we develop a new, reproducible, and stable model of IFLT in pigs for investigating mechanisms of IFLT in IRI. Methods: Ten pigs were subjected to IFLT or conventional liver transplantation (CLT). Donor livers in IFLT underwent 6-h continuous normothermic machine perfusion (NMP) throughout graft procurement, preservation, and implantation, whereas livers in CLT were subjected to 6-h cold storage before implantation. The early reperfusion injury was compared between the 2 groups. Results: Continuous bile production, low lactate, and liver enzyme levels were observed during NMP in IFLT. All animals survived after liver transplantation. The posttransplant graft function was improved with IFLT when compared with CLT. Minimal histologic changes, fewer apoptotic hepatocytes, less sinusoidal endothelial cell injury, and proinflammatory cytokine (interleukin [IL]-1ß, IL-6, and tumor necrosis factor-α) release after graft revascularization were documented in the IFLT group versus the CLT group. Conclusions: We report that the concept of IFLT is achievable in pigs. This innovation provides a potential strategy to investigate the mechanisms of IRI and provide better transplant outcomes for clinical practice.

RESUMO

BACKGROUND/AIMS: The shortage of donor liver hinders the development of liver transplantation. This study aimed to clarify the poor outcomes of functionally marginal liver grafts (FMLs) and provide evidence for the improvement of ischemia-free liver transplantation (IFLT) after FML transplantation. METHODS: Propensity score matching was used to control for confounding factors. The outcomes of the control group and FML group were compared to demonstrate the negative impact of FMLs on 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 had a significantly greater hazard ratio (HR: 1.969, P=0.018) than did other marginal livers. A worse 90-day survival (Mortality: 12.3% vs. 5.0%, P=0.007) was observed in patients who underwent FML transplantation. Patients who received FMLs had a significant improvement in overall survival after IFLT (Mortality: 10.4% vs 31.3%, P=0.006). Pyroptosis and inflammation were inhibited in patients who underwent IFLT. The infiltration of natural killer cells was lower in liver grafts from these patients. Bulk transcriptome profiles revealed a positive relationship between IL-32 and Caspase 1 (R=0.73, P=0.01) and between IL-32 and Gasdermin D (R=0.84, P=0.0012). CONCLUSION: FML is a more important negative prognostic parameter than other marginal liver parameters. 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.

Assuntos

Transplante de Fígado , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Fígado/patologia , Fígado/metabolismo , Adulto , Interleucinas/genética , Interleucinas/metabolismo , Transcriptoma , Piroptose , Células Matadoras Naturais/metabolismo , Sobrevivência de Enxerto , Doadores de Tecidos , Pontuação de Propensão

RESUMO

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.

Assuntos

Transplante de Fígado , Preservação de Órgãos , Perfusão , Receptores Citoplasmáticos e Nucleares , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Camundongos , Receptores Citoplasmáticos e Nucleares/metabolismo , Humanos , Suínos , Preservação de Órgãos/métodos , Masculino , Camundongos Endogâmicos C57BL , Fígado/metabolismo

RESUMO

BACKGROUND AND AIMS: HBV infection is a major etiology of acute-on-chronic liver failure (ACLF). At present, the pattern and regulation of hepatocyte death during HBV-ACLF progression are still undefined. Evaluating the mode of cell death and its inducers will provide new insights for developing therapeutic strategies targeting cell death. In this study, we aimed to elucidate whether and how immune landscapes trigger hepatocyte death and lead to the progression of HBV-related ACLF. APPROACH AND RESULTS: We identified that pyroptosis represented the main cell death pattern in the liver of patients with HBV-related ACLF. Deficiency of MHC-I in HBV-reactivated hepatocytes activated cytotoxic NK cells, which in turn operated in a perforin/granzyme-dependent manner to trigger GSDMD/caspase-8-dependent pyroptosis of hepatocytes. Neutrophils selectively accumulated in the pyroptotic liver, and HMGB1 derived from the pyroptotic liver constituted an important factor triggering the generation of pathogenic extracellular traps in neutrophils (NETs). Clinically, elevated plasma levels of myeloperoxidase-DNA complexes were a promising prognostic biomarker for HBV-related ACLF. More importantly, targeting GSDMD pyroptosis-HMGB1 release in the liver abrogates NETs that intercept the development of HBV-related ACLF. CONCLUSIONS: Studying the mechanisms that selectively modulate GSDMD-dependent pyroptosis, as well as its immune landscapes, will provide a novel strategy for restoring the liver function of patients with HBV-related ACLF.

RESUMO

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.

Assuntos

Transplante de Fígado , Fígado , Preservação de Órgãos , Perfusão , Humanos , Perfusão/métodos , Perfusão/instrumentação , Transplante de Fígado/métodos , Fígado/cirurgia , Fígado/patologia , Preservação de Órgãos/métodos , Preservação de Órgãos/instrumentação , Masculino , Pessoa de Meia-Idade , Feminino , Hepatopatias/patologia

RESUMO

Dysregulation of cholesterol homeostasis is implicated in the development and progression of hepatocellular carcinoma (HCC) that is characterized by intrahepatic and early extrahepatic metastases. A better understanding of the underlying mechanisms regulating cholesterol metabolism in HCC could help identify strategies to circumvent the aggressive phenotype. Here, we found that high expression of intracellular SPARC (secreted protein acidic and rich in cysteine) was significantly associated with elevated cholesterol levels and an enhanced invasive phenotype in HCC. SPARC potentiated cholesterol accumulation in HCC cells during tumor progression by stabilizing the ApoE protein. Mechanistically, SPARC competitively bound to ApoE, impairing its interaction with the E3 ligase tripartite motif containing 21 (TRIM21) and preventing its ubiquitylation and subsequent degradation. ApoE accumulation led to cholesterol enrichment in HCC cells, stimulating PI3K-AKT signaling and inducing epithelial-mesenchymal transition (EMT). Importantly, sorafenib-resistant HCC cells were characterized by increased expression of intracellular SPARC, elevated cholesterol levels, and enhanced invasive capacity. Inhibiting SPARC expression or reducing cholesterol levels enhanced the sensitivity of HCC cells to sorafenib treatment. Together, these findings unveil interplay between SPARC and cholesterol homeostasis. Targeting SPARC-triggered cholesterol-dependent oncogenic signaling is a potential therapeutic strategy for advanced HCC. SIGNIFICANCE: Intracellular SPARC boosts cholesterol availability to fuel invasion and drug resistance in hepatocellular carcinoma, providing a rational approach to improve the treatment of advanced liver cancer.

Assuntos

Apolipoproteínas E , Carcinoma Hepatocelular , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas , Osteonectina , Sorafenibe , Animais , Humanos , Masculino , Camundongos , Antineoplásicos/farmacologia , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Colesterol/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos Nus , Invasividade Neoplásica , Osteonectina/metabolismo , Osteonectina/genética , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto

RESUMO

INTRODUCTION: Preservation fluid (PF) contaminations are common in conventional liver transplantation (CLT) and presumably originate from organ or PF exposures to the external environment in a non-strict sterile manner. Such exposures and PF contamination may be avoided in ischaemia-free liver transplantation (IFLT) because of the strict sterile surgical procedures. In this study, the authors evaluated the impact of IFLT on organ PF contamination. METHODS: A post-hoc analysis using data from the first randomized controlled trial of IFLT was performed to compare the incidence, pathogenic spectrum of PF contamination, and incidence of early recipient infection between IFLT and CLT. Multivariable logistic regression was used to explore risk factors for PF contamination. RESULTS: Of the 68 cases recruited in the trial, 64 were included in this post-hoc analysis. The incidence of culture-positive PF was 9.4% (3/32) in the IFLT group versus 78.1% (25/32) in the CLT group ( P <0.001). Three microorganisms were isolated from PF in the IFLT group, while 43 were isolated in the CLT group. The recipient infection rate within postoperative day 14 was 3.1% (1/32) in the IFLT group vs 15.6% (5/32) in the CLT group, although this difference did not reach statistical significance ( P =0.196). Multivariate analysis revealed that adopting IFLT is an independent protective factor for culture-positive PF. CONCLUSION: PF contamination is substantially decreased in IFLT, and IFLT application is an independent protective factor for PF contamination. Using rigorous sterile measures and effective antibiotic therapy during IFLT may decrease PF contamination.

Assuntos

Transplante de Fígado , Soluções para Preservação de Órgãos , Preservação de Órgãos , Humanos , Transplante de Fígado/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Preservação de Órgãos/métodos , Adulto , Idoso

RESUMO

Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.

Assuntos

Neoplasias Colorretais , Interleucina-6 , Humanos , Carcinogênese/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/patologia , Histonas/metabolismo , Interleucina-6/metabolismo , Lactatos/metabolismo , Macrófagos/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Microambiente Tumoral

RESUMO

Background and Aims: Increasing utilization of extended criteria donor leads to an increasing rate of early allograft failure after liver transplantation. However, consensus of definition of early allograft failure is lacking. Methods: A retrospective, multicenter study was performed to validate the Liver Graft Assessment Following Transplantation (L-GrAFT) risk model in a Chinese cohort of 942 adult patients undergoing primary liver transplantation at three Chinese centers. L-GrAFT (L-GrAFT7 and L-GrAFT10) was compared with existing models: the Early Allograft Failure Simplified Estimation (EASE) score, the model of early allograft function (MEAF), and the Early Allograft Dysfunction (EAD) model. Univariate and multivariate logistic regression were used to find risk factors of L-GrAFT high-risk group. Results: L-GrAFT7 had an area under the curve of 0.85 in predicting 90-day graft survival, significantly superior to MEAF [area under the curve (AUC=0.78, p=0.044)] and EAD (AUC=0.78, p=0.006), while there was no statistical significance between the predicting abilities of L-GrAFT7 and EASE (AUC=0.84, p>0.05). Furthermore, L-GrAFT7 maintains good predicting ability in the subgroup of high-donor risk index (DRI) cases (AUC=0.83 vs. MEAF, p=0.007 vs. EAD, p=0.014) and recipients of donors after cardiac death (AUC=0.92 vs. EAD, p<0.001). Through multivariate analysis, pretransplant bilirubin level, units of packed red blood cells, and the DRI score were selected as independent risk factors of a L-GrAFT7 high-risk group. Conclusions: The accuracy of L-GrAFT7 in predicting early allograft failure was validated in a Chinese multicenter cohort, indicating that it has the potential to become an accurate endpoint of clinical practice and transitional study of machine perfusion.

RESUMO

BACKGROUND: There is no consensus on the usage of extended criteria donor (ECD) grafts in liver transplantation (LT) for acute-on-chronic liver failure (ACLF) patients. AIM: To summarize the experience of using ECD livers in ACLF-LT. METHODS: A retrospective cohort study was conducted, enrolling patients who underwent LT at the First Affiliated Hospital of Sun Yat-Sen University from January 2015 to November 2021. The patients were divided into ECD and non-ECD groups for analysis. RESULTS: A total of 145 recipients were enrolled in this study, of which ECD and non-ECD recipients accounted for 53.8% and 46.2%, respectively. Donation after cardiac death (DCD) recipients accounted for the minority compared with donation after brain death (DBD) recipients (16.6% vs 83.4%). Neither overall survival nor graft survival significantly differed between ECD and non-ECD and DCD and DBD recipients. ECD grafts were associated with a significantly higher incidence of early allograft dysfunction (EAD) than non-ECD grafts (67.9% vs 41.8%, P = 0.002). Postoperative outcomes between DCD and DBD recipients were comparable (P > 0.05). ECD graft (P = 0.009), anhepatic phase (P = 0.034) and recipient gamma glutamyltransferase (P = 0.016) were independent risk factors for EAD. Recipient preoperative number of extrahepatic organ failures > 2 (P = 0.015) and intraoperative blood loss (P = 0.000) were independent predictors of poor post-LT survival. CONCLUSION: Although related to a higher risk of EAD, ECD grafts can be safely used in ACLF-LT. The main factors affecting post-LT survival in ACLF patients are their own severe preoperative disease and intraoperative blood loss.

Assuntos

Insuficiência Hepática Crônica Agudizada , Transplante de Fígado , Obtenção de Tecidos e Órgãos , Humanos , Transplante de Fígado/efeitos adversos , Insuficiência Hepática Crônica Agudizada/cirurgia , Insuficiência Hepática Crônica Agudizada/etiologia , Estudos Retrospectivos , Perda Sanguínea Cirúrgica , Seleção do Doador , Doadores de Tecidos , Morte Encefálica , Sobrevivência de Enxerto , Morte

RESUMO

BACKGROUND: Primary non-function (PNF) and early allograft failure (EAF) after liver transplantation (LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function (MEAF), PNF score by King's College (King-PNF) and Balance-and-Risk-Lactate (BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. METHODS: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic (ROC) and the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses. RESULTS: Of all 720 patients, 28 (3.9%) developed PNF and 67 (9.3%) developed EAF in 3 months. The overall early allograft dysfunction (EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0 (3.5-6.3), -2.1 (-2.6 to -1.2), and 5.0 (2.0-11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves (AUCs) of 0.871 and 0.891, superior to BAR-Lac (AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. CONCLUSIONS: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.

RESUMO

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.

Assuntos

Transplante de Coração , RNA Longo não Codificante , Animais , Camundongos , Humanos , Camundongos Endogâmicos C57BL , RNA Longo não Codificante/genética , Transplante de Coração/efeitos adversos , Doadores de Tecidos , Apoptose , Modelos Animais de Doenças , Aloenxertos

Assuntos

Transplante de Fígado , Humanos , Transplante de Fígado/efeitos adversos , Universidades , China , Doadores de Tecidos

RESUMO

BACKGROUND: Normothermic machine perfusion (NMP) provides a novel platform to preserve isolated organs in an artificial condition. Our study aimed to explore the interaction between the liver and kidney at an ex vivo organ level by adding a liver to the kidney NMP circuit. METHODS: Porcine kidney and liver obtained from abattoir were subjected to 9 h NMP after suffering 30-min warm ischemia time and 90-min cold ischemia time. The liver-kidney NMP group (n = 5) and the single-kidney NMP group (n = 5) were designed. During the NMP, perfusion parameters, blood gas analysis, and tissue samples were compared. RESULTS: The perfusate of both groups remained stable, and continuous urine production was observed during NMP. In the liver-kidney NMP group, the lactate level was low, while blood urea nitrogen increased and glucose levels decreased. After the NMP, the renal tissue in the liver-kidney group exhibited fewer histological changes such as tubular epithelium vacuolization, along with reduced expression of IL-6, IL-8, IL-1ß, NLRP3, and GSDMD. CONCLUSIONS: Our results indicated that the expression of renal pro-inflammatory factors was reduced in the liver-kidney NMP system.

Assuntos

Fígado , Preservação de Órgãos , Suínos , Animais , Preservação de Órgãos/métodos , Perfusão/métodos , Rim/patologia , Isquemia Quente/métodos

RESUMO

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.