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Objective: Preoperative neutrophil-to-lymphocyte ratio (NLR) is a well-known prognostic indicator in various malignancies; however, the impact of postoperative NLR on living donor liver transplant (LDLT) recipients is unknown. Immunotherapy with donor liver-derived activated natural killer (NK) cells may improve postoperative NLR by coactivating immune cells or suppressing activated neutrophils. This study aims to clarify the clinical significance of postoperative NLR in recipients after LDLT with HCC and assess whether immunotherapy improves postoperative NLR., Methods: We conducted a retrospective study of LDLT recipients between 2001 and 2022 to evaluate the clinical significance of postoperative NLR. Furthermore, the correlation between postoperative NLR and the activation marker of infused NK cells was also evaluated. The postoperative NLR was examined 4 weeks after LDLT., Results: The postoperative high NLR group (N = 78) had preoperative lower NLR and higher model for end-stage liver disease and a higher rate of postoperative infection within 30 days after LDLT than the postoperative low NLR group (N = 41). Postoperative high NLR (hazard ratio [HR], 2.62; 95% confidence interval [CI], 1.01-6.79; P = .047) and nontreatment of immunotherapy (HR, 3.10; 95% CI, 1.33-7.22; P < .01) were independent risk factors for poor overall survival in multivariate analysis. Furthermore, the activation marker of infused NK cells is inversely correlated with decreased postoperative NLR., Conclusions: The higher level of postoperative NLR was independently associated with poor prognosis in patients after LDLT with HCC. Immunotherapy using activated NK cells may improve postoperative NLR and long-term prognosis., Competing Interests: Declaration of competing interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Abdominal aortic calcification (AAC) is associated with cardiovascular-related mortality, along with an elevated risk of coronary, cerebrovascular, and cardiovascular events. Notably, AAC is strongly associated with poor overall and recurrence free survival posthepatectomy for hepatocellular carcinoma. Despite the acknowledged significance of atherosclerosis in systemic inflammation, its response to ischemia/reperfusion injury (IRI) remains poorly elucidated. In this study, we aimed to clarify the impact of atherosclerosis on the liver immune system using a warm IRI mouse model., Methods: Injury was induced in an atherosclerotic mouse model (ApoE -/- ) or C57BL/6J wild-type (WT) mice through 70% clamping for 1 hour and analyzed after 6 hours of reperfusion., Results: Elevated serum levels of aspartate and alanine aminotransferase, along with histological assessment, indicated considerable damage in the livers of ApoE -/- mice than that in WT mice. This indicates a substantial contribution of atherosclerosis to IRI. Furthermore, T and natural killer (NK) cells in ApoE -/- mouse livers displayed a more inflammatory phenotype than those in WT mouse livers. Reverse transcription-polymerase chain reaction analysis revealed a significant upregulation of interleukin (IL)-15 and its transcriptional regulator, interferon regulatory factor-1 (IRF-1) in ApoE -/- mouse livers compared with that in WT mouse livers., Conclusions: These findings suggest that in an atherosclerotic mouse model, atherosclerosis can mirror intrahepatic immunity, particularly activating liver NK and T cells through IL-15 production, thereby exacerbating hepatic damage. The upregulation of IL-15 expression is associated with IRF-1 overexpression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Cytomegalovirus (CMV), the most common opportunistic infection of kidney transplantation (KT), is preventable by prophylactic and preemptive antiviral drugs in CMV-immunoglobulin (Ig)G-positive donors. Our preemptive therapy optimized immunosuppressive doses based on mixed lymphocyte response (MLR) results, regardless of preoperative CMV-IgG serostatus pairing. This study used the MLR to compare the anti-donor T-cell responses between CMV antigenemia-positive and -negative cases., Methods: One hundred patients underwent KT using a cyclosporine (CsA)-based immunosuppressive regimen at Hiroshima University Hospital. CMV antigenemia-positive cells were defined as 4/50,000 CMVpp65-positive cells. T-cell responses to allo-antigens were measured using MLR assays to evaluate patients' anti-donor immune reactivity. After analyzing the proliferation of CD4 + and CD8 + T-cell subsets, the stimulation indices of CD4 + or CD8 + T cells were quantified. The study used no prisoners, and the participants were neither coerced nor paid. The manuscript was created in compliance with the Helsinki Congress and the Declaration of Istanbul., Results: Forty-three patients tested positive for CMV antigenemia within 3 months after KT. No significant differences were found between the CMV antigenemia-positive and -negative groups in the stimulation indices for CD4 + and CD8 + T-cell responses to anti-donor stimulation. However, T-cell responses to third-party stimuli during the postoperative month 1 were significantly less in the CMV antigenemia-positive than -negative group., Conclusion: Anti-donor T-cell responses are not necessarily attenuated during CMV infection in KT recipients. In CMV-infected KT recipients, caution should be exercised against inadvertent dose reduction of immunosuppressants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Natural killer (NK) cells are involved in innate immunity and have been reported to play an important role in hepatocellular carcinoma recurrence and post-liver transplantation (LT) infection. However, the relationship between donor age and liver-resident NK cell activity remains to be elucidated., Methods: We successfully performed NK cell immunotherapy in 19 living donor LT recipients to prevent post-LT bloodstream infections. Liver mononuclear cells (LMNCs) were collected from the liver graft perfusate and stimulated with interleukin 2 for 3 days. Liver-resident NK cells were analyzed using flow cytometry and a chromium release assay before and after cell culture., Results: The median donor age was 44 years (range, 24-64 years). The graft weight was 492 g (range, 338-642 g), and the median number of LMNCs was 584 million cells (range, 240-1472 million cells). The proportion of NK cells before and after culture was 22% and 33%, respectively. A significant correlation was found between graft weight and the number of LMNCs. However, no correlation was found between donor age and the number or percentage of NK cells in the liver. Moreover, donor age showed a significant inverse correlation with NKp46 and NKp44 expression before culture and with NKp44, tumor necrosis factor-related apoptosis-inducing ligand, and CD69 expression after culture., Conclusion: A significant inverse correlation was observed between donor age and NK cell activity in the liver. This information may be useful for cell therapy during LT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have seemed to influence in the work in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: This study aimed to assess the risk factors for components of metabolic syndrome, such as diabetes mellitus, hypertension, and dyslipidemia, more than a year after liver transplantation., Methods: This study included 164 patients with liver failure secondary to acute and chronic liver disease or hepatocellular carcinoma who underwent liver transplantation between 2000 and 2019. Univariate and multivariate analyses were performed to identify the risk factors associated with metabolic syndrome components after liver transplantation., Results: The median follow-up period was 10.5 years. Of the 164 patients who underwent liver transplantation, 144 (87.8%) developed components of metabolic syndrome after liver transplantation. The most common cause of liver failure was hepatitis C virus infection (34.1%). The incidence of hepatocellular carcinoma was 36.0%. In univariate analysis, preoperative diabetes mellitus was a significantly more common component of metabolic syndrome than the others. In multivariate analysis, preoperative abdominal aortic calcification was a risk factor for the new onset of all components of metabolic syndrome after liver transplantation, despite the varying degree of calcification at risk of development (odds ratio for diabetes mellitus = 3.487, P = .0069; odds ratio for hypertension = 2.914, P = .0471; odds ratio for dyslipidemia = 3.553, P = .0030)., Conclusions: Preoperative abdominal aortic calcification was significantly associated with the development of each metabolic syndrome component after liver transplantation., Competing Interests: Declaration of competing interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: In kidney transplantation (KT), efforts to minimize rewarming and optimize anastomosis time during vascular anastomosis improve graft outcomes. We recently reported the safety and efficacy of a pouch-type thermal barrier bag (TBB) made of elastomer gel to reduce second-warm ischemic injury during vascular anastomosis. We aimed to examine the usefulness of the TBB in prolonged vascular anastomosis in KT performed by young transplant fellows., Methods: Young transplant fellows performed KT under the supervision of certified transplant surgeons. The kidney graft was placed inside the TBB with an outlet for vessels and preserved during vascular anastomosis. A non-contact infrared thermometer measured the graft surface temperature before and after vascular anastomosis. After completion of the anastomosis, the TBB was manually slid out of the transplanted kidney and removed before graft reperfusion. Clinical data, including patient characteristics and perioperative variables, were collected. The primary endpoint was the median graft surface temperature at the end of the anastomosis., Results: Ten living-donor kidney transplant recipients with a median age of 56.5 years (range, 40-69 years) underwent KT procedures performed by young transplant fellows. The median anastomosis time was 53 (43-67) min. At the end of anastomosis, the median graft surface temperature was 17.7°C (16.3-18.3°C); no serious adverse events or delayed graft function were observed., Conclusion: The TBB can keep transplanted kidneys at a low temperature even with prolonged vascular anastomosis time, thus contributing to the functional preservation of transplanted kidneys and stable transplant outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Risk prediction of de novo donor-specific antibody (dnDSA) formation is crucial for understanding the long-term prognostic impact of kidney transplantation (KT). Recently, follicular helper T (Tfh) cells, a subtype of CD4 + T cells, have been reported to play an important role in dnDSA formation after solid organ transplantation. Given the growing recognition of the importance of Tfh cells in generating a strong humoral immune response, we examined whether polymorphisms in Tfh cell-related molecules were associated with dnDSA formation after KT., Methods: Eighty-three patients who underwent living-donor KT between January 2013 and February 2020 at Hiroshima University Hospital were included in the study. Six Tfh cell-related molecules (BCL6, CXCR5, CXCL13, ICOS, CD40L, and IL21) that are important for Tfh cell differentiation and maturation in secondary lymphoid tissues were investigated. CTLA4, which is important for Tfh-cell activation, was also investigated. Single nucleotide polymorphisms (SNPs) in the genes for these molecules were detected using Taq Man SNP genotyping and evaluated for their association with dnDSA formation after KT., Results: Of the 83 KT recipients, 8 developed dnDSAs during the observation period. No statistically significant differences were observed in the baseline characteristics between patients with and without dnDSA formation, except for donor age. Among the 7 Tfh cell-related molecules, the incidence of dnDSA formation was associated with CXCR5 and CTLA4 SNPs. Furthermore, combining these 2 SNPs enabled more significant stratification of dnDSA formation., Conclusion: Our findings indicate that genetic polymorphisms in Tfh cell-related molecules are predisposing factors for dnDSA formation after KT., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is critical for natural killer (NK) cell-mediated anti-tumor and anti-microbe killing. The TRAIL expression on the donor's liver NK cells from the liver perfusate after interleukin-2 stimulation varies between individuals and is unpredictable. This study aimed to clarify the risk factors for low TRAIL expression by analyzing perioperative donor characteristics., Methods: This retrospective study of living donor liver transplant (LDLT) donors between 2006 and 2022 was performed to analyze low TRAIL expression risk factors. Seventy-five donors who had undergone hepatectomy for LDLT were divided into 2 groups, low and high TRAIL, according to their TRAIL expression on liver NK cells, using median values., Results: The low TRAIL group (N = 38) was older and had lower nutrition and a higher low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio, related to arteriosclerosis, than the high TRAIL group (N = 37). In multivariate analysis, the geriatric nutritional risk index (GNRI) (odds ratio, 0.86; 95% CI, 0.76-0.94; P < .001) and LDL/HDL cholesterol ratio (odds ratio, 2.32; 95% CI, 1.10-4.86; P = .005) were independent predictive factors for low TRAIL expression on liver NK cells. Furthermore, the TRAIL expression of liver NK cells decreased in donors who already had atherosclerosis and in donors at risk of potentially developing atherosclerosis., Conclusions: The TRAIL expression on liver NK cells in donors had a strong relationship with atherosclerosis and GNRI. Atherosclerosis can reflect the TRAIL expression on liver NK cells., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Refractory ascites is one of the major complications of liver transplant (LT) and is associated with increased morbidity and mortality. The aim of this study was to analyze the efficacy and safety of novel cell-free and concentrated ascites reinfusion therapy (KM-CART) for the treatment of refractory ascites during preoperative living donor liver transplant., Methods: Forty KM-CART procedures were performed on 8 liver transplant candidates. We investigated the safety and efficacy of KM-CART in terms of the processed ascites, adverse events, laboratory data, and patient condition., Results: By using KM-CART, an average of 12.5 L (range, 2.6-26.1 L) of ascites was filtered and concentrated to 0.5 L (range, 0.1-1.6 L) in 62 minutes (range, 8-187 minutes). Final products contained 21.5 g (range, 2.5-65.6 g) of albumin and 13.5 g (range, 1.5-61.8 g) of globulin. No endotoxin contamination was detected in the ascites. Although the incidence of adverse events was 35.0% (including fever, hypotension, bleeding, leg cramps, and nausea), all of these could be treated conservatively. Body weight and oral intake were significantly improved after KM-CART. Furthermore, the use of fresh frozen plasma for the LT recipients with KM-CART was significantly lower than that for patients without KM-CART. In addition, no patients lost their opportunity for LT because of adverse events due to KM-CART., Conclusions: Our findings show that KM-CART could be a promising option for the treatment of refractory ascites during the preoperative period of LT. This study provides the foundation for further large-scale prospective studies., (Copyright © 2019 Elsevier Inc. All rights reserved.)