Liver Graft Research Articles

Are there any benefits of prolonged hypothermic oxygenated perfusion? - Results from a national retrospective study.

Dual hypothermic oxygenated perfusion (DHOPE) is increasingly being used to extend liver preservation to improve transplant logistics. However, little is known about its benefits in high-risk liver grafts. This study aimed to investigate whether prolonged DHOPE provides benefits other than improved logistics in all liver types. We performed a national retrospective cohort study of 177 liver transplants from 12 Italian centers preserved with DHOPE for ≥4h between 2015 and 2022. A control group of 177 DHOPEs of <4h during the same period was created using 1:1 propensity score matching. The impact of risk profiles and preservation times on the outcomes was assessed using univariable and multivariable regression models. No significant differences in post-transplant outcomes were found between prolonged and short DHOPEs. However, the prolonged group had a significantly lower incidence of post-transplant acute kidney injury (AKI) compared to the short group (30.5% vs. 44.6%, p=0.008). Among prolonged DHOPEs, no differences in transplant outcomes were observed according to donor risk index (DRI), Eurotransplant definition for marginal grafts, and balance of risk (BAR) score. DHOPE duration was associated with a lower risk of AKI in multivariable models adjusted for DRI, Eutrotransplant marginal grafts, and BAR score. Prolonged HOPE confirmed its protective effect against AKI in a multivariable model adjusted for donor and recipient risk factors [OR: 0.412, 95%CI: 0.200-0.850, p=0.016]. Prolonged DHOPE is widely used to improve transplant logistics, provides good results with high-risk grafts, and appears to be associated with a lower risk of post-transplant AKI. These results provide further insight into the important role of DHOPE in preventing post-transplant complications.

Comparison of Clinical Outcomes Using Left and Right Liver Grafts in Adult-to-adult Living-donor Liver Transplantation: A Retrospective Cohort Study Using the Korean Organ Transplantation Registry

Background. Living-donor liver transplantation has been widely performed as an alternative to the scarce liver grafts from deceased donors. More studies are reporting favorable outcomes of left liver graft (LLG). This study compared the clinical outcomes between living-donor liver transplantation using LLG and right liver graft (RLG) with similar graft-to-recipient body weight ratios. Methods. This study analyzed 4601 patients from a multicenter observational cohort using the Korean Organ Transplantation Registry between 2014 and 2021. After matching the Model for End-stage Liver Disease score and graft-to-recipient body weight ratios because of the extremely different number in each group, the LLG and RLG groups comprised 142 (25.1%) and 423 (74.9%) patients, respectively. Results. For donors, the median age was higher in the LLG group than in the RLG group (34 y [range, 16–62 y] versus 30 y [16–66 y] ; P = 0.002). For recipients, the LLG group showed higher 90-d mortality than the RLG group (11 [7.7%] versus 9 [2.1%]; P = 0.004). The long-term graft survival was significantly worse in the LLG group (P = 0.011). In multivariate Cox proportional hazards regression analysis for graft survival, LLG was not a significant risk factor (hazard ratio, 1.01 [0.54-1.87]; P = 0.980). Otherwise, donor age (≥40 y; 2.18 y [1.35-3.52 y]; P = 0.001) and recipients’ body mass index (&lt;18.5 kg/m2; 2.98 kg/m2 [1.52-5.84 kg/m2]; P = 0.002) were independent risk factors for graft survival. Conclusions. Although the short-term and long-term graft survival was worse in the LLG group, LLG was not an independent risk factor for graft survival in multivariate analysis. LLGs are still worth considering for selected donors and recipients regarding risk factors for graft survival.

The First Case of Intra-portal Islet Implantation During Liver Machine Perfusion Allowing Simultaneous Islet-liver Transplantation in A Human: A New and Safe Treatment for End-stage Liver Disease Combined With Diabetes Mellitus.

Evaluating the safety and efficacy of implanting a liver with islet grafts into patients with end-stage liver disease and diabetes mellitus (DM). DM and end-stage liver diseases are significant health concern worldwide, often coexisting and mutually influencing each other. Addressing both diseases simultaneously is paramount. 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. 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. 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.

Adverse effects of graft congestion and ameliorative effects of hepatocyte growth factor after liver transplantation in rats.

Living donor liver transplantation (LT) and deceased donor split-LT often result in congestion within liver grafts. The regenerative process and function of congested areas, especially graft congestion associated with LT, are not well understood. Therefore, we created new rat models with congested areas in partially resected livers and orthotopically transplanted these livers into syngeneic rats to observe liver regeneration and function in congested areas. This study aimed to compare liver regeneration and the function of congested areas after liver resection and LT, and to explore a new approach to ameliorate the adverse effects of graft congestion. Although the congested areas after liver resection regenerated normally on postoperative day 7, the congested areas after LT had poor regeneration with abscess development on postoperative day 7. Necrotic areas in congested areas were larger after LT than after liver resection on postoperative days 1, 3, and 7 (p < 0.05, p < 0.05, and p < 0.01, respectively). Although congested areas after liver resection did not affect survival, in the LT model, the survival of rats with congested areas was significantly poorer even with larger grafts than that of rats with smaller noncongested grafts (p = 0.04). hepatocyte growth factor administration improved the survival rate of rats with congested grafts from 41.7% to 100%, improved the regeneration of congested areas, and significantly reduced the size of necrotic areas (p < 0.05). Thus, congested areas in liver grafts may negatively impact recipients. Short-term administration of hepatocyte growth factor may improve postoperative outcomes of recipients with graft congestion and contribute to more effective use of liver grafts (approval number: MedKyo-23137, Institutional Ethics Committee/Kyoto University).

The Rationale for Combining Normothermic Liver Machine Perfusion with Continuous Renal Replacement Therapy to Maintain Physiological Perfusate during Ex Vivo Organ Perfusion.

Background: The possibility of keeping liver grafts viable and functioning until transplantation has been explored since the 1950s. However, the current modalities of Normothermic Machine Perfusion (NMP) have shown several limitations, such as the inability to correct electrolytes and pH derangements efficiently. Combining NMP with continuous kidney replacement therapy (CKRT) might provide a promising new model to overcome these issues. Methods: An NMP that covers the organ perfusion, oxygenation, carbon dioxide removal, and thermal balance was connected to a CKRT circuit to ensure physiological hydro-electrolytes, acid-base balance, and catabolite removal from the perfusate. Results: The integration of NMP and CKRT maintains a neoplastic liver in a perfusion system with physiological perfusate for 100 h. CKRT re-established and maintained the hydro-electrolyte and acid-base status throughout the 100 h of perfusion. Significant limitations were the need for frequent monitoring of electrolytes and acid-base disorders and the loss of low molecular weight nutrients, which have to be replenished by manual infusion into the system. Conclusions: This novel CKRT-NMP integrated system may represent a practical and versatile model to support organs' perfusion and extend preservation times. Further experiments are needed to fix monitoring and adjusting processes.

The current landscape of in situ and ex situ machine perfusion utilization for liver grafts from cardiac donation after circulatory death donors in the US

Donation after circulatory death (DCD) is driving the increase in deceased organ donors in the United States. Normothermic regional perfusion (NRP) and ex situ machine perfusion (es-MP) have been instrumental in improving liver transplant outcomes and graft utilization. This study examines the current landscape of liver utilization from cardiac DCD donors in the United States. Using the United Network for Organ Sharing Standard Transplant Analysis and Research file, all adult (≥18 years old) DCD donors in the United States from which the heart was used for transplantation from October 1, 2020, to September 30, 2023, were compared by procurement technique (NRP versus super rapid recovery [SRR]) and storage strategy (es-MP versus static cold storage). One hundred eighty-eight livers were transplanted from 309 thoracoabdominal NRP donors (61% utilization) versus 305 (56%) liver transplants from 544 SRR donors. es-MP was used in 20% (n = 38) of NRP cases versus 32% (98) of SRR cases. Of the liver grafts, 281 (59%) were exposed to NRP, es-MP, or both. While there is widespread utilization of machine perfusion, more research is needed to determine optimal graft management strategies, particularly concerning the use of multiple technologies in complementary ways. More complete data collection is necessary at a national level to address these important research questions.

Laparoscopic-assisted full-sized liver transplantation with magnetically fast portal vein anastomosis: an initial cohort study.

Some cases of laparoscopic-assisted liver transplantation (LA-LT) with utilization of reduced-size grafts has been reported. The authors here introduced successful utilization of LA-LT with whole liver grafts and magnetic portal vein anastomosis. Eight patients with liver cirrhosis were included for LA-LT using donor organs after cardiac death. The surgical procedures included purely laparoscopic explant hepatectomy and whole-liver graft implantation via the midline incision. After explant removal, the whole-liver graft was then placed in situ, and a side-to-side cavo-caval anastomosis with 4-5cm oval opening was performed. The magnetic rings were everted on the donor and recipient portal vein, respectively, and the instant attachment of the two magnets at the donor and recipient portal vein allowed fast blood reperfusion, followed by continuous suturing on the surface of the magnets. The median operation time was 495 (range 420-630). The median time of explant hepatectomy and inferior vena cava anastomosis was 239 (range 150-300) min and 14.5 (range 10-19) min, respectively. Of note, the median anhepatic time was 25 (range 20-35) min. All the patients were discharged home with no major complications after more than 12 months follow-up. LA-LT with full-size graft is feasible and utilization of magnetic anastomosis would further simplify the procedure.

Assessment of liver graft quality during hypothermic oxygenated perfusion: the first international validation study

Background and AimWhile it is currently assumed that liver assessment is only possible during normothermic machine perfusion (NMP), there is uncertainty regarding a reliable and quick prediction of graft injury during ex situ hypothermic oxygenated perfusion (HOPE). We therefore intended to test, in an international liver transplant cohort, recently described mitochondrial injury biomarkers measured during HOPE before liver transplantation. Study designPerfusate samples of human livers from 10 centers in 7 countries with HOPE-experience were analyzed for released mitochondrial compounds, i.e. flavin mononucleotide (FMN), NADH, purine derivates and inflammatory markers. Perfusate FMN was correlated with graft loss due to primary non-function or symptomatic non-anastomotic biliary strictures (NAS), and kidney failure, as well as liver injury after transplantation. Livers deemed unsuitable for transplantation served as negative control. ResultsWe collected 473 perfusate samples of human DCD (n=315) and DBD livers (n=158). Fluorometric assessment of FMN in perfusate was validated by mass spectrometry (R=0.7011,p<0.0001). Graft loss due to primary non-function or cholangiopathy was predicted by perfusate FMN values (c-statistic mass spectrometry 0.8418 (95%CI 0.7466-0.9370,p<0.0001), c-statistic fluorometry 0.7733 (95%CI 0.7006-0.8461,p<0.0001). Perfusate FMN values were also significantly correlated with symptomatic NAS and kidney failure, and superior in prediction of graft loss when compared to conventional scores derived from donor and recipient parameters, such as the donor risk index and the balance of risk score. Mitochondrial FMN values in liver tissues of non-utilized livers were low, and inversely correlated to high perfusate FMN values and purine metabolite release. ConclusionsThis first international study validates the predictive value of the mitochondrial co-factor FMN, released from complex I during HOPE, and may therefore contribute to a better risk stratification of injured livers before implantation. Impact and ImplicationsAnalysis of 473 perfusates, collected from 10 international centers during hypothermic oxygenated perfusion (HOPE), revealed that mitochondria derived flavin mononucleotide (FMN) values in perfusate is predictive for graft loss, cholangiopathy, and kidney failure after liver transplantation. This result is of high clinical relevance, as recognition of graft quality is urgently needed to improve the safe utilization of marginal livers. Ex-situ machine perfusion approaches, such as HOPE, are therefore likely to increase the number of useable liver grafts.

Contrast-Enhanced Ultrasonography Findings Within 3 Days Postoperatively Are Associated With 1-Month Graft Failure After Split Liver Transplantation

Purpose:To evaluate whether Doppler ultrasonography (DUS) and contrast-enhanced ultrasonography (CEUS) within 3 days postoperative can identify 1-month graft failure after split liver transplantation (SLT). Materials and methodsA total of 58 consecutive patients who underwent SLT between February 2022 and September 2023 were included. The DUS and CEUS images and parameters within 3 days postoperatively were analyzed and recorded. The DUS parameters included peak systolic velocity (PSV), resistive index, and systolic acceleration time for the hepatic artery, PSV for the portal vein and hepatic vein. The CEUS qualitative analysis variables included the liver parenchyma enhancement pattern and the posterior enhancement attenuation. Logistic regression and Cox proportional hazard regression were used to evaluate the relationship between DUS/CEUS findings and 1-month graft failure. ResultsSeven of the 58 liver grafts failed within one month. Poor CEUS enhancement (pattern Ⅱ/Ⅲ) was observed in 5 of 7 patients (71.4%) of graft failure, whereas good contrast enhancement (pattern Ⅰ) was found in 47 of the 51 patients (92.1%) in the successful group on postoperative day 3. Multivariate logistic regression analysis revealed that 1-month graft failure was independently predicted by operative time (OR=3.79, 95% CI: 1.27–11.29, p=.017) and CEUS enhancement pattern on postoperative day 3 (OR=90.88, 95% CI: 2.77–2979.56, p=.011). Cox proportional hazard regression showed that operative time ( HR=1.6, 95% CI: 1.15–2.22, p =.005) and CEUS enhancement pattern on postoperative day 3 (HR=11.947, 95% CI: 2.04–69.98, p =.006) were independent predictors for graft failure. ConclusionsPoor CEUS enhancement (pattern Ⅱ/Ⅲ) was associated with 1-month graft failure in SLT recipients. CEUS may serve as a noninvasive, valuable prognostic tool to predict clinical outcomes early after SLT.

364.5: Assessment of long term pediatric graft liver volume post living donor liver transplantation.

364.5: Assessment of long term pediatric graft liver volume post living donor liver transplantation.

Vliv polymorfizmů PNPLA3 rs738409 a TM6SF2 rs58542926 dárce a příjemce na dlouhodobé přežívání pacientů po transplantaci jater

Summary Introduction: The variants rs738409 c.444C&gt;G (p.I148M) in patatin-like phospholipase domain-containing 3 (PNPLA3) and rs58542926 c.499G&gt;A (p.E167K) in TM6SF2 (transmembrane 6 superfamily member 2) are significant genetic risk factors of development and progression of non-alcoholic fatty liver disease (NAFLD). In both variants, increased liver-specific mortality was described, while the impact on all-cause mortality was not proved. The aim of the study was to evaluate the impact of PNPLA3 rs738409 and TM6SF2 rs58542926 genotypes of the donor and recipient respectively on long-term patient survival after LT. Methods: We evaluated long-term patient survival in a cohort of 268 adult LT recipients, in whom PNPLA3 rs738409 and TM6SF2 rs58542926 genotypes of the donor and recipient respectively were available and steatosis was evaluated in liver graft biopsy 6–30 months after LT. The median fol low-up was 17 years. The Kaplan-Meier model was used for the survival estimates and the Cox proportional hazard model was used to assess the predictive value of the chosen variables. Results: Increased recipient age (P &lt; 0.001), male sex (P = 0.014), alcoholic (P = 0.021) or HCV (P = 0.042) etiology of liver cirrhosis, and presence of hepatocellular carcinoma (P = 0.009) negatively influenced long-term patient survival after LT. PNPLA3 rs738409 and TM6SF2 rs58542926 genotypes of the recipient and donor respectively had no effect on patient survival. Conclusion: Although PNPLA3 c.444G and TM6SF2 c.499A variants of the donor increase the risk of steatosis of the liver graft after LT, we did not prove a negative impact of these genotypes of the donor and recipient on long-term patient survival after LT. Keywords PNPLA3, TM6SF2, steatosis, MASLD, NAFLD, liver transplantation, patient survival

MRI-serum-based score accurately identifies patients undergoing liver transplant without rejection avoiding the need for liver biopsy: A multisite European study.

Serum liver tests (serum tests) and histological assessment for T-cell-mediated rejection are essential for post-liver transplant monitoring. Liver biopsy carries a risk of complications that are preferably avoided in low-risk patients. Multiparametric magnetic resonance imaging (mpMRI) is a reliable noninvasive diagnostic method that quantifies liver disease activity and has prognostic utility. Our aim was to determine whether using mpMRI in combination with serum tests could noninvasively identify low-risk patients who underwent liver transplants who are eligible to avoid invasive liver biopsies. In a multicenter prospective study (RADIcAL2), including 131 adult and pediatric (children and adolescent) patients with previous liver transplants from the Netherlands, Portugal, and the United Kingdom, concomitant mpMRI and liver biopsies were performed. Biopsies were centrally read by 2 expert pathologists. T-cell-mediated rejection was assessed using the BANFF global assessment. Diagnostic accuracy to discriminate no rejection versus indeterminate or T-cell-mediated liver transplant rejection was performed using the area under the receiver operating characteristic curve. In this study, 52% of patients received a routine (protocol) biopsy, while 48% had a biopsy for suspicion of pathology. Thirty-eight percent of patients had no rejection, while 62% had either indeterminate (21%) or T-cell-mediated rejection (41%). However, there was a high interobserver variability (0 < Cohen's Kappa < 0.85) across all histology scores. The combined score of mpMRI and serum tests had area under the receiver operating characteristic curve 0.7 (negative predictive value 0.8) to identify those without either indeterminate or T-cell-mediated rejection. Combining both imaging and serum biomarkers into a composite biomarker (imaging and serum biomarkers) has the potential to monitor the liver graft to effectively risk stratify patients and identify those most likely to benefit from a noninvasive diagnostic approach, reducing the need for liver biopsy.

Outcomes of Liver Transplantation From Hepatitis C Virus-positive DCD Donors and Its Utilization Among Centers in the United States.

Donation after circulatory death (DCD) or hepatitis C virus (HCV+) liver grafts are underused among transplant centers in the United States. The study aimed to evaluate organ utilization and outcomes of liver grafts from DCD donors with HCV infection. National registry and local center data of all deceased donor liver transplants performed between November 2016 and December 2021 were analyzed. All transplants were divided into 4 groups: HCV- DCD, HCV- donation after brain death [DBD], HCV+ DCD, and HCV+ DBD. The outcome of interest was 1-y graft survival. Out of 146 liver transplant centers in the United States, liver transplants were not performed from DCD donors, HCV+ donors, and a combination of DCD and HCV+ donors by 28.7%, 27%, and 70%-72% of centers, respectively. In multivariate analysis, increasing center acceptance ratio was associated with increased utilization of liver grafts from DCD HCV- and DCD HCV antibody-positive nucleic acid test negative donors. Nationally, 1-y graft survival of HCV- DCD liver grafts was lower compared with other groups (89% versus 92% HCV+ DCD versus 93% HCV+ DBD versus 92% HCV- DBD, log rank P < 0.0001). There was no difference in 1-y graft survival among groups locally. Liver grafts from HCV+ DCD donors have 1-y patient and graft survival comparable with DBD liver grafts from donors with or without HCV infection. These results encourage the widespread use of liver grafts from DCD and HCV+ donors and standardization of practice in DCD donation to expand the donor pool without compromising short-term outcomes.

Exercise Preconditioning of the Donor Liver Decreases Cold Ischemia/Reperfusion Injury in a Mouse Model.

Liver transplantation stands as the primary treatment for end-stage liver disease, with demand surging in recent decades because of expanded indications. However, hepatic ischemia/reperfusion injury can lead to liver transplant failure in both deceased donor and living donor transplantation. This study explored whether preconditioning donor livers through exercise training (ExT) could mitigate cold ischemic injury posttransplantation. Donor C57BL/6 mice underwent ExT via treadmill running or remained sedentary. After 4 wk, the donor liver underwent cold storage and subsequent orthotopic liver transplantation or ex vivo warm reperfusion. Donor liver from mice subjected to ExT showed significantly decreased hepatic injury on reperfusion. Tissue histology revealed decreased sinusoidal congestion, vacuolization, and hepatocellular necrosis in livers from ExT mice, and immunofluorescence staining further revealed a decreased number of apoptotic cells in ExT grafts. Livers from ExT donors expressed decreased intragraft inflammatory cytokines cascade, decreased neutrophil infiltration and neutrophil extracellular traps, and increased M2 phenotype of recipient macrophages compared with grafts from sedentary mice. After cold storage, liver grafts from ExT donors showed decreased accumulation of reactive oxygen species and decreased levels of cytochrome c and high mobility group box 1 released in the liver effluent. In addition, ExT grafts showed upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and higher levels of mitochondrial content. Similar effects of decreased hepatic injury were observed in wild-type mice when pretreated with a PGC-1α stimulator ZLN005 instead of ExT. These findings suggest that augmenting hepatocytic mitochondrial content through donor exercise or PGC-1α stimulation may offer therapeutic avenues to mitigate postreperfusion inflammation and improve transplant outcomes.

Comparison of Long-Term Outcomes Achieved With Live Donor and Split Deceased Donor Liver Grafts in Pediatric Liver Transplantation.

The aim of the present study was to compare the outcomes of pediatric LT with left liver grafts, obtained either from a living donor (LD) or a split deceased donor (sDD). Retrospective single-center study from 2002 to 2022. All pediatric LT with left liver grafts (not including middle hepatic vein) from LD or sDD were included. Reduced grafts were not included. A total of 112 pediatric LT were performed: 58 with LD grafts and 54 with sDD grafts (17 split ex situ and 37 insitu). Donor characteristics were similar, apart from donor age (33 years in LD vs. 30 years in sDD, p = 0.03). Indications were similar with 55% biliary atresia in each group. Retransplantation was more frequently performed in the sDD group (2% vs. 15%, p = 0.01). Recipient age, weight, and PELD score at transplant were not significantly different between groups. Cold ischemia time was longer for sDD (158 min in LD vs. 390 min in sDD; p < 0.0001). Posttransplant peak ALT was higher with sDD grafts (1470 vs. 1063, p = 0.018), and hospital stay was longer with sDD grafts (27 vs. 21 days, p = 0.005). However, there was no difference between groups in terms of major morbidity (Dindo-Clavien grade ≥3), vascular and biliary complications, and 90-day mortality. Patient survival at 10 years was 93.1% for LD and 92.8% for sDD (p = 0.807). Graft survival at 10 years was 89.7% for LD and 83.1% for sDD (p = 0.813). Technically similar LD and sDD grafts achieve very similar postoperative and long-term outcomes with excellent patient and graft survival.

Multinational Analysis of Marginal Liver Grafts Based on the Eurotransplant Extended Donor Criteria.

To evaluate the outcome of marginal liver grafts based on the Eurotransplant extended donor criteria (ECD) criteria. Eurotransplant uses a broad definition of ECD criteria (age >65 years, steatosis >40%, BMI >30kg/m2, ICU stay >7 days, DCD, and certain laboratory parameters) for allocating organs to recipients who have consented to marginal grafts. Historically, marginal liver grafts were associated with increased rates of dysfunction. Retrospective cohort analysis using the German Transplant Registry (GTR) and the US Scientific Registry of Transplant Recipients (SRTR) from 2006-2016. Results were validated with recent SRTR data (2017-2022). Donors were classified according to the Eurotransplant ECD criteria, DCD was excluded. Data were analyzed with cut-off prediction, binomial logistic regression, and multivariate Cox regression. The study analyzed 92,330 deceased brain-dead donors (87% SRTR) and 70,374 transplants (87% SRTR) in adult recipients. Predominant ECD factors were donor age in Germany (30%) and BMI in the US (28%). Except for donor age, grafts meeting ECD criteria were not associated with impaired 1- or 3-year survival. Cut-offs had little to no predictive value for 30-day graft survival (AUROC 0.49 - 0.52) and were nominally higher for age (72 vs. 65 years) in Germany as compared to those defined by current Eurotransplant criteria. The outcome of transplanted grafts from higher risk donors was nearly equal to standard donors with Eurotransplant criteria failing to predict survival of marginal grafts. Modifying ECD criteria could improve graft allocation and potentially expand the donor pool.

Interleukin-33 and liver natural killer cells: A novel perspective on antitumor activity in liver fibrosis.

Liver fibrosis, heralding the potential progression to cirrhosis and hepatocellular carcinoma (HCC), compromises patient survival and augments post-hepatectomy recurrence. This study examined the detrimental effects of liver fibrosis on the antitumor functions of liver natural killer (NK) cells and the interleukin-33 (IL-33) signaling pathway. Our investigation, anchored in both human physiologies using living and deceased donor livers and the carbon tetrachloride (CCl4)-induced mouse fibrosis model, aimed to show a troubling interface between liver fibrosis and weakened hepatic immunity. The Fibrosis-4 (FIB-4) index emerged as a salient, non-invasive prognostic marker, and its elevation correlated with reduced survival and heightened recurrence after HCC surgery even after propensity matching (n=385). We established a strong correlation between liver fibrosis and liver NK cell dysfunction by developing a method for extracting liver NK cells from the liver graft perfusate. Furthermore, liver fibrosis ostensibly disrupted chemokines and promoted IL-33 expression, impeding liver NK cell antitumor activities, as evidenced in mouse models. Intriguingly, our results implicated IL-33 in diminishing the antitumor responses of NK cells. This interrelation, consistent across both mouse and human studies, coincides with clinical data suggesting that liver fibrosis predisposes patients to an increased risk of HCC recurrence. Our study revealed a critical relationship between liver fibrosis and compromised tumor immunity, emphasizing the potential interference of IL-33 with NK cell function. These insights advocate for advanced immunostimulatory therapies targeting cytokines, such as IL-33, aiming to bolster the hepatic immune response against HCC in the context of liver fibrosis.

Impact of Religious Affiliation on Clinical Outcomes in Liver Transplant Patients.

While the impact of spirituality as it relates to quality of life post-liver transplant (LT) has been studied, there are limited data showing how religious affiliation impacts objective measures such as survival. The aim of the study is to investigate whether LT recipientswho identified as having a religious affiliation had better clinical outcomes when compared to LT recipientswho did not. Religious affiliation is obtained as part of general demographic information for patients within our institution (options of "choose not to disclose" and "no religious affiliation" are available). Subjects in this retrospective cohort study which conformed with the Declarations of Helsinki and Istanbul were separated into cohorts: LT recipientswho self-reported religious affiliation and LT recipients who did not. All LT recipients between March 2007 and September 2018 who had available information regarding their reported religion were included. Excluded patients included those who received a multi-organ transplant, underwent re-transplantation, received a partial liver graft, and identified as agnostic. Outcomes included 30-day readmission, death, and the composite outcome of re-transplantation/death. In an unadjusted analysis of 378 patients, there were no statistically significant differences between the two groups for 30-day readmission (OR=1.15, P=0.71), death (HR=0.63, P=0.19), or re-transplantation/death (HR=0.90, P=0.75). In multivariable analysis, adjusting for age at transplant and hospital admittance status when called for transplant, results were similar. We found no statistically significant difference in the outcomes measured between patients with and without self-reported religious affiliation. Further studies into the role of participation in religious activity and the impact of engagement with a religious community should be conducted in the future.

Combined Organ Transplantation in Patients with Advanced Liver Disease.

Transplantation of the liver in combination with other organs is an increasingly performed procedure. Over the years, continuous improvement in survival could be realized through careful patient selection and refined organ preservation techniques, in spite of the challenges posed by aging recipients and donors, as well as the increased use of steatotic liver grafts. Herein, we revisit the epidemiology, allocation policies in different transplant zones, indications, and outcomes with regard to simultaneous organ transplants involving the liver, that is combined heart-liver, liver-lung, liver-kidney, and multivisceral transplantation. We address challenges surrounding combined organ transplantation such as equity, utility, and logistics of dual organ implantation, but also advantages that come along with combined transplantation, thereby focusing on molecular mechanisms underlying immunoprotection provided by the liver to the other allografts. In addition, the current standing and knowledge of machine perfusion in combined organ transplantation, mostly based on center experience, will be reviewed. Notwithstanding all the technical advances, shortage of organs, and the lack of universal eligibility criteria for certain multi-organ combinations are hurdles that need to be tackled in the future.

Herbal and Non-Herbal Dietary Supplements for Psychiatric Indications: Considerations in Liver Transplantation.

Traditional, complementary, and integrative medicine (TCIM) modalities are widely employed. However, TCIM, specifically herbal and non-herbal dietary supplements, can pose challenges in the context of organ transplantation. In this review, we discuss common supplements used for psychiatric purposes and highlight important considerations for candidates and recipients of liver transplants. Ashwagandha, kava kava, green tea extract, skullcap, turmeric, and valerian have known idiosyncratic hepatotoxic potential and may complicate the liver transplantation course. Multiple supplements reportedly carry a lower risk of hepatotoxicity, though evidence for widespread use in those at risk for or with hepatic impairment is limited. Psychiatrists caring for candidates and recipients of liver transplants must recognize that patients may find supplements helpful in alleviating psychiatric symptoms, despite an overall limited evidence base. Evaluating benefit versus risk ratios and reviewing drug-drug interactions is essential to promote transplant candidacy and mitigate the possibility of native or graft liver dysfunction.