Ischemia-reperfusion injury (IRI) is a major obstacle in liver transplantation, especially with steatotic donor livers. Dysbiosis of the gut microbiota has been implicated in modulating IRI, and Lachnospiraceae plays a pivotal role in regulating host inflammatory and immune responses, but its specific role in liver transplantation IRI remains unclear. This study explores whether Lachnospiraceae can mitigate IRI and its underlying mechanisms. We found Lachnospiraceae-bacterium (Lachn.) abundance was significantly reduced in rats with liver cirrhosis. Lachn.-treated rats exhibited improved intestinal permeability, reduced IRI severity in both normal and steatotic donor livers, and decreased levels of neutrophil and macrophage infiltration, and inflammatory cytokines. Multi-omics analysis revealed elevated pyruvate levels in transplanted livers after Lachn. treatment, alongside reduced Alox15 and Foxo3 expression. Mechanistically, Lachn.-derived pyruvate inhibited Alox15 expression and reduced ferroptosis in normal and steatotic donor livers. Furthermore, reduced nuclear translocation of Foxo3 further suppressed Alox15 expression, alleviating IRI, especially in steatotic donor livers. Clinical samples confirmed reduced donor livers IRI in cirrhotic recipients with high Lachn. abundance after liver transplantation. In conclusion, Lachn. alleviates IRI in steatotic donor liver transplantation by inhibiting ferroptosis via the Foxo3-Alox15 axis, providing a potential therapeutic strategy to modulate gut microbiota to alleviate IRI following liver transplantation.

The potential of everolimus (EVR) in reducing hepatocellular carcinoma (HCC) among recipients following liver transplantation has been reported. This nationwide population-based quasi-cohort study investigated whether combining EVR with calcineurin inhibitor therapy affects the risk of HCC and extrahepatic cancers compared to a time duration-matched cohort of recipients not receiving EVR. Using data covering the entire population from Korea, liver transplant recipients who had initiated immunosuppressants between June 2015 and February 2020 were included, and divided into 2 groups: the EVR combination and noncombination groups. We calculated adjusted hazard ratios (aHRs) and absolute risk reduction for the risk of HCC and extrahepatic cancer with EVR combination therapy using a Cox regression model. A time duration-matched retrospective cohort of 932 recipients in both of the groups was identified. The EVR combination group showed a lower risk of HCC (aHR, 0.53; 95% confidence interval, 0.30-0.94) and extrahepatic cancers (aHR, 0.30; 95% confidence interval, 0.14-0.63) compared to the noncombination group. The absolute risk reduction was 0.004 for HCC and 0.012 for extrahepatic cancer. The findings suggest that adding EVR to calcineurin inhibitor therapy reduces cancer risk in liver transplant recipients, highlighting the importance of considering cancer risk when choosing immunosuppressive therapies.

Tacrolimus is a potent macrolide immunosuppressant frequently used to prevent graft rejection in organ transplantation. Despite the known side effect of hemorrhage, there are no extensive descriptive series of patients who experience hemorrhage events associated with tacrolimus. We sought to review and describe tacrolimus-related hemorrhage events reported by healthcare professionals to the United States Food and Drug Association Adverse Event Reporting System (FAERS) database.

The FAERS database (2004q1-2022q4) was retrospectively analyzed to characterize reporting of hemorrhage adverse events (AEs) with tacrolimus. Subgroup analysis was completed on the hemorrhage.

A total of 75,310 tacrolimus-associated AEs were identified, of which 1,511 cases met specific inclusion/exclusion criteria with most occurring in the gastrointestinal tract (422 cases, 27.93% of all included cases). Death was reported in 558 patients (36.93% of hemorrhage cases), the most of which occurred in cases of brain hemorrhage (219 cases, 39.25% of death cases). Among definitive organ transplants, renal transplant was the most common indication for tacrolimus (62 cases, 4.10%) followed by bone marrow transplant (44 cases, 2.91%) and liver transplant (30 cases, 1.99%).

This study presents the largest collective description of tacrolimus-related hemorrhage events. We additionally described a number of previously unreported tacrolimus-related hemorrhage events.

SLP65/SLP76, Csk-interacting membrane protein (SCIMP), is a membrane protein plays a crucial role in the regulation of macrophage polarization. This study aimed to investigate the mechanism of SCIMP-mediated M1 polarization in liver macrophages and ischemia-reperfusion injury (IRI) in liver transplantation.

Mice underwent orthotopic liver transplantation. In in vivo experiments, mice were divided into the Sham group, LT group, LT+Scramble group, LT+SCIMP (-) group, and LT+ERK1/2 (-) group, and SCIMP or ERK1/2 knockdown was performed using AAV-Erk1/2-RNAi-F4/80-EGFP and AAV-SCIMP-RNAi-F4/80-EGFP. In the subsequent in vitro experiments with primary cells, macrophages were divided into the Ctrl group, H/R group, H/R+Scramble group, H/R+SCIMP (-) group, and H/R+ERK1/2 (-) group, with SCIMP knockdown achieved using siRNA. Immunoprecipitation (IP) was used to detect the interaction between TLR4 and Erk1/2. Liver damage was detected by Hematoxylin and eosin (HE) staining. Polarization was detected by western blot (WB), RT-PCR, immunohistochemistry (IHC), immunofluorescence technique (IF), enzyme-linked immunosorbent assay (ELISA) and flow cytometry (FC).

Knockdown of SCIMP ameliorated hepatic IRI and liver macrophages M1 polarization. Mechanically, SCIMP promoted the interaction between Erk1/2 and TLR4 in hypoxia/reoxygenation (H/R)-induced liver macrophages, while the inhibition of Erk1/2 reduced liver macrophages M1 polarization and liver IRI.

SCIMP promotes hepatic ischemia-reperfusion injury by activating TLR4/Erk1/2-mediated liver macrophages M1 polarization, which might become a potential therapeutic target in clinic.

Advanced cystic fibrosis (CF) liver disease can necessitate liver transplantation. This study aims to investigate characteristics, waiting list dynamics, and waiting list mortality of people with CF (pwCF) registered for liver transplantation within Eurotransplant countries, to understand and improve transplant outcomes for this group.

We analysed Eurotransplant liver transplantation registration data (January 2007-December 2022), comparing pwCF to people with no CF (pwnoCF) and non-CF age/liver disease severity score (Lab-MELD) matched controls, with subgroup comparisons between pwCF receiving isolated liver transplantation (LiverTx) and combined liver-lung transplantation (Liver+LungTx).

215 out of 38,125 liver transplantation registrations were for pwCF. 65.1 % of the pwCF were listed for LiverTx and 34.9 % for Liver+LungTx. At registration, pwCF were younger (17.9 ± 0.8 vs. 55.0 ± 0.1; P < 0.05) and had lower Lab-MELD scores (10.0 ± 0.4 vs. 15.0 ± 0.0; P < 0.05) compared to pwnoCF. PwCF listed for LiverTx were younger (15.1 ± 0.9 vs. 26.0 ± 1.1; P < 0.05) and had higher Lab-MELD scores at transplantation (12.0 ± 1.0 vs. 9.0 ± 0.5; P < 0.05) compared to Liver+LungTx. PwCF had a higher 2-year waiting list mortality than non-CF matched controls (14.9 % vs. 0.0 %; P < 0.05). Within pwCF, mortality was higher for pwCF listed for Liver+LungTx than for LiverTx (30.7 % vs. 6.4 %; P < 0.05).

CF represents a distinct indication for liver transplantation, with increased varying waiting list mortality risks across the different CF-groups, not adequately captured by standard liver disease severity scores. PwCF considered for liver transplantation require close monitoring as their disease severity and mortality risk are not well represented in the current allocation algorithm, necessitating adaptations to the organ allocation rules.

Liver transplantation is the most effective treatment for the sickest patients with acute-on-chronic liver failure (ACLF). However, the influence of donor age on liver transplantation, especially in ACLF patients, is still unclear.

In this study, we used the data of the Scientific Registry of Transplant Recipients. We included patients with ACLF who received liver transplantation from January 1, 2007, to December 31, 2017, and the total number was 13,857. We allocated the ACLF recipients by age into group I (donor age ≤17 years, n=647); group II (donor age 18-59 years, n=11,423); and group III (donor age ≥60 years, n=1,787). Overall survival (OS), graft survival, and mortality were compared among the three age groups and the four ACLF grades. Cox regression was also analyzed.

The 1-, 3-, and 5-year OS rates were 89.6%, 85.5%, and 82.0% in group I; 89.4%, 83.4%, and 78.2% in group II; and 86.8%, 78.4%, and 71.4% in group III, respectively (p<0.001). When we analyzed the different effects of donor age on OS with different ACLF grades, in groups II and III, we observed statistical differences. Finally, the cubic spline curve told us that the relative death rate changed linearly with increasing donor age.

Donor age is related to OS and graft survival of ACLF patients after transplantation, and poorer results were associated with elderly donors. In addition, different donor ages have different effects on recipients with different ACLF grades.

To determine the CEUS parameters that predict the likelihood of postoperative EAD.

Clinical and imaging data for 75 pairs of donors and recipients collected between September 2022 and July 2023 were retrospectively analyzed. Subjects were divided into those with early allograft dysfunction (EAD) and those without EAD. The liver parenchyma was selected as the region of interest to plot the CEUS time-intensity curve. CEUS parameters were compared between the two groups.

Peak intensity, area under the curve (AUC), and cholinesterase values were significantly lower in the EAD group than in the non-EAD group. The hepatic arterial-portal arrival interval (APAI) and aspartate aminotransferase level were significantly higher in the EAD group. Multivariate logistic analysis identified the APAI to be an independent risk factor for EAD (odds ratio 0.755; 95% confidence interval 0.577-0.989; p = 0.041). Receiver-operating characteristic curve analysis showed that the prediction probability P, which represents a combination of CEUS and clinical data, was best able to predict EAD (AUC 0.802; 95% confidence interval 0.679-0.926; p < 0.0001). Comparison of the AUC for prediction probability P and each single parameter identified statistically significant differences between the predicted probability P and aspartate aminotransferase and cholinesterase values (p = 0.042 and p = 0.020, respectively).

A longer APAI can be used as a biomarker to predict EAD after brain-dead donor liver transplantation. CEUS could be a valuable tool for assessment of donor livers and identifying recipients potentially at risk of developing postoperative EAD.

To explore the role of age at listing on outcomes for patients with acute-on-chronic liver failure (ACLF) awaiting liver transplantation (LT).

We assessed adult candidates listed for LT in the Scientific Registry of Transplant Recipients database from January 1, 2007 to June 30, 2018. Patients were divided into four groups based on age at listing: I (≤34), II (35-49), III (50-64), and IV (≥65). The ACLF grade was estimated (est-ACLF), and intent-to-treat survival, overall survival (OS), as well as potential predictors for OS was evaluated.

Est-ACLF-3 was associated with a higher 30-d cumulative dropout rate and inferior intent-to-treat survival across age groups. No difference was observed in OS among ACLF grades in group I, but significantly inferior OS was observed in higher ACLF grades in groups II-IV. Multivariate analysis showed age (P < 0.001, ref. group I; hazard ratio 0.995 for group II, P = 0.936; 1.196 for group III, P = 0.002; 1.651 for group IV, P < 0.001) and est-ACLF grade (P < 0.001, ref. est-ACLF-0; 1.214 for est-ACLF-1, P < 0.001; 1.246 for est-ACLF-2, P < 0.001; 1.578 for est-ACLF-3, P < 0.001) were independent predictors for OS. Generalized additive model showed different association between age and OS among different ACLF grades.

Young patients with high ACLF grades could achieve similar OS compared with those with low grades. Elderly patients with higher ACLF grades were associated with inferior outcomes after LT.

The increasing prevalence of fibrosis in donor livers raises concerns about its impact on post-transplantation outcomes, though this relationship remains unclear. This study aims to assess the effect of donor liver fibrosis on patient and graft survival following liver transplantation.

Data from the UNOS-SRTR registry (1987-2024) were analyzed, focusing on patients who received liver transplants with biopsy-proven fibrosis. The cohort was stratified based on fibrosis grade, and outcomes were compared using Cox regression and Kaplan-Meier survival analysis. Competing risk models were applied to assess specific causes for graft failure, and subgroup analyses explored the sensitivity of fibrosis on transplant outcomes.

Of the 22,897 patients, 17,926 received non-fibrotic grafts, and 4,971 had grafts with varying fibrosis grades. Donor fibrosis was associated with donor age, steatosis, and portal infiltrate, generally affecting those in better overall condition. Significant differences were observed in patient survival (p = 0.001) and graft survival (p = 0.002) between the fibrosis and non-fibrosis groups. Further analysis revealed that fibrosis increased the risk of malignancy (p = 0.028), cardiovascular disease (p = 0.017), and respiratory failure (p = 0.033), but showed lower rejection rates at six months and one year. Sensitivity analyses confirmed fibrosis as an independent risk factor, with varying effects in subgroups.

Donor liver fibrosis significantly impacts post-transplant outcomes, notably increasing the risk of all-cause mortality and graft failure. Specific causes of death, such as malignancy and cardiovascular disease, were more prevalent in recipients of fibrotic grafts, highlighting the need for further research to refine donor selection criteria.

Few published reports have addressed the feasibility of living-donor liver transplantation (LDLT) using elderly donors. We aimed to examine LDLT outcomes in elderly donors and identify clinical factors impacting safely conducted LDLT.

This study was conducted in collaboration with the Japanese Society of Hepatobiliary-Pancreatic Surgery. Data were collected from 140 patients who underwent LDLT using donors aged ≥50 years between 2013 and 2017 at nine collaborating hospitals.

The 1-, 3-, and 5-year graft survival rates in recipients after LDLT employing elderly donors were 84.3%, 78.5%, and 76.3%, respectively, with 6-month mortality of 12.1%. Specific recipient-donor age combinations did not emerge as adverse prognostic factors. A total of 32 recipients (22.9%) had major complications requiring reoperation after LDLT, and 15 donors (10.7%) had major complications of Clavien-Dindo grade ≥II. Multivariate analysis revealed that graft-to-recipient weight ratio (GRWR) <0.84% and neutrophil-to-lymphocyte ratio (NLR) >6.6 were independent predictors of 6-month graft loss after LDLT.

LDLT using elderly donors aged ≥50 years has acceptable graft survival and morbidity rates, and donor age >50 years should not be an absolute contraindication for LDLT. In LDLT involving elderly donors, it is crucial to consider that GRWR <0.84% and NLR >6.6 are adverse prognostic factors. Addressing these factors is necessary to enhance the prognosis, aligning with the increasing public demand for this surgical procedure.

The aim of this study was to collect and analyze information from pregnancies of organ transplanted women and partners of organ transplanted men. The goal was to enhance counseling regarding pregnancy planning and management and to enable more targeted monitoring to improve maternal and child health.

In this retrospective, multicenter cohort study, women and men aged 18 to 45 who had undergone organ transplantation in Germany, Austria, and Switzerland were surveyed about their pregnancies before and after transplantation by using a self-developed questionnaire.

Even through transplanted women planned their pregnancies more carefully than before transplantation, they still experienced more pregnancy complications afterward. The live birth rate for pregnancies of partners of transplanted men, especially men who received a thoracic organ, was lower compared to before transplantation. Furthermore, this study showed that pregnancies of the partners of male transplant recipients occurred significantly less by spontaneous conception in comparison to pregnancies of transplanted women.

Pregnancies after organ transplantation are possible but associated with an increased risk of pregnancy complications. Therefore, early counseling for transplanted women and men who wish to have children, along with extensive monitoring during pregnancy, is necessary.

With an aging global population, the proportion of aged donor livers in graft pools is steadily increasing. Compared to young livers, aged livers exhibit heightened susceptibility to hepatic ischemia/reperfusion injury (HIRI), which significantly limits their utilisation in liver transplantation (LT) and exacerbates organ shortages. Our previous study demonstrated that ferroptosis is a pivotal trigger for HIRI vulnerability in aged livers. However, effective clinical strategies for the inhibition of ferroptosis remain elusive. Utilizing an aged mouse HIRI model, primary hepatocytes, and human liver organoids, this study provides hitherto undocumented evidence that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) effectively alleviate HIRI in aged livers by inhibiting ferroptosis. Mechanistically, miR-1275, which was significantly enriched within MSC-EVs, was transferred to hepatocytes. Subsequently, miR-1275 downregulated the expression of SLC39A14, a crucial iron transporter that is upregulated in aged livers and plays a pivotal role in promoting ferroptosis. Furthermore, we found a negative correlation between SLC39A14 levels and prognosis of aged donor liver recipients using clinical LT samples. Silencing miR-1275 in MSC-EVs or modulating SLC39A14 levels in aged livers reversed MSC-EV-mediated mitigation of ferroptosis. Collectively, these findings revealed the novel therapeutic potential of MSC-EVs in attenuating aged HIRI, suggesting a promising treatment for improving prognosis and preventing serious complications in recipients of aged liver grafts during LT.

Donor age has traditionally been considered a factor associated with allograft failure in liver transplantation. We sought to examine the characteristics and outcomes of all liver allografts with a cumulative age of over 80 years within the US to better understand liver senescence.

Using the UNOS STARfile, allografts with a cumulative age (sum of age at transplant plus post-transplant survival) of octogenarian, 90-99 nonagenarian, and 100 years or greater (centurion) were identified from all adult transplant recipients between 1990 and 2022. Donor and recipient data as well as outcomes were analyzed.

There were 3437 octogenarian, 622 nonagenarian, and 29 centurion allografts. Donors from allografts with prolonged cumulative age had less diabetes, less alcohol use, and fewer infections compared to all other donors. Recipients had significantly lower MELD scores at the time of transplant and dialysis rates.

Careful matching of older donors with lower MELD recipients results in excellent outcomes as evidenced by the presence of prolonged cumulative age livers, demonstrating the resilience of the liver to senescent events in appropriately matched recipients.

The Tuscany Region has a quite high annual number of donors per million population (100 donors/pmp (annually)). Considering the increasing donor age and organ shortage, the donation and transplantation community needs to expand procurement and transplants from elderly donors. We assessed the utilization rate in donors aged ≥80 years during the study period (2018-2024) in Tuscany.

Our retrospective observational study comprised 809 donors aged ≥80 years. We compared Period 1 (from 2018 to 2020, before the COVID pandemic) to Period 2 (from 2021 to 2024, after the COVID pandemic).

cDCD donors significantly increased in Period 2 (0.0001). The utilization rate increased from Period 1 to Period 2 (81.5% vs. 91.7%). In the study period (2018-2024), 377 liver transplants were performed. Overall graft and patient survival at 1, 3, and 5 years when an octogenarian graft was used was 89.4%, 85.0%, 81.8% and 92.5%, 88.7%, 85.5%, respectively. EAD (early allograft dysfunction) was observed in 2.9% of the cases, and IC (ischemic cholangiopathy) developed in 6.3% of the cases. Forty kidneys were transplanted into 22 patients, including 18 dual kidney transplants.

During the 7-year study period, donors aged ≥80 years represented a consistent subgroup, since they accounted for one-third of the overall donor population. The increase in utilization rate observed during the study period may be related to several factors, both in the procurement and the transplant phase.

Clinicaltrial.gov: #NCT04744389.

Hepatocellular carcinoma (HCC) presents unique challenges in both the elderly and adolescent/young adult (AYA) populations, requiring distinct management approaches. Recent epidemiological data show an increasing incidence of HCC in both age groups, with elderly cases rising significantly and AYA cases showing trends in specific regions. The clinical characteristics and treatment considerations vary substantially among these populations. Elderly patients with HCC typically present with hepatitis C virus infection, metabolic dysfunction-associated steatotic liver disease, well-differentiated tumors, and multiple comorbidities. In contrast, AYA patients with HCC often present with more aggressive tumor characteristics and predominantly with hepatitis B virus-related diseases. Treatment decisions for elderly patients with HCC require careful consideration of physiological reserves, comprehensive geriatric assessments, and potential complications. Recent studies have demonstrated that elderly patients can achieve outcomes comparable to younger patients across various treatment modalities when properly selected. While surgical outcomes are comparable to those of younger patients with proper selection, less-invasive options such as radiofrequency ablation or transarterial therapies may be more appropriate for some elderly patients. The treatment approach for AYA HCC emphasizes curative intent while considering long-term effects. AYA patients require specialized attention to their psychosocial needs, fertility preservation, and long-term health maintenance. Although data on AYA patients remain limited, they are known to have relatively favorable prognoses despite exhibiting more aggressive tumor characteristics. Management of HCC in both the elderly and AYA populations requires individualized approaches that consider age-specific factors. Both groups benefit from multidisciplinary team involvement and careful consideration of quality of life.

Liver transplant recipients experience many uncertainties after transplantation. Also, sleep problems are common among them. This study aimed to examine intolerance of uncertainty and sleep quality in liver transplant recipients. A descriptive and cross-sectional study was conducted with 117 liver transplant recipients followed in the outpatient clinic of a liver transplant center. Data were collected using a sociodemographic and clinical features form, the Intolerance of Uncertainty Scale-12 and the Pittsburgh Sleep Quality Index between May and September in 2023. The data were analyzed using descriptive statistics, correlation analysis and regression analysis. The recipients had a high mean score of 41.04 ± 13.11 (min-max: 12-60) on the Intolerance of Uncertainty Scale-12. Age was predictive of uncertainty. Indeed, young recipients had higher intolerance of uncertainty. The recipients had a low score of 7.33 ± 3.57 (min-max: 1-21) on the Pittsburgh Sleep Quality Index. The prevalence of sleep problems was 65%. Experiencing complications after transplantation was predictive of and worsened sleep quality. The sleep quality of the recipients had no relation with intolerance of uncertainty and inhibitory anxiety, but it had a relation with prospective anxiety.

Split liver transplantation (SLT) has become an indispensable method for expanding the donor liver pool. However, advanced age in recipients can have significant adverse effects on prognosis. We report the case of an 82-year-old man with chronic liver failure and polycystic liver disease who underwent in vivo split right triple lobe donor liver transplantation on October 29, 2021. The patient made a remarkable recovery and was discharged 1 month after surgery. To date, he has been followed up for 32 months, with favorable laboratory and imaging test results, and no significant abnormalities or complications. Currently, this patient may be the oldest SLT recipient in the world. With comprehensive preoperative evaluation, optimized surgical techniques, and individually tailored postoperative care, older adults can safely undergo SLT. Therefore, advanced age should not be considered an absolute contraindication for this procedure.

Organ transplant is a life-saving treatment for patients with end-stage organ failure. Today, with the increase in the healthy aging geriatric population, transplant cases in elderly patients are also increasing. This study examined the effects of age differences on morbidity and mortality in kidney and liver transplant patients.

A total of 33 patients aged 65 years and over (elderly group) and 31 patients aged 25 to 64 years (younger group) were selected from 1273 kidney and 532 liver transplants performed at Başkent University Ankara Hospital between January 2000 and December 2023. In this descriptive study, we retrospectively compared graft survival and laboratory values between kidney and liver transplant patients in the elderly versus younger group.

The mean age was 73.67 ± 5.57 years in the elderly group and 57.77 ± 10.47 years in the younger group. Among patients with kidney transplant, the elderly group consisted of 4 female (19%) and 17 male (81%) patients, and the younger group consisted of 6 female (33%) and 12 male (67%) patients. Among patients with liver transplant, the elderly group consisted of 3 female (27%) and 8 male (73%) patients, and the younger group consisted of 2 female (15%) and 11 male (85%) patients. No significant differences were shown in graft survival duration between elderly and younger kidney transplant patients (P = .443). Liver transplant recipients in the elderly group had significantly higher aspartate aminotransferase levels at month 1 versus patients in the younger group (P = .012). Among kidney transplant patients, the younger group had urine protein and creatinine values at month 3 and creatinine values at month 12 that were significantly higher than in the elderly group (P = .016; P = .043).

Transplant had positive contributions in reducing mortality and morbidity in patients in the elderly group. Transplant studies of geriatric patients will benefit surgeons working with elderly patients and the literature in this field.

Liver transplantation has been at the forefront of medical research, with efforts concentrated on understanding the intricate cellular and molecular dynamics involved this complex procedure. This body of work has chronicled critical clinical advancements, identified challenges, and highlighted progressive improvements in surgical practices. These concerted efforts have significantly contributed to the evolution and enhancement of liver transplantation, elevating it to its current level of sophistication. A successful liver transplant now demands an integrated, multidisciplinary approach that includes not only expanding the donor pool from deceased to living donors but also embracing advances in surgical methods, efficiently managing post-transplant complications, and, importantly, achieving operational tolerance. The latter, operational tolerance, is a state wherein the recipient's immune system is coaxed into accepting the transplanted organ without the long-term use of immunosuppressive drugs, thereby minimizing potential side effects, and improving quality of life. Understanding the critical immune mechanisms that aim to prevent graft rejection is essential from an immunological perspective. This review aims to highlight the crucial areas of host versus graft immune responses, making a clear distinction between organs received from living and deceased donors. It examines how these immune responses, both innate and adaptive, are initiated and proposes the exploration of molecular docking sites as a strategy to curb unwanted immune reactions. Additionally, this review explores the promising potential of biomarkers in predicting graft rejection, and emphasizes the importance of achieving tolerance and the continuous quest for innovative strategies to enhance the success and longevity of liver transplants.

A precise model for predicting outcomes is needed to guide perioperative management. With the development of the liver transplantation (LT) discipline, previous models may become inappropriate or noncomprehensive. Thus, we aimed to develop a novel model integrating variables from donors and recipients for quick assessment of transplant outcomes.

The risk model was based on Cox regression in a randomly selected derivation cohort and verified in a validation cohort. Perioperative data and overall survival were compared between stratifications grouped by X-tile. Receiver-operating characteristic curve and decision curve analysis were used to compare the models. Violin and raincloud plots were generated to present post-LT complications distributed in different stratifications.

Overall, 528 patients receiving LT from 2 centers were included with 2/3 in the derivation cohort and 1/3 in the validation cohort. Cox regression analysis showed that cold ischemia time (CIT) ( P = 0.012) and Model for End-Stage Liver Disease (MELD) ( P = 0.007) score were predictors of survival. After comparison with the logarithmic models, the primitive algorithms of CIT and MELD were defined as the CIT-MELD Index (CMI). CMI was stratified by X-tile (grade 1 ≤1.06, 1.06 < grade 2 ≤ 1.87, grade 3 >1.87). In both cohorts, CMI performed better in calculating transplant outcomes than the balance of risk score, including perioperative incidents and prevalence of complications.

The model integrating variables from graft donors and recipients made the prediction more accurate and available. CMI provided new insight into outcome evaluation and risk factor management of LT.

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.

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.

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 (<18.5 kg/m 2 ; 2.98 kg/m 2 [1.52-5.84 kg/m 2 ]; P  = 0.002) were independent risk factors for graft survival.

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.

Liver transplantation (LT) has historically been associated with a high prevalence of osteoporosis, but most of the available data date back to late 1990s-early 2000s with limited sample size. Our aim was to assess the prevalence of bone fragility fractures and contributing factors in a large modern cohort of liver transplant recipients. Retrospective study of 429 consecutive patients receiving liver transplantation from 1/1/2010 to 31/12/2015. Final cohort included 366 patients. Electronic radiological images (lateral views of spine X-rays or Scout CT abdominal scans) performed within 6 months from LT, were blinded reviewed to screen for morphometric vertebral fractures. Symptomatic clinical fragility fractures were recorded from the medical records. Patients with fragility fractures in the cohort were 155/366 (42.3%), with no significant differences between sexes. Most sustained vertebral fractures (145/155, 93.5%), mild or moderate wedges, with severe fractures more frequently observed in women. Multiple vertebral fractures were common (41.3%). Fracture rates were similar across different etiologies of cirrhosis and independent of diabetes or glucocorticoids exposure. Kidney function was significantly worse in women with fractures. Independently of age, sex, alcohol use, eGFR, and etiology of liver disease, low BMI was significantly associated with an increased risk for fractures (adjusted OR 1.058, 95%CI 1.001-1.118, P = 0.046). Our study shows a considerable fracture burden in a large and modern cohort of liver transplant recipients. Given the very high prevalence of bone fractures, a metabolic bone disease screening should be implemented in patients awaiting liver transplantation.

Liver transplantation (LT) is an established life-saving procedure. The field of LT has changed in the past 10 years from several perspectives, with the expansion of indications, transplantation of patients with acute-on-chronic liver failure, evolution of transplant oncology, the use of donations after cardiac death, new surgical techniques, and prioritisation of recipients on the waiting list. In addition, the advent of organ perfusion machines, the recognition of new forms of rejection, and the attention paid to the transition from paediatric to adult patients, have all improved the management of LT recipients. The purpose of the EASL guidelines presented here is not to cover all aspects of LT but to focus on developments since the previous EASL guidelines published in 2016.

We compared the performance of the Liver Transplant Risk Score (LTRS) with the survival outcomes following liver transplantation (SOFT), pretransplant SOFT (P-SOFT), Balance of Risk Score (BAR), donor-age and model for end-stage liver disease (D-MELD), and Organ Procurement and Transplantation Network Risk Prediction Score (ORPS) for the prediction of 90-d mortality, 1-y mortality, and 5-y survival after first-time liver transplantation (LT).

A retrospective analysis of the Scientific Registry of Transplant Recipients was conducted using data collected between 2002 and 2021.

A total of 82 696 adult LT recipients with a median age of 56 y were included. The area under the curve for 90-d mortality were 0.61, 0.66, 0.65, 0.61, 0.58, and 0.56 for the LTRS, SOFT, P-SOFT, BAR, D-MELD, and ORPS, respectively (all pairwise comparisons: P < 0.05). The area under the curve for 1-y mortality were 0.60, 0.63, 0.62, 0.59, 0.60, 0.57, and 0.59 for the LTRS, SOFT, P-SOFT, BAR, D-MELD, and ORPS, respectively (all pairwise comparisons: P < 0.05). The c-statistics for 5-y survival were not statistically significant among the models. For 90-d mortality, 1-y mortality, and 5-y survival, the correlation coefficients between the LTRS and P-SOFT (the 2 models requiring only preoperative parameters) were 0.90. 0.91, and 0.81, respectively (P < 0.01).

None of the predictive models demonstrated sufficient precision to reliably identify LT recipients who died within 90 d and 1 y after LT. However, all models exhibited strong capabilities in perioperative risk stratification. Notably, the P-SOFT and LTRS models, the 2 models that can be calculated using only preoperative data, proved to be valuable tools for identifying candidates at a significant risk of poor outcomes.

Since April 2014 the age limitation on candidates listed for organ transplantation in Israel was abolished following the recommendations of a Public Committee. In this research the new policy was examined in light of scarce medical resources and the increased rate of aging in Israel.

The opinions of twelve medical staff regarding the policy change were analyzed by a qualitative methodology, using semi-structured interviews.

Interviews with medical staff members revealed three main themes: 1. positive acceptance of the new policy; 2. concerns and problems regarding the change; and 3. the influence of the policy change on the organ transplant allocation system and patient-doctor relationships.

The medical staff expressed positive views towards the new policy, based on age-free, individually determined admission to transplant waiting lists. However, some concerns were raised regarding the medical implications of this policy, thus potentially hindering its full application.

With the growth of the older adult population, the number of older adults waitlisted for and undergoing kidney and liver transplantation has increased. Transplantation is an important and definitive treatment for this population. We present a contemporary review of the unique preoperative, intraoperative, and postoperative issues that patients older than 65 y face when they undergo kidney or liver transplantation. We focus on geriatric syndromes that are common in older patients listed for kidney or liver transplantation including frailty, sarcopenia, and cognitive dysfunction; discuss important considerations for older transplant recipients, which may impact preoperative risk stratification; and describe unique challenges in intraoperative and postoperative management for older patients. Intraoperative challenges in the older adult include using evidence-based best anesthetic practices, maintaining adequate perfusion pressure, and using minimally invasive surgical techniques. Postoperative concerns include controlling acute postoperative pain; preventing cardiovascular complications and delirium; optimizing immunosuppression; preventing perioperative kidney injury; and avoiding nephrotoxicity and rehabilitation. Future studies are needed throughout the perioperative period to identify interventions that will improve patients' preoperative physiologic status, prevent postoperative medical complications, and improve medical and patient-centered outcomes in this vulnerable patient population.

The use of older donors after circulatory death (DCD) for liver transplantation (LT) has increased over the past decade. This study examined whether outcomes of LT using older DCD (≥50 y) have improved with advancements in surgical/perioperative care and normothermic machine perfusion (NMP) technology. A total of 7602 DCD LT cases from the United Network for Organ Sharing database (2003-2022) were reviewed. The impact of older DCD donors on graft survival was assessed using the Kaplan-Meier and HR analyses. In all, 1447 LT cases (19.0%) involved older DCD donors. Although there was a decrease in their use from 2003 to 2014, a resurgence was noted after 2015 and reached 21.9% of all LTs in the last 4 years (2019-2022). Initially, 90-day and 1-year graft survivals for older DCDs were worse than younger DCDs, but this difference decreased over time and there was no statistical difference after 2015. Similarly, HRs for graft loss in older DCD have recently become insignificant. In older DCD LT, NMP usage has increased recently, especially in cases with extended donor-recipient distances, while the median time from asystole to aortic cross-clamp has decreased. Multivariable Cox regression analyses revealed that in the early phase, asystole to cross-clamp time had the highest HR for graft loss in older DCD LT without NMP, while in the later phases, the cold ischemic time (>5.5 h) was a significant predictor. LT outcomes using older DCD donors have become comparable to those from young DCD donors, with recent HRs for graft loss becoming insignificant. The strategic approach in the recent period could mitigate risks, including managing cold ischemic time (≤5.5 h), reducing asystole to cross-clamp time, and adopting NMP for longer distances. Optimal use of older DCD donors may alleviate the donor shortage.

BRG1 (Brahma-related gene 1) is a member of the SWI/SNF (switch/sucrose nonfermentable) chromatin remodeling complex which utilizes the energy from ATP hydrolysis for its activity. In addition to its role of regulating the expression of a vast array of genes, BRG1 mediates DNA repair upon genotoxic stress and regulates senescence. During organismal ageing, there is accumulation of unrepaired/unrepairable DNA damage due to progressive breakdown of the DNA repair machinery. The present study investigates the expression level of BRG1 as a function of age in the liver of 5- and 21-month-old female mice. It also explores the impact of dietary restriction on BRG1 expression in the old (21-month) mice. Salient findings of the study are: Real-time PCR and Western blot analyses reveal that BRG1 levels are higher in 5-month-old mice but decrease significantly with age. Dietary restriction increases BRG1 expression in the 21-month-old mice, nearly restoring it to the level observed in the younger group. Similar expression patterns are observed for DNA damage response genes ATM (Ataxia Telangiectasia Mutated) and ATR (Ataxia Telangiectasia and Rad3-related) with the advancement in age and which appears to be modulated by dietary restriction. BRG1 transcriptionally regulates ATM as a function of age and dietary restriction. These results suggest that BRG1, ATM and ATR are downregulated as mice age, and dietary restriction can restore their expression. This implies that dietary restriction may play a crucial role in regulating BRG1 and related gene expression, potentially maintaining liver repair and metabolic processes as mice age.

Cause of death (COD) is a predictor of liver transplant (LT) outcomes independent of donor age, yet has not been recently reappraised.

Analyzing UNOS database (2013-2022), the study explored COD trends and impacts on one-year post-LT graft survival (GS) and hazard ratios (HR) for graft failure.

Of 80,282 brain-death donors, 55,413(69.0%) underwent initial LT. Anoxia became the predominant COD in 2015, increasing from 29.0% in 2013 to 45.1% in 2021, with notable increases in drug intoxication. Survival differences between anoxia and cerebrovascular accidents (CVA) recently became insignificant (P=0.95). Further analysis showed improved GS from intracranial hemorrhage/stroke (previously worse; P<0.01) (P=0.70). HRs for post-1-year graft failure showed reduced significance of CVA (vs.Anoxia) and intracranial hemorrhage/stroke (vs.any other COD) recently. Donors with intracranial hemorrhage/stroke, showing improved survival and HR, were allocated to recipients with lower MELD-Na, contrasting the trend for drug intoxication CODs.

CVA, traditionally linked with poorer outcomes, shows improved GS and HRs (vs.Anoxia). This could be due to rising drug intoxication cases and the allocation of donors with drug intoxication to recipients with higher MELD-Na, and those with CVA to recipients with lower scores. While COD remains crucial in donor selection, proper matching can mitigate differences among CODs.

The demand for liver transplants (LT) in the United States far surpasses the availability of allografts. New allocation schemes have resulted in occasional difficulties with allograft placement and increased intraoperative turndowns. We aimed to evaluate the outcomes related to use of late-turndown liver allografts.

A review of prospectively collected data of LTs at a single center from July 2019 to July 2023 was performed. Late-turndown placement was defined as an open offer 6 h prior to donation, intraoperative turndown by primary center, or post-cross-clamp turndown.

Of 565 LTs, 25.1% (n = 142) received a late-turndown liver allograft. There were no significant differences in recipient age, gender, BMI, or race (all p > 0.05), but MELD was lower for the late-turndown LT recipient group (median 15 vs 21, p < 0.001). No difference in 30-day, 6-month, or 1-year survival was noted on logistic regression, and no difference in patient or graft survival was noted on Cox proportional hazard regression. Late-turndown utilization increased during the study from 17.2% to 25.8%, and median waitlist time decreased from 77 days in 2019 to 18 days in 2023 (p < 0.001).

Use of late-turndown livers has increased and can increase transplant rates without compromising post-transplant outcomes with appropriate selection.

Compared with young liver donors, aged liver donors are more susceptible to ischemia-reperfusion injury (IRI) following transplantation, which may be related to excessive inflammatory response and macrophage dysfunction, but the specific mechanism is unclear. Macrophage scavenger receptor 1 (MSR1) is a member of the scavenger receptor family, and plays an important regulatory role in inflammation response and macrophage function regulation. But its role in IRI following aged-donor liver transplantation is still unclear. This study demonstrates that MSR1 expression is decreased in macrophages from aged donor livers, inhibiting their efferocytosis and pro-resolving polarisation. Decreased MSR1 is responsible for the more severe IRI suffered by aged donor livers. Overexpression of MSR1 using F4/80-labelled AAV9 improved intrahepatic macrophage efferocytosis and promoted pro-resolving polarisation, ultimately ameliorating IRI following aged-donor liver transplantation. In vitro co-culture experiments further showed that overexpression of MSR1 promoted an increase in calcium concentration, which further activated the PI3K-AKT-GSK3β pathway, and induced the upregulation of β-catenin. Overall, MSR1-dependent efferocytosis promoted the pro-resolving polarisation of macrophages through the PI3K-AKT-GSK3β pathway-induced up-regulating of β-catenin leading to improved IRI following aged-donor liver transplantation.

Aging is a contributor to liver disease. Hence, the concept of liver aging has become prominent and has attracted considerable interest, but its underlying mechanism remains poorly understood. In our study, the internal mechanism of liver aging was explored via multi-omics analysis and molecular experiments to support future targeted therapy. An aged rat liver model was established with d-galactose, and two other senescent hepatocyte models were established by treating HepG2 cells with d-galactose and H2O2. We then performed transcriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte models. In livers, genes related to peroxisomes, fatty acid elongation, and fatty acid degradation exhibited down-regulated expression with aging, and the hepatokine Fgf21 expression was positively correlated with the down-regulation of these genes. In senescent hepatocytes, similar to the results found in aged livers, FGF21 expression was also decreased. Moreover, the expressions of cell cycle-related genes were significantly down-regulated, and the down-regulated gene E2F8 was the key cell cycle-regulating transcription factor. We then validated that FGF21 overexpression can protect against liver aging and that FGF21 can attenuate the declines in the antioxidant and regenerative capacities in the aging liver. We successfully validated the results from cellular and animal experiments using human liver and blood samples. Our study indicated that FGF21 is an important target for inhibiting liver aging and suggested that pharmacological prevention of the reduction in FGF21 expression due to aging may be used to treat liver aging-related diseases.

The incidence of young patients diagnosed with hepatocellular carcinoma (HCC) is projected to rise. This study aimed to investigate the distinctive characteristics of adolescent and young adult (AYA) patients with HCC and identify the risk factors that impact their survival.

This study included 1005 AYA patients and 55,435 older adult (OA) patients with HCC, using data from the Surveillance, Epidemiology, and End Results database. Propensity score matching was used to adjust for baseline differences in patient characteristics. The Kaplan-Meier curve and log-rank test are utilized to compare the overall survival between the two groups. The Cox proportional hazards regression model was used for subgroup analysis to identify risk factors for overall survival in AYA patients.

AYA patients exhibited a higher proportion of advanced clinical stage (49.15% vs 37.57%, P < 0.001) and fibrolamellar hepatocellular carcinoma (14.13% vs 0.09%, P < 0.001), but a lower incidence of alpha-fetoprotein positivity (32.04% vs 45.32%, P < 0.001) and cirrhosis (8.86% vs 18.32%, P < 0.001). The subgroup analysis results indicated that AYA patients had a more favorable prognosis than OA patients in most subgroups. Undifferentiated carcinoma emerged as the predominant risk factor for AYA patients (Hazard Ratio [HR], 6.08 [2.53-14.62]), whereas partial hepatectomy was determined to be the most advantageous factor (HR, 0.29 [0.23-0.37]).

AYA patients with HCC exhibit more aggressive characteristics but demonstrate a better prognosis compared to the OA group, necessitating personalized surveillance and treatment.

Frailty is a multidimensional syndrome predominantly studied in the elderly, characterized by reduced resistance to stressors due to diminished physiological reserve and resilience. Advances in surgical techniques and immunosuppressive drugs have improved long-term survival rates in solid organ transplant recipients, yet the 10-year survival is satisfying. However, liver transplant recipients have a noteworthy risk of developing frailty status. After liver transplant, frailty can be favored by socioeconomic, cultural, and health-related factors, leading to increased risks of hospitalization, morbidity, and mortality. Various tools for frailty assessment exist, but none are universally validated for post-transplant patients. The integration of socioeconomic and psychological factors into frailty evaluation could improve quality of life and long-term outcomes for transplant recipients. Multidisciplinary approaches, including psychosocial support, are essential for managing frailty and enhancing the overall care of transplanted patients. This narrative review aims to comprehensively address the principal frailty risk factors associated with liver transplantation.