Donor and recipient genetics: Implications for the development of posttransplant diabetes mellitus.

Posttransplant diabetes mellitus (PTDM) is a prevalent complication of liver transplantation and is associated with cardiometabolic complications. We studied the consequences of genetic effects of liver donors and recipients on PTDM outcomes, focusing on the diverse genetic pathways related to insulin that play a role in the development of PTDM. One thousand one hundred fifteen liver transplant recipients without a pretransplant diagnosis of type 2 diabetes mellitus (T2D) and their paired donors recruited from 2 transplant centers had polygenic risk scores (PRS) for T2D, insulin secretion, and insulin sensitivity calculated. Among recipients in the highest T2D-PRS quintile, donor T2D-PRS did not contribute significantly to PTDM. However, in recipients with the lowest T2D genetic risk, donor livers with the highest T2D-PRS contributed to the development of PTDM (OR [95% CI] = 3.79 [1.10-13.1], P = .035). Recipient risk was linked to factors associated with insulin secretion (OR [95% CI] = 0.85 [0.74-0.98], P = .02), while donor livers contributed to PTDM via gene pathways involved in insulin sensitivity (OR [95% CI] = 0.86 [0.75-0.99], P = .03). Recipient and donor PRS independently and collectively serve as predictors of PTDM onset. The genetically influenced biological pathways in recipients primarily pertain to insulin secretion, whereas the genetic makeup of donors exerts an influence on insulin sensitivity.

Financial toxicity in living donor liver transplantation: A call to action for financial neutrality.

After 2 decades of limited growth, living donor liver transplant (LDLT) has been increasingly accepted as a promising solution to the growing organ shortage in the US. With experience, LDLT offers superior graft and patient survival with low rates of rejection. However, not all waitlisted patients have equal access to LDLT, with financial toxicity representing a substantial barrier. Potential living liver donors face indirect, direct, and opportunity costs associated with donation as well as insurance-based discrimination and variable employer leave policies. There are multiple potential national, local, and patient-centered solutions to address some of the cost-related issues associated with living LDLT. These include standardization of employer leave policies, creation of federal and state-led tax relief programs, optimization of National Living Donor Assistance Center use, engagement of independent living donor advocates, creation of financial toolkits, and encouragement of recipient or donor-led fundraising. In this piece, members of the North American Living Liver Donation Group, a consortium of 37 LDLT programs, explore these financial challenges and discuss solutions to achieve financial neutrality, where individuals can donate free from financial constraints or gains. As a community, it is imperative that we confront factors driving financial toxicity to improve equity and access to LDLT.

Characterizing proximity and transfers of deceased organ donors to donor care units in the United States.

Some United States organ procurement organizations transfer deceased organ donors to donor care units (DCUs) for recovery procedures. We used Organ Procurement and Transplantation Network data, from April 2017 to June 2021, to describe the proximity of adult deceased donors after brain death to DCUs and understand the impact of donor service area (DSA) boundaries on transfer efficiency. Among 19 109 donors (56.1% of the cohort) in 25 DSAs with DCUs, a majority (14 593 [76.4%]) were in hospitals within a 2-hour drive. In areas with DCUs detectable in the study data set, a minority of donors (3582 of 11 532 [31.1%]) were transferred to a DCU; transfer rates varied between DSAs (median, 27.7%, range, 4.0%-96.5%). Median hospital-to-DCU driving times were not meaningfully shorter among transferred donors (50 vs 51 minutes for not transferred, P < .001). When DSA boundaries were ignored, 3241 cohort donors (9.5%) without current DCU access were managed in hospitals within 2 hours of a DCU and thus potentially eligible for transfer. In summary, approximately half of United States deceased donors after brain death are managed in hospitals in DSAs with a DCU. Transfer of donors between DSAs may increase DCU utilization and improve system efficiency.

Biliary complications after adult-to-adult living-donor liver transplantation: An international multicenter study of 3633 cases.

In living-donor liver transplantation, biliary complications including bile leaks and biliary anastomotic strictures remain significant challenges, with incidences varying across different centers. This multicentric retrospective study (2016-2020) included 3633 adult patients from 18 centers and aimed to identify risk factors for these biliary complications and their impact on patient survival. Incidences of bile leaks and biliary strictures were 11.4% and 20.6%, respectively. Key risk factors for bile leaks included multiple bile duct anastomoses (odds ratio, [OR] 1.8), Roux-en-Y hepaticojejunostomy (OR, 1.4), and a history of major abdominal surgery (OR, 1.4). For biliary anastomotic strictures, risk factors were ABO incompatibility (OR, 1.4), blood loss >1 L (OR, 1.4), and previous abdominal surgery (OR, 1.7). Patients experiencing biliary complications had extended hospital stays, increased incidence of major complications, and higher comprehensive complication index scores. The impact on graft survival became evident after accounting for immortal time bias using time-dependent covariate survival analysis. Bile leaks and biliary anastomotic strictures were associated with adjusted hazard ratios of 1.7 and 1.8 for graft survival, respectively. The study underscores the importance of minimizing these risks through careful donor selection and preoperative planning, as biliary complications significantly affect graft survival, despite the availability of effective treatments.

Living Donor Liver Transplantation for Hepatocellular Carcinoma Within and Outside Traditional Selection Criteria: A Multicentric North American Experience.

OBJECTIVE: To evaluate long-term oncologic outcomes of patients post-living donor liver transplantation (LDLT) within and outside standard transplantation selection criteria and the added value of the incorporation of the New York-California (NYCA) score. BACKGROUND: LDLT offers an opportunity to decrease the liver transplantation waitlist, reduce waitlist mortality, and expand selection criteria for patients with hepatocellular carcinoma (HCC). METHODS: Primary adult LDLT recipients between October 1999 and August 2019 were identified from a multicenter cohort of 12 North American centers. Posttransplantation and recurrence-free survival were evaluated using the Kaplan-Meier method. RESULTS: Three hundred sixty LDLTs were identified. Patients within Milan criteria (MC) at transplantation had a 1, 5, and 10-year posttransplantation survival of 90.9%, 78.5%, and 64.1% versus outside MC 90.4%, 68.6%, and 57.7% ( P = 0.20), respectively. For patients within the University of California San Francisco (UCSF) criteria, respective posttransplantation survival was 90.6%, 77.8%, and 65.0%, versus outside UCSF 92.1%, 63.8%, and 45.8% ( P = 0.08). Fifty-three (83%) patients classified as outside MC at transplantation would have been classified as either low or acceptable risk with the NYCA score. These patients had a 5-year overall survival of 72.2%. Similarly, 28(80%) patients classified as outside UCSF at transplantation would have been classified as a low or acceptable risk with a 5-year overall survival of 65.3%. CONCLUSIONS: Long-term survival is excellent for patients with HCC undergoing LDLT within and outside selection criteria, exceeding the minimum recommended 5-year rate of 60% proposed by consensus guidelines. The NYCA categorization offers insight into identifying a substantial proportion of patients with HCC outside the MC and the UCSF criteria who still achieve similar post-LDLT outcomes as patients within the criteria.

Neighborhood-level social determinants of health measures independently predict receipt of living donor liver transplantation in the United States.

Disparities exist in the access to living donor liver transplantation (LDLT) in the United States. However, the association of neighborhood-level social determinants of health (SDoH) on the receipt of LDLT is not well-established. This was a retrospective cohort study of adult liver transplant recipients between January 1, 2005 and December 31, 2021 at centers performing LDLT using the United Network for Organ Sharing database, which was linked through patients' ZIP code to a set of 24 neighborhood-level SDoH measures from different data sources. Temporal trends and center differences in neighborhood Social Deprivation Index (SDI), a validated scale of socioeconomic deprivation ranging from 0 to 100 (0=least disadvantaged), were assessed by transplant type. Multivariable logistic regression evaluated the association of increasing SDI on receipt of LDLT [vs. deceased donor liver transplantation (DDLT)]. There were 51,721 DDLT and 4026 LDLT recipients at 59 LDLT-performing centers during the study period. Of the 24 neighborhood-level SDoH measures studied, the SDI was most different between the 2 transplant types, with LDLT recipients having lower SDI (ie, less socioeconomic disadvantage) than DDLT recipients (median SDI 37 vs. 47; p < 0.001). The median difference in SDI between the LDLT and DDLT groups significantly decreased from 13 in 2005 to 3 in 2021 ( p = 0.003). In the final model, the SDI quintile was independently associated with transplant type ( p < 0.001) with a threshold SDI of ~40, above which increasing SDI was significantly associated with reduced odds of LDLT (vs. reference SDI 1-20). As a neighborhood-level SDoH measure, SDI is useful for evaluating disparities in the context of LDLT. Center outreach efforts that aim to reduce disparities in LDLT could preferentially target US ZIP codes with SDI > 40.

Mortality and morbidity after combined heart and liver transplantation in the failing Fontan: An updated dual center retrospective study.

INTRODUCTION: As the adult Fontan population with Fontan associated liver disease continues to increase, more patients are being referred for transplantation, including combined heart and liver transplantation. METHODS: We report updated mortality and morbidity outcomes after combined heart and liver transplant in a retrospective cohort series of 40 patients (age 14 to 49 years) with Fontan circulation across two centers from 2006-2022. RESULTS: The 30-day, 1-year, 5-year and 10-year survival rate was 90%, 80%, 73% and 73% respectively. Sixty percent of patients met a composite comorbidity of needing either post-transplant mechanical circulatory support, renal replacement therapy or tracheostomy. Cardiopulmonary bypass time > 283 min (4.7 h) and meeting the composite comorbidity were associated with mortality by Kaplan Meier analysis. CONCLUSION: Further study to mitigate early mortality and the above comorbidities as well as the high risk of bleeding and vasoplegia in this patient population is warranted.

Racial and ethnic disparities in psychosocial evaluation and liver transplant waitlisting.

Health disparities have been well-described in all stages of the liver transplantation (LT) process. Using data from psychosocial evaluations and the Stanford Integrated Psychosocial Assessment, our objective was to investigate potential racial and ethnic inequities in overall LT waitlisting and not waitlisting for medical or psychosocial reasons. In a cohort of 2271 candidates evaluated for LT from 2014 to 2021 and with 1-8 years of follow-up, no significant associations were noted between race/ethnicity and overall waitlisting and not waitlisting for medical reasons. However, compared with White race, Black race (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.07-2.56) and Hispanic/Latinx ethnicity (OR, 2.10; 95% CI, 1.16-3.78) were associated with not waitlisting for psychosocial reasons. After adjusting for sociodemographic variables, the relationship persisted in both populations: Black (OR, 1.95; 95% CI, 1.12-3.38) and Hispanic/Latinx (OR, 2.29; 95% CI, 1.08-4.86) (reference group, White). High-risk Stanford Integrated Psychosocial Assessment scores were more prevalent in Black and Hispanic/Latinx patients, likely reflecting upstream factors and structural racism. Health systems and LT centers should design programs to combat these disparities and improve equity in access to LT.

Addressing sex-based disparities in solid organ transplantation in the United States - a conference report.

Solid organ transplantation provides the best treatment for end-stage organ failure, but significant sex-based disparities in transplant access exist. On June 25, 2021, a virtual multidisciplinary conference was convened to address sex-based disparities in transplantation. Common themes contributing to sex-based disparities were noted across kidney, liver, heart, and lung transplantation, specifically the existence of barriers to referral and wait listing for women, the pitfalls of using serum creatinine, the issue of donor/recipient size mismatch, approaches to frailty and a higher prevalence of allosensitization among women. In addition, actionable solutions to improve access to transplantation were identified, including alterations to the current allocation system, surgical interventions on donor organs, and the incorporation of objective frailty metrics into the evaluation process. Key knowledge gaps and high-priority areas for future investigation were also discussed.

Normothermic Machine Perfusion of Donor Livers for Transplantation in the United States: A Randomized Controlled Trial.

OBJECTIVE: To compare conventional low-temperature storage of transplant donor livers [static cold storage (SCS)] with storage of the organs at physiological body temperature [normothermic machine perfusion (NMP)]. BACKGROUND: The high success rate of liver transplantation is constrained by the shortage of transplantable organs (eg, waiting list mortality >20% in many centers). NMP maintains the liver in a functioning state to improve preservation quality and enable testing of the organ before transplantation. This is of greatest potential value with organs from brain-dead donor organs (DBD) with risk factors (age and comorbidities), and those from donors declared dead by cardiovascular criteria (donation after circulatory death). METHODS: Three hundred eighty-three donor organs were randomized by 15 US liver transplant centers to undergo NMP (n = 192) or SCS (n = 191). Two hundred sixty-six donor livers proceeded to transplantation (NMP: n = 136; SCS: n = 130). The primary endpoint of the study was "early allograft dysfunction" (EAD), a marker of early posttransplant liver injury and function. RESULTS: The difference in the incidence of EAD did not achieve significance, with 20.6% (NMP) versus 23.7% (SCS). Using exploratory, "as-treated" rather than "intent-to-treat," subgroup analyses, there was a greater effect size in donation after circulatory death donor livers (22.8% NMP vs 44.6% SCS) and in organs in the highest risk quartile by donor risk (19.2% NMP vs 33.3% SCS). The incidence of acute cardiovascular decompensation at organ reperfusion, "postreperfusion syndrome," as a secondary outcome was reduced in the NMP arm (5.9% vs 14.6%). CONCLUSIONS: NMP did not lower EAD, perhaps related to the inclusion of lower-risk liver donors, as higher-risk donor livers seemed to benefit more. The technology is safe in standard organ recovery and seems to have the greatest benefit for marginal donors.

Novel Benchmark for Adult-to-Adult Living-donor Liver Transplantation: Integrating Eastern and Western Experiences.

OBJECTIVE: To define benchmark values for adult-to-adult living-donor liver transplantation (LDLT). BACKGROUND: LDLT utilizes living-donor hemiliver grafts to expand the donor pool and reduce waitlist mortality. Although references have been established for donor hepatectomy, no such information exists for recipients to enable conclusive quality and comparative assessments. METHODS: Patients undergoing LDLT were analyzed in 15 high-volume centers (≥10 cases/year) from 3 continents over 5 years (2016-2020), with a minimum follow-up of 1 year. Benchmark criteria included a Model for End-stage Liver Disease ≤20, no portal vein thrombosis, no previous major abdominal surgery, no renal replacement therapy, no acute liver failure, and no intensive care unit admission. Benchmark cutoffs were derived from the 75th percentile of all centers' medians. RESULTS: Of 3636 patients, 1864 (51%) qualified as benchmark cases. Benchmark cutoffs, including posttransplant dialysis (≤4%), primary nonfunction (≤0.9%), nonanastomotic strictures (≤0.2%), graft loss (≤7.7%), and redo-liver transplantation (LT) (≤3.6%), at 1-year were below the deceased donor LT benchmarks. Bile leak (≤12.4%), hepatic artery thrombosis (≤5.1%), and Comprehensive Complication Index (CCI ® ) (≤56) were above the deceased donor LT benchmarks, whereas mortality (≤9.1%) was comparable. The right hemiliver graft, compared with the left, was associated with a lower CCI ® score (34 vs 21, P < 0.001). Preservation of the middle hepatic vein with the right hemiliver graft had no impact neither on the recipient nor on the donor outcome. Asian centers outperformed other centers with CCI ® score (21 vs 47, P < 0.001), graft loss (3.0% vs 6.5%, P = 0.002), and redo-LT rates (1.0% vs 2.5%, P = 0.029). In contrast, non-benchmark low-volume centers displayed inferior outcomes, such as bile leak (15.2%), hepatic artery thrombosis (15.2%), or redo-LT (6.5%). CONCLUSIONS: Benchmark LDLT offers a valuable alternative to reduce waitlist mortality. Exchange of expertise, public awareness, and centralization policy are, however, mandatory to achieve benchmark outcomes worldwide.

Variation in adult living donor liver transplantation in the United States: Identifying opportunities for increased utilization.

In the United States, living donor liver transplantation (LDLT) is limited to transplant centers with specific experience. However, the impact of recipient characteristics on procedure selection (LDLT vs. deceased donor liver transplant [DDLT]) within these centers has not been described. Transplant registry data for centers that performed ≥1 LDLT in 2002-2019 were analyzed using hierarchal regression modeling to quantify the impact of patient and center factors on the adjusted odds ratio (aOR) of LDLT (vs DDLT). Among 73,681 adult recipients, only 4% underwent LDLT, varying from <1% to >60% of total liver transplants. After risk adjustment, the likelihood of receiving an LDLT rose by 73% in recent years (aOR 1.73 for 2014-2019 vs. 2002-2007) but remained lower for older adults, men, racial and ethnic minorities, and obese patients. LDLT was less commonly used in patients with hepatocellular carcinoma or alcoholic cirrhosis, and more frequently in those with hepatitis C and with lower severity of illness (Model for End-Stage Liver Disease (MELD) score < 15). Patients with public insurance, lower educational achievement, and residence in the Northwest and Southeast had decreased access. While some differences in access to LDLT reflect clinical factors, further exploration into disparities in LDLT utilization based on center practice and socioeconomic determinants of health is needed.

Living donor liver transplantation: A multi-disciplinary collaboration towards growth, consensus, and a change in culture.

INTRODUCTION: Living donor liver transplantation (LDLT) reduces liver transplant waitlist mortality and provides excellent long-term outcomes for persons with end stage liver disease. Yet, utilization of LDLT has been limited in the United States (US). METHODS: In October 2021, the American Society of Transplantation held a consensus conference to identify important barriers to broader expansion of LDLT in the US, including data gaps, and make recommendations for impactful and feasible mitigation strategies to overcome these barriers. Domains addressed encompassed the entirety of the LDLT process. Representation from international centers and living donor kidney transplantation were included for their perspective/experience in addition to members across disciplines within the US liver transplantation community. A modified Delphi approach was employed as the consensus methodology. RESULTS: The predominant theme permeating discussion and polling results centered on culture; the beliefs and behaviors of a group of people perpetuated over time. CONCLUSIONS: Creating a culture of support for LDLT in the US is key for expansion and includes engagement and education of stakeholders across the spectrum of the process of LDLT. A shift from awareness of LDLT to acknowledgement of benefit of LDLT is the primary goal. Propagation of the maxim "LDLT is the best option" is pivotal.

A survey of transplant providers regarding attitudes, barriers, and facilitators to living donor liver transplantation in the United States.

INTRODUCTION: A successful living donor liver transplant (LDLT) is the culmination of a multifaceted process coordinated among key stakeholders. METHODS: We conducted an electronic survey of US liver transplant (LT) centers (August 26, 2021-October 10, 2021) regarding attitudes, barriers, and facilitators of LDLT to learn how to expand LDLT safely and effectively in preparation for the American Society of Transplantation Living Donor Liver Transplant Consensus Conference. RESULTS: Responses were received from staff at 58 programs (40.1% of US LT centers). There is interest in broadening LDLT (100% of LDLT centers, 66.7% of non-LDLT centers) with high level of agreement that LDLT mitigates donor shortage (93.3% of respondents) and that it should be offered to all suitable candidates (87.5% of respondents), though LDLT was less often endorsed as the best first option (29.5% of respondents). Key barriers at non-LDLT centers were institutional factors and surgical expertise, whereas those at LDLT centers focused on waitlist candidate and donor factors. Heterogeneity in candidate selection for LDLT, candidate reluctance to pursue LDLT, high donor exclusion rate, and disparities in access were important barriers. CONCLUSION: Findings from this study may help guide current and future expansion of LDLT more efficiently in the US. These efforts require clear and cohesive messaging regarding LDLT benefits, engagement of the public community, and dedicated resources to equitably increase LDLT access.

Assessment of long-term outcomes post living liver donation highlights the importance of scientific integrity when presenting transplant registry data.

Living donor liver transplantation has expanded in recent years, particularly in North America. As experience with this procedure has matured over the last 25 years, centers are increasingly faced with potential living donors who are more medically complex. As donors move through the evaluation process, completing the informed consent process continues to be challenged by a paucity of granular data demonstrating long-term outcomes and overall safety specifically in the otherwise "healthy" living liver donor population. Two recently published studies examined long-term outcomes post-living liver donation using Korean registry data and reported similar results, with excellent overall survival when compared to appropriately matched controls. However, the authors of these studies were presented differently, with one reporting an alarmist view based on one aspect of a suboptimal analysis approach using an inappropriate comparator group. Herein, the North American Living Liver Donor Innovation Group (NALLDIG) consortium discusses these two studies and their potential impact on living liver donation in North America, ultimately highlighting the importance of scientific integrity in data presentation and dissemination when using transplant registry data.

Genetic and Epigenetic Fine Mapping of Complex Trait Associated Loci in the Human Liver.

Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory elements of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the effects of genetic variation on histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 74 GWAS loci that have been associated with at least one complex phenotype. Our results reveal a repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

Novel Benchmark Values for Redo Liver Transplantation: Does the Outcome Justify the Effort?

OBJECTIVE: To define benchmark cutoffs for redo liver transplantation (redo-LT). BACKGROUND: In the era of organ shortage, redo-LT is frequently discussed in terms of expected poor outcome and wasteful resources. However, there is a lack of benchmark data to reliably evaluate outcomes after redo-LT. METHODS: We collected data on redo-LT between January 2010 and December 2018 from 22 high-volume transplant centers. Benchmark cases were defined as recipients with model of end stage liver disease (MELD) score ≤25, absence of portal vein thrombosis, no mechanical ventilation at the time of surgery, receiving a graft from a donor after brain death. Also, high-urgent priority and early redo-LT including those for primary nonfunction (PNF) or hepatic artery thrombosis were excluded. Benchmark cutoffs were derived from the 75th percentile of the medians of all benchmark centers. RESULTS: Of 1110 redo-LT, 373 (34%) cases qualified as benchmark cases. Among these cases, the rate of postoperative complications until discharge was 76%, and increased up to 87% at 1-year, respectively. One-year overall survival rate was excellent with 90%. Benchmark cutoffs included Comprehensive Complication Index CCI ® at 1-year of ≤72, and in-hospital and 1-year mortality rates of ≤13% and ≤15%, respectively. In contrast, patients who received a redo-LT for PNF showed worse outcomes with some values dramatically outside the redo-LT benchmarks. CONCLUSION: This study shows that redo-LT achieves good outcome when looking at benchmark scenarios. However, this figure changes in high-risk redo-LT, as for example in PNF. This analysis objectifies for the first-time results and efforts for redo-LT and can serve as a basis for discussion about the use of scarce resources.

Incidence of acute rejection and patient survival in combined heart-liver transplantation.

Combined heart-liver transplantation (CHLT) is indicated for patients with concomitant end-stage heart and liver disease or patients with amyloid heart disease where liver transplantation mitigates progression. Limited data suggest that the liver allograft provides immunoprotection for heart and kidney allografts in combined transplantation from the same donor. We hypothesized that CHLT reduces the incidence of acute cellular rejection (ACR) and the development of de novo donor-specific antibodies (DSAs) compared with heart-alone transplantation (HA). We conducted a retrospective analysis of 32 CHLT and 280 HA recipients in a single-center experience. The primary outcome was incidence of ACR based on protocol and for-cause myocardial biopsy. Rejection was graded by the International Society of Heart and Lung Transplantation guidelines with Grade 2R and higher considered significant. Secondary outcomes included the development of new DSAs, cardiac function, and patient and cardiac graft survival rates. Of CHLT patients, 9.7% had ACR compared with 45.3% of HA patients (p < 0.01). Mean pretransplant calculated panel reactive antibody (cPRA) levels were similar between groups (CHLT 9.4% vs. HA 9.5%; p = 0.97). Among patients who underwent testing, 26.9% of the CHLT and 16.7% of HA developed DSA (p = 0.19). Despite the difference in ACR, patient and cardiac graft survival rates were similar at 5 years (CHLT 82.1% vs. HA 80.9% [p = 0.73]; CHLT 82.1% vs. HA 80.9% [p = 0.73]). CHLT reduced the incidence of ACR in the cardiac allograft, suggesting that the liver offers immunoprotection against cellular mechanisms of rejection without significant impacts on patient and cardiac graft survival rates. CHLT did not reduce the incidence of de novo DSA, possibly portending similar long-term survival among cardiac allografts in CHLT and HA.

Functional Characterization of Organoids Derived From Irreversibly Damaged Liver of Patients With NASH.

BACKGROUND AND AIMS: NASH will soon become the leading cause of liver transplantation in the United States and is also associated with increased COVID-19 mortality. Currently, there are no Food and Drug Administration-approved drugs available that slow NASH progression or address NASH liver involvement in COVID-19. Because animal models cannot fully recapitulate human NASH, we hypothesized that stem cells isolated directly from end-stage liver from patients with NASH may address current knowledge gaps in human NASH pathology. APPROACH AND RESULTS: We devised methods that allow the derivation, proliferation, hepatic differentiation, and extensive characterization of bipotent ductal organoids from irreversibly damaged liver from patients with NASH. The transcriptomes of organoids derived from NASH liver, but not healthy liver, show significant up-regulation of proinflammatory and cytochrome p450-related pathways, as well as of known liver fibrosis and tumor markers, with the degree of up-regulation being patient-specific. Functionally, NASH liver organoids exhibit reduced passaging/growth capacity and hallmarks of NASH liver, including decreased albumin production, increased free fatty acid-induced lipid accumulation, increased sensitivity to apoptotic stimuli, and increased cytochrome P450 metabolism. After hepatic differentiation, NASH liver organoids exhibit reduced ability to dedifferentiate back to the biliary state, consistent with the known reduced regenerative ability of NASH livers. Intriguingly, NASH liver organoids also show strongly increased permissiveness to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vesicular stomatitis pseudovirus as well as up-regulation of ubiquitin D, a known inhibitor of the antiviral interferon host response. CONCLUSION: Expansion of primary liver stem cells/organoids derived directly from irreversibly damaged liver from patients with NASH opens up experimental avenues for personalized disease modeling and drug development that has the potential to slow human NASH progression and to counteract NASH-related SARS-CoV-2 effects.

Which recipient pretransplant factors, such as MELD, renal function, sarcopenia, and recent sepsis influence suitability for and outcome after living donor liver transplantation? A systematic review of the literature and expert panel recommendations.

BACKGROUND: Varied access to deceased donors across the globe has resulted in differential living donor liver transplant (LDLT) practices and lack of consensus over the influence of models for end stage liver disease (MELD), renal function, sarcopenia, or recent infection on short-term outcomes. OBJECTIVES: Consider these risk factors in relation to patient selection and provide recommendations. DATA SOURCES: Ovid MEDLINE, Embase, Scopus, Google Scholar, Cochrane Central. METHODS: PRIMSA systematic review and GRADE. PROSPERO ID: RD42021260809 RESULTS: MELD >25-30 alone is not a contraindication to LDLT, and multiple studies found no increase in short term mortality in high MELD patients. Contributing factors such as muscle mass, acute physiologic assessment and chronic health evaluation score, donor age, graft weight/recipient weight ratio, and inclusion of the middle hepatic vein in a right lobe graft influence morbidity and mortality in high MELD patients. Higher mortality is observed with pretransplant renal dysfunction, but short-term mortality is rare. Sarcopenia and recent infection are not contraindications to LDLT. Morbidity and prolonged LOS are common, and more frequent in patients with renal dysfunction, nutritional deficiency or recent infection. CONCLUSIONS: When individual risk factors are studied mortality is low and graft loss is infrequent, but morbidity is common. MELD, especially with concomitant risk factors, had the greatest influence on short term outcome, and recent infection had the least. A multidisciplinary team of experts should carefully assess patients with multiple risk factors, and an optimal graft is recommended.