The Potential Utilization of Machine Perfusion to Increase Transplantation of Macrosteatotic Livers.

BACKGROUND: The demand for liver transplantation has led to the utilization of marginal grafts including moderately macrosteatotic livers (macrosteatosis ≥30% [Mas30]), which are associated with an elevated risk of graft failure. Machine perfusion (MP) has emerged as a technique for organ preservation and viability testing; however, little is known about MP in Mas30 livers. This study evaluates the utilization and outcomes of Mas30 livers in the era of MP. METHODS: The Organ Procurement and Transplantation Network database was queried to identify biopsy-proven Mas30 deceased donor liver grafts between June 1, 2016, and June 23, 2023. Univariable and multivariable models were constructed to study the association between MP and graft utilization and survival. RESULTS: The final cohort with 3317 Mas30 livers was identified, of which 72 underwent MP and were compared with 3245 non-MP livers. Among Mas30 livers, 62 (MP) and 1832 (non-MP) were transplanted (utilization of 86.1% versus 56.4%, P < 0.001). Donor and recipient characteristics were comparable between MP and non-MP groups. In adjusted analyses, MP was associated with significantly increased Mas30 graft utilization (odds ratio, 7.89; 95% confidence interval [CI], 3.76-16.58; P < 0.001). In log-rank tests, MP was not associated with 1- and 3-y graft failure (hazard ratio, 0.49; 95% CI, 0.12-1.99; P = 0.319 and hazard ratio 0.43; 95% CI, 0.11-1.73; P = 0.235, respectively). CONCLUSIONS: The utilization rate of Mas30 grafts increases with MP without detriment to graft survival. This early experience may have implications for increasing the available donor pool of Mas30 livers.

Beyond the Granuloma: New Insights into Cardiac Sarcoidosis Using Spatial Proteomics.

Cardiac sarcoidosis is poorly understood, challenging to diagnose, and portends a poor prognosis. A lack of animal models necessitates the use of residual human samples to study sarcoidosis, which in turn necessitates the use of analytical tools compatible with archival, fixed tissue. We employed high-plex spatial protein analysis within a large cohort of archival human cardiac sarcoidosis and control tissue samples, studying the immunologic, fibrotic, and metabolic landscape of sarcoidosis at different stages of disease, in different cardiac tissue compartments, and in tissue regions with and without overt inflammation. Utilizing a small set of differentially expressed protein biomarkers, we also report the development of a predictive model capable of accurately discriminating between control cardiac tissue and sarcoidosis tissue, even when no histologic evidence of sarcoidosis is present. This finding has major translational implications, with the potential to markedly improve the diagnostic yield of clinical biopsies obtained from suspected sarcoidosis patients.

A heart transplant center experience with basiliximab induction strategies: A double edged sword?

BACKGROUND: The use of induction immunosuppression for heart transplantation (HT) is debated given the uncertain benefit and potential risks of infection and malignancy. METHODS: This is a retrospective single-center analysis of 475 consecutive HT recipients from 2003 to 2020 grouped by use of induction with basiliximab group (BG) and the no basiliximab group (NBG). Subgroup analysis by era compared pre-2016 standard-basiliximab (BX) induction and 2016-2020 with selective-BX use as part of a calcineurin-inhibitor-sparing regimen. RESULTS: When adjusted for confounders (sex, age, PRA, eGFR), the BG was less likely to have acute cellular rejection (ACR) (OR.42, p < .001), but had more antibody mediated rejection (AMR) (OR 11.7, p < .001) and more cardiac allograft vasculopathy (CAV) (OR 3.8, p = .04). There was no difference between BG and NBG in the incidence of malignancies or infections. When stratified by era (pre-2016 vs. 2016-2020), ACR remained less common in the BG than the NBG (36% vs. 50%, p = .045) groups, while AMR remained more common (9.7 vs. 0% p = .005). There was no significant difference in conditional survival comparing pre-and post-2016 NBG (HR 2.20 (95% CI.75-6.43); however, both pre-2016 BG and post-2016 BG have significantly higher mortality (HR 2.37 [95% CI 1.02-5.50) and HR 2.69 (95% CI 1.08-6.71), p = .045 and.03, respectively]. CONCLUSION: Basiliximab reduces the incidence of ACR but increases the risk of AMR, CAV, and may be associated with increased mortality. Mechanistic studies are needed to describe a potential T-cell-escape mechanism with enhanced humoral immunity.

Living Donor Liver Transplantation for Adults With High Model for End-stage Liver Disease Score: The US Experience.

BACKGROUND: Outcomes after living-donor liver transplantation (LDLT) at high Model for End-stage Liver Disease (MELD) scores are not well characterized in the United States. METHODS: This was a retrospective cohort study using Organ Procurement and Transplantation Network data in adults listed for their first liver transplant alone between 2002 and 2021. Cox proportional hazards models evaluated the association of MELD score (<20, 20-24, 25-29, and ≥30) and patient/graft survival after LDLT and the association of donor type (living versus deceased) on outcomes stratified by MELD. RESULTS: There were 4495 LDLTs included with 5.9% at MELD 25-29 and 1.9% at MELD ≥30. LDLTs at MELD 25-29 and ≥30 LDLT have substantially increased since 2010 and 2015, respectively. Patient survival at MELD ≥30 was not different versus MELD <20: adjusted hazard ratio 1.67 (95% confidence interval, 0.96-2.88). However, graft survival was worse: adjusted hazard ratio (aHR) 1.69 (95% confidence interval, 1.07-2.68). Compared with deceased-donor liver transplant, LDLT led to superior patient survival at MELD <20 (aHR 0.92; P = 0.024) and 20-24 (aHR 0.70; P < 0.001), equivalent patient survival at MELD 25-29 (aHR 0.97; P = 0.843), but worse graft survival at MELD ≥30 (aHR 1.68, P = 0.009). CONCLUSIONS: Although patient survival remains acceptable, the benefits of LDLT may be lost at MELD ≥30.

The Association Between Homelessness and Key Liver-Related Outcomes in Veterans With Cirrhosis.

INTRODUCTION: Homelessness adversely affects patient outcomes in broad cohort studies; however, its impact on key liver-related outcomes in patients with cirrhosis is understudied. We aimed to address this knowledge gap using data from the Veterans Health Administration, a cohort disproportionately affected by homelessness. METHODS: This was a retrospective cohort study of the Veterans Health Administration patients with incident cirrhosis diagnosis between January 2008 and February 2022. Homeless status was classified at baseline and as time-updating variable during follow-up. Inverse probability treatment weighted Cox regression was performed to evaluate the association between homelessness and outcomes of all-cause mortality, cirrhosis decompensation, and hepatocellular carcinoma. RESULTS: A total of 117,698 patients were included in the cohort, of whom 14,243 (12.1%) were homeless at baseline. In inverse probability treatment weighted Cox regression, homelessness was associated with a 24% higher hazard of all-cause mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.22-1.26, P < 0.001). However, in competing risk regression models, homelessness was associated with a reduced subhazard of decompensation (subhazard ratio 0.86, 95% CI 0.84-0.88, P < 0.001) and hepatocellular carcinoma (subhazard ratio 0.86, 95% CI 0.83-0.89, P < 0.001). In cause-specific mortality analysis, homeless patients had significantly increased non-liver-related and liver-related mortality; however, the magnitude of effect size was greater for non-liver-related mortality (csHR 1.38, 95% CI 1.35-1.40, P < 0.001). DISCUSSION: Homelessness in veterans with cirrhosis is associated with increased all-cause mortality; however, this is likely mediated primarily through non-liver-related factors. Future studies are needed to explore drivers of mortality and improve mitigation strategies in these patients.

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.

Can ex-situ normothermic perfusion improve graft survival compared to static cold storage among donation after circulatory death liver allografts?

Limited data suggest that ex-situ normothermic liver perfusion (ENLP) may improve the outcomes of donation after circulatory death (DCD) liver transplants compared to static cold storage (SCS). All adult DCD liver transplants performed between 2016 and 2021 were identified in the United Network of Organ Sharing database. ENLP liver transplants were compared to SCS using inverse probability of treatment weighting to balance clinical and demographic confounders. The primary analysis simulated intention-to-treat with inverse probability of treatment weighting-adjusted Cox models. Compared to SCS DCDs (N = 3,079), recipients of ENLP DCDs (N = 65) had lower Model of End Stage Liver Disease scores at transplant (16.5 v. 18.8, p = 0.033), longer wait times (468 ± 720 vs. 246 ± 467 d; p < 0.001), and received livers from donors with a greater BMI (29.2 vs. 27.5; p = 0.008). ENLP preservation was associated with a lower risk of graft failure (HR 0.31 vs. SCS, 95% CI:0.12-0.86, p = 0.023) and a lower incidence of retransplantation. A sub-analysis restricted to the 20 centers performing ENLP, encompassing 946 SCS DCDs, demonstrated similar results: (HR 0.33 vs. SCS, 95% CI: 0.13-0.94, p = 0.021). Among 111 patients who required retransplantation and where the etiology of graft failure was identified, graft failure due to ischemic cholangiopathy was noted in 1 ENLP and 46 SCS. In this retrospective analysis of the early US DCD ENLP experience, there may exist a graft survival benefit to transplants performed with ENLP compared to SCS.

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.

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.

The effectiveness and safety of antibody induction immunosuppression in a large cohort of United States pediatric liver transplant recipients.

Data on the potential benefits and risks of induction therapy in pediatric liver transplantation (LT) are limited. This was a retrospective cohort study of 2748 pediatric LT recipients at 26 children's hospitals between January 1, 2006 to May 31, 2017 using data from the pediatric health information system linked to the United Network for Organ Sharing database. The induction regimen was obtained from the pediatric health information system day-by-day pharmacy resource utilization. Cox proportional hazards evaluated the association of induction regimen (none/corticosteroid-only, nondepleting, and depleting) on patient and graft survival. Additional outcomes, including opportunistic infections and posttransplant lymphoproliferative disorder, were studied using multivariable logistic regression. Overall, 64.9% received none/corticosteroid-only induction, whereas 28.1% received nondepleting, 8.3% received depleting, and 2.5% other antibody regimens. Differences in patient characteristics were small, but center practices were heterogeneous. Compared with none/corticosteroid-only induction, nondepleting induction was associated with reduced acute rejection (odd ratio [OR], 0.53; P <.001) but with the increased posttransplant lymphoproliferative disorder (OR, 1.75; P =.021). Depleting induction was associated with improved graft survival (hazard ratio [HR], 0.64; P =.028) but with increased noncytomegalovirus opportunistic infections (OR, 1.46; P =.046). Depleting induction is underused yet may offer long-term benefits in this large multicenter cohort. Greater consensus guidance in this aspect of pediatric LT care is warranted.

Center expansion of liver transplants using donation after circulatory death organs is associated with reduced overall waitlist mortality.

INTRODUCTION: Waitlist outcomes in liver transplantation (LT) for individual recipients are improved by use of allografts procured through donation after circulatory death (DCD). However, the impact of increased DCD acceptance on overall center outcomes is unknown. METHODS: Using the United Network for Organ Sharing database, 88 centers performing an average of ≥10 LTs/year between 1/2004 and 12/2019 were compared by percent DCD use quartile and categorized into four phenotypes according to temporal usage trends. Overall center median Model for End-stage Liver Disease at LT (MMaT), waitlist mortality, and waiting time were evaluated. RESULTS: The overall DCD rate was 6.1% (N = 4906/80,709), ranging from 0% to 25.5%. Centers in the top DCD use quartile had lower MMaT (24 vs. 26; p < .001) and shorter overall waiting times (median 66 days vs. 90 days; p < .001) compared to bottom quartile centers. MMaT increased less over time at centers with increasing DCD use and was lower than at centers with declining DCD use (27 vs. 32; p = .017). Overall waitlist mortality between 2016 and 2019 was lower at increasing DCD use centers (17.8% vs. 22.5%, p = .034), yet did not affect 1-year mortality (p = .747). CONCLUSIONS: The improved waitlist outcomes at centers with expanded DCD use extend beyond DCD recipients alone without negative consequences to overall post-LT center metrics.

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.

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.