Excess waitlist mortality among candidates for multivisceral liver-intestine transplant in acuity circle allocation.

Candidates for multivisceral transplant (MVT) have experienced decreased access to transplant in recent years. Using Organ Procurement and Transplantation Network data, transplant and waiting list outcomes for MVT (ie, liver-intestine, liver-intestine-pancreas, and liver-intestine-kidney-pancreas) candidates listed between February 4, 2018, and February 3, 2022, were analyzed, including model for end-stage liver disease/pediatric end-stage liver disease and exception scores by era (before and after acuity circle [AC] implementation on February 4, 2020) and age group (pediatric and adult). Of 284 MVT waitlist registrations (45.6% pediatric), fewer had exception points at listing post-AC compared to pre-AC (10.0% vs 19.1%), and they were less likely to receive transplant (19.1% vs 35.9% at 90 days; 35.7% vs 57.2% at 1 year). Of 177 MVT recipients, exception points at transplant were more common post-AC compared to pre-AC (30.8% vs 20.2%). Postpolicy, adult MVT candidates were more likely to be removed due to death/too sick compared with liver-alone candidates (13.5% vs 5.6% at 90 days; 24.2% vs 9.8% at 1 year), whereas no excess waitlist mortality was observed among pediatric MVT candidates. Under current allocation policy, multivisceral candidates experience inferior waitlist outcomes compared with liver-alone candidates. Clarification of guidance around submission and approval of multivisceral exception requests may help improve their access to transplantation and achieve equity between multivisceral and liver-alone candidates on the liver transplant waiting list.

A cost comparison of liver acquisition fees for donation after circulatory death versus donation after brain death donors.

Donation after circulatory death (DCD) donors now represent over 30% of the deceased donor pool in the United States. Compared to donation after brain death, DCD is less likely to result in transplantation. For each potential donor whose organs cannot be utilized for transplantation (ie, dry run), fees are associated with the attempted donation, which add to the overall costs of organ acquisition. To better characterize the true costs of DCD liver acquisition, we performed a cost comparison of the fees associated with organ acquisition for DCD versus donation after brain death at a single transplant institute that comprises 2 liver transplant centers. Cost, recipient, and transportation data for all cases, including fees associated with liver acquisition from July 1, 2019, to October 31, 2021, were collected. We found that the total cost of DCD liver acquisition per liver transplant was $15,029 more than that for donation after brain death donation, with 18% of the costs of the DCD transplant attributed to dry runs. Overall, the costs associated with DCD transplantation accounted for 34.5% of the total organ acquisition costs; however, DCD transplantation accounted for 30.3% of the transplantation volume. Because the expansion of DCD is essential to increasing the availability of liver grafts for transplantation, strategies need to be implemented to decrease the costs associated with dry runs, including using local recovery, transferring donors to hospitals close to transplant centers, and performing more prerecovery organ analysis. Moreover, these strategies are needed to ensure that financial disincentives to DCD procurement and utilization do not reverse the gains made by expanding the organ donor pool using machine perfusion technologies.

Implementation of a National Liver Review Board for exception requests in the United States: A 2-year monitoring report.

The exception point system for liver allocation in the United States allows for additional waitlist priority for candidates where the Model for End-Stage Liver Disease or Pediatric End-stage Liver Disease does not effectively represent their urgency or need for a transplant. In May 2019, the review process for liver exception cases transitioned from 11 Regional Review Boards (RRBs) to 1 National Liver Review Board (NLRB), intended to increase consistency nationwide, improve efficiency, and balance transplant access for candidates with and without exception scores. This report provides a review of liver exception request and review practices, waitlist outcomes, and transplant activity in the first 2 years after implementation of the NLRB and acuity circle-based distribution in the United States. We compared initial and extension exception request forms submitted from May 13, 2017 to May 13, 2019 (prepolicy or RRB era) to the period from February 4, 2020 to February 3, 2022 (postpolicy or NLRB era). During this time, the NLRB reviewed 10,083 initial exception requests and 12,686 extension requests. Notable postpolicy highlights include (1) an increase in the proportion of initial and extension requests that were automatically approved instead of manually reviewed; (2) a decrease in the overall approval rates of initial exception requests (87.8% for adult HCC, 64.3% for adult other diagnoses, and 71.5% for pediatric); and (3) reduction in the time from exception request submission to adjudication to a median of 3.73 days. The proportions of waitlist registration and deceased donor liver transplants for patients with exception scores decreased, and waitlist outcomes between patients with and without exception scores are now comparable. Implementation of the NLRB improved efficiency, reduced case workloads, and standardized criteria for exception cases, with similar waitlist outcomes between patients with and without exception scores and improved equity in terms of access to liver transplants.

Long-term outcomes (beyond 5 years) of liver transplant recipients-A transatlantic multicenter study.

The long-term (>5 y) outcomes following liver transplantation (LT) have not been extensively reported. The aim was to evaluate outcomes of LT recipients who have survived the first 5 years. A multicenter retrospective analysis of prospectively collected data from 3 high volume LT centers (Dallas-USA, Birmingham-UK, and Barcelona-Spain) was undertaken. All adult patients, who underwent LT since the inception of the program to December 31, 2010, and survived at least 5 years since their LT were included. Patient survival was the primary outcome. A total of 3682 patients who survived at least 5 years following LT (long-term survivors) were included. Overall, median age at LT was 52 years (IQR 44-58); 53.1% were males; and 84.6% were Caucasians. A total of 49.4% (n=1820) died during a follow-up period of 36,828 person-years (mean follow-up 10 y). A total of 80.2% (n=1460) of all deaths were premature deaths. Age-standardized all-cause mortality as compared to general population was 3 times higher for males and 5 times higher for females. On adjusted analysis, besides older recipients and older donors, predictors of long-term mortality were malignancy, cardiovascular disease, and dialysis. Implementation of strategies such as noninvasive cancer screening, minimizing immunosuppression, and intensive primary/secondary cardiovascular prevention could further improve survival.

Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years. METHODS: Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events. RESULTS: Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p <0.0001). More participants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups. CONCLUSIONS: These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH. IMPACT AND IMPLICATIONS: Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.

Early liver transplantation for severe acute alcohol-related hepatitis after more than a decade of experience.

In patients with severe acute alcohol-related hepatitis not responding to medical therapy, early liver transplantation (LT) represents the only effective therapy and, when performed within strict and well-defined protocols, it is associated with a clear survival benefit and acceptable rates of return to alcohol use after transplantation. However, there is still high variability in access to LT for patients with severe alcohol-related hepatitis, mainly due to a persistent overemphasis in the pre-LT evaluation on duration of pre-transplant abstinence and the stigma that patients with alcohol-related liver disease often experience, leading to marked inequity of access to this potentially lifesaving procedure and negative health outcomes. Therefore, there is an increasing need for prospective multicentre studies focusing on pre-transplant selection practices and on better interventions to treat alcohol use disorder after LT.

Living donor liver transplant candidate and donor selection and engagement: Meeting report from the living donor liver transplant consensus conference.

INTRODUCTION: Living donor liver transplantation (LDLT) is a promising option for mitigating the deceased donor organ shortage and reducing waitlist mortality. Despite excellent outcomes and data supporting expanding candidate indications for LDLT, broader uptake throughout the United States has yet to occur. METHODS: In response to this, the American Society of Transplantation hosted a virtual consensus conference (October 18-19, 2021), bringing together relevant experts with the aim of identifying barriers to broader implementation and making recommendations regarding strategies to address these barriers. In this report, we summarize the findings relevant to the selection and engagement of both the LDLT candidate and living donor. Utilizing a modified Delphi approach, barrier and strategy statements were developed, refined, and voted on for overall barrier importance and potential impact and feasibility of the strategy to address said barrier. RESULTS: Barriers identified fell into three general categories: 1) awareness, acceptance, and engagement across patients (potential candidates and donors), providers, and institutions, 2) data gaps and lack of standardization in candidate and donor selection, and 3) data gaps regarding post-living liver donation outcomes and resource needs. CONCLUSIONS: Strategies to address barriers included efforts toward education and engagement across populations, rigorous and collaborative research, and institutional commitment and resources.

A cell-based framework for modeling cardiac mechanics.

Cardiomyocytes are the functional building blocks of the heart-yet most models developed to simulate cardiac mechanics do not represent the individual cells and their surrounding matrix. Instead, they work on a homogenized tissue level, assuming that cellular and subcellular structures and processes scale uniformly. Here we present a mathematical and numerical framework for exploring tissue-level cardiac mechanics on a microscale given an explicit three-dimensional geometrical representation of cells embedded in a matrix. We defined a mathematical model over such a geometry and parametrized our model using publicly available data from tissue stretching and shearing experiments. We then used the model to explore mechanical differences between the extracellular and the intracellular space. Through sensitivity analysis, we found the stiffness in the extracellular matrix to be most important for the intracellular stress values under contraction. Strain and stress values were observed to follow a normal-tangential pattern concentrated along the membrane, with substantial spatial variations both under contraction and stretching. We also examined how it scales to larger size simulations, considering multicellular domains. Our work extends existing continuum models, providing a new geometrical-based framework for exploring complex cell-cell and cell-matrix interactions.

Assessment of donor quality and risk of graft failure after liver transplantation: The ID2 EAL score.

Accurate assessment of donor quality at the time of organ offer for liver transplantation candidates may be inadequately captured by the donor risk index (DRI). We sought to develop and validate a novel objective and simple model to assess donor risk using donor level variables available at the time of organ offer. We utilized national data from candidates undergoing primary LT (2013-2019) and assessed the prediction of graft failure 1 year after LT. The final components were donor Insulin-dependent diabetes mellitus, Donor type (DCD or DBD), cause of Death = CVA, serum creatinine, Age, height, and weight (length). The ID2 EAL score had better discrimination than DRI using bootstrap corrected concordant index over time, especially in the current era. We explored donor-recipient matching. Relative risk of graft failure ranged from 1.15 to 3.5 based on relevant donor-recipient matching by the ID2 EAL score. As an example, for certain recipients, a young DCD donor offer was preferable to an older DBD with relevant comorbidities. The ID2 EAL score may serve as an important tool for patient discussion about donor risk and decisions regarding offer acceptance. In addition, the score may be preferable to succinctly capture donor risk in future organ allocation that considers continuous distribution (www.iddealscore.com).

Belatacept Treatment of Recurrent Late-onset T Cell-mediated Rejection/Antibody-mediated Rejection With De Novo Donor-specific Antibodies in a Liver Transplant Patient.

T cell-mediated rejection that appears and persists late after transplantation is often associated with development of de novo donor-specific antibodies. Treatment of this condition often presents a conundrum because of the uncertainty regarding the trade-off between immunosuppression-related toxicities/complications and restoration of allograft function and structure. Methods: Herein, we report an illustrative case of a young 20-y-old otherwise healthy woman who underwent liver replacement for Alagille's syndrome from an ABO-compatible, 6 antigen-mismatched crossmatch-negative 24-y-old man. Although triple baseline immunosuppression was used (tacrolimus, mycophenolate mofetil, and prednisone), she developed rejection 3 d after liver replacement. Despite verified continual immunosuppression compliance, 1.5 y after liver replacement she experienced 6 more rejection episodes over the following 18 mo and development of de novo donor-specific antibody. Results: Treatment with belatacept began 3.5 y after transplantation, normalizing her liver tests with no further rejections. A biopsy obtained 6 y after transplantation (postoperative day 2221) was normal, appearing without inflammation or residual fibrosis. Conclusions: Belatacept may be a useful treatment approach in this setting.

Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes.

Post-transplant diabetes mellitus (PTDM) reduces allograft and recipient life span. Polygenic risk scores (PRSs) show robust association with greater risk of developing type 2 diabetes (T2D). We examined the association of PTDM with T2D PRS in liver recipients (n = 1,581) and their donors (n = 1,555), and kidney recipients (n = 2,062) and their donors (n = 533). Recipient T2D PRS was associated with pre-transplant T2D and the development of PTDM. T2D PRS in liver donors, but not in kidney donors, was an independent risk factor for PTDM development. The inclusion of a combined liver donor and recipient T2D PRS significantly improved PTDM prediction compared with a model that included only clinical characteristics: the area under the curve (AUC) was 67.6% (95% confidence interval (CI) 64.1-71.1%) for the combined T2D PRS versus 62.3% (95% CI 58.8-65.8%) for the clinical characteristics model (P = 0.0001). Liver recipients in the highest quintile of combined donor and recipient T2D PRS had the greatest risk of PTDM, with an odds ratio of 3.22 (95% CI 2.07-5.00) (P = 1.92 × 10-7) compared with those in the lowest quintile. In conclusion, T2D PRS identifies transplant candidates with high risk of PTDM for which pre-emptive diabetes management and donor selection may be warranted.

Prediction of long-term morbidity and mortality after liver transplantation using two-dimensional shear wave elastography compared with liver biopsy.

The role of noninvasive liver disease assessment by two-dimensional shear wave elastography (2D-SWE) to diagnose fibrosis is well described in patients with chronic liver disease. However, its role in prognosis, especially after liver transplantation (LT) has not been adequately examined. We hypothesized that elevated liver stiffness measurement (LSM) as measured by 2D-SWE after LT predicts future morbidity and mortality independent of fibrosis by liver biopsy. In a prospective cohort study, consecutive LT recipients underwent concomitant protocol 2D-SWE and protocol liver biopsy (2012-2014), with the assessor blinded to biopsy findings. We examined the baseline correlation of LSM with fibrosis stage and the association between elevated LSM and the development of subsequent clinical outcomes and all-cause mortality. A total of 187 LT recipients (median age 58 years, 38.5% women, median body mass index 26.5 kg/m2 , 55.1% hepatitis C virus, 17.6% nonalcoholic steatohepatitis/cryptogenic) were examined. Median time between LT and biopsy/2D-SWE assessment was 4.0 years, and the median follow-up time after LSM determination was 3.5 years. Median LSM was 9 kPa (8 kPa [F0/F1], 11.5 kPa [F2], 12 kPa [F3/F4]). There was a positive correlation between LSM and fibrosis stage (rs  = 0.41; p < 0.001). LSM ≥11 kPa was associated with lower survival within 3 years (84.8 vs. 93.7%; p = 0.04). After adjusting for age, sex, and fibrosis stage, LSM ≥11 kPa was independently associated with mortality (hazard ratio, 2.45; 95% confidence interval, 1.08-5.60). Elevated LSM by 2D-SWE is associated with increased mortality after LT independent of hepatic fibrosis. Given the overall decrease in the use of liver biopsy in the current era, 2D-SWE may serve as a novel noninvasive prognostic tool to predict relevant outcomes late after LT.