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Immunosuppression is a critical aspect of post-transplant management, yet practices at intermediate and late time points after liver transplantation (LT) are poorly characterized.A retrospective cohort of 11 326 adult first LT alone recipients between 2007 and 2016 was identified by linking United Network for Organ Sharing transplant data to Medicare administrative claims. The immunosuppression regimen was obtained from Medicare billing claims. Factors associated with calcineurin inhibitor (CNI) monotherapy at 1-, 3-, and 5-y post-LT were investigated using mixed-effects logistic regression. Center practice heterogeneity was evaluated. The association of immunosuppression regimen (time-updating) with patient and graft survival was studied.CNI monotherapy was used in 51.9% at 1-y post-LT and 68.6% at 5-y post-LT. Center-specific rates ranged from 20.0%-79.9% to 15.4%-95.2%, respectively. CNI monotherapy at 1- and 3-y post-LT was less likely among Black recipients ( P = 0.027 and P = 0.015 versus White, respectively). CNI plus antimetabolite was associated with improved adjusted patient (hazard ratio, 0.59; P0.001) and graft (hazard ratio, 0.62; P0.001) survival versus CNI monotherapy. The benefit of CNI plus antimetabolite on patient and graft survival increased with older age.In this first longitudinal analysis of LT immunosuppression practices among Medicare beneficiaries, a CNI plus antimetabolite approach led to improved outcomes. Significant center heterogeneity in practice was observed.

Since its inception in 2002, Model for End-Stage Liver Disease (MELD)-based allocation has undergone a series of revisions, especially with respect to exception points. Hepatocellular carcinoma (HCC) is the most common indication for MELD exceptions, and as a result of higher transplant proportions and lower waitlist mortality, a series of policy changes have been implemented to deprioritize HCC transplants. We examined the impact of HCC exception policy changes on transplant and waitlist mortality rates. We evaluated Organ Procurement and Transplantation Network/United Network for Organ Sharing data on adult patients from January 1, 2005, to June 4, 2021, focusing on waitlist mortality and deceased donor liver transplantation (DDLT) proportions. The data were divided into four policy eras: (1) MELD 22 points at waitlisting with an increase in points every 3 months (i.e., elevator) (January 2005-October 2015), (2) delay and cap at MELD 34 points (October 2015-May 2019), (3) delay and fixed exceptions based on donor service area (DSA) median MELD at transplantation minus three (MMaT-3; May 2019-February 2020), and (4) delay and fixed exceptions based on the MMaT-3 of centers within 250 nautical miles (i.e., acuity circles; February 2020-June 2021). We evaluated (a) changes in the proportions of DDLTs for patients with HCC exceptions within each era nationally and by DSA and (b) waitlist mortality in the three recent policy eras, focusing on mortality in the 6 months after the 6-month delay period. The percentage of adult DDLT with HCC exceptions decreased through the four eras: 22.9% (n = 14,049), 17.9% (n = 4598), 14.3% (n = 851), and 12.4% (n = 1425), respectively. Of the 51 DSAs analyzed, the annual percent change in DDLTs for patients with HCC exceptions was negative (i.e., decreased) in 47 (92.2%). Waitlist mortality remained stable. All HCC policy implementations led to a decrease in the percentage of transplants for HCC without an increase in waitlist mortality. The impact is not uniform across geographic areas.

Much of our understanding regarding geographic issues in transplantation is based on statistical techniques that do not formally account for geography and is based on obsolete boundaries such as donation service area.We applied spatial epidemiological techniques to analyze liver-related mortality and access to liver transplant services at the county level using data from the Centers for Disease Control and Prevention and Scientific Registry of Transplant Recipients from 2010 to 2018.There was a significant negative spatial correlation between transplant rates and liver-related mortality at the county level (Moran's I, -0.319; P = 0.001). Significant clusters were identified with high transplant rates and low liver-related mortality. Counties in geographic clusters with high ratios of liver transplants to liver-related deaths had more liver transplant centers within 150 nautical miles (6.7 versus 3.6 centers; P 0.001) compared with all other counties, as did counties in geographic clusters with high ratios of waitlist additions to liver-related deaths (8.5 versus 2.5 centers; P 0.001). The spatial correlation between waitlist mortality and overall liver-related mortality was positive (Moran's I, 0.060; P = 0.001) but weaker. Several areas with high waitlist mortality had some of the lowest overall liver-related mortality in the country.These data suggest that high waitlist mortality and allocation model for end-stage liver disease do not necessarily correlate with decreased access to transplant, whereas local transplant center density is associated with better access to waitlisting and transplant.

Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a retrospective cohort at four centers. We matched recipients of HCV-viremic kidneys to highly similar recipients of HCV-aviremic kidneys on established risk factors for BKPyV. To limit bias, matches were within the same center. The primary outcome was BKPyV viremia ≥1000 copies/ml or biopsy-proven BKPyV nephropathy; a secondary outcome was BKPyV viremia ≥10 000 copies/ml or nephropathy. Outcomes were analyzed using weighted and stratified Cox regression. The median days to peak BKPyV viremia level was 119 (IQR 87-182). HCV-viremic KT was not associated with increased risk of the primary BKPyV outcome (HR 1.26, p = .22), but was significantly associated with the secondary outcome of BKPyV ≥10 000 copies/ml (HR 1.69, p = .03). One-year eGFR was similar between the matched groups. Only one HCV-viremic kidney recipient had primary graft loss. In summary, HCV-viremic KT was not significantly associated with the primary outcome of BKPyV viremia, but the data suggested that donor HCV might elevate the risk of more severe BKPyV viremia ≥10 000 copies/ml. Nonetheless, one-year graft function for HCV-viremic recipients was reassuring.

The safety and efficacy of direct-acting antiviral therapies have allowed the transplantation of organs from hepatitis C virus (HCV)-viremic donors into uninfected recipients. This novel strategy contrasts with the previous standard-of-care practice of limiting the transplantation of HCV infected-donor organs to HCV-infected recipients, or all too often, discarding viable organs. In this review, we summarize the published literature about the safety and feasibility of transplanting organs from HCV-viremic donors, the challenges that hinder wider adoption of this strategy, and future research needs.

Estimated glomerular filtration rate (eGFR) is adjusted for Black race in commonly used formulas. This has potential implications for access to simultaneous liver-kidney transplantation (SLKT) as qualifying criteria rely on eGFR. We performed a retrospective study of United Network for Organ Sharing national transplant registry data between February 28, 2002, and March 31, 2019, to evaluate the proportion of Black patients who would be reclassified as meeting SLKT criteria (as defined per current policies) if race adjustment were removed from 2 prominent eGFR equations (Modification of Diet in Renal Disease-4 [MDRD-4] and Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). Of the 7937 Black patients listed for transplant during the study period, we found that 3.6% would have been reclassified as qualifying for chronic kidney disease (CKD)-related SLKT with removal of race adjustment for MDRD-4, and 3.0% would have been reclassified with CKD-EPI; this represented 23.7% and 18.7% increases in SLKT candidacy, respectively. Reclassification impacted women more than men (eg, 4.5% versus 3.0% by MDRD-4; P

With advances in computing and information technology, large health care research databases are becoming increasingly accessible to investigators across the world. These rich, population-level data sources can serve many purposes, such as to generate "real-world evidence," to enhance disease phenotyping, or to identify unmet clinical needs, among others. This is of particular relevance to the study of patients with end-stage liver disease (ESLD), a socioeconomically and clinically heterogeneous population that is frequently under-represented in clinical trials. This review describes the recommended "best practices" in the execution, reporting, and interpretation of large database clinical epidemiology research in hepatology. The advantages and limitations of selected data sources are reviewed, as well as important concepts on data linkages. The appropriate classification of exposures and outcomes is addressed, and the strategies needed to overcome limitations of the data and minimize bias are explained as they pertain to patients with ESLD and/or liver transplantation (LT) recipients. Lastly, selected statistical concepts are reviewed, from model building to analytic decision making and hypothesis testing. The purpose of this review is to provide the practical insights and knowledge needed to ensure successful and impactful research using large clinical databases in the modern era and advance the study of ESLD and LT.

BACKGROUND Transplantation of kidneys from hepatitis C virus (HCV)-viremic donors into HCV-negative patients followed by direct-acting antiviral therapy was an important breakthrough to increase the number of life-saving kidney transplants. Data suggest that these transplants offer several benefits; however, it is unknown whether adoption of this practice has been shared equitably, especially among disadvantaged groups. METHODS We evaluated United Network for Organ Sharing data on HCV-seronegative adult deceased-donor kidney transplant recipients from January 1, 2017, to June 12, 2020. We compared recipients of a kidney from an HCV antibody- (Ab-)/nucleic acid test- (NAT-), HCV Ab+/NAT-, and HCV NAT+ donor. The primary covariates were as follows: (1) race/ethnicity; (2) female sex; and (3) highest level of education. Models included variables associated with being offered an HCV NAT+ kidney. We fit mixed-effects multinomial logistic regression models with the center as a random effect to account for patient clustering. RESULTS Of 48 255 adult kidney-alone deceased-donor kidney transplant HCV-seronegative recipients, 1641 (3.4%) donors were HCV NAT+-, increasing from 0.3% (January 2017-June 2017) to 6.9% (January 2020-June 2020). In multivariable models, racial/ethnic minorities, women, and those with less education were significantly less likely to receive a kidney from an HCV NAT+ donor relative to an HCV Ab-/NAT- and HCV Ab+/NAT- donor. The disparities were most pronounced among Hispanic and Asian patients with less educational attainment (grade school, high school, or some college/tech school). CONCLUSIONS Despite an increase in transplants from HCV NAT+ donors, we found substantial racial/ethnic disparities in transplantation of these kidneys. These data highlight how the benefits of a scientific breakthrough are often made less available to disadvantaged patients.

Cirrhosis poses an increased risk of postoperative mortality, yet it remains challenging to accurately risk stratify patients in clinical practice. The VOCAL-Penn cirrhosis surgical risk score was recently developed and internally validated in the national Veterans Affairs health system; however, to date this score has not been evaluated in independent cohorts. The goal of this study was to compare the predictive performance of the VOCAL-Penn to the Mayo risk, Model for End-Stage Liver Disease (MELD), and MELD-sodium (MELD-Na) scores in 2 large health systems. We performed a retrospective cohort study of patients with cirrhosis undergoing surgical procedures of interest at the Beth Israel Deaconess Medical Center or University of Pennsylvania Health System from January 1, 2008, to October 1, 2015. The outcomes of interest were 30-day and 90-day postoperative mortality. Concordance statistics (C-statistics), calibration curves, Brier scores, and the index of prediction accuracy (IPA) were compared for each predictive model. A total of 855 surgical procedures were identified. The VOCAL-Penn score had the numerically highest C-statistic for 90-day postoperative mortality (eg, 0.82 versus 0.79 Mayo versus 0.78 MELD-Na versus 0.79 MELD), although differences were not statistically significant. Calibrations were excellent for the VOCAL-Penn, MELD, and MELD-Na; however, the Mayo score consistently overestimated risk. The VOCAL-Penn had the lowest Brier score and highest IPA at both time points, suggesting superior overall predictive model performance. In subgroup analyses of patients with higher MELD scores, the VOCAL-Penn had significantly higher C-statistics compared with the MELD and MELD-Na. The VOCAL-Penn score (www.vocalpennscore.com) has excellent discrimination and calibration for postoperative mortality among diverse patients with cirrhosis. Overall performance is superior to the Mayo, MELD, and MELD-Na scores. In contrast to the MELD/MELD-Na, the VOCAL-Penn retains excellent discrimination among patients with higher MELD scores.

Patients are prioritized for liver transplantation (LT) under an "urgency-based" system using the Model for End-Stage Liver Disease score. This system focuses solely on waitlist mortality, without considerations of posttransplant morbidity, mortality, and health care use. We sought to develop and internally validate a continuous posttransplant risk score during 5-year and 10-year time horizons. This retrospective cohort study used national registry data of adult deceased donor LT (DDLT) recipients with ≥90 days of pretransplant waiting time from February 27, 2002 to December 31, 2018. We fit Cox regression models at 5 and 10 years to estimate beta coefficients for a risk score using manual variable selection and calculated the absolute predicted survival time. Among 21,103 adult DDLT recipients, 11 variables were selected for the final model. The area under the curves at 5 and 10 years were 0.63 (95% confidence interval [CI], 0.60-0.66) and 0.67 (95% CI, 0.64-0.70), respectively. The group with the highest ("best") scores had 5-year and 10-year survivals of 89.4% and 85.4%, respectively, compared with 45.9% and 22.2% for those with the lowest ("worst") scores. Our score was significantly better at predicting long-term survival compared with the existing scores. We developed and validated a risk score using nearly 17 years of data to prioritize patients with end-stage liver disease based on projected posttransplant survival. This score can serve as the building block by which the transplant field can change the entire approach to prioritizing patients to an approach that is based on considerations of maximizing benefits (ie, survival benefit-based allocation) rather than simply waitlist mortality.

BACKGROUND AND AIMS The impact of sex on the postcirrhosis progression of primary biliary cholangitis (PBC) has not been well defined. Prior studies have suggested that men have worse outcomes but present at more advanced stages of fibrosis than women. This observation, however, has been limited by small numbers of men and even fewer patients with cirrhosis. APPROACH AND RESULTS We investigated the association of sex with the development of all-cause and liver-related mortality or transplantation, decompensation, and hepatocellular carcinoma (HCC), using competing-risk time-updating Cox proportional hazards models in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. In a cohort of 532 participants (418 male) with PBC-related cirrhosis with a total follow-up of 3,231.6 person-years (PY) from diagnosis of compensated cirrhosis, male participants had a higher unadjusted rates of death or transplantation (8.5 vs. 3.8 per 100 PY; P

BACKGROUND AND AIMS: Patients with cirrhosis and males have been under-represented in most studies examining the clinical benefit of response to Ursodeoxycholic Acid (UDCA) in primary biliary cholangitis (PBC). The aim of this study was to study the association of UDCA response and liver-related death or transplantation, hepatic decompensation and hepatocellular carcinoma (HCC) in patients with PBC cirrhosis. METHODS: We conducted a retrospective cohort study of Veterans, predominantly males, with PBC and compensated cirrhosis, to assess the association of UDCA response, with the development of all-cause and liver-related mortality or transplantation, hepatic decompensation and hepatocellular carcinoma (HCC), using competing risk time-updating Cox proportional hazards models. RESULTS: We identified 501 subjects with PBC and compensated cirrhosis, including 287 UDCA responders (1692.8 patient-years (PY) of follow up) and 214 partial responders (838.9 PY of follow up). The unadjusted rates of hepatic decompensation (3.8 vs. 7.9 per 100 PY, p

With a rising burden of cirrhosis surgeries, understanding risk factors for postoperative mortality is more salient than ever. The role of baseline frailty has not been assessed in this context. We evaluated the association between patient frailty and postoperative risk among diverse patients with cirrhosis and determined if frailty improves prognostication of cirrhosis surgical risk scores. This was a retrospective cohort study of U.S. veterans with cirrhosis identified between 2008 and 2016 who underwent nontransplant major surgery. Frailty was ascertained using the Hospital Frailty Risk Score (HFRS). Cox regression analysis was used to investigate the impact of patient frailty on postoperative mortality. Logistic regression was used to identify incremental changes in discrimination for postoperative mortality when frailty was added to the risk prediction models, including the Model for End-Stage Liver Disease (MELD), MELD-sodium (MELD-Na), Child-Turcotte-Pugh (CTP), Mayo Risk Score (MRS), and Veterans Outcomes and Costs Associated With Liver Disease (VOCAL)-Penn. A total of 804 cirrhosis surgeries were identified. The majority of patients (48.5%) had high-risk frailty at baseline (HFRS >15). In adjusted Cox regression models, categories of increasing frailty scores were associated with poorer postoperative survival. For example, intermediate-risk frailty (HFRS 5-15) conferred a 1.77-fold increased hazard relative to low-risk frailty (HFRS

The SARS-CoV2 pandemic has resulted in the deaths of more than 600,000 Americans to date, and millions more worldwide. The rapid development of multiple vaccines with exceedingly high (>90%) efficacy at preventing death from SARS-CoV2 is one of the recent miracles of medicine. Early vaccination efforts targeted those with the highest risk of contracting and/or dying from SARS-CoV2, including the elderly and those with chronic medical conditions (e.g., cancer, immunosuppression).

There is significant interest in identifying risk factors associated with acute-on-chronic liver failure (ACLF). In transplant candidates, frailty predicts wait-list mortality and posttransplant outcomes. However, the impact of frailty on ACLF development and mortality is unknown. This was a retrospective study of US veterans with cirrhosis identified between 2008 and 2016. First hospitalizations were characterized as ACLF or non-ACLF admissions. Prehospitalization patient frailty was ascertained using a validated score based on administrative coding data. We used logistic regression to investigate the impact of an increasing frailty score on the odds of ACLF hospitalization and short-term ACLF mortality. Cox regression was used to analyze the association between frailty and longterm survival from hospitalization. We identified 16,561 cirrhosis hospitalizations over a median follow-up of 4.19 years (interquartile range, 2.47-6.34 years). In adjusted models, increasing frailty score was associated with significantly increased odds of ACLF hospitalization versus non-ACLF hospitalization (odds ratio, 1.03 per point; 95% CI 1.02-1.03; P < 0.001). By contrast, frailty score was not associated with ACLF 28- or 90-day mortality (P = 0.13 and P = 0.33, respectively). In an adjusted Cox analysis of all hospitalizations, increasing frailty scores were associated with poorer longterm survival from the time of hospitalization (hazard ratio, 1.02 per 5 points; 95% confidence interval, 1.01-1.03; P = 0.004). Frailty increases the likelihood of ACLF hospitalization among patients with cirrhosis, but it does not impact short-term ACLF mortality. These findings have implications for clinicians caring for frail outpatients with cirrhosis, including tailored follow-up, risk mitigation strategies, and possible expedited transplant evaluation.

In December of 2019, the Centers for Medicare and Medicaid Services (CMS) put out a notice of proposed rule-making for 42 CFR Part 486, specifically the section that covers the organ procurement organization (OPO) Conditions for Coverage. Most crucially, the proposed rule included two new OPO performance metrics using objective, standardized data from the Centers for Disease Control and Prevention (CDC). These new metrics would employ a denominator that included inpatient deaths from certain causes that could lead to organ donation, rather than the current unverifiable eligible death metric. Although there has been near-uniform support for replacing the eligible death denominator with CDC data, a source of contention is CMS's proposal not to adjust risk for race in their OPO outcome. Nonetheless, there have been calls for race and ethnicity to be included as risk-adjusted variables in the CMS donation metric. Herein, we lay out an argument as to why inclusion of race and ethnicity as risk adjustment variables in an OPO performance metric is not only statistically suspect but also will hide the inequities that are detrimental to optimal system performance and assurance that all patients have timely access to donation.

Recipients of donation after circulatory death (DCD) LTs historically have an increased risk of graft failure. Antibody induction (AI) with antithymocyte globulin (ATG) or anti-interleukin 2 receptor (anti-IL2R) immunotherapy may decrease the incidence of graft failure by mitigating ischemia/reperfusion injury. A retrospective review of the United Network for Organ Sharing (UNOS) database for LTs between 2002 and 2015 was conducted to determine whether ATG or anti-IL2R AI was associated with graft survival in DCD. A secondary endpoint was postoperative renal function as measured by estimated glomerular filtration rate at 6 and 12 months. Among DCD recipients, ATG (hazard ratio [HR] = 0.71; P = 0.03), but not anti-IL2R (HR = 0.82; P = 0.10), was associated with a decrease in graft failure at 3 years when compared with recipients without AI. ATG (HR = 0.90; P = 0.02) and anti-IL2R (HR = 0.94; P = 0.03) were associated with a decreased risk of graft failure in donation after brain death (DBD) liver recipients at 3 years compared with no AI. When induction regimens were compared between DCD and DBD, only ATG (HR = 1.19; P = 0.19), and not anti-IL2R (HR = 1.49; P

Liver transplantation (LT) is curative for most patients with hepatocellular carcinoma (HCC). However, 10%-15% of patients experience HCC recurrence. Patients who are reported as within Milan criteria by imaging are frequently found to be outside the criteria on explant. This under-staging of HCC worsens post-LT outcomes. However, risk factors for under-staging have not been elucidated. Furthermore, it is not known if there is regional or center-level variation in under-staging. We conducted a retrospective analysis of adult patients transplanted for HCC in the United Network for Organ Sharing (UNOS) database between 2012 and 2016. Under-staging was determined on the basis of comparing pre-LT imaging to explant findings. Kaplan-Meier methods and Cox regression were used to evaluate the impact of under-staging on HCC recurrence and post-LT survival. Mixed effects logistic regression was used to identify risk factors for under-staging and to study regional and center-level variation in adjusted analyses. A total of 5424 patients were included in the cohort, of whom 24.9% (n = 1353) were under-staged. Post-LT HCC recurrence and death were significantly associated with under-staging (each P < 0.001). In adjusted analyses, independent predictors of under-staging included age (odds ratio [OR], 1.13 per 10 years; 95% confidence interval [CI], 1.03-1.25), male sex (OR, 1.61; 95% CI, 1.36-1.89), down-staging (OR, 4.03; 95% CI, 2.65-6.11), and pre-LT alpha-fetoprotein (P < 0.001). There was also significant variation in under-staging between UNOS regions and among transplant centers, ranging from 14.8% to 38.1%. We report novel risk factors for HCC under-staging, which worsens post-LT outcomes. Significant center-level and regional variation in under-staging highlights the need for standards that achieve greater uniformity in staging.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become an unprecedented pandemic that has impacted society, disrupted hospital functions, strained health care resources, and impacted the lives of transplant professionals. Despite this, organ failure and the need for transplant continues throughout the United States. Considering the perpetual scarcity of deceased donor organs, Kates et al present a viewpoint that advocates for the utilization of coronavirus disease 2019 (COVID-19)-positive donors in selected cases. We present a review of the current literature that details the potential negative consequences of COVID-19-positive donors. The factors we consider include (1) the risk of blood transmission of SARS-CoV-2, (2) involvement of donor organs, (3) lack of effective therapies, (4) exposure of health care and recovery teams, (5) disease transmission and propagation, and (6) hospital resource utilization. While we acknowledge that transplant fulfills the mission of saving lives, it is imperative to consider the consequences not only to our recipients but also to the community and to health care workers, particularly in the absence of effective preventative or curative therapies. For these reasons, we believe the evidence and risks show that COVID-19 infection should continue to remain a contraindication for donation, as has been the initial response of donation and transplant societies.

BACKGROUND A safety net policy was implemented in August 2017 giving liver transplant alone (LTA) recipients with significant renal dysfunction posttransplant priority for subsequent kidney transplantation (KT). This study was undertaken to evaluate early outcomes under this policy. METHODS Adults undergoing LTA after implementation of the safety net policy and were subsequently listed for KT between 60 and 365 days after liver transplantation contained in United Network for Organ Sharing data were examined. Outcomes of interest were receipt of a kidney transplant and postliver transplant survival. Safety net patients were compared with LTA recipients not subsequently listed for KT as well as to patients listed for simultaneous liver-kidney (SLK) transplant yet underwent LTA and were not subsequently listed for KT. RESULTS There were 100 patients listed for safety net KT versus 9458 patients undergoing LTA without subsequent KT listing. The cumulative incidence of KT following listing was 32.5% at 180 days. The safety net patients had similar 1-year unadjusted patient survival (96.4% versus 93.4%; P = 0.234) but superior adjusted survival (hazard ratio0.133, 0.3570.960; P = 0.041) versus LTA recipients not subsequently listed for KT. Safety net patients had superior 1-year unadjusted (96.4% versus 75.0%; P

PURPOSE OF REVIEW Since 2014, the liver transplant community has been debating the pros and cons of broader sharing. Over the last 6 years, lung and heart transplantation have moved to broader sharing based on 'zones' or circles around a donor hospital, with the Organ Procurement and Transplantation Network (OPTN) approving a broader kidney sharing proposal in December of 2019 (set to be implemented in December 2020). RECENT FINDINGS In 2017, the OPTN Board of Directors approved a broader sharing policy in liver transplantation that was rooted in expanding the first-line of liver sharing beyond the donor service area (DSA). Faced with the threat of litigation, this proposal was replaced with a circle-based sharing policy titled 'Acuity Circles'. After a long legal challenge, the implementation of this new policy was delayed from April 2019 until February 2020. SUMMARY In this review, concerns related to broader sharing in liver allocation will be addressed, in terms of the basis for broader sharing and the potential implications to liver transplantation, rooted in the Final Rule and concerns around variability in organ donation rates and access to the waiting list.

The development of multiple highly effective and safe direct-acting antivirals to treat hepatitis C virus (HCV) has resulted in greater ease and confidence in managing HCV infection in transplant recipients that in turn has impacted the solid organ transplant community as well. In the United States, the opioid epidemic has increased the number of overdose deaths with a concomitant increase in younger HCV viremic donors after brain death being identified. At the same time, a decrease in HCV viremic transplant candidates has led to a growing interest in exploring the use of HCV viremic liver and kidney donor allografts in HCV-negative recipients. To date, experience with the use of HCV viremic liver and kidney allografts in HCV-negative recipients is limited to a few small prospective research trials, case series, and case reports. There are also limited data on recipient and donor selection for HCV viremic liver and kidney allografts. In response to this rapidly changing landscape in the United States, experts in the field of viral hepatitis and liver and kidney transplantation convened a meeting to review current data on liver and kidney recipient selection and developed consensus opinions related specifically to recipient and donor selection of HCV viremic liver and kidney allografts.

Historically, many organs from deceased donors with hepatitis C virus (HCV) were discarded. The advent of highly curative direct-acting antiviral (DAA) therapies motivated transplant centers to conduct trials of transplanting HCV-viremic organs (nucleic acid amplification test positive) into HCV-negative recipients, followed by DAA treatment. However, the factors that influence candidates' decisions regarding acceptance of transplant with HCV-viremic organs are not well understood.To explore patient-level perceptions, influences, and experiences that inform candidate decision-making regarding transplant with organs from HCV-viremic donors, we conducted a qualitative semistructured interview study embedded within 3 clinical trials investigating the safety and efficacy of transplanting lungs and kidneys from HCV-viremic donors into HCV-negative recipients. The study was conducted from June 2019 to March 2021.Among 44 HCV-negative patients listed for organ transplant who were approached for enrollment in the applicable clinical trial, 3 approaches to decision-making emerged: positivist, risk analyses, and instinctual response. Perceptions of risk contributed to conceptualizations of factors influencing decisions. Moreover, most participants relied on multiple decision-making approaches, either simultaneously or sequentially.Understanding how different decisional models influence patients' choices regarding transplant with organs from HCV-viremic donors may promote shared decision-making among transplant patients and providers.

Despite increases in the number of deceased donors in the US, the donor supply fails to meet the ever-increasing demand. Centers have had to increase utilization of 'marginal' liver grafts to increase the number of deceased donor liver transplants (DDLT).

Effective health policies are crucial for mitigating barriers to adequate access to treatment for our most vulnerable patients, including those with liver disease. Patients with liver disease are especially reliant on sound healthcare policies as their mortality is strongly tied to expensive medications (e.g., direct acting antivirals [DAAs]) and surgical procedures such as transplantation.

To meet new Centers for Medicare and Medicaid Services (CMS) metrics, organ procurement organizations (OPOs) will benefit from understanding performance across decedent and hospital types. We sought to determine the utility of existing data-reporting structures for this purpose by reviewing Scientific Registry of Transplant Recipient (SRTR) OPO-Specific Reports (OSRs) from 2013 to 2019. OSRs contain both the Standardized donation rate ratio (SDRR) metric and OPO-reported numbers of "eligible deaths" and donors by hospital. Donor hospitals were characterized using information from Homeland Infrastructure Foundation-Level Data, Dartmouth Atlas Hospital Service Area data, and the US Census Bureau. Hospital data reported by OPOs showed 51% higher eligible death donors and 140% higher noneligible death donors per 100 inpatient beds in CMS ranked top versus bottom-quartile OPOs. Top-quartile OPOs by the CMS metric recovered 78% more donors than those in the bottom quartile, but were indistinguishable by SDRR rankings. These differences persisted across hospital sizes, trauma case mix, and area demographics. OPOs with divergent performance were indistinguishable over time by SDRR, but showed changes to hospital-level recovery patterns in SRTR data. Contemporaneous recognition of underperformance across hospitals may provide important and actionable data for regulators and OPOs for focused quality improvement projects.

BACKGROUND In the United States, nearly 30% of liver transplants (LT) are performed for hepatocellular carcinoma (HCC). Although overall long-term survival is highest with LT, there are limited data on the incremental survival benefit of LT versus other curative options (resection or ablation) due to shunting of patients towards LT. METHODS We performed a retrospective cohort study of patients aged 50-69 with cirrhosis and HCC in the Veterans Health Administration (population enriched with 3 curative treatments) from 2008 to 2016. The cohort was restricted to patients who received LT, resection, or ablation and a calculated model for end-stage liver disease score

We sought to characterize the trend in alanine aminotransferase elevations prior to transplant and the impact on the pattern of enzyme elevations on organ utilization and graft function. We performed a retrospective cohort study of UNOS data on all deceased donors between 2007 and 2016. Serum alanine aminotransferase (ALT) was categorized into six study groups with peak ALT 3000 IU/L. The change from peak ALT to terminal ALT prior to transplant was categorized as no change/increasing at time transplant, 0.1–9.9%, 10–24.9%, 25–49.9%, 50–74.9% and >75% change. In multivariable models evaluating liver utilization, the interaction between peak ALT and percent change in ALT was most pronounced at the highest peak ALT levels, where liver utilization varied markedly as a function of percentage drop from peak to terminal ALT. There was no increased risk of graft failure based on peak ALT. Conclusion: Markers of ischemic liver injury and recovery are significantly associated with liver utilization, yet among transplanted livers they were not associated with graft outcomes and may represent an area to expand the donor pool.

BACKGROUND Centers for Medicare and Medicaid Services (CMS) has proposed a rule change to redefine the metric by which organ procurement organizations (OPOs) are evaluated. The metric relies on Centers for Disease Control and Prevention (CDC) data on inpatient deaths from causes consistent with donation among patients

Background Recent pilot trials have demonstrated the safety of transplanting HCV-viremic kidneys into HCV-seronegative recipients. However, it remains unclear if allograft function is impacted by donor HCV-viremia or recipient HCV-serostatus. Methods We used national United States registry data to examine trends in HCV-viremic kidney use between 4/1/2015 and 3/31/2019. We applied advanced matching methods to compare eGFR for similar kidneys transplanted into highly similar recipients of kidney transplants. Results Over time, HCV-seronegative recipients received a rising proportion of HCV-viremic kidneys. During the first quarter of 2019, 200 HCV-viremic kidneys were transplanted into HCV-seronegative recipients, versus 69 into HCV-seropositive recipients, while 105 HCV-viremic kidneys were discarded. The probability of HCV-viremic kidney discard has declined over time. Kidney transplant candidates willing to accept a HCV-seropositive kidney increased from 2936 to 16,809 from during this time period. When transplanted into HCV-seronegative recipients, HCV-viremic kidneys matched to HCV-non-viremic kidneys on predictors of organ quality, except HCV, had similar 1-year eGFR (66.3 versus 67.1 ml/min per 1.73 m2, P=0.86). This was despite the much worse kidney donor profile index scores assigned to the HCV-viremic kidneys. Recipient HCV-serostatus was not associated with a clinically meaningful difference in 1-year eGFR (66.5 versus 71.1 ml/min per 1.73 m2, P=0.056) after transplantation of HCV-viremic kidneys. Conclusions By 2019, HCV-seronegative patients received the majority of kidneys transplanted from HCV-viremic donors. Widely used organ quality scores underestimated the quality of HCV-viremic kidneys based on 1-year allograft function. Recipient HCV-serostatus was also not associated with worse short-term allograft function using HCV-viremic kidneys.

Hepatitis C virus (HCV) seroconversion among HCV-uninfected transplant recipients from HCV-infected (NAT+/Antibody+) or HCV-exposed (NAT-/Antibody+) donors has been reported. However, the origin of anti-HCV antibody and the implications of seroconversion remain unknown. We longitudinally tested plasma from HCV-uninfected kidney (n = 31) or heart transplant recipients (n = 9) of an HCV NAT+ organ for anti-HCV antibody (both IgG and IgM isotypes). Almost half of all participants had detectable anti-HCV antibody at any point during follow-up. The majority of antibody-positive individuals became positive within 1-3 days of transplantation, and 6 recipients had detectable antibody on the first day posttransplant. Notably, all anti-HCV antibody was IgG, even in samples collected posttransplant day 1. Late seroconversion was uncommon (≈20%-25% of antibody+ recipients). Early antibody persisted over 30 days in kidney recipients, whereas early antibody dropped below detection in 50% of heart recipients within 2 weeks after transplant. Anti-HCV antibody is common in HCV-uninfected recipients of an HCV NAT+ organ. The IgG isotype of this antibody and the kinetics of its appearance and durability suggest that anti-HCV antibody is donor derived and is likely produced by a cellular source. Our data suggest that transfer of donor humoral immunity to a recipient may be much more common than previously appreciated.

Rationale & Objective Hepatitis C virus (HCV) infection is common among maintenance dialysis patients. Few studies have examined both dialysis survival and transplantation outcomes for HCV-seropositive patients because registry data sets lack information for HCV serostatus. Study Design Retrospective cohort study. Setting & Participants Adult long-term dialysis patients treated by a US national dialysis provider between January 1, 2004, and December 31, 2014. Exposure HCV antibody serostatus obtained as part of clinical data from a national dialysis provider. Outcomes Mortality on dialysis therapy, entry onto the kidney transplant waiting list, kidney transplantation, and estimated survival benefit from kidney transplantation versus remaining on the waitlist. Analytical Approach After linking clinical data with data from the Organ Procurement and Transplantation Network, Cox and cause-specific hazards regression were implemented to estimate the associations between HCV seropositivity and mortality, as well as entry onto the kidney transplant waitlist. Cox regression was also used to estimate the survival benefit from transplantation versus dialysis among HCV-seropositive individuals. Results Among 442,171 dialysis patients, 31,624 (7.2%) were HCV seropositive. HCV seropositivity was associated with a small elevation in the rate of death (adjusted HR [aHR], 1.09; 95% CI, 1.07-1.11) and a substantially lower rate of entry onto the kidney transplant waitlist (subdistribution HR [sHR], 0.67; 95% CI, 0.61-0.74). Once wait-listed, the kidney transplantation rate was not different for HCV-seropositive (sHR 1.10; 95% CI, 0.96-1.27) versus HCV-seronegative patients. HCV-seropositive patients lived longer with transplantation (aHR at 3 years, 0.42; 95% CI, 0.27-0.63). Receiving an HCV-seropositive donor kidney provided a survival advantage at the 2-year posttransplantation time point compared to remaining on dialysis therapy waiting for an HCV-negative kidney. Limitations No data for HCV viral load or liver biopsy. Conclusions HCV-seropositive patients experience reduced access to the kidney transplantation waitlist despite deriving a substantial survival benefit from transplantation. HCV-seropositive patients should consider foregoing HCV treatment while accepting kidneys from HCV-infected donors to facilitate transplantation and prolong survival.

Patients heterozygous for an abnormal α-1 antitrypsin (A1AT) mutation may have an increased risk of liver disease in the setting of a secondary contributing factor.This single-center retrospective cohort study compared donor and recipient outcomes of A1AT heterozygous versus normal phenotype adult living-donor liver transplants (LDLTs).Between 2010 and 2016, 11 A1AT heterozygous donors and 10 recipients were compared to 57 normal donors and 41 recipients. There were no significant differences in sex, age, or race/ethnicity by A1AT phenotype. Heterozygous donors had significantly lower serum A1AT (median 100 mg/dL versus 131 mg/dL; P0.001). Median liver volume at 3 months post-LDLT was not different among donors or their recipients (1164 mm in heterozygous versus 1257 mm in normal [P = 0.449] for donors; 1563 mm versus 1606 mm [P = 0.387], respectively, for recipients). Recipient serum alkaline phosphatase at 1 month and 1 year post-LDLT was significantly higher in recipients of A1AT heterozygous grafts (160 U/L versus 99.5 U/L; P = 0.025 at 1 mo) but did not persist at 2 years. In addition, there was no association between A1AT level and liver volume at 3 months posttransplant in donors or recipients.Patients with a heterozygous A1AT mutation should be considered for living-liver donation.

Purpose of review Acute-on-chronic liver failure (ACLF) is a clinical syndrome in patients with chronic liver disease that is associated with multiple organ failures and a high short-term mortality. Systemic inflammation is suggested to play a key role in its pathogenesis, although the precise causative mechanism is unknown. The purpose of this review is to present and discuss new findings related to: mechanisms underlying ACLF, therapeutic targets, risk prediction models for developing ACLF, and liver transplantation for ACLF. Recent findings Recent studies of ACLF pathophysiology classified the immunosuppressive phenotype in monocytes. Investigation of therapeutic strategies identified inhibition of toll-like receptor-4 (TLR-4) and glutamine synthetase (GLUL) as potential targets. Recent studies identified novel risk prediction models for developing ACLF and enhanced our understanding of liver transplantation for ACLF to guide clinicians in determining that patients will benefit from transplantation. Summary Improved knowledge on the pathogenesis of ACLF and identification of TLR-4 and GLUL may lead to clinical trials to study the efficacy of these novel therapeutic targets for patients with ACLF. Liver transplantation is the only current treatment for ACLF. Given the limited availability of donor organs, recent studies have identified ACLF patients who may merit the highest waitlist priority.

BACKGROUND AND AIMS Successful liver transplantation offers the possibility of improved survival among patients with decompensated cirrhosis. However, there is wide variability in access to care and promptness of the transplant evaluation process in the United States. METHODS We performed a multi-center retrospective study of 1,118 patients who underwent evaluation for liver transplantation at the six Veterans Affairs' transplant centers from 2013-2018. Of these, 832 patients were evaluated within 30 days and 286, more than 30 days after referral. We studied the differential effects of the time from referral to evaluation on pre and post-transplant mortality and transplant list drop out and explored predictors of early transplant evaluation. RESULTS Patients in the early evaluation group had a shorter adjusted time from referral to listing by 29.5 days (95% CI -50.4, -8.5, p

BACKGROUND The aging of liver transplant (LT) recipients, the weighting of the model for end-stage liver disease score, and the increased prevalence of nonalcoholic steatohepatitis has led to an increased number of older LT recipients with pre-LT chronic kidney disease (CKD). There are limited data on the impact of increased recipient age on post-simultaneous liver-kidney (SLK) transplant outcomes among patients with CKD, leading some centers to employ subjective age cutoffs for potential SLK recipients. METHODS We evaluated United Network for Organ Sharing data of adult SLK recipients from February 27, 2002, to December 31, 2018, restricted to recipients with ≥90 days of waiting time and CKD (estimated glomerular filtration rate persistently

Background There are little data to compare the post-transplant survival between lung-liver transplant (LLT) and liver-alone recipients. This study was undertaken to compare survival between LLT and liver-alone transplant. Methods UNOS data for patients undergoing LLT from 2002 to 2017 was analyzed. LLT recipients (n = 81) were matched 1:4 to liver-alone recipients (n = 324) by propensity score and patient survival was compared in the matched cohorts. Results Unadjusted 1, 3, and 5-year patient survival in the matched cohort was significantly worse in the LLT (82.5%, 72.2%, and 62.2%) versus liver-alone (92.2%, 82.8%, and 80.9%; p = 0.005). This difference persisted after adjusting for covariates with residual imbalance (HR 2.05, 95% CI 1.37–3.08; p = 0.001). Conclusion LLT has significantly worse survival than liver-alone transplant. With an increasing organ shortage, medical necessity criteria such as those developed for simultaneous liver-kidney transplantation should be developed for simultaneous lung-liver transplants to assure liver allografts are only allocated when truly needed.

BACKGROUND Substantial differences exist in the clinical characteristics of donors across the 58 donor service areas (DSAs). Organ procurement organization (OPO) performance metrics incorporate organs donated after circulatory determination of death (DCDD) donors but do not measure potential DCDD donors. METHODS Using 2011-2016 United Network for Organ Sharing data, we examined the variability in DCDD donors/all deceased donors (%DCDD) across DSAs. We supplemented United Network for Organ Sharing data with CDC death records and OPO statistics to characterize underlying process and system factors that may correlate with donors and utilization. RESULTS Among 52 184 deceased donors, the %DCDD varied widely across DSAs, with a median of 15.1% (interquartile range [9.3%, 20.9%]; range 0.0%-32.0%). The %DCDD had a modest positive correlation with 4 DSA factors: median match model for end-stage liver disease, proportion of white deaths out of total deaths, kidney center competition, and %DCDD livers by a local transplant center (all Spearman coefficients 0.289-0.464), and negative correlation with 1 factor: mean kidney waiting time (Spearman coefficient -0.388). Adjusting for correlated variables in linear regression explained 46.3% of the variability in %DCDD. CONCLUSIONS Donor pool demographics, waitlist metrics, center competition, and DCDD utilization explain only a portion of the variability of DCDD donors. This requires further studies and policy changes to encourage consideration of all possible organ donors.

Hepatitis B virus (HBV) can be transmitted from organ donor to recipient, but details of transmission events are not widely published. The Disease Transmission Advisory Committee (DTAC) evaluated 105 cases of potential donor derived transmission events of HBV between 2009-2017. Proven, probable or possible transmission of HBV occurred in 25 (23.8%) cases. Recipients of liver grafts were most commonly infected (20 of 21 exposed recipients) compared to 9 of 21 exposed non-hepatic recipients. Eleven of 25 donors were HBV core antibody (HBcAb) positive/HBV surface antigen (HBsAg) negative and infected 8/20 recipients. Of the 10 liver recipients and 1 liver-kidney recipient who received organs from these donors: six were not given antiviral prophylaxis, two developed infection after antiviral prophylaxis was discontinued, two developed HBV while on lamivudine prophylaxis, one was on antiviral prophylaxis and did not develop HBV viremia or antigenemia. One recipient of a HBcAb positive/HBsAg negative kidney developed active HBV infection. Unexpected donor-derived transmission of HBV was a rare event in reports to DTAC, but was often detected in the recipient late post-transplant. Six of 11 recipients (54.5%) of a liver from a HBcAb positive donor did not receive prophylaxis; all of these were potentially preventable with the use of anti-viral prophylaxis.

Background Single-center trials and retrospective case series have reported promising outcomes using kidneys from donors with hepatitis C virus (HCV) infection. However, multicenter trials are needed to determine if those findings are generalizable. Methods We conducted a prospective trial at seven centers to transplant 30 kidneys from deceased donors with HCV viremia into HCV-uninfected recipients, followed by 8 weeks of once-daily coformulated glecaprevir and pibrentasvir, targeted to start 3 days posttransplant. Key outcomes included sustained virologic response (undetectable HCV RNA 12 weeks after completing treatment with glecaprevir and pibrentasvir), adverse events, and allograft function. Results We screened 76 patients and enrolled 63 patients, of whom 30 underwent kidney transplantation from an HCV-viremic deceased donor (median kidney donor profile index, 53%) in May 2019 through October 2019. The median time between consent and transplantation of a kidney from an HCV-viremic donor was 6.3 weeks. All 30 recipients achieved a sustained virologic response. One recipient died of complications of sepsis 4 months after achieving a sustained virologic response. No severe adverse events in any patient were deemed likely related to HCV infection or treatment with glecaprevir and pibrentasvir. Three recipients developed acute cellular rejection, which was borderline in one case. Three recipients developed polyomavirus (BK) viremia near or >10,000 copies/ml that resolved after reduction of immunosuppression. All recipients had good allograft function, with a median creatinine of 1.2 mg/dl and median eGFR of 57 ml/min per 1.73 m2 at 6 months. Conclusions Our multicenter trial demonstrated safety and efficacy of transplantation of 30 HCV-viremic kidneys into HCV-negative recipients, followed by early initiation of an 8-week regimen of glecaprevir and pibrentasvir.

Recently proposed rulemaking from Centers for Medicare and Medicaid Services would change how organ procurement organizations (OPOs) are evaluated. The proposals include using national inpatient death data to define a standardized denominator to calculate comparable donation rates among OPOs. Based on these objective metrics, OPOs not performing at a prespecified threshold will be required to rapidly improve performance to avoid decertification. We sought to determine whether rapid OPO improvement was possible based on objective donation metrics, and whether leadership change was associated with rapid improvement. We evaluated United Network for Organ Sharing and Centers for Disease Control and Prevention (CDC) data from 2011 to 2018, and measured donation rates using CDC data on inpatient deaths from causes consistent with donation, based on the location of deaths. During the two 4-year cycles, we found that an OPO's ranking relative to other OPOs was fairly static, with more than 90% of the OPOs at risk of flagging at the end of each 4-year cycle (2014, 2018) being in the bottom 75% of OPOs in the preceding 3 years. In multivariable logistic regression models, leadership changes were only statistically significantly associated with an improvement in OPO rankings during the 2011-2014 cycle. These data demonstrate that rapid improvements in OPO performance are uncommon, and while leadership changes increase the odds of rapid improvement, they do not guarantee improvement.

BACKGROUND: Increasing recipient and donor age are independently associated with survival after liver transplantation (LT). Whether donor age differentially impacts post-LT outcomes based on recipient age is unknown. METHODS: This was a retrospective cohort study using Organ Procurement and Transplantation Network data. All adult deceased-donor, single organ, primary LTs from 2002–2015 were included. Donor and recipient age were categorized as