Liver Transplantation In US Research Articles

Development of post-transplant diabetes mellitus in US Liver Transplant recipients is influenced by OPTN region

Background: Post-transplant diabetes mellitus (PTDM) is associated with significant morbidity and mortality in liver transplant recipients (LTRs). We utilized the Organ Procurement and Transplantation Network (OPTN) database to compare incidence of developing PTDM across the US and develop a risk prediction model for new-onset PTDM using OPTN region as well as donor-, recipient-, and transplant-related factors. Methods: All US adult, primary, deceased donor, LTRs between January 1, 2007, and December 31, 2016, with no prior history of diabetes noted, were identified. Kaplan Meier estimators were utilized to calculate cumulative incidence of PTDM, stratified by OPTN region. Multivariable Cox-proportional hazards models were fitted to estimate hazards of PTDM in each OPTN region and build a risk prediction model, via backward selection. Results: Cumulative incidence of PTDM at 1-year, 3-years and 5-years post-transplant was 12.0%, 16.1%, and 18.9%, respectively. Region 3, followed by region 8, 2 and 9, had the highest adjusted hazards of developing PTDM. Inclusion of OPTN region in a risk prediction model for PTDM in LTRs (including recipient age, sex, race, education, insurance coverage, BMI, primary liver disease, cold ischemia time and donor history of diabetes), modestly improved performance (C-statistic=0.60). Conclusions: In patients without pre-existing, confirmed DM, the incidence of PTDM in LTRs varied across OPTN regions, with highest hazards in region 3, followed by region 8, 2 and 9. Performance of a novel risk prediction model for PTDM in LTRs has improved performance with the inclusion of OPTN region. Vigilance is recommended to centers in high-risk regions to identify PTDM and mitigate its development.

Body Size Remains the Major Source of Sex Disparity Despite Updated Liver Transplant Allocation Policies.

Efforts to address US liver transplant (LT) access inequities continue, yet disparities linked to candidate traits persist. Analyzing national registry data pre- and post-Acuity Circle (AC) policy, our study assessed the impact of low body surface area (BSA) on LT waitlist mortality. The outcomes of LT candidates listed in the pre-AC era (n = 39 227) and post-AC (n = 38 443) were compared for patients with low BSA (22.9% pre-AC and 23.3% post-AC). Fine-Gray competing risk models highlighted that candidates with low BSA had a lower likelihood of LT both pre-AC (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.92-0.95) and post-AC (HR 0.96; 95% CI, 0.94-0.98), with minimal improvement in waitlist mortality/dropout risk from pre-AC (HR 1.15; 95% CI, 1.09-1.21) to post-AC (HR 1.13; 95% CI, 1.06-1.19). Findings were mostly reaffirmed by Cox regression models incorporating the trajectory of Model for End-stage Liver Disease (MELD) scores as time-dependent covariates. Regions 3, 5, and 7 showed notable LT waitlist disparities among low BSA patients post-AC policy. Causal mediation analysis revealed that low BSA and the difference between MELD-sodium and MELD 3.0 (MELD_D, as a proxy for the potential impact of the introduction of MELD 3.0) largely explained the sex disparity in AC allocation (percent mediated 90.4). LT waitlist disparities for female candidates persist, largely mediated by small body size. Although MELD 3.0 may reduce some disparities, further body size adjustments for in allocation models are justified.

The Survival Benefit of Reabstinence After Harmful Alcohol Use Following Early Liver Transplant for Severe Alcohol-Associated Hepatitis: A Multicenter ACCELERATE Study.

Early (i.e., without mandated period of abstinence) liver transplant (LT) for alcohol-associated hepatitis is the fastest-growing indication for LT in the United States and Europe. Harmful alcohol use after LT is associated with poor outcomes, but the distinction of establishing abstinence after return to drinking (i.e., reabstinence) is understudied. This study aims to characterize the survival outcomes of achieving reabstinence after post-LT harmful alcohol use. We analyzed early LT recipients from 12 US LT centers between 2006 and 2021. Post-LT alcohol use was characterized as harmful using criteria of "binge" (≥5 [men] or ≥4 [women] drinks in < 24 hours) or "frequent" (≥4 days in one week) by interview or phosphatidylethanol >20 ng/mL. Reabstinence was defined as ≥12 consecutive months without harmful alcohol use after harmful alcohol use. Among 347 LT recipients (64% male, median age 43, median Model for End-Stage Liver Disease-Sodium score 38) with median post-LT follow-up of 2.2 years (interquartile interval 1.1-3.6), 276 (80%) recipients had no evidence of harmful alcohol use, 35 (10%) recipients had reabstinence, and 36 (10%) recipients had continued harmful alcohol use without reabstinence. Five-year predicted survival, adjusted for age, sex, and Model for End-Stage Liver Disease-Sodium score, was lowest among LT recipients with continued harmful alcohol use (77%), but similar among those with no harmful use (93%) and reabstinence (94%). Achieving reabstinence after post-LT harmful alcohol use is associated with similar 5-year post-LT survival compared with those without evidence of post-LT harmful alcohol use. Our findings highlight the importance of early detection and treatment of post-LT alcohol use.

Evolving trends and outcomes on the US liver transplant waitlist of alcohol-associated hepatitis patients with very high MELD scores.

Liver transplantation (LT) in patients with alcohol-associated hepatitis (AH) has rapidly increased following the coronavirus disease 2019 pandemic and the implementation of the Acuity Circle policy, raising questions of equity and utility. Waitlist mortality among high (≥37) Model for End-Stage Liver Disease LT candidates with AH and post-transplant survival were assessed with a semiparametric survival regression and a generalized linear mixed-effect model with LT centre- and listing date-level random intercepts. These models demonstrate a lower mortality for the candidates listed with AH (adjusted sub-hazard ratio .58_.72_.90 and odds ratio .44_.66_.99) when compared to other diagnoses (autoimmune hepatitis, metabolic dysfunction-associated fatty liver disease and primary biliary cholangitis). Post-LT survival was comparable. This study highlights the limitations of current tools in characterizing the risk of mortality, and thus need for the modifications in prioritizing LT candidates with AH. Policy revision may be needed to ensure equivalent access to LT regardless of diagnosis.

US Liver Transplant Outcomes After Normothermic Regional Perfusion vs Standard Super Rapid Recovery

Normothermic regional perfusion (NRP) is an emerging recovery modality for transplantable allografts from controlled donation after circulatory death (cDCD) donors. In the US, only 11.4% of liver recipients who are transplanted from a deceased donor receive a cDCD liver. NRP has the potential to safely expand the US donor pool with improved transplant outcomes as compared with standard super rapid recovery (SRR). To assess outcomes of US liver transplants using controlled donation after circulatory death livers recovered with normothermic regional perfusion vs standard super rapid recovery. This was a retrospective, observational cohort study comparing liver transplant outcomes from cDCD donors recovered by NRP vs SRR. Outcomes of cDCD liver transplant from January 2017 to May 2023 were collated from 17 US transplant centers and included livers recovered by SRR and NRP (thoracoabdominal NRP [TA-NRP] and abdominal NRP [A-NRP]). Seven transplant centers used NRP, allowing for liver allografts to be transplanted at 17 centers; 10 centers imported livers recovered via NRP from other centers. cDCD livers were recovered by either NRP or SRR. The primary outcome was ischemic cholangiopathy (IC). Secondary end points included primary nonfunction (PNF), early allograft dysfunction (EAD), biliary anastomotic strictures, posttransplant length of stay (LOS), and patient and graft survival. A total of 242 cDCD livers were included in this study: 136 recovered by SRR and 106 recovered by NRP (TA-NRP, 79 and A-NRP, 27). Median (IQR) NRP and SRR donor age was 30.5 (22-44) years and 36 (27-49) years, respectively. Median (IQR) posttransplant LOS was significantly shorter in the NRP cohort (7 [5-11] days vs 10 [7-16] days; P < .001). PNF occurred only in the SRR allografts group (n = 2). EAD was more common in the SRR cohort (123 of 136 [56.1%] vs 77 of 106 [36.4%]; P = .007). Biliary anastomotic strictures were increased 2.8-fold in SRR recipients (7 of 105 [6.7%] vs 30 of 134 [22.4%]; P = .001). Only SRR recipients had IC (0 vs 12 of 133 [9.0%]; P = .002); IC-free survival by Kaplan-Meier was significantly improved in NRP recipients. Patient and graft survival were comparable between cohorts. There was comparable patient and graft survival in liver transplant recipients of cDCD donors recovered by NRP vs SRR, with reduced rates of IC, biliary complications, and EAD in NRP recipients. The feasibility of A-NRP and TA-NRP implementation across multiple US transplant centers supports increasing adoption of NRP to improve organ use, access to transplant, and risk of wait-list mortality.

Use of Transesophageal Echocardiography for Liver Transplantation: A Global Comparison of Practice From the ILTS, SATA, and LICAGE.

Anesthesiologists frequently use intraoperative transesophageal echocardiography (TEE) to aid in the diagnosis and management of hemodynamic problems during liver transplantation (LT). Although the use of TEE in US centers continues to increase, data regarding international use are lacking. This prospective, global, survey-based study evaluates international experience with TEE for LT. Responses from 252 LT (105 US and 147 non-US) centers representing 1789 anesthesiologists were analyzed. Routine use of TEE in the United States has increased in the last 5 y (from 37% to 47%), but only 21% of non-US LT anesthesiologists use TEE routinely. Lack of training (44% US versus 70% non-US) and equipment (9% non-US versus 34% US) were cited as obstacles. Most survey participants preferred not to perform a complete cardiac examination but rather use only 6 of 11 basic views. Although non-US LT anesthesiologists more frequently had additional clinical training than their US counterparts, they had less TEE experience (13% versus 44%) and less frequently, TEE certification (22% versus 35%). Most LT anesthesiologists agreed that TEE certification is essential for proficiency. Of all respondents, 89% agreed or strongly agreed that TEE provides valuable information needed for immediate clinical decision-making, and >86% agreed or strongly agreed that that information could not be derived from other sources. The use of TEE for LT surgery in the US LT centers is currently higher compared with non-US LT centers. This may become a standard monitoring modality during LT in the near future.

Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes

Biliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA. We performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models. A GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p= 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p= 1.34E-7), both supported by credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA was associated with 6,005 SNPs in 102 CPLANE genes (p= 5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants (allele frequency <1%) that were assigned Human Phenotype Ontology terms related to hepatobiliary anomalies by predictive algorithms, 87% vs. 40%, p <0.0001. Rare variants were present in multiple genes distinct from those with BA-associated common variants in most BA cases. AFAP1 and TUSC3 knockdown blocked ciliogenesis in mouse tracheal cells. Inhibition of ciliogenesis caused biliary dysgenesis in zebrafish. AFAP1 and TUSC3 were expressed in fetal liver organoids, as well as fetal and BA livers, but not in normal or disease-control livers. Integrative analysis of BA-associated variants and liver transcripts revealed abnormal vasculogenesis and epithelial tube formation, explaining portal vein anomalies that co-exist with BA. BA is associated with polygenic susceptibility in CPLANE genes. Rare variants contribute to polygenic risk in vulnerable pathways via unique genes. Liver transplantation is needed to cure most children born with biliary atresia, a poorly understood rare disease. Transplant immunosuppression increases the likelihood of life-threatening infections and cancers. To improve care by preventing this disease and its progression to transplantation, we examined its genetic basis. We find that this disease is associated with both common and rare mutations in highly specialized genes which maintain normal communication and movement of cells, and their organization into bile ducts and blood vessels during early development of the human embryo. Because defects in these genes also cause other birth defects, our findings could lead to preventive strategies to lower the incidence of biliary atresia and potentially other birth defects.

National survey of second opinions for hospitalized patients in need of liver transplantation.

Decisions about patient candidacy for liver transplant (LT) can mean the difference between life and death. We surveyed LT centers across the United States to assess their perceptions of and barriers to second-opinion referrals for inpatients declined for transplant. The medical and surgical directors of 100 unique US LT programs that had done >20 LTs in 2021 were surveyed with a 33-item questionnaire including both multiple-choice and free-response questions. The response rate was 60% (60 LT centers) and included 28 larger-volume ( ≥100 LTs in 2021) and 32 smaller-volume (<100 LTs in 2021) programs. The top 3 reasons for inpatient denial for LT included lack of social support (21%), physical frailty (20%), and inadequate remission duration from alcohol use (11%). Twenty-five percent of the programs reported "frequently" facilitating a second opinion for a declined inpatient, 52% of the programs reported "sometimes" doing so, and 7% of the programs reported never doing so. One hundred percent of the programs reported that they receive referrals for second opinions. Twenty-five percent of the programs reported transplanting these referrals frequently (over 20% of the time). Neither program size nor program location statistically impacted the findings. When asked if centers would be in favor of standardizing the evaluation process, 38% of centers would be in favor, 39% would be opposed, and 23% were unsure. The practices and perceptions of second opinions for hospitalized patients evaluated for LT varied widely across the United States. Opportunities exist to improve equity in LT but must consider maintaining individual program autonomy.

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

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

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

A successful living donor liver transplant (LDLT) is the culmination of a multifaceted process coordinated among key stakeholders. 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. 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. 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.

Association of Frailty With Health-Related Quality of Life in Liver Transplant Recipients

Frailty has been recognized as a risk factor for mortality after liver transplant (LT) but little is known of its association with functional status and health-related quality of life (HRQL), termed global functional health, in LT recipients. To evaluate the association between pre-LT and post-LT frailty with post-LT global functional health. This prospective cohort study was conducted at 8 US LT centers and included adults who underwent LT from October 2016 to February 2020. Frail was defined by a pre-LT Liver Frailty Index (LFI) score of 4.5 or greater. Global functional health at 1 year after LT, assessed using surveys (Short Form-36 [SF-36; summarized by physical component scores (PFC) and mental component summary scores (MCS)], Instrumental Activities of Daily Living scale) and performance-based tests (LFI, Fried Frailty Phenotype, and Short Physical Performance Battery). Of 358 LT recipients (median [IQR] age, 60 [53-65] years; 115 women [32%]; 25 [7%] Asian/Pacific Islander, 21 [6%] Black, 54 [15%] Hispanic White, and 243 [68%] non-Hispanic White individuals), 68 (19%) had frailty pre-LT. At 1 year post-LT, the median (IQR) PCS was lower in recipients who had frailty vs those without frailty pre-LT (42 [31-53] vs 50 [38-56]; P = .002), but the median MCS was similar. In multivariable regression, pre-LT frailty was associated with a -5.3-unit lower post-LT PCS (P < .001), but not MCS. The proportion who had difficulty with 1 or more Instrumental Activities of Daily Living (21% vs 10%) or who were unemployed/receiving disability (38% vs 29%) was higher in recipients with vs without frailty. In a subgroup of 210 recipients with LFI assessments 1 year post-LT, 13% had frailty at 1 year post-LT. Recipients who had frailty post-LT reported lower adjusted SF-36-PCS scores (coefficient, -11.4; P < .001) but not SF-36-MCS scores. Recipients of LT who had frailty vs those without frailty 1 year post-LT also had worse median (IQR) Fried Frailty Phenotype scores (1 [1-2] vs 1 [0-1]) and higher rates of functional impairment by a Short Physical Performance Battery of 9 or less (42% vs 20%; P = .01). In this cohort study, pre-LT frailty was associated with worse global functional health 1 year after LT. The presence of frailty after LT was also associated with worse HRQL in physical, but not mental, subdomains. These data suggest that interventions and therapeutics that target frailty that are administered before and/or early post-LT may help to improve the health and well-being of LT recipients.

Survival Benefit of Living-Donor Liver Transplant

Despite the acceptance of living-donor liver transplant (LDLT) as a lifesaving procedure for end-stage liver disease, it remains underused in the United States. Quantification of lifetime survival benefit and the Model for End-stage Liver Disease incorporating sodium levels (MELD-Na) score range at which benefit outweighs risk in LDLT is necessary to demonstrate its safety and effectiveness. To assess the survival benefit, life-years saved, and the MELD-Na score at which that survival benefit was obtained for individuals who received an LDLT compared with that for individuals who remained on the wait list. This case-control study was a retrospective, secondary analysis of the Scientific Registry of Transplant Recipients database of 119 275 US liver transplant candidates and recipients from January 1, 2012, to September 2, 2021. Liver transplant candidates aged 18 years or older who were assigned to the wait list (N = 116 455) or received LDLT (N = 2820) were included. Patients listed for retransplant or multiorgan transplant and those with prior kidney or liver transplants were excluded. Living-donor liver transplant vs remaining on the wait list. The primary outcome of this study was life-years saved from receiving an LDLT. Secondary outcomes included 1-year relative mortality and risk, time to equal risk, time to equal survival, and the MELD-Na score at which that survival benefit was obtained for individuals who received an LDLT compared with that for individuals who remained on the wait list. MELD-Na score ranges from 6 to 40 and is well correlated with short-term survival. Higher MELD-Na scores (>20) are associated with an increased risk of death. The mean (SD) age of the 119 275 study participants was 55.1 (11.2) years, 63% were male, 0.9% were American Indian or Alaska Native, 4.3% were Asian, 8.2% were Black or African American, 15.8% were Hispanic or Latino, 0.2% were Native Hawaiian or Other Pacific Islander, and 70.2% were White. Mortality risk and survival models confirmed a significant survival benefit for patients receiving an LDLT who had a MELD-Na score of 11 or higher (adjusted hazard ratio, 0.64 [95% CI, 0.47-0.88]; P = .006). Living-donor liver transplant recipients gained an additional 13 to 17 life-years compared with patients who never received an LDLT. An LDLT is associated with a substantial survival benefit to patients with end-stage liver disease even at MELD-Na scores as low as 11. The findings of this study suggest that the life-years gained are comparable to or greater than those conferred by any other lifesaving procedure or by a deceased-donor liver transplant. This study's findings challenge current perceptions regarding when LDLT survival benefit occurs.

OPTN/SRTR 2020 Annual Data Report: COVID

OPTN/SRTR 2020 Annual Data Report: COVID

Discordance in categorization of acute-on-chronic liver failure in the United Network for Organ Sharing database

Studies regarding acute-on-chronic liver failure (ACLF) among liver transplant (LT) candidates from the United Network for Organ Sharing (UNOS) database are being used to inform LT policy changes worldwide. We assessed the validity of identifying ACLF in UNOS. We performed stratified random sampling among 3 US LT centers between 2013-2019 to obtain a representative patient sample across ACLF grades. We compared the concordance of ACLF classification by UNOS vs. blinded manual chart review, according to EASL-CLIF. Among 481 sampled LT registrants, 250 (52%) had no ACLF, 75 (16%) had ACLF grade 1, 79 (16%) had ACLF grade 2, and 77 (16%) had ACLF grade 3 per UNOS categorization. Concordance of ACLF grade by UNOS vs. chart review was: 72%, 64%, 56%, and 64% for no ACLF, grade 1, grade 2, and grade 3, respectively, with an overall Cohen's kappa coefficient of 0.48 (95% CI 0.42-0.54). Absence of acute decompensation was the most common reason for overestimation, and discordant brain and respiratory failure categorization were the most common reasons for underestimation of ACLF by UNOS. In this retrospective multi-center study, ACLF categorization by UNOS showed weak agreement with manual chart review. These findings are informative for ongoing allocation policy discussions, highlight the importance of prospective studies regarding ACLF in LT, and should encourage UNOS reform. Acute-on-chronic-liver-failure (ACLF) is a specific and common form of liver failure associated with high death rates. Studies have been published using the United States transplant registry (UNOS) to identify and describe outcomes of transplant candidates and recipients with ACLF, and these data are driving policy changes for transplant allocation around the world, but nobody has shown whether these data are reliable. We found that UNOS was not categorizing ACLF in concordance or accurately when compared to chart review, which shows the need for UNOS reform and non-UNOS studies to appropriately inform policies regarding the transplantation of patients with ACLF.

Impact of Portable Normothermic Blood-Based Machine Perfusion on Outcomes of Liver Transplant

Ischemic cold storage (ICS) of livers for transplant is associated with serious posttransplant complications and underuse of liver allografts. To determine whether portable normothermic machine perfusion preservation of livers obtained from deceased donors using the Organ Care System (OCS) Liver ameliorates early allograft dysfunction (EAD) and ischemic biliary complications (IBCs). This multicenter randomized clinical trial (International Randomized Trial to Evaluate the Effectiveness of the Portable Organ Care System Liver for Preserving and Assessing Donor Livers for Transplantation) was conducted between November 2016 and October 2019 at 20 US liver transplant programs. The trial compared outcomes for 300 recipients of livers preserved using either OCS (n = 153) or ICS (n = 147). Participants were actively listed for liver transplant on the United Network of Organ Sharing national waiting list. Transplants were performed for recipients randomly assigned to receive donor livers preserved by either conventional ICS or the OCS Liver initiated at the donor hospital. The primary effectiveness end point was incidence of EAD. Secondary end points included OCS Liver ex vivo assessment capability of donor allografts, extent of reperfusion syndrome, incidence of IBC at 6 and 12 months, and overall recipient survival after transplant. The primary safety end point was the number of liver graft-related severe adverse events within 30 days after transplant. Of 293 patients in the per-protocol population, the primary analysis population for effectiveness, 151 were in the OCS Liver group (mean [SD] age, 57.1 [10.3] years; 102 [67%] men), and 142 were in the ICS group (mean SD age, 58.6 [10.0] years; 100 [68%] men). The primary effectiveness end point was met by a significant decrease in EAD (27 of 150 [18%] vs 44 of 141 [31%]; P = .01). The OCS Liver preserved livers had significant reduction in histopathologic evidence of ischemia-reperfusion injury after reperfusion (eg, less moderate to severe lobular inflammation: 9 of 150 [6%] for OCS Liver vs 18 of 141 [13%] for ICS; P = .004). The OCS Liver resulted in significantly higher use of livers from donors after cardiac death (28 of 55 [51%] for the OCS Liver vs 13 of 51 [26%] for ICS; P = .007). The OCS Liver was also associated with significant reduction in incidence of IBC 6 months (1.3% vs 8.5%; P = .02) and 12 months (2.6% vs 9.9%; P = .02) after transplant. This multicenter randomized clinical trial provides the first indication, to our knowledge, that normothermic machine perfusion preservation of deceased donor livers reduces both posttransplant EAD and IBC. Use of the OCS Liver also resulted in increased use of livers from donors after cardiac death. Together these findings indicate that OCS Liver preservation is associated with superior posttransplant outcomes and increased donor liver use. ClinicalTrials.gov Identifier: NCT02522871.

Perioperative Viscoelastic Assay Use for Monitoring Coagulation Among US Liver Transplantation Centers

Viscoelastic assay has been used in liver transplantation since 1985 and shown to be beneficial in detecting coagulopathy and to guide transfusion. The objective of this study was to review and evaluate the current uses of viscoelastic assay among US liver transplantation programs. Anesthesia program directors at all 137 liver transplantation centers in the United States were contacted via email and asked to complete a 21-item survey. The primary outcome measure was the percentage of viscoelastic assay used in the perioperative management of liver transplantation. Secondary outcome measures were institutional demographics, physician training level, and device demographics. Sixty-one of 137 (46%) centers responded. Liver transplantations were performed in the university setting at 48 of the 61 centers (77%), with a modal value of 11 to 50 liver transplantations a year and 74% in adult patients only. Most of the institutions (n=57, 92%) had access to either rotational thromboelastometry or thrombelastography during liver transplantation. Most centers (n=54; 87%) also used viscoelastic monitoring routinely (>60% of the time), including 42 (67.7%) that always used viscoelastic assay intraoperatively during liver transplantation. Thirty-five centers (59%) used it preoperatively, and 51 (84%) used it postoperatively. Most viscoelastic assay users (68%) learned how to use it through self-education and 10.5% learned during their fellowship or from a superuser or colleagues. Currently, viscoelastic monitoring is widely available and routinely used in most US liver transplantation centers regardless of university or private practice setting, but training in it is limited. Only 21.1% of respondents reported that they received any type of official training in viscoelastic assay interpretation.

Associations Among Different Domains of Quality Among US Liver Transplant Programs

US liver transplant programs have traditionally been evaluated on 1-year patient and graft survival. However, there is concern that a narrow focus on recipient outcomes may not incentivize programs to improve in other ways that would benefit patients with end-stage liver disease. To determine the correlation among different potential domains of quality for adult liver transplant programs. This retrospective cohort study was conducted from 2014 to 2019 among adult liver transplant programs included in the United Network for Organ Sharing and Scientific Registry of Transplant Recipients program-specific reports. Liver transplant programs in the United States completing at least 10 liver transplants per year were included. Data were analyzed from March 2 to August 13, 2020. The potential domains of quality examined included recipient outcomes (1-year graft and patient survival), aggressiveness (ie, marginal graft use, defined as the rate of use of donors with body mass index [calculated as weight in kilograms divided by height in meters squared] greater than 40, age older than 65 years, or deceased by cardiac death), and waiting list management (ie, waiting list mortality). The correlation among measures, aggregated at the center level, was evaluated using linear regression to control for mean Model for End Stage Liver Disease-Sodium score at organ allocation. The extent to which programs were able to achieve high quality across multiple domains was also evaluated. Among 114 transplant programs that performed a total of 44 554 transplants, the mean (SD) 1-year graft and patient survival was 90.3% (3.0%) with a total range of 75.9% to 96.6%. The mean (SD) waiting list mortality rate was 16.7 (6.1) deaths per 100 person-years, with a total range of 6.3 to 53.0 deaths per 100 person years. The mean (SD) marginal graft use rate was 15.8 (8.8) donors per 100 transplants, with a total range of 0 to 49.3 donors. There was no correlation between 1-year graft and patient survival and waiting list mortality (β = -0.053; P = .19) or marginal graft use (β = -0.007; P = .84) after correcting for mean allocation Model for End Stage Liver Disease-Sodium scores. There were 2 transplant programs (1.8%) that performed in the top quartile on all 3 measures, while 4 transplant programs (3.6%) performed in the bottom quartile on all 3 measures. This cohort study found that among US liver transplant programs, there were no correlations among 1-year recipient outcomes, measures of program aggressiveness, or waiting list management. These findings suggest that a program's performance in one domain may be independent and unrelated to its performance on others and that the understanding of factors contributing to these domains is incomplete.

Current status: meeting the regulatory goals of your liver transplant program.

The regulatory framework set by the Organ Procurement and Transplantation Network (OPTN) and Center for Medicare and Medicaid Services (CMS) for practice of liver transplantation in US is periodically updated and risk adjusted. Therefore, it is prudent for transplant centers to know the rules of engagement as it pertains to their practice. OPTN besides providing the regulatory oversight for safe and continued practice of transplant centers, provides necessary tools like: advanced statistical models and technological platforms to aid, and guide transplant centers including the necessary safeguards for high-quality transplant care.CMS regulations although had different thresholds to flag underperformance, often covered common grounds similar to the OPTN, therefore considered duplicative and unnecessary. But with much deliberation and consideration CMS undertook a major overhaul to the final rule for re-approval applications, a giant leap in the positive direction for transplant innovation and growth. The duplicative regulatory framework of OPTN and CMS has although achieved the goal of improving 1-year patient outcomes, it has proven costly in terms of slowing innovation, increasing organ discard and stunting growth of transplant volume. But the new updates in effect and also in the pipeline are a long-awaited opportunity for waiting transplant patients.

Association of Frailty and Sex With Wait List Mortality in Liver Transplant Candidates in the Multicenter Functional Assessment in Liver Transplantation (FrAILT) Study

Female liver transplant candidates experience higher rates of wait list mortality than male candidates. Frailty is a critical determinant of mortality in patients with cirrhosis, but how frailty differs between women and men is unknown. To determine whether frailty is associated with the gap between women and men in mortality among patients with cirrhosis awaiting liver transplantation. This prospective cohort study enrolled 1405 adults with cirrhosis awaiting liver transplant without hepatocellular carcinoma seen during 3436 ambulatory clinic visits at 9 US liver transplant centers. Data were collected from January 1, 2012, to October 1, 2019, and analyzed from August 30, 2019, to October 30, 2020. At outpatient evaluation, the Liver Frailty Index (LFI) score was calculated (grip strength, chair stands, and balance). The risk of wait list mortality was quantified using Cox proportional hazards regression by frailty. Mediation analysis was used to quantify the contribution of frailty to the gap in wait list mortality between women and men. Of 1405 participants, 578 (41%) were women and 827 (59%) were men (median age, 58 [interquartile range (IQR), 50-63] years). Women and men had similar median scores on the laboratory-based Model for End-stage Liver Disease incorporating sodium levels (MELDNa) (women, 18 [IQR, 14-23]; men, 18 [IQR, 15-22]), but baseline LFI was higher in women (mean [SD], 4.12 [0.85] vs 4.00 [0.82]; P = .005). Women displayed worse balance of less than 30 seconds (145 [25%] vs 149 [18%]; P = .003), worse sex-adjusted grip (mean [SD], -0.31 [1.08] vs -0.16 [1.08] kg; P = .01), and fewer chair stands per second (median, 0.35 [IQR, 0.23-0.46] vs 0.37 [IQR, 0.25-0.49]; P = .04). In unadjusted mixed-effects models, LFI was 0.15 (95% CI, 0.06-0.23) units higher in women than men (P = .001). After adjustment for other variables associated with frailty, LFI was 0.16 (95% CI, 0.08-0.23) units higher in women than men (P < .001). In unadjusted regression, women experienced a 34% (95% CI, 3%-74%) increased risk of wait list mortality than men (P = .03). Sequential covariable adjustment did not alter the association between sex and wait list mortality; however, adjustment for LFI attenuated the mortality gap between women and men. In mediation analysis, an estimated 13.0% (IQR, 0.5%-132.0%) of the gender gap in wait list mortality was mediated by frailty. These findings demonstrate that women with cirrhosis display worse frailty scores than men despite similar MELDNa scores. The higher risk of wait list mortality that women experienced appeared to be explained in part by frailty.

Liver Transplantation in Unauthorized Immigrants in the United States.

Eleven million unauthorized immigrants reside in the United States and may account for 3% of deceased organ donors. Recently introduced federal and state legislation propose to address access to organ transplantation among unauthorized immigrants. The national landscape of liver transplantation (LT) for unauthorized immigrants is unknown. We included all US LT recipients between March 2012 and December 2018 who were linked to Pew Center of Research data to estimate the population of unauthorized immigrants in each US state and by country of origin, based on US Census data. We categorized patients as unauthorized immigrants versus US citizens/residents. The main outcome measures were (1) the proportion of LTs performed for unauthorized immigrants compared with the proportion of unauthorized immigrants among total population in each US state and (2) graft failure and death post-LT. Of 43,192 LT recipients, 43,026 (99.6%) were US citizens/residents and 166 (0.4%) were unauthorized immigrants. Among unauthorized immigrants, most LTs were performed in California (47%) and New York (18%). The absolute difference in proportion of LTs performed for unauthorized immigrants compared with the proportion of unauthorized immigrants among the total population differed among states, ranging from +20% in California to -12% in Texas. The most common countries of birth among LT recipients who were unauthorized immigrants were Mexico (52%), Guatemala (7%), China (6%), El Salvador (5%), and India (5%). In competing risk analysis, unauthorized immigration status (vs. US citizens/residents) was associated with a similar risk of graft failure (subdistribution hazard ratio [sHR] 0.74; 95% confidence interval [CI], 0.40-1.34; P=0.38) and death (sHR 0.68; 95% CI, 0.36-1.29; P=0.23). LT for unauthorized immigrants is rare, and disparities in access to LT by state are present. Patient and graft survival among unauthorized immigrants is comparable with citizens/residents.