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BACKGROUND AND AIMS: In otherwise near-normal appearing biopsies by routine light microscopy, next-generation pathology (NGP) detected close pairings (immune pairs; iPAIRs) between lymphocytes and antigen-presenting cells (APCs) that predicted immunosuppression weaning failure in pediatric liver transplant (LTx) recipients (Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients [iWITH], NCT01638559). We hypothesized that NGP-detected iPAIRs enrich for true immune synapses, as determined by nuclear shape metrics, intercellular distances, and supramolecular activation complex (SMAC) formation. APPROACH AND RESULTS: Intralobular iPAIRs (CD45 high lymphocyte-major histocompatibility complex II + APC pairs; n = 1167, training set) were identified at low resolution from multiplex immunohistochemistry-stained liver biopsy slides from several multicenter LTx immunosuppression titration clinical trials (iWITH; NCT02474199 (Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction (ARTEMIS); Prospective Longitudinal Study of iWITH Screen Failures Secondary to Histopathology). After excluding complex multicellular aggregates, high-resolution imaging was used to examine immune synapse formation ( n = 998). By enriching for close intranuclear lymphocyte-APC distance (mean: 0.713 μm) and lymphocyte nuclear flattening (mean ferret diameter: 2.1), SMAC formation was detected in 29% of iPAIR-engaged versus 9.5% of unpaired lymphocytes. Integration of these morphometrics enhanced NGP detection of immune synapses (ai-iSYN). Using iWITH preweaning biopsies from eligible patients ( n = 53; 18 tolerant, 35 nontolerant; testing set), ai-iSYN accurately predicted (87.3% accuracy vs. 81.4% for iPAIRs; 100% sensitivity, 75% specificity) immunosuppression weaning failure. This confirmed the presence and importance of intralobular immune synapse formation in liver allografts. Stratification of biopsy mRNA expression data by immune synapse quantity yielded the top 20 genes involved in T cell activation and immune synapse formation and stability. CONCLUSIONS: NGP-detected immune synapses (subpathological rejection) in LTx patients prior to immunosuppression reduction suggests that NGP-detected (allo)immune activity usefulness for titration of immunosuppressive therapy in various settings.

IntroductionDonation after circulatory death (DCD) liver transplantation (LT) makes up well less than 1% of all LTs with a Model for End-Stage Liver Disease (MELD)≥35 in the United States. We hypothesized DCD-LT yields acceptable ischemia-reperfusion and reasonable outcomes for recipients with MELD≥35.MethodsWe analyzed recipients with lab-MELD≥35 at transplant within the UCSF (n=41) and the UNOS (n=375) cohorts using multivariate Cox regression and propensity score matching.ResultsIn the UCSF cohort, five-year patient survival was 85% for DCD-LTs and 86% for matched-Donation after Brain Death donors-(DBD) LTs (p=0.843). Multivariate analyses showed that younger donor/recipient age and more recent transplants (2011-2021 versus 1999-2010) were associated with better survival. DCD vs. DBD graft use did not significantly impact survival (HR: 1.2, 95%CI 0.6-2.7). The transaminase peak was approximately doubled, indicating suggesting an increased ischemia-reperfusion hit. DCD-LTs had a median post-LT length of stay of 11 days, and 34% (14/41) were on dialysis at discharge versus 12 days and 22% (9/41) for DBD-LTs. 27% (11/41) DCD-LTs versus 12% (5/41) DBD-LTs developed a biliary complication (p=0.095). UNOS cohort analysis confirmed patient survival predictors, but DCD graft emerged as a risk factor (HR: 1.5, 95%CI 1.3-1.9) with five-year patient survival of 65% versus 75% for DBD-LTs (p=0.016). This difference became non-significant in a sub-analysis focusing on MELD 35-36 recipients. Analysis of MELD≥35 DCD recipients showed that donor age of

Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (Tregs) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen-reactive Treg (darTreg) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darTreg infusion, 5 received darTregs, and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 106 cells. darTreg infusion was not associated with adverse events. Two darTreg-infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darTregs. Mechanistic studies revealed generalized Treg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of Treg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.

For pediatric liver transplant (LT) recipients, an ideal outcome is to survive and thrive into adulthood. However, outcomes reporting for all LT recipients typically rely on much shorter-term outcomes, 1-5 years post-LT. Using Organ Procurement and Transplantation Network (OPTN) registry data from 1990 to 2018, this analysis seeks to determine if long-term follow-up and outcome data are complete for pediatric LT recipients age 0 to 12 years who survive at least 1 year post-LT without graft loss (n = 9309). Of the 7948 pediatric transplant recipients who did not die or require re-LT, 1 in 6 was reported as lost to follow-up by their transplant center during long-term follow-up. Rates of lost to follow-up were highest in those transplanted between 1990 and 1999 and increased in early adulthood for all recipients. Almost 10% of pediatric LT recipients who remained in follow-up required relisting for LT. 8% of children remaining in follow-up had graft failure. Lost to follow-up may bias estimates of long-term outcomes and risk factors for poor outcomes. For those remaining in follow-up, graft failure and death continue to occur in the decades after LT. Continued proactive monitoring, management, and innovations are needed to truly optimize post-LT survival for all children.

BackgroundDeceased donor and recipient predictors of posttransplant steatosis/steatohepatitis and fibrosis are not well known. Our aim was to evaluate the prevalence and assess donor and recipient predictors of steatosis, steatohepatitis, and fibrosis in liver transplantation recipients.MethodsUsing the immune tolerance network A-WISH multicenter study (NCT00135694), donor and recipient demographic and clinical features were collected. Liver biopsies were taken from the donor liver at transplant, and from recipients per protocol and for-cause (ie, abnormal transaminases and to rule out rejection) and were interpreted by a central pathologist.ResultsOne hundred eighty-three paired donor/recipients liver biopsies at the time of transplant and posttransplant follow-up (median time 582 d; average time to last biopsies was 704 d [SD ± 402 d]) were analyzed. Donor steatosis did not influence recipient steatosis or fibrosis. Ten of 183 recipients had steatohepatitis on the last biopsy. Recipient body mass index at the time of liver biopsy was the most influential factor associated with posttransplant steatosis. Both donor and recipient metabolic syndrome features were not associated with graft steatosis. Untreated hepatitis C viral (HCV) infection was the most influential factor associated with the development of allograft fibrosis.ConclusionsIn a large experience evaluating paired donor and recipient characteristics, recipient body mass index at the time of liver biopsy was most significantly associated with posttransplant steatosis. Untreated HCV etiology influenced graft fibrosis. Thus relative to untreated HCV, hepatic fibrosis in those with steatosis/steatohepatitis is less common though long-term follow-up is needed to determine the course of posttransplant fibrosis. Emphasis on recipient weight control is essential.

Autoimmune hepatitis (AIH) is a poorly understood, chronic disease, for which corticosteroids are still the mainstay of therapy and most patients undergo liver biopsy to obtain a diagnosis. We aimed to determine if there was a transcriptomic signature of AIH in the peripheral blood and investigate underlying biologic pathways revealed by gene expression analysis. Whole blood RNA from 75 AIH patients and 25 healthy volunteers was extracted and sequenced. Differential gene expression analysis revealed 249 genes that were significantly differentially expressed in AIH patients compared to controls. Using a random forest algorithm, we determined that less than 10 genes were sufficient to differentiate the two groups in our cohort. Interferon signaling was more active in AIH samples compared to controls, regardless of treatment status. Pegivirus sequences were detected in five AIH samples and 1 healthy sample. The gene expression data and clinical metadata were used to determine 12 genes that were significantly associated with advanced fibrosis in AIH. AIH patients with a partial response to therapy demonstrated decreased evidence of a CD8+ T cell gene expression signal. These findings represent progress in understanding a disease in need of better tests, therapies, and biomarkers.

Long-term immunosuppression (IS) leads to systemic complications affecting health-related quality of life (HRQOL) in pediatric liver transplantation (LT) recipients. We serially assessed HRQOL using the PedsQL Generic and Multidimensional Fatigue Scales and Family Impact and Transplant Modules as part of a multicenter prospective immunosuppression withdrawal (ISW) trial between 2012 and 2018. Participants received a primary LT ≥4 years before the study and were on stable IS with normal liver tests and without rejection in the prior 2 years. IS was withdrawn in 7 steps over 36 to 48 weeks. HRQOL was assessed at regular intervals. The primary endpoint was change in disease-specific HRQOL measured by the PedsQL Transplant Module. Generic HRQOL was measured by the PedsQL Generic Scale and was compared with an age-matched and sex-matched multicenter cohort. Of the 88 participants, 39 were boys, median age was 11 years (range, 8-13), and time since transplant was 9 years (range, 6-11). For 36 months, disease-specific HRQOL improved for all participants, whereas generic HRQOL was unchanged. Neither generic nor disease-specific HRQOL changed for the 35 participants who developed acute rejection during ISW. In the first use of patient-reported outcome measures during an ISW trial, we found improvements in disease-specific HRQOL in all participants and no lasting detrimental effects in those who experienced rejection.

Background: Scoring systems have been proposed to select donation after circulatory death (DCD) donors and recipients for liver transplantation (LT). We hypothesized that complex scoring systems derived in large datasets might not predict outcomes locally. Methods: Based on 1-year DCD-LT graft survival predictors in multivariate logistic regression models, we designed, validated, and compared a simple index using the University of California, San Francisco (UCSF) cohort (n = 136) and a universal-comprehensive (UC)-DCD score using the United Network for Organ Sharing (UNOS) cohort (n = 5,792) to previously published DCD scoring systems. Results: The total warm ischemia time (WIT)-index included donor WIT (dWIT) and hepatectomy time (dHep). The UC-DCD score included dWIT, dHep, recipient on mechanical ventilation, transjugular-intrahepatic-portosystemic-shunt, cause of liver disease, model for end-stage liver disease, body mass index, donor/recipient age, and cold ischemia time. In the UNOS cohort, the UC-score outperformed all previously published scores in predicting DCD-LT graft survival (AUC: 0.635 vs. ≤0.562). In the UCSF cohort, the total WIT index successfully stratified survival and biliary complications, whereas other scores did not. Conclusion: DCD risk scores generated in large cohorts provide general guidance for safe recipient/donor selection, but they must be tailored based on non-/partially-modifiable local circumstances to expand DCD utilization.

BackgroundAlthough hospital systems have largely halted elective surgical practices in preparing their response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, transplantation remains an essential and lifesaving surgical practice. To continue transplantation while protecting immunocompromised patients and health care workers, significant restructuring of normal patient care practice habits is required.MethodsThis is a nonrandomized, descriptive study of the abdominal transplant program at 1 academic center (University of California, San Francisco) and the programmatic changes undertaken to safely continue transplantations. Patient transfers, fellow use, and patient discharge education were identified as key areas requiring significant reorganization.ResultsThe University of California, San Francisco abdominal transplant program took an early and aggressive approach to restructuring inpatient workflows and health care worker staffing. The authors formalized a coronavirus disease 2019 (COVID-19) transfer system to address patients in need of services at their institution while minimizing the risk of SARS-CoV-2 in their transplant ward and used technological approaches to provide virtual telehealth where possible. They also modified their transplant fellow staffing and responsibilities to develop an adequate backup system in case of potential exposures.ConclusionEvery transplant program is unique, and an individualized plan to adapt and modify standard clinical practices will be required to continue providing essential transplantation services. The authors' experience highlights areas of attention specific to transplant programs and may provide generalizable solutions to support continued transplantation in the COVID-19 era.

BackgroundThe novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease has transformed innumerable aspects of medical practice, particularly in the field of transplantation.Main bodyHere we describe a single-center approach to creating a generalizable, comprehensive, and graduated set of recommendations to respond in stepwise fashion to the challenges posed by these conditions, and the underlying principles guiding such decisions.ConclusionsCreation of a stepwise plan will allow transplant centers to respond in a dynamic fashion to the ongoing challenges posed by the COVID-19 pandemic.

The purpose of the STAR 2019 Working Group was to build on findings from the initial STAR report to further clarify the expectations, limitations, perceptions, and utility of alloimmune assays that are currently in use or in development for risk assessment in the setting of organ transplantation. The goal was to determine the precision and clinical feasibility/utility of such assays in evaluating both memory and primary alloimmune risks. The process included a critical review of biologically driven, state-of-the-art, clinical diagnostics literature by experts in the field and an open public forum in a face-to-face meeting to promote broader engagement of the American Society of Transplantation and American Society of Histocompatibility and Immunogenetics membership. This report summarizes the literature review and the workshop discussions. Specifically, it highlights (1) available assays to evaluate the attributes of HLA antibodies and their utility both as clinical diagnostics and as research tools to evaluate the effector mechanisms driving rejection; (2) potential assays to assess the presence of alloimmune T and B cell memory; and (3) progress in the development of HLA molecular mismatch computational scores as a potential prognostic biomarker for primary alloimmunity and its application in research trial design.

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.

The Immune Tolerance Network ITN030ST A-WISH assessed immunosuppression withdrawal in liver transplant recipients with hepatitis C or nonimmune nonviral liver disease. Of 275 recipients enrolled before transplantation, 95 were randomly assigned 4:1 to withdrawal (n = 77) or maintenance (n = 18) 1- to 2-years posttransplant. Randomization eligibility criteria included stable immunosuppression monotherapy; adequate liver and kidney function; ≤Stage 2 Ishak fibrosis; and absence of rejection on biopsy. Immunosuppression withdrawal followed an 8-step reduction algorithm with ≥8 weeks per level. Fifty-two of 77 subjects (67.5%) reduced to ≤50% of baseline dose, and 10 of 77 (13.0%) discontinued all immunosuppression for ≥1 year. Acute rejection and/or abnormal liver tests were treated with increased immunosuppression; 5 of 32 rejection episodes required a methylprednisolone bolus. The composite end point (death or graft loss; grade 4 secondary malignancy or opportunistic infection; Ishak stage ≥3; or >25% decrease in glomerular filtration rate within 24 months of randomization) occurred in 12 of 66 (18%) and 4 of 13 (31%) subjects in the withdrawal and maintenance groups. Early immunosuppression minimization is feasible in selected liver recipients, while complete withdrawal is successful in only a small proportion. The composite end point comparison was inconclusive for noninferiority of the withdrawal to the maintenance group.

Although liver biopsy is the gold standard for assessing allograft health, its attendant risk has deterred its use in routine monitoring of stable liver transplant recipients during long-term follow-up. We utilized prospectively collected data on adverse events from 2 clinical trials of immunosuppression withdrawal to quantify the risk of liver biopsy in pediatric liver transplant recipients. The trials included 451 liver biopsies in 179 children. No biopsies led to bleeding requiring transfusion or intervention, suggesting a clinically significant bleeding risk of

Background & aimsA substantial proportion of pediatric liver transplant recipients develop subclinical chronic allograft injury. We studied whether there are distinct patterns of injury based on histopathologic features and identified associated immunologic profiles.MethodsWe conducted a cross-sectional study of 157 stable, long-term pediatric recipients of transplanted livers (70 boys; > 6 years old at time of transplantation; mean, 8.9 ± 3.46 years after liver transplantation) who underwent liver biopsy analysis from August 13, 2012, through May 1, 2014. Participants had received livers from a living or deceased donor and had consistently normal results from liver tests. Liver biopsy specimens were scored by a central pathologist; an unsupervised hierarchical cluster analysis of histologic features was used to sort biopsy samples into 3 clusters. We conducted transcriptional and cytometric analyses of liver tissue samples and performed a systems biology analysis that incorporated clinical, serologic, histologic, and transcriptional data.ResultsThe mean level of alanine aminotransferase in participants was 27.6 ± 14.57 U/L, and the mean level of γ-glutamyl transferase was 17.4 ± 7.93 U/L. Cluster 1 was characterized by interface activity (n = 34), cluster 2 was characterized by periportal or perivenular fibrosis without interface activity (n = 45), and cluster 3 had neither feature (n = 78). We identified a module of genes whose expression correlated with levels of alanine aminotransferase, class II donor-specific antibody, portal inflammation, interface activity, perivenular inflammation, portal and perivenular fibrosis, and cluster assignment. The module was enriched in genes that regulate T-cell-mediated rejection (TCMR) of liver and other transplanted organs. Functional pathway analysis showed overrepresentation of TCMR gene sets for cluster 1 but not clusters 2 or 3.ConclusionIn an analysis of biopsies from an apparently homogeneous group of stable, long-term pediatric liver transplant recipients with consistently normal liver test results, we found evidence of chronic graft injury (inflammation and/or fibrosis). Biopsy samples with interface activity had a gene expression pattern associated with TCMR.

Frailty is prevalent in liver transplant candidates, but little is known of what happens to frailty after liver transplantation. We analyzed data for 214 adult liver transplant recipients who had ≥1 frailty assessment using the Liver Frailty Index (LFI) at 3- (n = 178), 6- (n = 139), or 12- (n = 107) months posttransplant (higher values=more frail). "Frail" and "robust" were defined as LFI ≥4.5 and

ObjectivesFrailty, a critical determinant of health outcomes, is most commonly assessed in patients with cirrhosis by general clinician assessment that is limited by its subjectivity. We aimed to compare the objective Liver Frailty Index (LFI), consisting of three performance-based tests (grip, chair stands, balance), with a subjective hepatologist assessment.MethodsOutpatients with cirrhosis awaiting liver transplantation (LT) underwent: (1) objective measurement using the LFI and (2) subjective clinician assessment. Spearman's correlation assessed associations between the LFI and clinician assessment; Cox regression with waitlist mortality (death/delisting for sickness); discriminative ability with Concordance(C) statistics. The net reclassification index evaluated the percentage of patients correctly reclassified by adding the LFI to the clinician assessment.ResultsOf the 529 patients with cirrhosis, median LFI was 3.8 (range 1.0-7.0) and clinician assessment was 3 (range 0-5). Correlation between LFI and the clinician assessment was modest (ρ=0.38) with high variability by hepatologist (ρ=0.26-0.70). At a median of 11 months, 102 (19%) died/were delisted. Both the LFI (hazard ratio (HR) 2.2, 95% confidence interval (CI) 1.7-2.9) and clinician assessment (HR 1.6, 95% CI 1.3-1.9) were associated with adjusted waitlist mortality risk (P

Cirrhosis is characterized by muscle wasting, malnutrition, and functional decline that confer excess mortality not well quantified by the Model for End-Stage Liver Disease (MELD) Sodium (MELDNa) score. We aimed to develop a frailty index to capture these extrahepatic complications of cirrhosis and enhance mortality prediction in patients with cirrhosis. Consecutive outpatients listed for liver transplantation at a single transplant center without MELD exceptions were assessed with candidate frailty measures. Best subset selection analyses with Cox regression identified subsets of frailty measures that predicted waitlist mortality (=death or delisting because of sickness). We selected the frailty index by balancing statistical accuracy with clinical utility. The net reclassification index (NRI) evaluated the %patients correctly reclassified by adding the frailty index to MELDNa. Included were 536 patients with cirrhosis with median MELDNa of 18. One hundred seven (20%) died/were delisted. The final frailty index consisted of: grip strength, chair stands, and balance. The ability of MELDNa and the frailty index to correctly rank patients according to their 3-month waitlist mortality risk (i.e., concordance-statistic) was 0.80 and 0.76, respectively, but 0.82 for MELDNa+frailty index together. Compared with MELDNa alone, MELDNa+frailty index correctly reclassified 16% of deaths/delistings (P = 0.005) and 3% of nondeaths/delistings (P = 0.17) with a total NRI of 19% (P < 0.001). Compared to those with robust frailty index scores (80th percentile) were more impaired by gait speed, difficulty with Instrumental Activities of Daily Living, exhaustion, and low physical activity (P < 0.001 for each).ConclusionOur frailty index for patients with cirrhosis, comprised of three performance-based metrics, has construct validity for the concept of frailty and improves risk prediction of waitlist mortality over MELDNa alone. (Hepatology 2017;66:564-574).

Pediatric liver transplant recipients arguably have the most to gain and the most to lose from discontinuing immunosuppression (IS). Whereas IS undoubtedly exerts a cumulative toll, there is concern that insufficient or no IS may contribute to allograft deterioration. Twelve pediatric recipients of parental living donor liver grafts, identified as operationally tolerant through complete IS withdrawal (WISP-R; NCT00320606), were followed for a total of 5 years (1 year of IS withdrawal and 4 years off IS) with serial liver tests and autoantibody and alloantibody assessments. Liver biopsies were performed 2 and 4 years off IS, and, at these time points, immunoglobulin G (IgG) subclass and C1q binding activity for donor-specific antibodies (DSAs) were determined. There were no cases of chronic rejection, graft loss, or death. Allografts did not exhibit progressive increase in inflammation or fibrosis. Smooth-muscle actin expression by stellate cells and CD34 expression by liver sinusoidal endothelial cells remained stable, consistent with the absence of progressive graft injury. Three subjects never exhibited DSA. However, 3 subjects showed intermittent de novo class I DSA, 4 subjects showed persistent de novo class II DSA, and 5 subjects showed persistent preexisting class II DSA. Class II DSA was predominantly against donor DQ antigens, often of high mean fluorescence intensity, rarely of the IgG3 subclass, and often capable of binding C1q.ConclusionOperationally tolerant pediatric liver transplant recipients maintain generally stable allograft histology in spite of apparently active humoral allo-immune responses. The absence of increased inflammation or progressive fibrosis suggests that a subset of liver allografts seem resistant to the chronic injury that is characteristic of antibody-mediated damage. (Hepatology 2017;65:647-660).

Purpose of reviewThe attainment of tolerance remains a highly desirable goal in recipients of kidney transplants. Achievement of this goal would extend graft survival and eradicate toxicities related to long-term immunosuppression. Understanding mechanisms of tolerance and strategies to induce tolerance - their risk/benefit profiles - is essential for future success.Recent findingsMechanistic studies of spontaneously tolerant kidney transplant recipients have uncovered potential roles for B or regulatory T cells, or both, in the maintenance of tolerance. Mixed hematopoietic chimerism has been the most commonly used approach to induce tolerance. Distinct protocols at three major transplant centers have led to successful withdrawal of immunosuppression in a subset of living donor kidney transplant recipients at the expense of complications such as infections and graft versus host disease. The addition of regulatory cell therapies to tolerance induction protocols could enhance success while minimizing complications.SummaryThis review summarizes the features of spontaneous tolerance in kidney transplant recipients, the results of clinical trials of tolerance induction in the context of living donor kidney transplant, and potential measures to improve the safety and efficacy of tolerance induction strategies.

BackgroundSarcopenia and functional impairment are common and lethal extrahepatic manifestations of cirrhosis. We aimed to determine the association between computed tomography (CT)-based measures of muscle mass and quality (sarcopenia) and performance-based measures of muscle function.MethodsAdults listed for liver transplant underwent testing of muscle function (grip strength, Short Physical Performance Battery [SPPB]) within 3 months of abdominal CT. Muscle mass (cm/m) = total cross-sectional area of psoas, paraspinal, and abdominal wall muscles at L3 on CT, normalized for height. Muscle quality = mean Hounsfield units for total skeletal muscle area at L3.ResultsAmong 292 candidates, median grip strength was 31 kg, SPPB score was 11, muscle mass was 49 cm/m, and muscle quality was 35 Hounsfield units. Grip strength weakly correlated with muscle mass (ρ = 0.26, P < 0.001) and quality (ρ = 0.27, P < 0.001) in men, and muscle quality (ρ = 0.23, P = 0.02), but not muscle mass, in women. Short Physical Performance Battery correlated weakly with muscle quality in men (ρ = 0.38, P < 0.001) and women (ρ = 0.25, P = 0.02), however, did not correlate with muscle mass in men or women. After adjustment for sex, model for end-stage liver disease (MELD)-Na, hepatocellular carcinoma, and body mass index, grip strength (hazard ratio [HR], 0.74; 95% confidence interval [95% CI], 0.59-0.92; P = 0.008), SPPB (HR, 0.89; 95% CI, 0.82-0.97; P = 0.01), and muscle quality (HR, 0.77; 95% CI, 0.63-0.95; P = 0.02) were associated with waitlist mortality, but muscle mass was not (HR, 0.91; 95% CI, 0.75-1.11; P = 0.35).ConclusionsPerformance-based tests of muscle function are only modestly associated with CT-based muscle measures. Given that they predict waitlist mortality and can be conducted quickly and economically, tests of muscle function may have greater clinical utility than CT-based measures of sarcopenia.

Background and aimsThe beneficial effect of one graft on another has been reported in combined transplantation but the associated mechanisms and biological influence of each graft have not yet been established.MethodsIn multiple analyses, we explored the PBMC phenotype and signature of 45 immune-related messenger RNAs and 754 microRNAs from a total of 235 patients, including combined liver-kidney transplant recipients (CLK), patients with a liver (L-STA) or kidney (K-STA) graft only under classical immunosuppression and patients with tolerated liver (L-TOL) or kidney grafts (K-TOL).ResultsCLK show an intermediary phenotype with a higher percentage of peripheral CD19(+) CD24(+) CD38(Low) memory B cells and Helios(+) Treg cells, two features associated with tolerance profiles, compared to L-STA and K-STA (P < 0.05, P < 0.01). Very few miRNA were significantly differentially expressed in CLK vs. K-STA and even fewer when compared to L-STA (35 and 8, P < 0.05). Finally, CLK are predicted to share common miRNA targets with K-TOL and even more with L-TOL (344 and 411, P = 0.005). Altogether CLK display an intermediary phenotype and gene profile, which is closer to that of liver transplant patients, with possible similarities with the profiles of tolerant patients.ConclusionThese data suggest that CLK patients show the immunological influence of both allografts with liver having a greater influence.

Purpose of reviewTransformative medical and surgical advances have remarkably improved short-term survival after liver transplantation. There is, however, pervasive concern that the cumulative toxicities of modern immunosuppression regimens severely compromise both quality and quantity of life for liver transplant recipients. The inherently tolerogenic nature of the liver offers the tantalizing opportunity to change the current paradigm of nonspecific and lifelong immunosuppression. Safe minimization or discontinuation of immunosuppression without damage to the liver allograft is an attractive strategy to improve long-term survival after liver transplantation.Recent findingsRecent prospective, multicenter clinical trials have demonstrated that immunosuppression can be safely withdrawn from selected liver transplant recipients with preservation of allograft histology. These successes have spurred multiple avenues of investigation to identify peripheral blood and/or tissue biomarkers and delineate mechanisms of tolerance. Concomitant advances in the ability to expand regulatory T cells in the laboratory have spawned clinical trials to facilitate immunosuppression minimization and/or discontinuation.SummaryThis review will delineate the unique liver immunobiology that has driven the recent clinical trials to unmask spontaneous tolerance or induce tolerance for liver transplant recipients. The emerging results of these trials over the next 5 years hold promise to reduce the burden of lifelong immunosuppression and thereby optimize the long-term health of liver transplant recipients.

UnlabelledCirrhosis is characterized by sarcopenia and malnutrition, leading to progressive functional decline. We aimed to objectively measure functional decline in patients with cirrhosis awaiting liver transplantation and its association with waiting list mortality. Consecutive adults listed for liver transplantation with laboratory Model for End-Stage Liver Disease (MELD) ≥12 at a single center underwent functional status assessments at every outpatient visit using the Short Physical Performance Battery (0 = impaired to 12 = robust), consisting of gait, chair stands, and balance tests. Joint linear time-to-event analyses modeled the simultaneous impact of the longitudinal trajectory of physical function on waiting list mortality (=death or delisted for being too sick for liver transplantation). Included were 309 liver transplantation candidates. Median laboratory MELD was 15, serum albumin was 3.0 g/dL, 28% had ascites, 18% had hepatic encephalopathy, and 83% were Child class B or C. At a median follow-up of 14 months, 15% died or were delisted and 28% underwent liver transplantation. Average physical function worsened per 3 months on the waiting list: -0.38 kg in grip strength, -0.05 meters/second in gait, 0.03 seconds in chair stands, and -0.16 Short Physical Performance Battery points. In joint models of longitudinal trajectories of physical function and waiting list mortality adjusted for MELD-Na, albumin, hepatocellular carcinoma, and baseline physical function, the longitudinal trajectories of each physical function measure were significantly associated with waiting list mortality: grip (hazard ratio = 0.89, 95% confidence interval 0.83-0.95), gait (hazard ratio = 0.72, 95% confidence interval 0.62-0.84), chair stands (hazard ratio = 1.17, 95% confidence interval 1.09-1.25), and Short Physical Performance Battery

Background & aimsThe US liver allocation system effectively prioritizes most liver transplant candidates by disease severity as assessed by the Model for End-Stage Liver Disease (MELD) score. Yet, one in five dies on the wait-list. We aimed to determine whether clinician assessments of health status could identify this subgroup of patients at higher risk for wait-list mortality.MethodsFrom 2012-2013, clinicians of all adult liver transplant candidates with laboratory MELD≥12 were asked at the clinic visit: 'How would you rate your patient's overall health today (0 = excellent, 5 = very poor)?' The odds of death/delisting for being too sick for the transplant by clinician-assessment score ≥3 vs. 0.05). Mean clinician assessment differed between men and women (2.3 vs. 2.6; P = 0.02). The association between clinician-assessment and MELD was ρ = 0.28 (P < 0.01). 53/347 (15%) died/were delisted. In univariable analysis, a clinician-assessment score ≥ 3 was associated with increased odds of death/delisting (2.57; 95% CI 1.42-4.66). After adjustment for MELD and age, a clinician-assessment score ≥ 3 was associated with 2.25 (95% CI 1.22-4.15) times the odds of death/delisting compared to a clinician-assessment score < 3.ConclusionsA standardized clinician assessment of health status can identify liver transplant candidates at high risk for wait-list mortality independent of MELD score. Objectifying this 'eyeball test' may inform interventions targeted at this vulnerable subgroup to optimize wait-list outcomes.

Donor age has become the dominant donor factor used to predict graft failure (GF) after liver transplantation (LT) in hepatitis C virus (HCV) recipients. The purpose of this study was to develop and validate a model of corrected donor age (CDA) for HCV LT recipients that transforms the risk of other donor factors into the scale of donor age. We analyzed all first LT recipients with HCV in the United Network for Organ Sharing (UNOS) registry from January 1998 to December 2007 (development cohort, n = 14,538) and January 2008 to December 2011 (validation cohort, n = 7502) using Cox regression, excluding early GF ( 8 hours and -1 year/hour

It is unclear whether a concomitant kidney transplant grants survival benefit to liver transplant (LT) candidates with renal dysfunction (RD). We retrospectively studied LT candidates without RD (n = 714) and LT candidates with RD who underwent either liver transplant alone (RD-LTA; n = 103) or simultaneous liver-kidney transplant (RD-SLKT; n = 68). RD was defined as renal replacement therapy (RRT) requirement or modification of diet in renal disease (MDRD)-glomerular filtration rate (GFR)

BackgroundThe proportion of older patients awaiting liver transplantation (LT) is rising. Although increased age and LT-MELD are known to increase the risk of graft loss, no studies have explored whether there is a synergistic effect between LT-age and LT-MELD.MethodsAll US adult, non-Status 1 recipients of primary deceased donor LT from 2/05 to 1/10 without MELD exceptions were included (n=15,677). Recipients were categorized by LT-age [18-59 yr (n=11,966), 60-64 yr (n=2181), 65-69 yr (n=1177), and ≥70 yr (n=343)] and LT-MELD [low (

BackgroundGeographic disparity in access to liver transplantation (LT) exists. This study sought to examine Model for End-Stage Liver Disease-era multiply listed (ML) LT candidate (ie, candidates who list at 2 or more LT centers to receive a liver transplant).Study designData on adult, primary, non-status 1 LT candidates (n = 59,557) listed from January 1, 2005 to December 31, 2011 were extracted from the United Network for Organ Sharing's Standard Transplant Analysis and Research files. Comparisons of ML vs singly listed LT candidates were performed, with additional analysis performed at the donor service area (DSA) and regional level, as well as assessment of the donor population used.ResultsThere were 1,358 (2.3%) ML candidates during the 7-year study period. Multiply listed candidates compared with singly listed candidates were more often male, white, blood type O, nondiabetic, college educated, and privately insured. The odds of pursuing ML increased considerably as time on the waitlist increased. Of the ML candidates, 918 (67.6%) went on to receive a liver transplant (ML-LT), 767 (83.6%) at the secondary listing DSA, which was a median of 588 miles (range 229 to 1095 miles) from the primary listing DSA. When compared with the primary listing DSA, the secondary listing DSA had significantly lower match Model for End-Stage Liver Disease scores, as well as shorter wait times. Regional analysis demonstrated significantly higher odds for pursuing ML from LT candidates located within regions 1, 5, and 9.ConclusionsA small and distinctive cohort of LT candidates pursue ML, indicating willingness and means to travel to receive a liver transplant. Efforts toward equalizing LT access across regional disparities are warranted, and can help obviate the need for ML.

The greatest challenge facing liver transplantation today is the shortage of donor livers. Demand far exceeds supply, and this deficit has driven expansion of what is considered an acceptable organ. The evolving standard has not come without costs, however, as each new frontier of expanded donor quality (i.e., advancing donor age, donation after cardiac death, and split liver) may have traded wait-list for post-transplant morbidity and mortality. This article delineates the nature and severity of risk associated with specific deceased donor liver characteristics and recommends strategies to maximally mitigate these risks.

This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N=260) to one of the following immunosuppressive regimens: (i) basiliximab+belatacept high dose [HD]+myc