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Introduction: Transplanting kidneys from hepatitis C virus (HCV) viremic donors into HCV-negative patients (HCV D-RNA-positive/R-negative) has evolved from experimental to “standard-of-care” at many centers. Nevertheless, most data derive from single centers and provide only short-term follow-up. Methods: The Multicenter Study to Transplant Hepatitis C-Infected Kidneys (MYTHIC) study was a multicenter (7 sites) trial of HCV D-RNA-positive/R-negative kidney transplantation (KT) followed by 8 weeks of glecaprevir/pibrentasvir (G/P) initiated 2 to 5 days post-KT. Prespecified outcomes included probability of KT (vs. matched waitlist comparators) and 1-year safety outcomes, allograft function, and survival. Results: Among 63 enrolled patients, 1-year cumulative incidence of KT was approximately 3.5-fold greater for the MYTHIC cohort versus 2055 matched United Network for Organ Sharing (UNOS) comparators who did not opt-in to receive a kidney from an HCV-viremic donor (68% vs. 19%, P < 0.0001). Of 30 HCV D-RNA-positive/R-negative KT recipients, all achieved HCV cure. None developed clinically significant liver disease or HCV-related kidney injury. Furthermore, 1-year survival was 93% and 1-year graft function was excellent (median creatinine 1.17; interquartile range [IQR]: 1.02–1.38 mg/dl). There were 4 cases of cytomegalovirus (CMV) disease among 10 CMV-negative patients transplanted with a kidney from an HCV-viremic/CMV-positive donor. Conclusion: The 1-year findings from this multicenter trial suggest that opting-in for HCV-viremic KT offers can increase probability of KT with excellent 1-year outcomes. Trial Registration: NCT03781726

Donor-derived cell-free DNA (dd-cfDNA) has been evaluated as a rejection marker in organ transplantation. This study sought to assess the utility of dd-cfDNA to diagnose graft injury in liver transplant recipients (LTR) and as a predictive biomarker prior to different causes of graft dysfunction. Plasma from single and multicenter LTR cohorts was analyzed for dd-cfDNA. Phenotypes of treated biopsy-proven acute rejection (AR, N = 57), normal function (TX, N = 94), and acute dysfunction no rejection (ADNR; N = 68) were divided into training and test sets. In the training set, dd-cfDNA was significantly different between AR versus TX (AUC 0.95, 5.3% cutoff) and AR versus ADNR (AUC 0.71, 20.4% cutoff). Using these cutoffs in the test set, the accuracy and NPV were 87% and 100% (AR vs. TX) and 66.7% and 87.8% (AR vs. ADNR). Blood samples collected serially from LTR demonstrated incremental elevations in dd-cfDNA prior to the onset of graft dysfunction (AR > ADNR), but not in TX. Dd-cfDNA also decreased following treatment of rejection. In conclusion, the serial elevation of dd-cfDNA identifies pre-clinical graft injury in the context of normal liver function tests and is greatest in rejection. This biomarker may help detect early signs of graft injury and rejection to inform LTR management strategies.

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.

This review will discuss the etiologies of kidney disease in liver transplant candidates, provide a historical background of the prior evolution of simultaneous liver–kidney (SLK) transplant indications, discuss the current indications for SLK including Organ Procurement and Transplantation Network policies and Model for End Stage Liver Disease exception points, as well as provide an overview of the safety net kidney transplant policy. Finally, the authors explore unanswered questions and future research needed in SLK transplantation.

Summary: Background: Survival of liver transplant recipients beyond 1 year since transplantation is compromised by an increased risk of cancer, cardiovascular events, infection, and graft failure. Few clinical tools are available to identify patients at risk of these complications, which would flag them for screening tests and potentially life-saving interventions. In this retrospective analysis, we aimed to assess the ability of deep learning algorithms of longitudinal data from two prospective cohorts to predict complications resulting in death after liver transplantation over multiple timeframes, compared with logistic regression models. Methods: In this machine learning analysis, model development was done on a set of 42 146 liver transplant recipients (mean age 48·6 years [SD 17·3]; 17 196 [40·8%] women) from the Scientific Registry of Transplant Recipients (SRTR) in the USA. Transferability of the model was further evaluated by fine-tuning on a dataset from the University Health Network (UHN) in Canada (n=3269; mean age 52·5 years [11·1]; 1079 [33·0%] women). The primary outcome was cause of death, as recorded in the databases, due to cardiovascular causes, infection, graft failure, or cancer, within 1 year and 5 years of each follow-up examination after transplantation. We compared the performance of four deep learning models against logistic regression, assessing performance using the area under the receiver operating characteristic curve (AUROC). Findings: In both datasets, deep learning models outperformed logistic regression, with the Transformer model achieving the highest AUROCs in both datasets (p

Early elimination of tacrolimus in favor of everolimus can improve renal function in liver transplant recipients. However, as this approach increases the risk of acute rejection, it may benefit from predictive biomarkers guiding weaning. We enrolled 20 recipients on stable tacrolimus + everolimus to undergo tacrolimus withdrawal early post-liver transplant. Blood samples were collected at month 3 (withdrawal initiation), 4 (withdrawal completion), 4.5 and 6 (both everolimus alone). 15 patients did not reject and 5 had mild rejection responding to tacrolimus resumption. Before tacrolimus withdrawal, eventual rejecters had higher percentages of CD56+ NK cells and CD19+CD27+CD24+ memory B cells, and lower levels of T cells expressing the exhaustion marker PD-1. Over time, memory B cells, Ki-67+CD3+ (proliferating) cells and CD4+CD127-CD25HIGH FOXP3+ Tregs increased in rejecters. Tregs also increased in non-rejecters over time. The number of differentially expressed genes progressively increased in rejecters, particularly in mTOR, Eukaryotic Initiation Factor 2, and Neuroinflammation signaling pathways. There was no difference in anti-HLA antibodies between the groups. In summary, blood mononuclear cell and gene expression may predict successful vs. failed early tacrolimus withdrawal in liver transplant recipients. While needing validation, these preliminary findings highlight the potential for cellular and molecular biomarkers to guide decision-making during tacrolimus weaning.

Extended survival of liver transplant recipients has brought rejection management to the forefront of liver transplant research. This article discusses T-cell-mediated rejection, antibody-mediated rejection, and chronic rejection. We focus on the prevention and then discuss treatment options. Future directions of rejection management include biomarkers of rejection, which may allow for monitoring of patients who are considered high risk for rejection and detection of rejection before there is any clinical evidence to improve graft and patient survival. With improved graft life and survival of liver transplant recipients, the new frontier of rejection management focuses on immunosuppression minimization, withdrawal, and personalization.

Purpose of review Achieving operational tolerance remains a priority in liver transplantation. Although several biomarkers of tolerance and rejection have been identified, few have been reproducible and validated across centers, and therefore have yet to reach clinical practice. Here we summarize findings from prior seminal studies and review current developments in profiling the liver allograft. Recent findings Substantial efforts and progress have been made in the recent years towards the discovery of reliable biomarkers that can predict and guide successful immunosuppression withdrawal. Recent studies have also investigated the transcriptomic signatures underlying not only acute rejection but also subclinical inflammation and chronic allograft injury. Summary As new genomic and sequencing technologies continue to develop, clinical trials are underway to validate biomarkers of tolerance, as well as better understand the mechanisms of both acute and subclinical rejection, with the goal of maximizing allograft survival. Altogether, this will hopefully enable the implementation of immunosuppression withdrawal protocols into clinical practice and make operational tolerance reliably attainable in the near future.

Background Most interventions for conditions with a small cohort size, such as transplantation, are unlikely to be part of a clinical trial. When condition-specific evidence is lacking, expert consensus can offer more precise guidance to improve care. Management of cardiovascular risk in liver-transplant recipients is one example for which clinicians have, to date, adapted evidence-based guidelines from studies in the general population. However, even when consensus is achieved, implementation of practice guidance is often inadequate and protracted. We report on a novel mixed-methods approach, the Northwestern Method©, for the development of clinical-practice guidance when condition-specific evidence is lacking. We illustrate the method through the development of practice guidance for managing cardiovascular risk in liver-transplant recipients. Methods The Northwestern Method© consists of (i) adaptation of relevant, existing, evidence-based clinical-practice guidelines for the target population; (ii) consensus by experts of the proposed practice guidance; (iii) identification of barriers to guidance adherence in current practice; and (iv) recommendation for implementation and dissemination of the practice guidance. The method is based on an iterative, user-centered approach in which the needs, wants, and limitations of all end users, including patients, are attended to at each stage of the design and development process. Conclusions The Northwestern Method© for clinical-practice-guidance development uses a mixed-methods approach to bring together broad representation from multiple disciplines and practice settings to develop consensus considering the unique needs and preferences of patients, caregivers, and practitioners who are directly impacted by clinical-practice-guidance recommendations. We hypothesize that a priori involvement of end users in the guidance-development process will lead to sustainable implementation of guidance statements into clinical practice.

Living donor liver transplantation (LDLT) provides a source for transplant in the setting of the deceased donor organ shortage. Seeing as living donors do not derive any medical benefit from the procedure, fully understanding the impact of donation on donor health-related quality of life (HRQOL) is essential. A systematic search of the MEDLINE database was performed from 2008-2020, using relevant Medical Subject Headings. Articles were evaluated for study design, cohort size and follow-up time and excluded if they contained significant methodological flaws. A total of 43 articles were included: 20 (47%) were cross-sectional and 23 (53%) were longitudinal. The mean number of donors per study was 142 (range:8-578) with follow-up ranging from 12-132 months. Forty-two unique HRQOL metrics were implemented across the 43 studies, the majority of which were questionnaires. Of the 31 studies that used the Medical Outcomes Study Short Form 36 questionnaire, 9.1% of donors reported physical QOL did not return to pre-LDLT levels for at least 2 years after donation. Mental QOL remained stable or improved after LDLT, with mean mental composite scores increasing from 50 to 52 at 3 months post-LDLT in one study. The predicted probability of poor sexual desire decreased at 1-year post-LDLT (male: 0.08, female: 0.26) relative to pre-LDLT (male: 0.44, female: 0.76; P0.001) and three months post-LDLT (male: 0.35, female 0.69; P=0.001). Forty percent of donors found LDLT to be financially burdensome at 3 months and 19% at 2 years post-LDLT. Female gender and obesity were consistent predictors of worse HRQOL. Laparoscopy-assisted donor hepatectomy was associated with shorter hospitalizations than open donor hepatectomy (10.3

Sex-based differences are known to significantly contribute to outcomes in patients with chronic liver diseases; however, the role of patient sex in cirrhosis is unclear. We aimed to study the relationship between patient sex and cirrhosis.We analyzed a cohort of 20,045 patients with cirrhosis using a Chicago-wide electronic health record database that was linked with the United Network for Organ Sharing and cause of death data from the state death registry. Adjusted Cox survival analyses and competing risk analyses were performed to obtain subdistribution hazard ratios (HRs) for liver-related cause of death.Female and male patients had similar age, racial distribution, insurance status, and comorbidity status by Elixhauser score. Females had higher rates of cholestatic liver disease (17.1% vs. 6.2%, p0.001) and non-alcoholic steatohepatitis (29.8% vs. 21.2%, p0.001) than males. They were less likely to have portal hypertensive complications and had lower peak MELD-Na scores during follow-up. Female sex was associated with a decreased hazard of all-cause mortality (adjusted HR 0.85; 95% CI 0.80-0.90). This effect was attenuated when liver-related mortality was examined (subdistribution HR 0.93; 95% CI 0.87-1.00). No significant difference was noted for women who were 'ever-listed' in competing risk analyses for either all-cause mortality (subdistribution HR 1.09; 95% CI 0.88-1.35) or liver-related death (subdistribution HR 1.12; 95% CI 0.87-1.43), despite lower rates of listing (7.5% vs. 9.8%; p0.001) and transplant (3.5% vs. 5.2%; p 0.001).In this longitudinal study of patients with cirrhosis, female sex was associated with a survival advantage likely driven by lower rates of non-liver-related death. Women were not at an increased risk of liver-related death despite lower rates of listing and transplantation.Patient sex is an important contributor in many chronic diseases, including cirrhosis. Prior studies have suggested that female sex is associated with worse outcomes. We analyzed a cohort of 20,045 patients with cirrhosis using a Chicago-wide electronic health record database. Using multivariate competing risk analyses, we found that female sex in cirrhosis is actually associated with a lower risk of all-cause mortality and has no association with liver-related mortality. Our findings are novel because we show that women with cirrhosis have a similar risk of liver-related death as their male counterparts, despite lower rates of listing and transplantation.

Little is known about national practices and use of in‐person outreach clinics and telemedicine in transplantation. We initially aimed to assess contemporary use of in‐person outreach and telemedicine in liver and intestinal transplantation in the U.S. We conducted a national survey of liver and intestinal transplant programs to assess use of outreach and telemedicine from January to March of 2019. Given the coronavirus disease 2019 (COVID‐19) pandemic, we distributed a second survey wave in April 2020 to assess changes in telemedicine use. Of the 143 programs surveyed, the initial response rate was 51% (n=73) representing all 11 Organ Procurement and Transplantation Network (OPTN) regions and 29 states. Pre‐COVID‐19, a total of 42 (59%) surveyed programs had in‐person outreach clinics only while 12 (16%) programs in only 6 states used telemedicine. Centers with higher median MELD at transplant were more likely to utilize telemedicine (p=0.02). During the COVID‐19 pandemic, among 55 of the 73 original responding programs (75%) from all 11 OPTN regions, telemedicine use increased from 16% to 98% and was used throughout all phases of transplant care. Telemedicine utilization was very low prior to COVID‐19 and has increased rapidly across all phases of transplant care presenting an opportunity to advocate for sustained future use.

Noninvasive biomarker profiles of acute rejection (AR) could affect the management of liver transplant (LT) recipients. Peripheral blood was collected following LT for discovery (Northwestern University [NU]) and validation (National Institute of Allergy and Infectious Diseases Clinical Trials in Organ Transplantation [CTOT]‐14 study). Blood gene profiling was paired with biopsies showing AR or ADNR (acute dysfunction no rejection) as well as stable graft function samples (Transplant eXcellent—TX). CTOT‐14 subjects had serial collections prior to AR, ADNR, TX, and after AR treatment. NU cohort gene expression (46 AR, 45 TX) was analyzed using random forest models to generate a classifier training set (36 gene probe) distinguishing AR vs TX (area under the curve 0.92). The algorithm and threshold were locked and tested on the CTOT‐14 validation cohort (14 AR, 50 TX), yielding an accuracy of 0.77, sensitivity 0.57, specificity 0.82, positive predictive value (PPV) 0.47, and negative predictive value (NPV) 0.87 for AR vs TX. The probability score line slopes were positive preceding AR, and negative preceding TX and non‐AR (TX + ADNR) (P ≤ .001) and following AR treatment. In conclusion, we have developed a blood biomarker diagnostic for AR that can be detected prior to AR‐associated graft injury as well a normal graft function (non‐AR). Further studies are needed to evaluate its utility in precision‐guided immunosuppression optimization following LT., This study reports on a novel peripheral blood gene signature intended to distinguish acute rejection from other causes and healthy graft function in liver transplant recipients and provide early detection to inform and enhance immunosuppression management.

Hepatitis B (HBV) infection and reactivation have a significant impact on solid organ transplantation. This review summarizes past significant studies and new findings in the field, and presents the latest recommendations for HBV management in solid organ transplant population. Significant advances in antiviral therapy have resulted in improved graft outcomes and have notably reduced the need for prophylaxis with hepatitis B immunoglobin. Emerging treatment avenues such as immunotherapies and small molecules inhibitors are being developed with the intent of eradicating HBV infection. Substantial suppression of HBV is obtained with the current antiviral prophylaxis in transplant patients. This has allowed for safely expanding the donor pool to HBcAb-positive grafts with good outcomes. Novel therapies are showing a promising future for achieving functional cure for HBV.

Patients with acute-on-chronic liver failure (ACLF) can be listed for liver transplantation (LT) because LT is the only curative treatment option. We evaluated whether the clinical course of ACLF, particularly ACLF-3, between the time of listing and LT affects 1-year post-transplant survival.We identified patients from the United Network for Organ Sharing database who were transplanted within 28 days of listing and categorized them by ACLF grade at waitlist registration and LT, according to the EASL-CLIF definition.A total of 3,636 patients listed with ACLF-3 underwent LT within 28 days. Among those transplanted, 892 (24.5%) recovered to no ACLF or ACLF grade 1 or 2 (ACLF 0-2) and 2,744 (75.5%) had ACLF-3 at transplantation. One-year survival was 82.0% among those transplanted with ACLF-3 vs. 88.2% among those improving to ACLF 0-2 (p 0.001). Conversely, the survival of patients listed with ACLF 0-2 who progressed to ACLF-3 at LT (n = 2,265) was significantly lower than that of recipients who remained at ACLF 0-2 (n = 17,631) at the time of LT (83.8% vs. 90.2%, p 0.001). Cox modeling demonstrated that recovery from ACLF-3 to ACLF 0-2 at LT was associated with reduced 1-year mortality after transplantation (hazard ratio0.65; 95% CI 0.53-0.78). Improvement in circulatory failure, brain failure, and removal from mechanical ventilation were also associated with reduced post-LT mortality. Among patients60 years of age, 1-year survival was significantly higher among those who improved from ACLF-3 to ACLF 0-2 than among those who did not.Improvement from ACLF-3 at listing to ACLF 0-2 at transplantation enhances post-LT survival, particularly in those who recovered from circulatory or brain failure, or were removed from the mechanical ventilator. The beneficial effect of improved ACLF on post-LT survival was also observed among patients60 years of age.Liver transplantation (LT) for patients with acute-on-chronic liver failure grade 3 (ACLF-3) significantly improves survival, but 1-year survival probability after LT remains lower than the expected outcomes for transplant centers. Our study reveals that among patients transplanted within 28 days of waitlist registration, improvement of ACLF-3 at listing to a lower grade of ACLF at transplantation significantly enhances post-transplant survival, even among patients aged 60 years or older. Subgroup analysis further demonstrates that improvement in circulatory failure, brain failure, or removal from mechanical ventilation have the strongest impact on post-transplant survival.

This article analyzes the ethical soundness of living donor liver transplantation (LDLT) in situations where the transplant team does not consider deceased donor liver transplantation (DDLT) a clinical or timely option. Given that patients with end-stage liver disease have a high risk of death without DDLT, the option of LDLT becomes compelling and may save lives. We present 3 representative cases from our center that raise concerns over social behavior, limited time constraints for decision making, and high potential for disease recurrence that render DDLT an unlikely option. Thereafter, we discuss ethical issues for each patient, which predominantly pertain to compromises to the living donor informed consent process and the feasibility of LDLT. We conclude with recommendations regarding whether LDLT is an acceptable ethical option for those patients, which may inform clinical practice in the broader transplant community.

Risk scoring for patients with cirrhosis has evolved greatly over the past several decades. However, patients with low Model for End-Stage Liver Disease-Sodium scores still suffer from liver-related morbidity and mortality. Unfortunately, it is not clear which of these low Model for End-Stage Liver Disease-Sodium score patients would benefit from earlier consideration of liver transplantation. This article reviews the literature of risk prediction in patients with cirrhosis, identifies which patients may benefit from earlier interventions, such as transplantation, and proposes directions for future research.

Background and aims Among patients with cirrhosis awaiting liver transplantation, prediction of wait-list (WL) mortality is adjudicated by the Model for End Stage Liver Disease-Sodium (MELD-Na) score. Replacing serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) in the MELD-Na score may improve prediction of WL mortality, especially for women and highest disease severity. Approach and results We developed (2014) and validated (2015) a model incorporating eGFR using national data (n = 17,095) to predict WL mortality. Glomerular filtration rate (GFR) was estimated using the GFR assessment in liver disease (GRAIL) developed among patients with cirrhosis. Multivariate Cox proportional hazard analysis models were used to compare the predicted 90-day WL mortality between MELD-GRAIL-Na (re-estimated bilirubin, international normalized ratio [INR], sodium, and GRAIL) versus MELD-Na. Within 3 months, 27.8% were transplanted, 4.3% died on the WL, and 4.7% were delisted for other reasons. GFR as estimated by GRAIL (hazard ratio [HR] 0.382, 95% confidence interval [CI] 0.344-0.424) and the re-estimated model MELD-GRAIL-Na (HR 1.212, 95% CI 1.199-1.224) were significant predictors of mortality or being delisted on the WL within 3 months. MELD-GRAIL-Na was a better predictor of observed mortality at highest deciles of disease severity (≥ 27-40). For a score of 32 or higher (observed mortality 0.68), predicted mortality was 0.67 (MELD-GRAIL-Na) and 0.51 (MELD-Na). For women, a score of 32 or higher (observed mortality 0.67), the predicted mortality was 0.69 (MELD-GRAIL-Na) and 0.55 (MELD-Na). In 2015, use of MELD-GRAIL-Na as compared with MELD-Na resulted in reclassification of 16.7% (n = 672) of patients on the WL. Conclusion Incorporation of eGFR likely captures true GFR better than SCr, especially among women. Incorporation of MELD-GRAIL-Na instead of MELD-Na may affect outcomes for 12%-17% awaiting transplant and affect organ allocation.

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-1-reading-nilles a video presentation of this article Answer questions and earn https://www.wileyhealthlearning.com/Activity/7025330/disclaimerspopup.aspx.

Supplemental Digital Content is available in the text., Background. Chronic kidney disease (CKD) is associated with cardiovascular (CV) events, a leading complication in liver transplant recipients (LTRs). Timely subspecialty care is associated with improved clinical outcomes in patients with CKD. This study sought to assess associations between nephrology comanagement and CV events among LTRs at risk for or with CKD. Methods. LTRs with CKD plus those at risk were identified in an inception cohort at a single tertiary care network between 2010 and 2016, using electronic health record data and manual chart review. CKD was defined as estimated glomerular filtration rate

Noninvasive biomarkers distinguishing early immune activation before acute rejection (AR) could more objectively inform immunosuppression management in liver transplant recipients (LTRs). We previously reported a genomic profile distinguishing LTR with AR versus stable graft function. This current study includes key phenotypes with other causes of graft dysfunction and uses a novel random forest approach to augment the specificity of predicting and diagnosing AR.Gene expression results in LTRs with AR versus non-AR (combination of other causes of graft dysfunction and normal function) were analyzed from single and multicenter cohorts. A 70:30 approach (61 ARs; 162 non-ARs) was used for training and testing sets. Microarray data were normalized using a LT-specific vector.Random forest modeling on the training set generated a 59-probe classifier distinguishing AR versus non-AR (area under the curve 0.83; accuracy 0.78, sensitivity 0.70, specificity 0.81, positive predictive value 0.54, negative predictive value [NPV] 0.89; F-score 0.61). Using a locked threshold, the classifier performed well on the testing set (accuracy 0.72, sensitivity 0.67, specificity 0.73, positive predictive value 0.48, NPV 0.86; F-score 0.56). Probability scores increased in samples preceding AR versus non-AR, when liver function tests were normal, and decreased following AR treatment (P 0.001). Ingenuity pathway analysis of the genes revealed a high percentage related to immune responses and liver injury.We have developed a blood-based biologically relevant biomarker that can be detected before AR-associated graft injury distinct from LTR never developing AR. Given its high NPV ("rule out AR"), the biomarker has the potential to inform precision-guided immunosuppression minimization in LTRs.

Recent studies have suggested a negative impact of hepatocellular carcinoma (HCC) on sustained virologic response (SVR) to hepatitis C virus (HCV) direct acting antivirals (DAAs). We compared the effectiveness of DAAs in patients with cirrhosis, with and without HCC, and in those with HCC partially treated or untreated (PT/UT‐HCC) versus completely treated (CT‐HCC). HCC status was based on imaging 6 months before or 2 months after start of DAA therapy. Absence and presence of enhancing lesions after HCC treatment defined CT‐HCC and PT/UT‐HCC, respectively. Using minimally adjusted logistic regression, the association between the presence of HCC and SVR rates was estimated. Among the 1,457 patients with cirrhosis from HCV‐TARGET with complete virologic data (per‐protocol population) who did not undergo liver transplantation during treatment and followup, 1,300 were without HCC, 91 with CT‐HCC, and 66 with PT/UT‐HCC. Most patients were genotype 1 (81%) and treatment‐experienced (56%), 41% had history of prior decompensation, and the median pretreatment Model for End‐Stage Liver Disease was 9 (range 6‐39). The SVR rates were 91% for patients without HCC, 84% for CT‐HCC, and 80% for PT/UT‐HCC. The presence of HCC (versus not having HCC) was associated with significantly lower odds of achieving SVR (odds ratio [OR] = 0.51, 95% confidence interval [CI]: 0.33‐0.81; P = 0.003). However, among those with HCC, HCC treatment status (PT/UT‐HCC versus CT‐HCC) did not show association with SVR (OR = 0.79, 95% CI: 0.35‐1.79, P = 0.569). Conclusions: The presence of HCC reduces the likelihood of SVR by 50%, but with no evident difference in those with completely treated HCC versus partially treated/untreated HCC.

In patients with end-stage liver disease, the ability to predict recovery of renal function following liver transplantation (LT) remains elusive. However, several important clinical decisions depend on whether renal dysfunction is recoverable after LT. We used a cohort of patients undergoing LT to independently validate a published pre-LT model predictive of post-transplant renal recovery (Renal Recovery Assessment at Liver Transplant [REVERSE]: high osteopontin [OPN] and tissue inhibitor of metalloproteinases-1 [TIMP-1] levels, age 50 mL/minute/1.73 m2 after LT (reversible AKI [rAKI]) (3) eGFR > 50 mL/minute/1.73 m2 prior to and after LT (no AKI). In patients with elevated pre-LT serum levels of OPN and TIMP-1, recovery of renal function correlated with decreases in the level of both proteins. At 4 weeks post-LT (n = 77 subset), the largest decline in OPN and TIMP-1 was seen in the rAKI group. Validation of the REVERSE model in this independent data set had high area under the curve (0.78) in predicting full post-LT renal recovery (sensitivity 0.86, specificity 0.6, positive predictive value 0.81, negative predictive value 0.69). Our eGFR findings were confirmed using measured GFR. Conclusion: The REVERSE model, derived from an initial training set combining plasma biomarkers and clinical characteristics, demonstrated excellent external validation performance characteristics in an independent patient cohort using serum samples. Among patients with kidney injury pre-LT, the predictive ability of this model may prove beneficial in clinical decision-making both prior to and following transplantation.

To prevent rejection, liver transplant providers largely base their management decisions on their clinical impression and pharmacokinetics. Clinical impression relies on assessing graft function, liver enzymes, and biopsy. High immunosuppressive drug levels, although minimizing rejection, are related to significant side effects such as nephrotoxicity and metabolic syndrome, contributing to long-term morbidity and mortality. Similarly, levels that are lower than necessary can decrease the rate of side effects with a potential toll on rejection and graft survival. Herein, the authors present an update on immunosuppressive drug level monitoring and manipulation strategies according to different scenarios and time from transplant. They also provide a brief overview of next level immunosuppression monitoring strategies that aim to properly balance rejection rates with drug side effect profiles.

The average age of liver transplant donors and recipients has increased over the years. Independent of the cause of liver disease, older candidates have more comorbidities, higher waitlist mortality and higher post-transplant mortality than younger patients. However, transplant benefit may be similar in older and younger recipients, provided older recipients are carefully selected. The cohort of elderly patients transplanted decades ago is also increasingly raising issues concerning long-term exposure to immunosuppression and aging of the transplanted liver. Excellent results can be achieved with elderly donors and there is virtually no upper age limit for donors after brain death liver transplantation. The issue is how to optimise selection, procurement and matching to ensure good results with elderly donors. The impact of old donor age is more pronounced in younger recipients and patients with a high model for end-stage liver disease score. Age matching between the donor and the recipient should be incorporated into allocation policies with a multistep approach. However, age matching may vary depending on the objectives of different allocation policies. In addition, age matching must be revisited in the era of direct-acting antivirals. More restrictive limits have been adopted in donation after circulatory death. Perfusion machines which are currently under investigation may help expand these limits. In living donor liver transplantation, donor age limit is essentially guided by morbidity related to procurement. In this review we summarise changing trends in recipient and donor age. We discuss the implications of older age donors and recipients. We also consider different options for age matching in liver transplantation that could improve outcomes.

The development of human leukocyte antigen (HLA) donor-specific antibody/antibodies (DSA) is not well described in liver transplant (LT) patients undergoing immunosuppression (IS) withdrawal protocols despite the allograft risk associated with de novo DSA (dnDSA). We analyzed the development of dnDSA in 69 LT patients who received calcineurin inhibitor monotherapy and were enrolled in the ITN030ST study. Of these 69 patients, 40 stable patients were randomized to IS maintenance (n = 9) or IS minimization (n = 31). Nine of the 31 IS minimization patients achieved complete withdrawal and were free of IS. Among patients who achieved stable IS monotherapy 1 year after transplantation, the prevalence of dnDSA was 18.8%. Acute rejections and the biopsy-proven findings disqualifying patients from IS withdrawal attempt were factors associated with dnDSA development (P = 0.011 and P = 0.041, respectively). Among randomized patients, dnDSA prevalence was 51.7% after IS minimization and 66.7% in IS-free patients. dnDSA prevalence in patients on IS maintenance was 44.4%. dnDSA development during IS minimization was a risk factor for acute rejection (P = 0.015). The majority of dnDSA were against HLA-DQ antigens (78.7%). Conclusion. During the first year following transplantation, acute rejections increase the risk of developing dnDSA, so dnDSA positivity should be considered for IS withdrawal eligibility; during IS minimization, dnDSA development was associated with acute rejection, which prevented further IS withdrawal attempts.

Posttransplant lymphoproliferative disorder (PTLD) in liver transplant recipients is relatively uncommon, with an estimated incidence of 1%–3%. Retrospective reviews of liver transplant recipients have mainly reported posttransplant lymphoproliferative disorder affecting the liver, gastrointestinal tract, or lymph nodes. In this case report, we describe a 45-y-old female with a history of deceased donor liver transplantation for autoimmune hepatitis who had recurrent hospital admissions for acute pancreatitis. Ultimately, imaging revealed numerous complex pancreatic and peripancreatic masses, appearing to originate from pancreatic lymphoid tissue. Tissue biopsy later confirmed monomorphic Epstein-Barr virus-negative large B-cell lymphoma. Overall, PTLD involving the pancreas after liver transplantation is incredibly rare. The patient’s cumulative immunosuppression drug dose and time posttransplant were suspected to be her main risk factors, given that she had been exposed to several years of treatment with tacrolimus, azathioprine, mycophenolate mofetil, and prednisone. She was treated with rituximab monotherapy and later escalated to chemoimmunotherapy due to lack of response. PTLD involving the pancreas is an unusual cause of pancreatitis and should be considered in cases of recurrent pancreatitis in transplant recipients.

Immunosuppression withdrawal (ISW) is considered in liver transplant recipients (LTRs) and autoimmune hepatitis patients (AIHPs). Immunosuppressive therapy (IST) can be burdensome both financially and due to its side effect profile, making ISW an important intervention to consider. Data on patient interest in ISW would be helpful to providers in ISW decision-making. We conducted independent single-center surveys of LTR and AIHP attitudes on IST and withdrawal interest. Of 325 LTRs screened, 120 completed the survey (50% female, mean age 58 ± 14 years, mean time since transplant 8 ± 10.5 years and 79.5% Caucasian). Of 100 AIHPs screened, 45 completed the survey (77.8% female, mean age 54 ± 2 and 82.2% Caucasian). A higher percentage of AIHPs expressed concern with their IST and were interested in ISW compared with LTRs. However, over a third of LTRs were interested in ISW, particularly those with knowledge of this potential intervention. LTRs who discussed ISW with a physician were more likely to desire withdrawal (p = 0.02, OR = 2.781 (95% CI = 1.125, 6.872)). As patient interest in ISW is of growing interest, investigators should continue to assess patient-reported desires and outcomes and pursue strategies to achieve immunological tolerance.

Objective Autoimmune hepatitis (AIH) is a chronic liver disease associated with impaired regulatory T cell (Treg) number and function. Erythropoietin (EPO) is a kidney-produced erythropoietic hormone that has known immune-modulating effects, including Treg induction. Whether EPO administration increases Treg in patients with AIH is unknown. Methods We treated six stable AIH patients with a single 1000 IU dose of EPO and comprehensively characterized changes in Treg overall and in Treg subsets before and at 4 and 12 weeks after treatment using mass cytometry (CyTOF) combined with an unbiased clustering approach (Phenograph) based on 22 Treg-relevant cell-surface markers. Results EPO was well-tolerated and no patients showed significant changes in hematological parameters, liver enzymes, or IgG levels from baseline to 12 weeks following EPO administration. Total Treg and Treg/CD8+ T cell ratios significantly increased at 4 weeks and returned to baseline levels at 12 weeks after EPO injection. We identified 17 Treg subsets of which CD4+CD25HICD127NEG HLADR+ Treg had the highest increase and the most favorable Treg/CD8+ ratio upon EPO treatment. At 12 weeks after EPO administration, the HLADR+ Treg subset also returned to values comparable to those at baseline. Ex vivo assays documented that Treg were functional and the ones isolated at 12 weeks after EPO injection were significantly more suppressive than the ones isolated at baseline. In Treg-depleted assays, EPO did not show a significant effect on IFN-γ+, IL-2+, and IL-17+ CD4+ T cells. Conclusion In stable AIH patients, EPO increases overall Treg and particularly those expressing the high function marker HLA-DR. These results provide the rationale for future studies testing the hypothesis that EPO or EPO analogues improve outcomes of AIH patients by increasing Treg.

BACKGROUND AND AIMS Estimates of racial disparity in cirrhosis have been limited by lack of large-scale, longitudinal data, which track patients from diagnosis to death and/or transplant. APPROACH AND RESULTS We analyzed a large, metropolitan, population-based electronic health record data set from seven large health systems linked to the state death registry and the national transplant database. Multivariate competing risk analyses, adjusted for sex, age, insurance status, Elixhauser score, etiology of cirrhosis, HCC, portal hypertensive complication, and Model for End-Stage Liver Disease-Sodium (MELD-Na), examined the relationship between race, transplant, and cause of death as defined by blinded death certificate review. During the study period, 11,277 patients met inclusion criteria, of whom 2,498 (22.2%) identified as Black. Compared to White patients, Black patients had similar age, sex, MELD-Na, and proportion of alcohol-associated liver disease, but higher comorbidity burden, lower rates of private insurance, and lower rates of portal hypertensive complications. Compared to White patients, Black patients had the highest rate all-cause mortality and non-liver-related death and were less likely to be listed or transplanted (P

Exhaustion of T cells limits their ability to clear chronic infections or eradicate tumors. Here, in the context of transplant, we investigated whether T cell exhaustion occurs and has a role in determining transplant outcome. A peptide/MHC tetramer-based approach was used to track exhausted CD8(+) T cells in a male-to-female skin transplant model. Transplant of large whole-tail skins, but not small tail skins (0.8 cm × 0.8 cm), led to exhaustion of anti-male tetramer(+) CD8(+) T cells and subsequently the acceptance of skin grafts. To study CD4(+) T cell exhaustion, we used the TCR-transgenic B6 TEa cells that recognize a major transplant antigen I-Eα from Balb/c mice. TEa cells were adoptively transferred either into B6 recipients that received Balb/c donor skins or into CB6F1 mice that contained an excessive amount of I-Eα antigen. Adoptively transferred TEa cells in skin-graft recipients were not exhausted. By contrast, virtually all adoptively transferred TEa cells were exhausted in CB6F1 mice. Those exhausted TEa cells lost ability to reject Balb/c skins upon further transfer into lymphopenic B6.Rag1(−/−) mice. Hence, T cell exhaustion develops in the presence of abundant antigen and promotes transplant acceptance. These findings are essential for better understanding the nature of transplant tolerance.

Individuals with kidney failure are at increased risk of cardiovascular events, as well as infections and malignancies, but the associated immunological abnormalities are unclear. We hypothesized that the uremic milieu triggers a chronic inflammatory state that, while accelerating atherosclerosis, promotes T cell exhaustion, impairing effective clearance of pathogens and tumor cells. Clinical and demographic data were collected from 78 patients with chronic kidney disease (CKD) (n = 42) or end-stage kidney disease (ESKD) (n = 36) and from 18 healthy controls (HC). Serum cytokines were analyzed by Luminex. Immunophenotype of T cells was performed by flow cytometry on peripheral blood mononuclear cells. ESKD patients had significantly higher serum levels of IFN-γ, TNF-α, sCD40L, GM-CSF, IL-4, IL-8, MCP-1, and MIP-1β than CKD and HC. After mitogen stimulation, both CD4+ and CD8+ T cells in ESKD group demonstrated a pro-inflammatory phenotype with increased IFN-γ and TNF-α, whereas both CKD and ESKD patients had higher IL-2 levels. CKD and ESKD were associated with increased frequency of exhausted CD4+ T cells (CD4+KLRG1+PD1+CD57−) and CD8+ T cells (CD8+KLRG1+PD1+CD57−), as well as anergic CD4+ T cells (CD4+KLRG1−PD1+CD57−) and CD8+ T cells (CD8+KLRG1−PD1+CD57−). Although total percentage of follicular helper T cell (TFH) was similar amongst groups, ESKD had reduced frequency of TFH1 (CCR6−CXCR3+CXCR5+PD1+CD4+CD8−), but increased TFH2 (CCR6−CXCR3−CXCR5+PD1+CD4+CD8−), and plasmablasts (CD3−CD56−CD19+CD27highCD38highCD138−). In conclusion, kidney failure is associated with pro-inflammatory markers, exhausted T cell phenotype, and upregulated TFH2, especially in ESKD. These immunological changes may account, at least in part, for the increased cardiovascular risk in these patients and their susceptibility to infections and malignancies.

BACKGROUND The vast majority of patients with cirrhosis have low Model for End-Stage Liver Disease-Sodium (MELD-Na) scores; however, the ability for the MELD-Na score to predict patient outcomes at low scores is unclear. METHODS Adult patients in a multicenter, Chicago-wide database of medical records with International Classification of Disease, Ninth Edition codes of cirrhosis and without a history of hepatocellular carcinoma were included. Records were linked with the state death registry, and death certificates were manually reviewed. Deaths were classified as "liver-related," "non-liver-related," and "non-descript" as adjudicated by a panel comprised of a transplant surgeon, a hepatologist, and an internist. A sensitivity analysis was performed where patients with hepatocellular carcinoma were included. RESULTS Among 7922 identified patients, 3999 patients had MELD-Na scores that were never higher than 15. In total, 2137 (27%) patients died during the study period with higher mortality rates for the patients in the high MELD-Na group (19.4 (41.6%) versus 4.1 (12.6%) per 100 person-y, P < 0.001). The high MELD-Na group died of a liver-related cause in 1142 out of 1632 (70%) as compared to 240 out of 505 (47.5%) deaths in the low MELD-Na group. There was no difference in the distribution of subcategory of liver-related death between low and high MELD-Na groups. Among subclassification of liver-related deaths, the most common cause of death was "Infectious" in both groups. CONCLUSIONS Despite persistently low MELD-Na scores, patients with cirrhosis still experience high rates of liver-related mortality.

The International Workshop on Clinical Transplant Tolerance is a biennial meeting that aims to provide an update on the progress of studies of immunosuppression minimization or withdrawal in solid organ transplantation. The Fourth International Workshop on Clinical Tolerance was held in Pittsburgh, Pennsylvania, September 5-6, 2019. This report is a summary of presentations on the status of clinical trials designed to minimize or withdraw immunosuppressive drugs in kidney, liver, and lung transplantation without subsequent evidence of rejection. All protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. The workshop also included presentations of mechanistic studies designed to improve understanding of the cellular and molecular basis of tolerance and to identify potential predictors/biomarkers of tolerance. Strategies to enhance the safety of hematopoietic cell transplantation and to improve patient selection/risk stratification for clinical trials were also discussed.

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.

The pathogenesis of primary sclerosing cholangitis (PSC), a progressive biliary tract disease without approved medical therapy, is not well understood. The relationship between PSC and inflammatory bowel disease has inspired theories that intestinal factors may contribute to the development and progression of hepatobiliary fibrosis in PSC. There is evidence from both fecal and mucosa-associated microbial studies that patients with PSC harbor an abnormal enteric microbiome. These organisms are thought to produce toxic byproducts that stimulate immune-mediated damage of hepatocytes and the biliary tree. The link between these mechanisms may be related to altered intestinal permeability leading to migration of bacteria or associated toxins to the liver through the portal circulation. In support of these concepts, early trials have demonstrated improved biochemical parameters and symptoms of PSC with oral antibiotics, ostensibly through manipulation of the enteric microbiota. This article reviews the published literature for evidence as well as gaps in knowledge regarding these mechanisms by which intestinal aberrations might drive the development of PSC. We also identify areas of future research that are needed to link and verify these pathways to enhance diagnostic and therapeutic approaches.

Donor-derived infections are defined as any infection present in the donor that is transmitted to 1 or more recipients. Donor-derived infections can be categorized into 2 groups: "expected" and "unexpected" infections. Expected transmissions occur when the donor is known to have an infection, such as positive serology for cytomegalovirus, Epstein Barr virus, or hepatitis B core antibody, at the time of donation. Unexpected transmissions occur when a donor has no known infection before donation, but 1 or more transplant recipients develop an infection derived from the common donor. Unexpected infections are estimated to occur in far less than 1% of solid organ transplant recipients. We will review the epidemiology, risk factors, and approaches to prevention and management of donor-derived viral infectious disease transmission in liver transplantation.

Interferon treatment of hepatitis C virus (HCV) infection after liver transplantation (LT) can result in immune-mediated graft dysfunction (IGD). The occurrence of, risk factors for, and outcomes of IGD with direct-acting antiviral (DAA) therapy have not been reported. We conducted a multicenter study of HCV+LT recipients who did or did not develop DAA-IGD (1 case: 2 controls-33 vs 66). Among all treated between 2014 and 2016, DAA-IGD occurred in 3.4% (33/978). IGD occurred only after treatment completion (76.0 [IQR, 47.0;176]). Among those treated, 48% had plasma cell hepatitis, 36% acute cellular rejection, 6% chronic rejection, and 9% combined findings. Median time to liver enzyme resolution was 77.5 days (IQR, 31.5;126). After diagnosis, hospitalizations, steroid-induced hyperglycemia, and infection occurred in a higher percentage of cases vs controls (33% vs 7.5%, 21% vs 1.5%, 9% vs 0%; all P < .05). Only one IGD patient died and none required retransplant. A multivariate regression analysis found that liver enzyme elevations during and soon after DAA therapy completion correlated with subsequent IGD. In conclusion, while DAA-IGD is uncommon, liver enzyme elevations during or after DAA therapy may be a sign of impending IGD. These indicators should guide clinicians to diagnose and treat IGD early before the more deleterious later clinical presentation.

Effective immunosupression management is central to achieving optimal outcomes in liver transplant recipients. Current immunosuppression regimens and agents are highly effective in minimizing graft loss due to acute and chronic rejection but can also produce a substantial array of toxicities. The utilization of immunosuppression varies widely, contributing to the wide disparities in posttransplant outcomes reported between transplant centers. The International Liver Transplantation Society (ILTS) convened a consensus conference, comprised of a global panel of expert hepatologists, transplant surgeons, nephrologists, and pharmacologists to review the literature and experience pertaining to immunosuppression management to develop guidelines on key aspects of immunosuppression. The consensus findings and recommendations of the ILTS Consensus guidelines on immunosuppression in liver transplant recipients are presented in this article.

Baseline resistance-associated substitutions (RASs) have variable impacts in clinical trials but their prevalence and impact in real-world patients remains unclear. We performed baseline resistance testing using a commercial assay (10% cutoff) for 486 patients treated with LDV/SOF or SMV/SOF, with or without ribavirin, in the multi-center, observational HCV-TARGET cohort. Linkage of RASs was evaluated in selected samples using a novel quantitative single variant sequencing assay. Our results showed that the prevalence of NS3, NS5A, NS5B RASs was 45%, 13%, and 8%, respectively, and 10% of patients harbored RASs in 2 or more drug classes. Baseline LDV RASs in GT1a, TE, and cirrhosis LDV/SOF subgroup was associated with 2–4% lower SVR12 rates. SMV RASs was associated with lower SVR12 rates in GT1a, treatment-experienced, cirrhotics SMV/SOF subgroup. Pooled analysis of all patients with baseline RASs revealed that SVR12 was 100% (19/19) in patients treated for longer than 98 days but was 87% (81/93) in patients treated for shorter than 98 days. These results demonstrate that RASs prevalence and their impact in real world practice are in general agreement with registration trials, and suggest that longer treatment duration may overcome the negative impact of baseline RASs on SVR12 rates in clinical practice.

High out-of-pocket medication costs negatively impact adherence in transplantation. We evaluated the association of "medication trade-offs"-defined as choosing to spend money on other expenses over medications-with medication nonadherence and transplant outcomes. From 2011 to 2012, we performed a prospective study of 201 transplanted recipients (n = 103 liver, n = 98 kidney and) at two large US transplant centers. Structured interviews assessed socio-demographics, medication adherence, and medication trade-offs. Multivariable models assessing risk factors for medications trade-offs and the association between medications trade-offs and post-transplant hospital admissions were performed. A total of 17% of patients reported medication trade-offs; the most common trade-offs were inability to afford a prescription in the past 12 months and making choices between prescriptions and food. In multivariable analysis, insurance type (RR: 2.97, 95% CI: 1.19-7.40), limited health literacy (RR: 2.64, 95% CI: 1.23-5.64), and ≥3 comorbid conditions (RR: 2.48, 95% CI: 1.09-5.62; all P < 0.05) were associated with trade-offs. Patients with trade-offs were more likely to report nonadherence to medications (mean adherence: 77 ± 23% with trade-offs vs. 89 ± 19% without trade-offs, P < 0.01). The presence of medication trade-offs was associated with post-transplant hospital admissions (RR 1.64, 95% CI 1.14-2.35, P < 0.01). Assessments of financial barriers are warranted in clinical practice to identify nonadherence and improve post-transplant outcomes.

The focus in liver transplantation in the next 10 years will likely change from preventing viral disease recurrence to minimizing the toll of rejection and fatty liver disease, minimizing the complications from immunosuppression with withdrawal strategies, and more optimal management of long-term risks, such as malignancy, cardiovascular disease, and renal failure. In addition, now that short-term results (

The availability of direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) infection has resulted in a profound shift in the approach to the management of this infection. These changes have affected the practice of solid organ transplantation by altering the framework by which patients with end-stage organ disease are managed and receive organ transplants. The high level of safety and efficacy of these medications in patients with chronic HCV infection provides the opportunity to explore their use in the setting of transplanting organs from HCV-viremic patients into non-HCV-viremic recipients. Because these organs are frequently discarded and typically come from younger donors, this approach has the potential to save lives on the solid organ transplant waitlist. Therefore, an urgent need exists for prospective research protocols that study the risk versus benefit of using organs for hepatitis C-infected donors. In response to this rapidly changing practice and the need for scientific study and consensus, the American Society of Transplantation convened a meeting of experts to review current data and develop the framework for the study of using HCV viremic organs in solid organ transplantation.

Data outside of clinical trials with direct-acting antiviral regimens with or without ribavirin as treatment of chronic hepatitis C virus in solid organ transplant recipients are limited. Liver transplant (LT), kidney transplant (KT), and dual liver kidney (DLK) transplant recipients from the Hepatitis C Therapeutic Registry and Research Network database, a multicenter, longitudinal clinical care treatment cohort, treated with direct-acting antiviral regimens between January 1, 2014, and February 15, 2016, were included to assess safety and efficacy. Included were 443 posttransplant patients (KT = 60, LT = 347, DLK = 36); 42% had cirrhosis, and 54% had failed prior antiviral therapy. Most had genotype (GT) 1 (87% with 52% GT1a, 27% GT1b, and 8% GT1 no subtype) and were treated with sofosbuvir (SOF)/ledipasvir ± ribavirin (85%) followed by SOF + daclatasvir ± ribavirin (9%) and ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (6%). Rates of sustained virologic response (SVR) at 12 weeks were available on 412 patients, and 395 patients (95.9%) achieved SVR at 12 weeks: 96.6%, 94.5%, and 90.9% among LT, KT, and DLK transplant recipients, respectively. Ribavirin did not influence SVR rates and was more often used in those with higher BMI, higher estimated glomerular filtration rate and lower creatinine. Female gender, baseline albumin ≥3.5 g/dL, baseline total bilirubin ≤1.2 mg/dL, absence of cirrhosis, and hepatic decompensation predicted SVR at 12 weeks. Six episodes of acute rejection (n = 2 KT, 4 LT) occurred, during hepatitis C virus treatment in 4 and after cessation of treatment in 2. Conclusion In a large prospective observational cohort study, direct-acting antiviral therapy with SOF/ledipasvir, ombitasvir/paritaprevir/ritonavir + dasabuvir, and SOF plus daclatasvir was efficacious and safe in LT, KT, and DLK transplant recipients; ribavirin did not influence SVR, and graft rejection was rare. (Hepatology 2017;66:1090-1101).

Biomarker profiles of acute rejection in liver transplant recipients could enhance the diagnosis and management of recipients. Our aim was to identify diagnostic proteoform signatures of acute rejection in circulating immune cells, using an emergent "top-down" proteomics methodology. We prepared differentially processed and cryopreserved cell lysates from 26 nonviral liver transplant recipients by molecular weight-based fractionation and analyzed them by mass spectrometry of whole proteins in three steps: (i) Nanocapillary liquid chromatography coupled with high-resolution tandem mass spectrometry; (ii) database searching to identify and characterize intact proteoforms; (iii) data processing through a hierarchical linear model matching the study design to quantify proteoform fold changes in patients with rejection versus normal liver function versus acute dysfunction without rejection. Differentially expressed proteoforms were seen in patients with rejection versus normal and nonspecific controls, most evidently in the cell preparations stored in traditional serum-rich media. Mapping analysis of these proteins back to genes through gene ontology and pathway analysis tools revealed multiple signaling pathways, including inflammation mediated by cytokines and chemokines. Larger studies are needed to validate these novel rejection signatures and test their predictive value for use in clinical management.