Clinically relevant cut-points for changes in the Liver Frailty Index are associated with waitlist mortality in patients with cirrhosis.

BACKGROUND & AIMS: Physical frailty is a critical determinant of mortality in patients with cirrhosis and can be objectively measured using the Liver Frailty Index (LFI) that is potentially modifiable.. We aimed to LFI cut-points associated with waitlist mortality. APPROACH & RESULTS: Ambulatory adults with cirrhosis without HCC awaiting liver transplantation (LT) from 9 centers from 2012-2021 for ≥3 months with ≥2 pre-LT LFI assessments were included. The primary explanatory variable was change in LFI from first to second assessments per 3 months (∆LFI); we evaluated clinically-relevant ∆LFI cut-points at 0.1, 0.2, 0.3, and 0.5. The primary outcome was waitlist mortality (death or delisting for being too sick) with transplant considered as a competing event. Among 1029 patients, median (IQR) age was 58 (51-63) years; 42% were female; and median lab MELDNa at first assessment was 18 (15-22). For each 0.1 improvement in ∆LFI, risk of overall mortality decreased by 6% (cause-specific hazard ratio [cHR] 0.94, 95%CI 0.92-0.97, p < 0.001). ∆LFI was associated with waitlist mortality at cut-points as low as 0.1 (cHR 0.63, 95%CI 0.46-0.87) and 0.2 (HR 0.61, 95%CI 0.42-0.87). CONCLUSIONS: An improvement in LFI per 3 months as small as 0.1 in the pre-LT period is associated with a clinically meaningful reduction in waitlist mortality. These data provide estimates of the reduction in mortality risk associated with improvements in LFI that can be used to assess effectiveness of interventions targeting physical frailty in cirrhosis patients.

Utilizing a novel MRI technique to identify adverse muscle composition in end-stage liver disease: A pilot study.

INTRODUCTION AND OBJECTIVES: Sarcopenia is a common complication of end-stage liver disease (ESLD), but its exact relationship to myosteatosis and frailty remains unclear. In this pilot study, we tested the feasibility of a specialized MRI protocol and automated image analysis in patients with ESLD. MATERIALS AND METHODS: In a single-center prospective study, adult liver transplant candidates with ESLD underwent assessment of muscle composition between 3/2022 and 6/2022 using the AMRA® MAsS Scan. The primary outcome of interest was feasibility of the novel MRI technique in patients with ESLD. We also tested if thigh muscle composition correlated with validated measures of frailty and sarcopenia. RESULTS: Eighteen subjects (71 % male, mean age 59 years) were enrolled. The most common etiologies of cirrhosis were alcohol-related liver disease (44 %) and non-alcohol-associated fatty liver disease (33 %), with a mean MELD-Na of 13 (± 4). The mean time needed to complete the MRI protocol was 14.9 min and only one patient could not complete it due to metal hardware in both knees. Forty-one percent of patients had adverse muscle composition (high thigh fat infiltration and low-fat free muscle volume) and these patients were more likely to have undergone a recent large volume paracentesis (43 % vs. 0 %, p < 0.02). The adverse muscle composition group performed significantly worse on the 6-minute walk test compared to the remainder of the cohort (379 vs 470 m, p < 0.01). CONCLUSIONS: The AMRA® MAsS Scan is feasible to perform in patients with ESLD and can be used to quantify myosteatosis, a marker of muscle quality and potentially muscle functionality in ESLD.

Outcomes in liver transplant recipients with nonalcoholic fatty liver disease-related HCC: results from the US multicenter HCC transplant consortium.

NAFLD will soon be the most common indication for liver transplantation (LT). In NAFLD, HCC may occur at earlier stages of fibrosis and present with more advanced tumor stage, raising concern for aggressive disease. Thus, adult LT recipients with HCC from 20 US centers transplanted between 2002 and 2013 were analyzed to determine whether NAFLD impacts recurrence-free post-LT survival. Five hundred and thirty-eight (10.8%) of 4981 total patients had NAFLD. Patients with NAFLD were significantly older (63 vs. 58, p<0.001), had higher body mass index (30.5 vs. 27.4, p<0.001), and were more likely to have diabetes (57.3% vs. 28.8%, p<0.001). Patients with NAFLD were less likely to receive pre-LT locoregional therapy (63.6% vs. 72.9%, p<0.001), had higher median lab MELD (15 vs. 13, p<0.001) and neutrophil-lymphocyte ratio (3.8 vs. 2.9, p<0.001), and were more likely to have their maximum pre-LT alpha fetoprotein at time of LT (44.1% vs. 36.1%, p<0.001). NAFLD patients were more likely to have an incidental HCC on explant (19.4% vs. 10.4%, p<0.001); however, explant characteristics including tumor differentiation and vascular invasion were not different between groups. Comparing NAFLD and non-NAFLD patients, the 1, 3, and 5-year cumulative incidence of recurrence (3.1%, 9.1%, 11.5% vs. 4.9%, 10.1%, 12.6%, p=0.36) and recurrence-free survival rates (87%, 76%, and 67% vs. 87%, 75%, and 67%, p=0.97) were not different. In competing risks analysis, NAFLD did not significantly impact recurrence in univariable (HR: 0.88, p=0.36) nor in adjusted analysis (HR: 0.91, p=0.49). With NAFLD among the most common causes of HCC and poised to become the leading indication for LT, a better understanding of disease-specific models to predict recurrence is needed. In this NAFLD cohort, incidental HCCs were common, raising concerns about early detection. However, despite less locoregional therapy and high neutrophil-lymphocyte ratio, explant tumor characteristics and post-transplant recurrence-free survival were not different compared to non-NAFLD patients.

Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: Analysis of the US Multicenter HCC Transplant Consortium.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22-1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p < 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

Low Daily Step Count Is Associated With a High Risk of Hospital Admission and Death in Community-Dwelling Patients With Cirrhosis.

BACKGROUND & AIMS: Daily step count measures cardiorespiratory fitness and has been associated with clinical outcomes. However, its utility in patients with cirrhosis remains largely unexplored. We aimed to investigate the association between step count, frailty metrics, and clinical outcomes in cirrhosis. METHODS: All participants underwent frailty evaluation with the liver frailty index, 6-minute walk test, and gait speed test. To monitor step count, participants were given a personal activity tracker (PAT). A subset also was invited to use Exercise and Liver FITness (EL-FIT). Daily step counts from the first week of PAT use and frailty metrics were investigated as predictors of hospital admission and mortality. RESULTS: There were 116 patients included (age, 56 ± 11 y; male, 55%; body mass index, 31 ± 7; model for end-stage liver disease-sodium, 15 ± 7). The main etiologies of cirrhosis were alcohol-related (33%) and nonalcoholic steatohepatitis (30%). Monitoring for the week was accomplished in 80% of participants given both PAT+EL-FIT vs 62% in those with PAT only (P = .04). During follow-up evaluation, hospital admission was observed in 55% and death in 15%. Kaplan-Meir curves showed increased readmission and deaths among patients performing in the lowest quartile (ie, <1200 steps/d). When adjusted by model for end-stage liver disease-sodium and EL-FIT use, the lowest quartile was associated with hospital admission and death (hazard ratio, HR [95% confidence interval], 1.90 [1.09-3.30] and 3.46 [1.23-9.68], respectively), along with the 6-minute walk test (HR, 0.63 [0.47-0.83] and 0.66 [0.44-0.99] per 100 m, respectively) and gait speed test (HR, 0.29 [0.11-0.72] and 0.21 [0.05-0.84], respectively). CONCLUSIONS: Daily step count predicted hospital admission and mortality rates in patients with cirrhosis, similar to the current standard frailty metrics. Incorporation of a physical training-dedicated smartphone application was associated with increased PAT use and step reporting.

Back Table Preparation of the Right Lobe Live Donor Liver Allograft: A Crucial Part of the Adult Live Donor Liver Transplant Procedure.

INTRODUCTION: We aimed to describe our procedure for vascular reconstruction and back table bench preparation for the right lobe live donor allograft. Live donor liver transplantation (LDLT) remains an important option for the expansion of the donor pool. The procedure has been widely used, and its success is dependent on a technically perfect operation with appropriate inflow and outflow of the allograft. Adequate preparation of the right lobe (RL) allograft prior to implantation remains a vital part of the procedure. METHODS: Our technique of back table vascular reconstruction of the RL allograft has been performed using a hepatic vein patch venoplasty, inferior hepatic vein inclusion, portal vein reconstruction, and segment V and VIII reconstruction for all of our LDLTs. RESULTS: Between March 2009 and January 2020, 321 consecutive adult LDLTs were performed and underwent back table reconstruction with the techniques described. During that time period, no patients had hepatic insufficiency. There was a single thrombosis of a superior mesenteric vein (SMV) to PV jump conduit. CONCLUSIONS: Our technique of back table reconstruction of the LDLT right lobe graft remains a crucial part of the operative procedure. Our experience with RL grafts without middle hepatic vein (MHV) and our systematic approach for inflow and outflow reconstruction has yielded excellent results with no technical outflow issues and minimal inflow complications.

Rabbit antithymocyte globulin dose and early subclinical and clinical rejections in kidney transplantation.

Antithymocyte globulin (ATG) is a commonly used induction agent in kidney transplant recipients. However, the optimal dosing has not been well defined. Our protocol aims for a 5-6 mg/kg cumulative dose. It is unclear if a dose lower than 5 mg/kg is associated with more rejection. We performed a retrospective cohort study of patients who received a kidney transplant at our center between January 1, 2013 and December 31, 2016. Primary outcome was biopsy proven acute rejection (clinical and subclinical) in the first 6 months after kidney transplant. CMV viremia in high risk (D+/R-) recipients and BK viremia was compared as a secondary endpoint. Of the 543 patients, the Low Dose (LD) group (n = 56) received <5 mg/kg ATG and Regular Dose (RD) group (n = 487) received ≧5 mg/kg. Patients in RD were more sensitized (higher PRA and CPRA). LD received a dose of 4 ± 1.1 mg/kg ATG whereas RD received 5.6 ± .3 mg/kg ATG (P < .001). TCMR (Banff 1A or greater) was present in 34% of patients in LD versus 22% in RD (P = .04) (OR 2.1; 95%CI 1.12-3.81; P = .019). There was no difference in the incidence of CMV or BK viremia. ATG doses lower than 5 mg/kg may be associated with a heightened risk of rejection despite a low degree of sensitization.

The Clinical Impact of Anti-HLA Donor Specific Antibody Detection Through First Year Screening on Stable Kidney Transplant Recipients.

Anti-HLA Donor Specific Antibody (DSA) detection post kidney transplant has been associated with adverse outcomes, though the impact of early DSA screening on stable patients remain unclear. We analyzed impact of DSA detection through screening in 1st year stable patients (n = 736) on subsequent estimated glomerular filtration rate (eGFR), death censored graft survival (DCGS), and graft failure (graft loss including return to dialysis or re-transplant, patient death, or eGFR < 20 ml/min at last follow up). Patients were grouped using 1st year screening into DSA+ (Class I, II; n = 131) or DSA- (n = 605). DSA+ group were more DR mismatched (p = 0.02), more sensitized (cPRA ≥90%, p = 0.002), less Caucasian (p = 0.04), and had less pre-emptive (p = 0.04) and more deceased donor transplants (p = 0.03). DSA+ patients had similar eGFR (54.8 vs. 53.8 ml/min/1.73 m2, p = 0.56), DCGS (91% vs. 94%, p = 0.30), and graft failure free survival (76% vs. 82%, p = 0.11). DSA timing and type did not impact survival. Among those with a protocol biopsy (n = 515), DSA detected on 1st year screening was a predictor for graft failure on multivariate analysis (1.91, 95% CI 1.03-3.55, p = 0.04). Overall, early DSA detection in stable patients was an independent risk factor for graft failure, though only among those who underwent a protocol biopsy.

Poor Outcomes of Patients With NAFLD and Moderate Renal Dysfunction or Short-Term Dialysis Receiving a Liver Transplant Alone.

The outcomes of patients with moderate renal impairment and the impact of liver disease etiology on renal function recovery after liver transplant alone (LTA) are largely unknown. We explored whether NAFLD patients with pre-LTA moderate renal dysfunction (GFR 25-45 ml/min/1.73 m2) may be more susceptible to develop post-LTA severe renal dysfunction (GFR<15 ml/min/1.73 m2) than ALD patients, as well as other overall outcomes. Using the UNOS/OPTN database, we selected patients undergoing liver transplant for NAFLD or ALD (2006-2016), 15,103 of whom received LTA. NAFLD patients with moderate renal dysfunction were more likely to develop subsequent GFR<15 ml/min/1.73 m2 than ALD patients (11.1% vs. 7.38%, p < 0.001). Patients on short-term dialysis pre-LTA (≤12 weeks) were more likely to develop severe renal dysfunction (31.7% vs. 18.1%), especially in NAFLD patients, and were more likely to receive a further kidney transplant (15.3% vs. 3.7%) and had lower survival (48.6% vs. 50.4%) after LTA (p < 0.001 for all). NAFLD was an independent risk factor for post-LTA severe renal dysfunction (HR = 1.2, p = 0.02). NAFLD patients with moderate renal dysfunction and those receiving short-term dialysis prior to LTA are at a higher risk of developing subsequent severe renal dysfunction. Underlying etiology of liver disease may play a role in predicting development and progression of renal failure in patients receiving LTA.

Trends and impact on cold ischemia time and clinical outcomes using virtual crossmatch for deceased donor kidney transplantation in the United States.

For assessing human leukocyte antigen compatibility in deceased donor kidney transplantation, virtual crossmatch is used as an alternative to physical crossmatch and has potential to reduce cold ischemia time. The 2014 United States kidney allocation system prioritized highly sensitized candidates but led to increased shipping of kidneys. Using data from the Scientific Registry of Transplant Recipients, we evaluated changes in virtual crossmatch use with the new allocation policy and the impact of virtual crossmatch use on cold ischemia time and transplant outcomes. This was a retrospective cohort study of adult deceased donor kidney recipients in the United States (2011-2018) transplanted with either 9,632 virtual or 71,839 physical crossmatches. Before allocation change, only 9% of transplants were performed relying on a virtual crossmatch. After the 2014 allocation change, this increased by 2.4%/year so that 18% transplants in 2018 were performed with just a virtual crossmatch. There was significant variation in virtual crossmatch use among transplant regions (range 0.7-36%) and higher use was noted among large volume centers. Compared to physical crossmatches, virtual crossmatches were significantly associated with shorter cold ischemia times (mean 15.0 vs 16.5 hours) and similar death-censored graft loss and mortality (both hazard ratios HR 0.99) at a median follow-up of 2.9 years. Thus, our results show that virtual crossmatch is an attractive strategy for shortening cold ischemia time without negatively impacting transplant outcomes. Hence, strategies to optimize use and reduce practice variation may allow for maximizing benefits from virtual crossmatch.

Positive flow cytometry crossmatch with discrepant antibody testing results following COVID-19 vaccination.

The impact of COVID-19 vaccination on the alloimmunity of transplant candidates is unknown. We report a case of positive B cell flow cytometry crossmatch in a patient waiting for second kidney transplantation, 37 days after receiving the COVID-19 vaccine. The preliminary crossmatch, using sample collected before COVID-19 vaccination, was negative. The antibodies to mismatched donor HLA-DR7 were detected only with multi-antigen beads but not with single-antigen beads, excluding possible prozone effects in solid-phase antibody assays. The crossmatches were positive with HLA-DR7-positive surrogates (n = 2) while negative with HLA-DR7-negative surrogates (n = 3), which confirms the HLA-DR7 alloreactivity. The antigen configurations on B lymphocytes are similar to that on the multi-antigen beads while distinct from the single-antigen beads. HLA-DR7 was the repeating mismatched antigen with the failing first kidney allograft. The newly emerged antibody to HLA-DR7 probably is the consequence of bystander activation of memory response by the COVID-19 vaccination. This case highlights the importance of verifying allo-sensitization history and utilizing multiple assays, including cell-based crossmatch and solid-phase assays with multi-antigens. COVID-19 immunization may deserve special attention when assessing the immunological risk before and after organ transplantation.

Prehabilitation-Driven Changes in Frailty Metrics Predict Mortality in Patients With Advanced Liver Disease.

INTRODUCTION: Frailty is a predictor of morbidity and mortality in cirrhosis. Although evidence for prehabilitation is promising, the data for liver transplant (LT) candidates are limited. The primary aim of this study was to evaluate the effect of a novel prehabilitation strategy on changes in frailty metrics and survival in LT candidates. The secondary aim was to determine liver-related and extrahepatic conditions associated with frailty. METHODS: In this ambispective cohort study, all patients underwent frailty assessment using the liver frailty index (LFI), 6-minute walk test, and gait speed test performed by a dedicated physical therapist. Home-based exercise prescription was individualized to each patient's baseline physical fitness. RESULTS: We included 517 patients (59% men, median age 61 years, and a model for end-stage liver disease score of 12) evaluated during 936 PT visits. Frailty metrics were affected by age, sex, and liver-related parameters, but not by model for end-stage liver disease. Patients with nonalcoholic fatty liver disease and alcohol-related cirrhosis had worse frailty metrics by all tools. We demonstrated the feasibility of prehabilitation in improving both LFI and 6-minute walk test, particularly in adherent patients. A median LFI improvement of 0.3 in frail patients was associated with improved survival in univariate analysis. Compliance with physical therapist visits (hazards ratio = 0.35 [0.18-0.67] for 2 visits and hazards ratio = 0.54 [0.31-0.94] for ≥3 visits) was independently associated with increased survival. DISCUSSION: Prehabilitation improves frailty metrics in LT candidates and is associated with a survival advantage. Our findings provide a framework for the standardized prehabilitation program in LT candidates while prioritizing compliance, adherence, and on-training LFI goal accomplishment.

Introducing EL-FIT (Exercise and Liver FITness): A Smartphone App to Prehabilitate and Monitor Liver Transplant Candidates.

Preserved physical function is key for successful liver transplantation (LT); however, prehabilitation strategies are underdeveloped. We created a smartphone application (app), EL-FIT (Exercise and Liver FITness), to facilitate exercise training in end-stage liver disease (ESLD). In this feasibility study, we tested EL-FIT app usage and the accuracy of physical activity data transfer and obtained feedback from initial users. A total of 28 participants used the EL-FIT app and wore a physical activity tracker for 38 ± 12 days (age, 60 ± 8 years; 57% males; Model for End-Stage Liver Disease-sodium, 19 ± 5). There was fidelity in data transfer from the tracker to the EL-FIT app. Participants were sedentary (1957 [interquartile range, 873-4643] steps/day) at baseline. Level of training assigned by the EL-FIT app agreed with that from a physical therapist in 89% of cases. Participants interacted with all app features (videos, perceived exertion, and gamification/motivational features). We rearranged training data to generate heart rate-validated steps as a marker of performance and showed that 35% of the participants had significant increases in their physical performance. Participants emphasized their interest in having choices to better engage in exercise, and they appreciated the sense of community the EL-FIT app generated. We showed that patients with ESLD are able to use and interact with the EL-FIT app. This novel smartphone app has the potential of becoming an invaluable tool for home-based prehabilitation in LT candidates.

Posttransplant Outcomes in Older Patients With Hepatocellular Carcinoma Are Driven by Non-Hepatocellular Carcinoma Factors.

The incidence of hepatocellular carcinoma (HCC) is growing in the United States, especially among the elderly. Older patients are increasingly receiving transplants as a result of HCC, but the impact of advancing age on long-term posttransplant outcomes is not clear. To study this, we used data from the US Multicenter HCC Transplant Consortium of 4980 patients. We divided the patients into 4 groups by age at transplantation: 18 to 64 years (n = 4001), 65 to 69 years (n = 683), 70 to 74 years (n = 252), and ≥75 years (n = 44). There were no differences in HCC tumor stage, type of bridging locoregional therapy, or explant residual tumor between the groups. Older age was confirmed to be an independent and significant predictor of overall survival even after adjusting for demographic, etiologic, and cancer-related factors on multivariable analysis. A dose-response effect of age on survival was observed, with every 5-year increase in age older than 50 years resulting in an absolute increase of 8.3% in the mortality rate. Competing risk analysis revealed that older patients experienced higher rates of non-HCC-related mortality (P = 0.004), and not HCC-related death (P = 0.24). To delineate the precise cause of death, we further analyzed a single-center cohort of patients who received a transplant as a result of HCC (n = 302). Patients older than 65 years had a higher incidence of de novo cancer (18.1% versus 7.6%; P = 0.006) after transplantation and higher overall cancer-related mortality (14.3% versus 6.6%; P = 0.03). Even carefully selected elderly patients with HCC have significantly worse posttransplant survival rates, which are mostly driven by non-HCC-related causes. Minimizing immunosuppression and closer surveillance for de novo cancers can potentially improve the outcomes in elderly patients who received a transplant as a result of HCC.

Liver Transplantation Outcomes in a U.S. Multicenter Cohort of 789 Patients With Hepatocellular Carcinoma Presenting Beyond Milan Criteria.

BACKGROUND AND AIMS: The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down-staged (DS) with locoregional therapy (LRT). We evaluated post-LT outcomes, predictors of down-staging, and the impact of LRT in patients with beyond-MC HCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002-2013). APPROACH AND RESULTS: Clinicopathologic characteristics, overall survival (OS), recurrence-free survival (RFS), and HCC recurrence (HCC-R) were compared between patients within MC (n = 3,570) and beyond MC (n = 789) who were down-staged (DS, n = 465), treated with LRT and not down-staged (LRT-NoDS, n = 242), or untreated (NoLRT-NoDS, n = 82). Five-year post-LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n = 324; 60.2% and 53.8%; overall P < 0.001). DS patients had superior RFS (60% vs. 54%, P = 0.043) and lower 5-year HCC-R (18% vs. 32%, P < 0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5-year HCC-R of 15.5% in DS/<5 cm and 39.1% in NoDS/>5 cm, P < 0.001). Multivariate predictors of down-staging included alpha-fetoprotein response to LRT, pathologic tumor number and size, and wait time >12 months. LRT-NoDS had greater HCC-R compared with NoLRT-NoDS (34.1% vs. 26.1%, P < 0.001), even after controlling for clinicopathologic variables (hazard ratio [HR] = 2.33, P < 0.001) and inverse probability of treatment-weighted propensity matching (HR = 1.82, P < 0.001). CONCLUSIONS: In LT recipients with HCC presenting beyond MC, successful down-staging is predicted by wait time, alpha-fetoprotein response to LRT, and tumor burden and results in excellent post-LT outcomes, justifying expansion of LT criteria. In LRT-NoDS patients, higher HCC-R compared with NoLRT-NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.

Donation after circulatory death is associated with increased fibrosis on 1-year post-transplant kidney allograft surveillance biopsy.

AIM: The use of kidneys donated after circulatory death (DCD) provides an invaluable expansion of the organ supply for transplantation. Here, we investigated the effect of DCD on fibrotic changes on 1 1-year post 1-transplant surveillance kidney allograft biopsy. METHODS: Recipients of a deceased donor kidney transplant between 2013 and 2017 at a single institution, who survived 1 year and underwent surveillance biopsy, were included in the analysis (n = 333: 87 DCD kidneys, 246 kidneys donated after brain death [DBD]). Banff scores for interstitial fibrosis and tubular atrophy were summed as IFTA and compared between the groups. RESULTS: DCD and DBD groups were comparable for baseline characteristics. Delayed graft function was 39% in DCD versus 19% in DBD, P = .0002. Patient and graft survival were comparable for DCD and DBD cohorts. IFTA scores were higher in DCD compared to DBD (2.43±..13 vs. 2.01±..08, P = .0054). On multivariate analysis, the odds of IFTA > 2 in the DCD group was 2.5× higher (95%CI: 1.354.63) than in the DBD group. Within the DCD group, kidneys with IFTA > 2 had inferior 5-year graft survival (P = .037). CONCLUSION: Compared to DBD kidneys, DCD kidneys developed a greater degree of fibrotic changes on 1-year post-transplant surveillance biopsy, which affected graft longevity within the DCD cohort.

An evaluation of the safety and preliminary efficacy of peri- and post-operative treprostinil in preventing ischemia and reperfusion injury in adult orthotopic liver transplant recipients.

BACKGROUND: Orthotopic liver transplantation (OLT) is the only treatment option for various end-stage liver diseases. Ischemia and reperfusion (I/R) injury is one of the unavoidable complications/conditions in OLT. In 2019, a total of 8896 livers were transplanted of which >94% organs were procured from deceased donors. An increase in the use of extended criteria donor (ECD) livers for transplantation further unraveled the role of hepatic I/R injury on short-term and long-term graft outcomes. Despite promising outcomes with the use of antioxidants, free radical scavengers, and vasodilators; I/R-mediated liver injury persists and significantly influences the overall clinical outcomes. Treprostinil, a synthetic prostacyclin I2  (PGI2 ) analog, due to its vasodilatory property, antiplatelet activity, and its ability to downregulate pro-inflammatory cytokines can potentially minimize I/R injury. AIM: We investigated the safety and preliminary efficacy of continuous intravenous infusion of treprostinil in liver transplant recipients in a prospective, single-center, non-randomized, interventional study. MATERIAL AND METHODS: This was a dose escalation (3 + 3 design) phase 1/2 study. Deceased donor liver transplant recipients received 5 ng/kg/min for two days, or 2.5, 5, and 7.5 ng/min/kg for 5 days as a continuous infusion. Multiple blood samples were collected for biochemical parameter assessment and for measuring treprostinil levels. Indocyanine green plasma disappearance rate was used as a measure of hepatic functional capacity. RESULTS: Subjects tolerated continuous infusion of treprostinil up to 5 ng/kg/min for 120 h with no occurrence of primary graft non-function (PNF), minimized need for ventilation support, reduced hospitalization time, 100% graft and patient survival, and improved hepatobiliary excretory function comparable to normal healthy adults. DISCUSSION: Treprostinil can be administered to liver transplant patients safely during the perioperative period. CONCLUSION: Based on this phase 1/2 study, further efficacy studies of treprostinil in preventing I/R injury of liver should be conducted to potentially increase the number of livers available for transplantation.

Early subclinical tubulitis and interstitial inflammation in kidney transplantation have adverse clinical implications.

This prospective observational cohort study compared the impact of subclinical tubulitis with or without interstitial inflammation to interstitial inflammation alone and to no inflammation in early post kidney transplant biopsies. A study cohort of 415 patients (living and deceased donor recipients) was divided into three groups on the basis of their three-month biopsy: 149 patients with No Inflammation (NI), 83 patients with Isolated Interstitial Inflammation (IIF), and 183 patients with Tubulitis [(with or without interstitial inflammation) (TIF) but not meeting criteria for Banff IA]. TIF was further divided into 56 patients with tubulitis without interstitial inflammation (TIF0) and 127 patients with tubulitis alongside interstitial inflammation (TIF1). TIF was significantly associated with higher incidence of subsequent T-cell mediated rejection (clinical or subclinical) at one year compared to IIF (31% vs 15%) and NI (31% vs 17%). Chronicity on one-year biopsy was significantly higher in TIF compared to IIF (22% vs 11%) and NI (22% vs 7%). De novo donor-specific antibody development was significantly higher in TIF compared to NI (6% vs 0.7%). Tubulitis subgroups (TIF0 and TIF1) revealed comparable effects on de novo donor-specific antibody and interstitial fibrosis/tubular atrophy development. However, tubulitis with interstitial inflammation had a significantly higher incidence of subsequent rejection and posed an increased hazard for the composite end point (subsequent acute rejection and death censored graft loss) compared to other groups [adjusted hazard 2.1 (95% confidence interval 1.2-3.5)]. Thus, subclinical tubulitis is a marker of adverse immunological events, but tubulitis with interstitial inflammation has a worse prognosis. Hence, the Banff 1997 (TIF1) and Banff 2005 classifications (TIF) for borderline change may have different implications.

Pathologic Response to Pretransplant Locoregional Therapy is Predictive of Patient Outcome After Liver Transplantation for Hepatocellular Carcinoma: Analysis From the US Multicenter HCC Transplant Consortium.

OBJECTIVE: The aim of the study was to determine the rate, predictors, and impact of complete pathologic response (cPR) to pretransplant locoregional therapy (LRT) in a large, multicenter cohort of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT). BACKGROUND: LRT is used to mitigate waitlist dropout for patients with HCC awaiting LT. Degree of tumor necrosis found on explant has been associated with recurrence and overall survival, but has not been evaluated in a large, multicenter study. METHODS: Comparisons were made among patients receiving pre-LT LRT with (n = 802) and without (n = 2637) cPR from the United States Multicenter HCC Transplant Consortium (UMHTC), and multivariable predictors of cPR were identified using logistic regression. RESULTS: Of 3439 patients, 802 (23%) had cPR on explant. Compared with patients without cPR, cPR patients were younger; had lower Model for End-stage Liver Disease (MELD) scores, AFP levels, and neutrophil-lymphocyte ratios (NLR); were more likely to have tumors within Milan criteria and fewer LRT treatments; and had significantly lower 1-, 3-, and 5-year incidence of post-LT recurrence (1.3%, 3.5%, and 5.2% vs 6.2%, 13.5%, and 16.4%; P < 0.001) and superior overall survival (92%, 84%, and 75% vs 90%, 78%, and 68%; P < 0.001). Multivariable predictors of cPR included age, sex, liver disease diagnosis, MELD, AFP, NLR, radiographic Milan status, and number of LRT treatments (C-statistic 0.67). CONCLUSIONS: For LT recipients with HCC receiving pretransplant LRT, achieving cPR portends significantly lower posttransplant recurrence and superior survival. Factors predicting cPR are identified, which may help prioritize patients and guide LRT strategies to optimize posttransplant cancer outcomes.

Frailty as Tested by Gait Speed Is a Risk Factor for Liver Transplant Respiratory Complications.

OBJECTIVES: Frailty and sarcopenia are known risk factors for adverse liver transplant outcomes and mortality. We hypothesized that frailty or sarcopenia could identify the risk for common serious transplant-related adverse respiratory events. METHODS: For 107 patients (74 men, 33 women) transplanted over 1 year, we measured frailty with gait speed, chair stands, and Karnofsky Performance Scale (KPS) and sarcopenia with Skeletal Muscle Index on computed tomography at L3. We recorded the stress-tested cardiac double product as an index of cardiac work capacity. Outcomes included days of intubation, aspiration, clinical pneumonia, reintubation/tracheostomy, days to discharge, and survival. We modeled the outcomes using unadjusted regression and multivariable analyses controlled for (i) age, sex, and either Model for End-Stage Liver Disease-Na (MELDNa) or Child-Turcotte-Pugh scores, (ii) hepatocellular carcinoma status, and (iii) chronic obstructive pulmonary disease and smoking history. Subgroup analysis was performed for living donor liver transplant and deceased donor liver transplant recipients. RESULTS: Gait speed was negatively associated with aspiration and pulmonary infection, both in unadjusted and MELDNa-adjusted models (adjusted odds ratio for aspiration 0.10 [95% confidence interval [CI] 0.02-0.67] and adjusted odds ratio for pulmonary infection 0.12 [95% CI 0.02-0.75]). Unadjusted and MELDNa-adjusted models for gait speed (coefficient -1.47, 95% CI -2.39 to -0.56) and KPS (coefficient -3.17, 95% CI -5.02 to -1.32) were significantly associated with shorter intubation times. No test was associated with length of stay or need for either reintubation or tracheostomy. DISCUSSION: Slow gait speed, an index of general frailty, indicates significant risk for post-transplant respiratory complications. Intervention to arrest or reverse frailty merits exploration as a potentially modifiable risk factor for improving transplant respiratory outcomes.