Multicenter validation of the liver graft assessment following transplantation (L-GrAFT) score for assessment of early allograft dysfunction.

BACKGROUND AIMS Early allograft dysfunction (EAD) following liver transplantation (LT) negatively impacts graft and patient outcomes. The Liver Graft Assessment Following Transplantation (L-GrAFT) risk-score estimates 3-month graft-failure-free survival (area under the receiver operator characteristic [AUROC] curve=0.83), and was superior to the binary EAD (AUROC=0.68) definition and Model for Early Allograft Function (MEAF, AUROC=0.70) in the single-center derivation cohort (DC, n=2008). We sought to externally validate L-GrAFT, and compare its prognostic performance to EAD and MEAF. METHODS Accuracies of L-GrAFT, EAD, and MEAF were compared in a 3-center US validation cohort (VC, n=3201), and Consortium for Organ Preservation in Europe (COPE) normothermic machine perfusion trial cohort (n=222), with comparison of characteristics to assess generalizability. RESULTS Compared to the DC, VC and COPE patients had lower recipient median MELD scores (18 and 14 vs 31); were less likely to require pretransplant hospitalization (23.3% and 0% vs 46.1%), renal replacement therapy (8.8% and 1.8% vs 31.7%), mechanical ventilation (3.7% and 0% vs 19.8%); and had superior 1-year overall (90% and 95% vs 84%) and graft-failure-free (88% and 93% vs 81%) survival, with a lower incidence of 3-month graft failure (7.4% and 4.0% vs. 11.1%; P<0.001 for all comparisons). Despite significant differences in cohort characteristics, L-GrAFT maintained an excellent validation AUROC of 0.78, significantly superior to the EAD (AUROC=0.68, P=0.001) and MEAF scores (AUROC=0.72, P<0.001). In post-hoc analysis of COPE NMP trial, highest tertile of L-GrAFT was significantly associated with time to liver allograft (HR 2.17, P=0.016) and Clavien ≥IIIB (HR 2.60, P=0.034) and ≥IVa (HR 4.99, P=0.011) complications, and post-LT length of hospitalization (P=0.002) and renal replacement therapy (OR 3.62, P=0.016). CONCLUSIONS We have validated the L-GrAFT risk score as a generalizable, highly accurate, individualized risk assessment of 3-month liver allograft failure that is superior to the existing EAD and MEAF scores. L-GrAFT may standardize grading of early hepatic allograft function, and serve as a clinical end-point in translational studies aiming to mitigate ischemia-reperfusion injury. LAY SUMMARY Early allograft dysfunction negatively affects outcomes following liver transplantation (LT). In independent multicenter US and European cohorts totaling 3423 patients undergoing LT, the Liver Graft Assessment Following Transplantation (L-GrAFT) risk score is validated as a superior measure of early allograft function that accurately discriminates 3-month graft failure free survival and post-LT complications

A multicentric study to estimate mortality and graft loss risk after liver transplantation (LT) in patients with recurrent primary biliary cholangitis (PBC)

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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&nbsp;=&nbsp;4001), 65 to 69 years (n&nbsp;=&nbsp;683), 70 to 74 years (n&nbsp;=&nbsp;252), and ≥75&nbsp;years (n&nbsp;=&nbsp;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&nbsp;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&nbsp;=&nbsp;0.004), and not HCC-related death (P&nbsp;=&nbsp;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&nbsp;=&nbsp;302). Patients older than 65&nbsp;years had a higher incidence of de novo cancer (18.1% versus 7.6%; P&nbsp;=&nbsp;0.006) after transplantation and higher overall cancer-related mortality (14.3% versus 6.6%; P&nbsp;=&nbsp;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

Coronavirus Disease 2019 in Solid Organ Transplant: A Multicenter Cohort Study

Background. The coronavirus disease 2019 (COVID-19) pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients. However, clinical features, outcomes, and predictors of mortality in SOT recipients are not well described. Methods. We performed a multicenter cohort study of SOT recipients with laboratory-confirmed COVID-19. Data were collected using standardized intake and 28-day follow-up electronic case report forms. Multivariable logistic regression was used to identify risk factors for the primary endpoint, 28-day mortality, among hospitalized patients. Results. Four hundred eighty-two SOT recipients from >50 transplant centers were included: 318 (66%) kidney or kidney/pancreas, 73 (15.1%) liver, 57 (11.8%) heart, and 30 (6.2%) lung. Median age was 58 (interquartile range [IQR] 46-57), median time post-transplant was 5 years (IQR 2-10), 61% were male, and 92% had >= 1 underlying comorbidity. Among those hospitalized (376 [78%]), 117 (31%) required mechanical ventilation, and 77 (20.5%) died by 28 days after diagnosis. Specific underlying comorbidities (age >65 [adjusted odds ratio [aOR] 3.0, 95% confidence interval [CI] 1.7-5.5, P < .001], congestive heart failure [aOR 3.2, 95% CI 1.4-7.0, P = .004], chronic lung disease [aOR 2.5, 95% CI 1.2-5.2, P = .018], obesity [aOR 1.9, 95% CI 1.0-3.4, P = .039]) and presenting findings (lymphopenia [aOR 1.9, 95% CI 1.1-3.5, P = .033], abnormal chest imaging [aOR 2.9, 95% CI 1.1-7.5, P = .027]) were independently associated with mortality. Multiple measures of immunosuppression intensity were not associated with mortality. Conclusions. Mortality among SOT recipients hospitalized for COVID-19 was 20.5%. Age and underlying comorbidities rather than immunosuppression intensity-related measures were major drivers of mortality

COVID-19 in solid organ transplant: A multi-center cohort study.

BACKGROUND: The COVID-19 pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients. However, clinical features, outcomes, and predictors of mortality in SOT recipients are not well-described. METHODS: We performed a multi-center cohort study of SOT recipients with laboratory-confirmed COVID-19. Data were collected using standardized intake and 28-day follow-up electronic case report forms. Multivariable logistic regression was used to identify risk factors for the primary endpoint, 28-day mortality, among hospitalized patients. RESULTS: Four hundred eighty-two SOT recipients from \u3e50 transplant centers were included: 318 (66%) kidney or kidney/pancreas, 73 (15.1%) liver, 57 (11.8%) heart, and 30 (6.2%) lung. Median age was 58 (IQR 46-57), median time post-transplant was 5 years (IQR 2-10), 61% were male, and 92% had ≥1 underlying comorbidity. Among those hospitalized (376 [78%]), 117 (31%) required mechanical ventilation, and 77 (20.5%) died by 28 days after diagnosis. Specific underlying comorbidities (age \u3e65 [aOR 3.0, 95%CI 1.7-5.5, p CONCLUSIONS: Mortality among SOT recipients hospitalized for COVID-19 was 20.5%. Age and underlying comorbidities rather than immunosuppression intensity-related measures were major drivers of mortality

Delayed mortality among solid organ transplant recipients hospitalized for COVID-19.

INTRODUCTION: Most studies of solid organ transplant (SOT) recipients with COVID-19 focus on outcomes within one month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been fully examined. METHODS: We used data from a multicenter registry to calculate mortality by 90 days following initial SARS-CoV-2 detection in SOT recipients hospitalized for COVID-19 and developed multivariable Cox proportional-hazards models to compare risk factors for death by days 28 and 90. RESULTS: Vital status at day 90 was available for 936 of 1117 (84%) SOT recipients hospitalized for COVID-19: 190 of 936 (20%) died by 28 days and an additional 56 of 246 deaths (23%) occurred between days 29 and 90. Factors associated with mortality by day 90 included: age \u3e 65 years [aHR 1.8 (1.3-2.4), p = CONCLUSIONS: In SOT recipients hospitalized for COVID-19, \u3e20% of deaths occurred between 28 and 90 days following SARS-CoV-2 diagnosis. Future investigations should consider extending follow-up duration to 90 days for more complete mortality assessment

Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic.

Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020-June 19, 2020) and late 2020 (June 20, 2020-December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p \u3c .001). Crude 28-day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46-0.98, p = .016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p \u3c .001 and 50/571 [8.8%] vs. 213/402 [52.2%], p \u3c .001, respectively), and the use of hydroxychloroquine and IL-6/IL-6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p \u3c .001 and 73/571 [12.8%] vs. 5/402 [1.2%], p \u3c .001, respectively). Mortality among SOTR hospitalized for COVID-19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study

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 &lt; 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p &lt; 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p &lt; 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p &lt; 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p &lt; 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p &lt; 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p &lt; 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