Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Incidence and risk factors for chronic rejection in pediatric liver transplantation.

Chronic rejection (CR) is a progressive immunological injury that frequently leads to long-term liver allograft dysfunction and loss. Although CR remains an important indication for retransplantation, as transplant immunosuppression has evolved, its prevalence in adults undergoing liver transplantation (LT) has declined. However, the incidence and factors that lead to CR in pediatric LT are poorly defined. Therefore, we sought to systematically measure CR's incidence and assess both the risk factors for developing CR and outcomes in a large cohort of pediatric recipients of LT. In this single-center study, we retrospectively analyzed and compared relevant recipient characteristics, surgical details, immunosuppression, graft, and patient survival in the CR and control groups over a 17-year period. After a median time of 1.9 years after LT, 19/356 recipients of LT (5.3%) developed CR in our cohort. Posttransplant lymphoproliferative disorder ( p = 0.01), infections ( p = 0.02), autoimmune liver diseases (HR = 7.3, p = <0.01), Black race (HR = 11.5, p = 0.01), and 2 or more episodes of T cell mediated rejection (HR = 5.1, p = <0.01) were associated with CR development. The retransplantation rate among CR cases was 15.8% at a median follow-up time of 4.1 years. Overall, patient survival was lower in the CR group (78.9%) versus controls (91.1%). While CR incidence in our pediatric cohort was lower than previously reported rates of >12%, the CR group had a higher graft failure rate that required retransplantation and lower overall patient survival. Thus, identifying risk factors may warrant specialized immunosuppression protocols and closer posttransplantation monitoring to reduce the risk of morbidity and mortality from CR.

Estimating risk of prolonged mechanical ventilation after liver transplantation in children: PROVE-ALT score.

BACKGROUND: Children at high risk for prolonged mechanical ventilation (PMV) after liver transplantation (LT) need to be identified early to optimize pulmonary support, allocate resources, and improve surgical outcomes. We aimed to develop and validate a metric that can estimate risk for Prolonged Ventilation After LT (PROVE-ALT). METHODS: We identified preoperative risk factors for PMV by univariable analysis in a retrospective cohort of pediatric LT recipients between 2011 and 2017 (n = 205; derivation cohort). We created the PROVE-ALT score by mapping multivariable logistic regression coefficients as integers, with cutoff values using the Youden Index. We validated the score by C-statistic in a retrospectively collected separate cohort of pediatric LT recipients between 2018 and 2021 (n = 133, validation cohort). RESULTS: Among total 338 patients, 21% (n = 72) were infants; 49% (n = 167) had cirrhosis; 8% (n = 27) required continuous renal replacement therapy (CRRT); and 32% (n = 111) required management in hospital (MIH) before LT. Incidence of PMV post-LT was 20% (n = 69) and 3% (n = 12) required tracheostomy. Independent risk factors (OR [95% CI]) for PMV were cirrhosis (3.8 [1-14], p = .04); age <1-year (8.2 [2-30], p = .001); need for preoperative CRRT (6.3 [1.2-32], p = .02); and MIH before LT (12.4 [2.1-71], p = .004). PROVE-ALT score ≥8 [Range = 0-21] accurately predicted PMV in the validation cohort with 73% sensitivity and 80% specificity (AUC: 0.81; 95% CI: 0.71-0.91). CONCLUSION: PROVE-ALT can predict PMV after pediatric LT with a high degree of sensitivity and specificity. Once externally validated in other centers, PROVE-ALT will empower clinicians to plan patient-specific ventilation strategies, provide parental anticipatory guidance, and optimize hospital resources.

Improved Survival After Liver Transplantation for Patients With Human Immunodeficiency Virus (HIV) and HIV/Hepatitis C Virus Coinfection in the Integrase Strand Transfer Inhibitor and Direct-Acting Antiviral Eras.

BACKGROUND: People with human immunodeficiency virus (HIV) with and without hepatitis C virus (HCV) coinfection had poor outcomes after liver transplant (LT). Integrase strand transfer inhibitors (INSTIs) and direct-acting antivirals (DAAs) have changed the treatment landscape for HIV and HCV, respectively, but their impact on LT outcomes remains unclear. METHODS: This retrospective analysis of adults with HIV monoinfection (n = 246) and HIV/HCV coinfection (n = 286) who received LT compared mortality in patients with HIV who received LT before versus after approval of INSTIs and in patients with HIV/HCV coinfection who received LT before versus after approval of DAAs. In secondary analysis, we compared the outcomes in the different eras with those of propensity score-matched control cohorts of LT recipients without HIV or HCV infection. RESULTS: LT recipients with HIV monoinfection did not experience a significant improvement in survival between the pre-INSTI and INSTI recipients with HIV (adjusted hazard ratio [aHR], 0.70 [95% confidence interval {CI}, .36-1.34]). However, recipients with HIV/HCV coinfection in the DAA era had a 47% reduction (aHR, 0.53 [95% CI, .31-9.2] in 1-year mortality compared with coinfected recipients in the pre-DAA era. Compared to recipients without HIV or HCV, HIV-monoinfected recipients had higher mortality during the pre-INSTI era, but survival was comparable between groups during the INSTI era. HIV/HCV-coinfected recipients also experienced comparable survival during the DAA era compared to recipients without HCV or HIV. CONCLUSIONS: Post-LT survival for people with HIV monoinfection and HIV/HCV coinfection has improved with the introduction of INSTI and DAA therapy, suggesting that LT has become safer in these populations.

Innate immune cell dysfunction and systemic inflammation in children with chronic liver diseases undergoing transplantation.

Advanced liver diseases (ALD) can affect immune function and compromise host defense against infections. In this study, we examined the phenotypic and functional alterations in circulating monocyte and dendritic cells (DCs) in children with ALD undergoing liver transplantation (LT). Children were stratified into 2 clusters, C1 (mild) and C2 (severe), on the basis of laboratory parameters of ALD and compared with healthy pediatric controls. Children in C2 had a significant reduction in frequencies of nonclassical monocytes and myeloid DCs. Children in C2 displayed monocyte and DC dysfunction, characterized by lower human leucocyte antigen DR expression and reduced interleukin 12 production, and had an increased incidence of infections before and after LT. Children in C2 demonstrated immune dysregulation with elevations of pro- and anti-inflammatory cytokines in plasma. Alterations of innate immune cells correlated with multiple laboratory parameters of ALD, including plasma bile acids. In vitro, monocytes cultured with specific bile acids demonstrated a dose-dependent reduction in interleukin 12 production, similar to alterations in children with ALD. In conclusion, a cohort of children with ALD undergoing LT exhibited innate immune dysfunction, which may be related to the chronic elevation of serum bile acids. Identifying at-risk patients may permit personalized management pre- and post-transplant, thereby reducing the incidence of infection-related complications.

Acute liver failure and unique challenges of pediatric liver transplantation amidst a worldwide cluster of adenovirus-associated hepatitis.

Investigation into a recent cluster of acute hepatitis in children from the southeastern United States identified human adenovirus (HAdV) DNAemia in all 9 cases. Molecular genotyping in 5 of 9 (56%) children identified HAdV type 41 in all cases (100%). Importantly, 2 children from this cluster progressed rapidly to pediatric acute liver failure (PALF) and required liver transplantation. HAdV type 41, a known cause of self-limited gastroenteritis, has not previously been associated with severe cholestatic hepatitis and liver failure in healthy children. Adenovirus polymerase chain reaction assay and sequencing of amplicons performed on DNA extracted from formalin-fixed, paraffin-embedded liver tissue also identified adenovirus species F (HAdV type 40 or 41) in these 2 children with PALF. Transplant considerations and successful liver transplantation in such situations remain scarce. In this report, we describe the clinical course, laboratory results, liver pathology, and treatment of 2 children with PALF associated with HAdV type 41, one of whom developed secondary hemophagocytic lymphohistiocytosis. Their successful posttransplant outcomes demonstrate the importance of early multidisciplinary medical management and the feasibility of liver transplantation in some children with PALF and HAdV DNAemia.

Long-term outcomes and trends in liver transplantation for hereditary hemochromatosis in the United States.

There have been conflicting data regarding liver transplantation (LT) outcomes for hereditary hemochromatosis (HH), with no recent data on LT outcomes in patients with HH in the past decade. Using the United Network for Organ Sharing registry, we evaluated waitlist and post-LT survival in all adult patients listed for HH without concomitant liver disease from 2003 to 2019. Post-LT survival for HH was compared with a propensity-matched (recipient and donor factors) cohort of recipients with chronic liver disease (CLD). From 2003 to 2019, 862 patients with HH were listed for LT, of which 55.6% ( n = 479) patients underwent LT. The 1- and 5-year post-LT survival rates in patients with HH were 88.7% (95% confidence interval [CI], 85.4%-91.4%) and 77.5% (95% CI, 72.8%-81.4%), respectively, and were comparable with those in the propensity-matched CLD cohort ( p value = 0.96). Post-LT survival for HH was lower than for Wilson's disease, another hereditary metabolic liver disease with similar LT volume ( n = 365). Predictors for long-term (5-year) post-LT mortality included presence of portal vein thrombosis (hazard ratio [HR], 1.96; 95% CI, 1.07-3.58), obesity measurements greater than Class II (HR, 1.98; 95% CI, 1.16-3.39), and Karnofsky performance status (HR, 0.98; 95% CI, 0.97-0.99) at the time of LT. The leading cause of post-LT death ( n = 145) was malignancy (25.5%), whereas cardiac disease was the cause in less than 10% of recipients. In conclusion, short- and long-term survival rates for HH are excellent and comparable with those of other LT recipients. Improving extrahepatic metabolic factors and functional status in patients with HH prior to LT may improve outcomes.

Survival Benefit of Solid-Organ Transplantation: 10-Year Update.

IMPORTANCE: Transplantation has transformed into a burgeoning field that is rapidly evolving to optimize organ distribution and survival outcomes. The years since 2012 (the last comprehensive study) have seen changes in transplantation, such as advances in immunotherapy and novel indices, that necessitate an updated analysis of survival benefit. DESIGN: Our goal was to determine the survival benefit for solid-organ transplants in the United Network for Organ Sharing (UNOS) database for a three decade period and provide updates on advancements since 2012. Our retrospective analysis examined data containing U.S. patient records from September 1, 1987, to September 1, 2021. RESULTS: We found that 3,430,272 life-years were saved over our transplant period (4.33 life-years saved per patient); kidney-1,998,492 life-years; liver -767,414; heart-435,312; lung-116,625; pancreas-kidney-123,463; pancreas-30,575; intestine-7901. After matching, 3,296,851 life-years were saved. Life-years saved and median survival increased for all organs between 2012 and 2021. Compared to 2012, median survival increased in kidney (from 12.4 to 14.76 years), liver (from 11.6 to 14.59), heart (9.5 to 11.73), lung (5.2 to 5.63), pancreas-kidney (from 14.5 to 16.88), pancreas (from 13.3 to 16.10). When compared to 2012, the percent transplanted increased in kidney, liver, heart, lung, and intestine, while pancreas-kidney and pancreas show decreased percent transplanted. CONCLUSION: Our study underscores the tremendous survival benefits of solid organ transplantation (over 3.4 million life-years saved) and shows improvements since 2012. Our study also highlights areas of transplantation, notably pancreas transplants, that may necessitate reinvigorated attention.

Hepatoblastomas with carcinoma features represent a biological spectrum of aggressive neoplasms in children and young adults.

BACKGROUND & AIMS: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS. METHODS: We tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8). RESULTS: Molecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes. CONCLUSIONS: Our study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms. LAY SUMMARY: We molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.

Trends in marginal lung allograft survival: Advanced-age donors improve.

INTRODUCTION: Although lung demand continues to outpace supply, 75% of potential donor lungs are discarded without being transplanted in the United States. To identify the discarded cohorts best suited to alleviate the lung shortage and reduce waitlist mortality, we explored changes in survival over time for five marginal donor definitions: age >60 years, smoking history >20 pack-years, PaO2 /FiO2  < 300 mmHg, purulent bronchoscopic secretions, and chest radiograph infiltrates. METHODS: Our retrospective cohort study separated 27 803 lung recipients in the UNOS Database into three 5-year eras by transplant date: 2005-2009, 2010-2014, and 2015-2019. Multivariable Cox proportional hazards regression and Kaplan-Meier analysis with log-rank test were used to compare survival across the eras. RESULTS: Three definitions-low PaO2 /FiO2 , purulent bronchoscopic secretions, and abnormal chest radiographs-did not bear out as truly marginal, demonstrating lack of significantly elevated risk. Advanced donor age demonstrated considerable survival improvement (HR (95% CI): 1.47 (1.26-1.72) in 2005-2009 down to 1.14 (.97-1.35) for 2015-2019), with protective factors being recipients <60 years, moderate recipient BMI, and low Lung Allocation Score (LAS). Donors with smoking history failed to demonstrate any significant improvement (HR (95% CI): 1.09 (1.01-1.17) in 2005-2009 increasing to 1.22 (1.08-1.38) in 2015-2019). CONCLUSIONS: Advanced donor age, previously the most significant risk factor, has improved to near-benchmark levels, demonstrating the possibility for matching older donors to healthier non-elderly recipients in selected circumstances. Low PaO2 /FiO2 , bronchoscopic secretions, and abnormal radiographs demonstrated survival on par with standard donors. Significant donor smoking history, a moderate risk factor, has failed to improve.

Marginal allografts in liver transplantation have a limited impact on length of stay.

The study of marginal liver transplant outcomes, including post-transplant length of stay (LOS), is necessary for determining the practicality of their use. 50 155 patients who received transplants from 2012 to 2020 were retrospectively analyzed with data from the Scientific Registry of Transplant Recipients database using Kaplan-Meier survival curves and multivariable Cox regression. Six different definitions were used to classify an allograft as being marginal: 90th percentile Donor Risk Index (DRI) allografts, donation after cardiac death (DCD) donors, national share donors, donors over 70, donors with > 30% macrovesicular steatosis, or 90th percentile Discard Risk Index donors. 24% (n = 12 124) of subjects received marginal allografts. Average LOS was 15.6 days among those who received standard allografts. Among those who received marginal allografts, LOS was found to be highest in those who received 90th percentile DRI allografts at 15.6 days, and lowest in those who received DCD allografts at 12.7 days. Apart from fatty livers (95% CI .86-.98), marginal allografts were not associated with a prolonged LOS. We conclude that accounting for experience and recipient matching, transplant centers may be more aggressive in their use of extended criteria donors with limited fear of increasing LOS and its associated costs.

Significant improvements, but consistent disparities in survival for African Americans after liver transplantation.

Despite improvements in survival across races in the past 20 years, African Americans have worse liver transplant outcomes after orthotopic liver transplantation (OLT). This study aims at quantifying the change in disparities between African Americans and other races in survival after OLT. We retrospectively analyzed the United Network for Organ Sharing (UNOS) database for patient data for candidates who received a liver transplant between January 1, 2007 and December 31, 2017. Multivariate Cox proportional hazards regression indicated similar decreases in mortality over time for each race with a decrease in mortality for African Americans: 2010-2012 (HR = .930), 2012-2015 (HR = .882), and 2015-2017 (HR = .883) when compared to 2007-2010. Risk of mortality for African Americans compared to Caucasians varied across the 4 eras: 2007-2010 (HR = 1.083), 2010-2012 (HR = 1.090), 2012-2015 (HR = 1.070), and 2015-2017 (HR = 1.125). While African Americans have seen increases in survival in the past decade, a similar increase in survival for other races leaves a significant survival disparity in African Americans.

A new chapter in an evolving pandemic: Successful pediatric liver transplantation with SARS-CoV-2+ donors.

BACKGROUND: Amid a viral pandemic with poorly understood transmissibility and pathogenicity in the pediatric patient, we report the first pediatric liver transplants utilizing allografts from SARS-CoV-2+ donors. METHODS: We describe the outcomes of two pediatric liver transplant recipients who received organs from SARS-CoV-2 nucleic acid test-positive (NAT+) donors. Data were obtained through the respective electronic medical record system and UNet DonorNet platform. RESULTS: The first donor was a 3-year-old boy succumbing to head trauma. One of four nasopharyngeal (NP) swabs and 1 of 3 bronchoalveolar lavage (BAL) NAT tests demonstrated SARS-CoV-2 infection before organ procurement. The second donor was a 16-month-old boy with cardiopulmonary arrest of unknown etiology. Three NAT tests (2 NP swab/1 BAL) prior to procurement failed to detect SARS-CoV-2. The diagnosis was made when the medical examiner repeated 2 NP swab NATs and an archive plasma NAT, all positive for SARS-CoV-2. Both 2-year-old recipients continue to do well 8 months post-transplant, with excellent graft function and no evidence of SARS-CoV-2 transmission. CONCLUSIONS: This is the first report to describe successful pediatric liver transplantation from SARS-CoV-2+ donors. These data reinforce the adult transplant experience and support the judicious use of SARS-CoV-2+ donors for liver transplantation in children. With SARS-CoV-2 becoming endemic, the concern for donor-derived viral transmission must now be weighed against the realized benefit of life-saving transplantation in the pediatric population as we continue to work toward donor pool maximization.

Our evolution in the treatment of hepatic artery and portal vein thrombosis in pediatric liver transplantation: Success with catheter-directed therapies.

BACKGROUND: In pediatric liver transplant recipients, hepatic artery thrombosis and portal vein thrombosis are major causes of acute graft failure and mortality within 30 days of transplantation. There is, however, a strong possibility of graft salvage if flow can be re-established to reduce ischemic injury. The current standard treatment is surgical revascularization, and if unsuccessful, retransplantation. Due to our success in treating these complications with catheter-directed therapies, we sought to summarize and publish the outcomes of all patients who experienced hepatic artery thrombosis or portal vein thrombosis within 30 days of liver transplantation. METHODS: We conducted a retrospective cohort analysis of 27 pediatric liver transplant recipients who experienced hepatic artery thrombosis (n = 13), portal vein thrombosis (n = 9), or both (n = 5) between September 2012 and March 2021. We collected and tabulated data on the patients and therapies performed to treat them, including success rates, primary and secondary patency, and clinical outcomes. RESULTS: Among these patients, 6 were managed with anticoagulation and relisting for transplant and 21 had a primary revascularization attempt. Surgical recanalization was attempted in 7 patients of which 3 had successful recanalization (43%) and catheter-directed recanalization was attempted in 14 patients with 100% success in re-establishing blood flow to the graft. Additionally, patency was increased, and mortality was decreased in patients treated with catheter-directed recanalization compared to surgical revascularization or anticoagulation alone. CONCLUSION: This data illustrates the need to further investigate catheter-directed thrombolysis as a potential first-line treatment for postoperative HAT and PVT in pediatric liver transplant recipients.

The impact of diabetes on young transplant recipients: An American perspective.

Despite advancements in diabetic care, diabetic kidney transplant recipients have significantly worse outcomes than non-diabetics. AIM: Our study aims to demonstrate the impact of diabetes, types I and II, on American young adults (18-40 years old) requiring kidney transplantation. METHODS: Using the United Network for Organ Sharing database, we conducted a population cohort study that included all first-time, kidney-only transplant recipients during 2002-2019, ages 18-40 years old. Patients were grouped according to indication for transplant. Primary outcomes were cumulative all-cause mortality and death-censored graft failure. Death-censored graft failure and patient survival at 1, 5, and 10 years were calculated via the Kaplan-Meier method. Multivariate Cox regression was used to assess for potential confounders. RESULTS: Of 42 466 transplant recipients, 3418 (8.1%) had end-stage kidney disease associated with diabetes. At each time-point, cumulative mortality was higher in diabetics compared to patients with non-diabetic causes of renal failure. Conversely, cumulative graft failure was similar between the groups. Adjusted hazard ratios for all-cause mortality and graft failure in diabetics were 2.99 (95% CI 2.67-3.35; p < .01) and 0.98 (95% CI 0.92-1.05, p < .01), respectively. CONCLUSION: Diabetes mellitus in young adult kidney transplant recipients is associated with a nearly three-fold increase in mortality, reflecting a relatively vulnerable patient population. Identifying the underlying causes of poor outcomes in this population should be a priority for future study.

Survey of public attitudes towards imminent death donation in the United States.

Imminent death donation (IDD) is described as living organ donation prior to a planned withdrawal of life-sustaining care in an imminently dying patient. Although IDD was ethically justified by United Network for Organ Sharing, the concept remains controversial due to presumed lack of public support. The aim of this study was to evaluate the public's attitudes towards IDD. A cross-sectional survey was conducted of US adults age >18 years (n = 2644). The survey included a case scenario of a patient with a devastating brain injury. Responses were assessed on a 5-point Likert scale. Results showed that 68% - 74% of participants agreed or strongly agreed with IDD when posed as a general question and in relation to the case scenario. Participants were concerned about "recovery after a devastating brain injury" (34%), and that "doctors would not try as hard to save a patient's life" (33%). Only 9% of participants would be less likely to trust the organ donation process. In conclusion, our study demonstrates strong public support for IDD in the case of a patient with a devastating brain injury. Notably, participants were not largely concerned with losing trust in the organ donation process. These results justify policy change towards imminent death donation.

Consistent improvements in short- and long-term survival following heart transplantation over the past three decades.

BACKGROUND: Despite noted improvements in short-term survival outcomes following orthotopic heart transplantation (OHT), review of the relevant literature suggests little improvement in long-term outcomes for patients surviving beyond 1 year. METHODS: All OHT cases performed between 1989 and 2019 within the United Network for Organ Sharing (UNOS) database were reviewed. Adults who underwent isolated OHT were included in a 1-year survival analysis. Those who survived at least 1 year post-transplant were included in a long-term survival analysis. Demographic factors were assessed using Students' t test and chi-square analysis. Survival trends and risk factors were assessed using the Kaplan-Meier and the Cox regression analysis, respectively. RESULTS: A total of 53 265 and 46 372 recipients were included in the short-term and long-term cohorts, respectively. In an adjusted analysis, the reference implant era 2014-2019 had significantly better short-term survival outcomes when compared with earlier implant eras: 1989-1993 (HR: 2.92), 1994-1998 (HR: 1.53), 1999-2003 (HR: 1.27), 2004-2008 (HR: 1.11), and 2009-2013 (HR: 1.02). The same trend was recognized for long-term outcomes: 1989-1993 (HR: 1.87), 1994-1998 (HR: 1.27), 1999-2003 (HR: 1.09), and 2004-2008 (HR: 1.03). CONCLUSIONS: Despite increases in multiple traditional risk factors, both short-term and long-term survival outcomes have consistently improved over the past 30 years, suggesting other factors are contributing to improved outcomes in recent eras.

Intent-to-treat survival in liver transplantation has not improved in 3 decades due to donor shortage relative to waitlist growth.

BACKGROUND: Liver Transplantation has advanced over the past 3 decades, with 1-year survival rates improving 25%. Survival rates for those transplanted has increased to remarkable levels, but survival from the time of listing may not be as revolutionary. METHODS: Kaplan-Meier with log-rank test as well as Cox regression analysis was used to retrospectively analyze 211 610 adults listed for LT and 116 299 adult transplant recipients from 1987 to 2016. Our primary endpoints were survival from time of listing to waitlist death or posttransplant death. RESULTS: One-year survival following LT improved dramatically (68% in 1987-1988 vs. 93% in 2016, P < .001). There was no improvement in 1-year intent-to-treat survival: 78.4% for those listed in 1987 and 81.8% for those listed in 2016 (P = .1). Also observed were decreases in the percentage of transplanted candidates from 74.8% in 1987-1988 to 54.7% in 2016 (P < .001) and increased 1-year wait-list mortality from 12.5% in 1987-1988 to 22.6% in 2016 (P = .002). CONCLUSION: As transplant rate has decreased while waitlist mortality has increased, no improvements have been made in intent-to-treat survival of patients listed for transplant over the past 3 decades. We speculate this observation to be resultant of a relative donor shortage outpaced by waitlist growth. SUMMARY: Liver Transplantation has experienced vast increases in survival rates over the past 3 decades; however, due to an increased donor supply outpaced by waitlist growth, the rate of transplantation has decreased significantly while the waitlist mortality has increased, leading to no improvement in 1-year intent-to-treat survival rates.

Allograft discard risk index for heart transplantation.

BACKGROUND: The numberof patients awaiting heart transplantation (HTx) substantially exceeds the number of donor hearts transplanted each year, yet nearly 65% of eligible donor hearts are discarded rather than transplanted. METHODS: Deceased organ donors listed within the UNOS Deceased Donor Database between 2010 and 2020 were reviewed. Those greater than 10 years old and consented for heart donation were included and randomly separated into training (n = 48 435) and validation (n = 24 217) cohorts. A discard risk index (DSRI) was created using the results of univariable and multivariable analyses. Discard data were assessed at DSRI value deciles, and stratum-specific likelihood ratio (SSLR) analysis and Kaplan-Meier survival function were used for mortality data. RESULTS: Factors associated with higher DSRI values included donor age > 45, LVEF, HBV-core antibodies, hypertension, and diabetes. The DSRI C-statistic was .906 in the training cohort and .904 in the validation cohort. The DSRI did not reliably predict 30-day or 1-year mortality after transplantation (C-statistic .539 and .532, respectively). CONCLUSIONS: The factors leading to heart allograft discard are not correlated to the same degree with post-transplant outcomes. This suggests that optimizing utilization of certain allografts with slightly higher risk of discard could increase the heart donor pool with limited impact on posttransplant mortality.

Presentation and Outcomes of Autoimmune Hepatitis Type 1 and Type 2 in Children: A Single-center Study.

OBJECTIVE: Autoimmune hepatitis (AIH) is designated as type 1 or 2 (AIH-1/2) on the basis of serum autoantibody (Ab) profiles. In children, AIH may present as acute or chronic liver failure or cirrhotic AIH (ALF/CLF/CAIH) with or without overlap sclerosing cholangitis (SC). The aim of this study was to compare demographics, presentation, and outcomes between groups in children. METHODS: A retrospective electronic chart review of children with AIH who met standard diagnostic criteria with histologic confirmation at Texas Children's Hospital was performed, with de novo AIH after liver transplant (LT) excluded. Patients were identified and divided into AIH-1, AIH-2, ALF, CAIH, AIH-SC, and LT and compared using chi-square analysis, Student t-test, and Mood median test. RESULTS: Among 91 children with AIH, 72 (79.1%) had AIH-1, 19 (20.9%) had AIH-2, 13 (14.3%) had ALF, 25 (27.5%) had CAIH, and 14 (15.4%) had AIH-SC. Both AIH-1/2 had female and Hispanic predominance (72.2/89.5%, 40.3/57.9%). AIH-2 presented at younger mean age in years than AIH-1 (6.8, 12.1, P < 0.05). Both AIH-1/2 had low rates of remission after 1 year of IS (25.4, 35.7%) and most recent (30.6, 54.5%) follow-up. Twenty-two (24.2) patients received LT: 16 had AIH-1 (72.7%), 6 had AIH-2 (27.3%), 9 (40.9%) had ALF, and 13 (59.1%) had CAIH. One-year patient and graft survivals were 100%. CONCLUSIONS: The epidemiology and clinical presentation of AIH-1 and -2 had a few subtle differences. AIH-1 was associated with more complications after LT. More data are needed to better characterize the 2 as separate disease entities.