Improved Survival With Higher-risk Donor Grafts in Liver Transplant With Acute-on-chronic Liver Failure

Use of higher-risk grafts in liver transplantation for patients with acute-on-chronic liver failure (ACLF) has been associated with poor outcomes. This study analyzes trends in liver transplantation outcomes for ACLF over time based on the donor risk index (DRI). Methods: Using the Organ Procurement and Transplantation Network and the United Network for Organ Sharing registry, 17 300 ACLF patients who underwent liver transplantation between 2002 and 2019 were evaluated. Based on DRI, adjusted hazard ratios for 1-y patient death were analyzed in 3 eras: Era 1 (2002-2007, n = 4032), Era 2 (2008-2013, n = 6130), and Era 3 (2014-2019, n = 7138). DRI groups were defined by DRI2.0. Results: ACLF patients had significantly lower risks of patient death within 1 y in Era 2 (adjusted hazard ratio, 0.69; 95% confidence interval, 0.61-0.78; P \u3c 0.001) and Era 3 (adjusted hazard ratio, 0.48; 95% confidence interval, 0.42-0.55; P \u3c 0.001) than in Era 1. All DRI groups showed lower hazards in Era 3 than in Era 1. Improvement of posttransplant outcomes were found both in ACLF-1/2 and ACLF-3 patients. In ACLF-1/2, DRI 1.2 to 1.6 and \u3e2.0 had lower adjusted risk in Era 3 than in Era 1. In ACLF-3, DRI 1.2 to 2.0 had lower risk in Era 3. In the overall ACLF cohort, the 2 categories with DRI \u3e1.6 had significantly higher adjusted risks of 1-y patient death than DRI \u3c1.2. When analyzing hazards in each era, DRI \u3e 2.0 carried significantly higher adjusted risks in Eras 1 and 3\u27 whereas DRI 1.2 to 2.0 had similar adjusted risks throughout eras. Similar tendency was found in ACLF-1/2. In the non-ACLF cohort, steady improvement of posttransplant outcomes was obtained in all DRI categories. Similar results were obtained when only hepatitis C virus-uninfected ACLF patients were evaluated. Conclusions: In ACLF patients, posttransplant outcomes have significantly improved, and outcomes with higher-risk organs have improved in all ACLF grades. These results might encourage the use of higher-risk donors in ACLF patients and provide improved access to transplant

On-The-Fly Observing System of the Nobeyama 45-m and ASTE 10-m Telescopes

We have developed spectral line On-The-Fly (OTF) observing mode for the Nobeyama Radio Observatory 45-m and the Atacama Submillimeter Telescope Experiment 10-m telescopes. Sets of digital autocorrelation spectrometers are available for OTF with heterodyne receivers mounted on the telescopes, including the focal-plane 5 x 5 array receiver, BEARS, on the 45-m. During OTF observations, the antenna is continuously driven to cover the mapped region rapidly, resulting in high observing efficiency and accuracy. Pointing of the antenna and readouts from the spectrometer are recorded as fast as 0.1 second. In this paper we report improvements made on software and instruments, requirements and optimization of observing parameters, data reduction process, and verification of the system. It is confirmed that, using optimal parameters, the OTF is about twice as efficient as conventional position-switch observing method.Comment: 11 pages, 13 figures, accepted for publication in PAS

Aperture Synthesis Observations of CO, HCN, and 89GHz Continuum Emission toward NGC 604 in M 33: Sequential Star Formation Induced by Supergiant Hii region

We present the results from new Nobeyama Millimeter Array observations of CO(1-0), HCN(1-0), and 89-GHz continuum emissions toward NGC 604, known as the supergiant H ii region in a nearby galaxy M 33. Our high spatial resolution images of CO emission allowed us to uncover ten individual molecular clouds that have masses of (0.8 -7.4) 10$^5$M_{\sun } and sizes of 5 -- 29 pc, comparable to those of typical Galactic giant molecular clouds (GMCs). Moreover, we detected for the first time HCN emission in the two most massive clouds and 89 GHz continuum emission at the rims of the "H${\alpha}$ shells". Three out of ten CO clouds are well correlated with the H${\alpha}$ shells both in spatial and velocity domains, implying an interaction between molecular gas and the expanding H ii region. Furthermore, we estimated star formation efficiencies (SFEs) for each cloud from the 89-GHz and combination of H${\alpha}$ and 24-${\mu}$m data, and found that the SFEs decrease with increasing projected distance measured from the heart of the central OB star cluster in NGC 604, suggesting the radial changes in evolutionary stages of the molecular clouds in course of stellar cluster formation. Our results provide further support to the picture of sequential star formation in NGC604 initially proposed by Tosaki et al. (2007) with the higher spatially resolved molecular clouds, in which an isotropic expansion of the H ii region pushes gases outward and accumulates them to consecutively form dense molecular clouds, and then induces massive star formations.Comment: 23 pages, 8 figures, accepted for publication in Ap

Impact on Waitlist Outcomes from Changes in the Medical Eligibility of Candidates for Simultaneous Liver-Kidney Transplantation Following Implementation of the 2017 Organ Procurement and Transplantation Network/United Network for Organ Sharing Policy in the United States

BACKGROUND: The new simultaneous liver-kidney transplantation (SLK) listing criteria in the United States was implemented in 2017. We aimed to investigate the impact on waitlist and post-transplantation outcomes from changes in the medical eligibility of candidates for SLK after policy implementation in the United States. MATERIAL AND METHODS: We analyzed adult primary SLK candidates between January 2015 and March 2019 using the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) registry. We compared waitlist practice, post-transplantation outcomes, and final transplant graft type in SLK candidates before and after the policy. RESULTS: A total of 4641 patients were eligible, with 2975 and 1666 registered before and after the 2017 policy, respectively. The daily number of SLK candidates was lower after the 2017 policy (3.25 vs 2.89, P=0.01); 1956 received SLK and 95 received liver transplant alone (LTA). The proportion of patients who eventually received LTA was higher after the 2017 policy (7.9% vs 3.0%; P\u3c0.001). The 1-year graft survival rate was worse in patients with LTA than in those with SLK (80.5% vs 90.4%; P=0.003). The adjusted risk of 1-year graft failure in patients with LTA was 2.01 (95% confidence interval 1.13-3.58, P=0.01) compared with patients with SLK among the SLK candidates. CONCLUSIONS: Although the number of registrations for SLK increased, the number of SLK transplants decreased, and the number of liver transplants increased. LTA in this patient cohort was associated with worse post-transplantation outcomes

Therapeutic effects of human mesenchymal stem cells in Wistar-Kyoto rats with anti-glomerular basement membrane glomerulonephritis.

INTRODUCTION: Multipotent mesenchymal stem cells (MSCs) have become a promising therapeutic approach in many clinical conditions. The hypothesis that MSCs can provide a potential therapy for human anti-glomerular basement membrane (GBM) glomerulonephritis (GN) was tested. METHODS: Nephrotoxic serum nephritis was induced in Wistar-Kyoto rats on day 0. Groups of animals were given either human MSCs (hMSCs, 3×10(6)) or vehicle by intravenous injection on day 4; all rats were sacrificed at either day 7 or day 13. RESULTS: Fluorescently labeled hMSCs were localized in glomeruli and tubulointerstitium 5 h after hMSC administration and persisted until 48 h, but hMSCs were barely detectable after 7 days. hMSC-treated rats had decreased kidney weight, proteinuria, and glomerular tuft area at each time point. The serum creatinine level and degree of glomerular crescent formation were decreased by hMSC treatment on day 13. ED1-positive macrophages, CD8-positive cells, and TUNEL-positive apoptotic cells in glomeruli were reduced by hMSC treatment on day 7, and this trend in apoptotic cells persisted to day 13. Renal cortical mRNA for TNF-α, IL-1β, and IL-17, and the serum IL-17A level were decreased, whereas renal cortical mRNA for IL-4 and Foxp3 and the serum IL-10 level were increased in the MSC-treated group on day 7. Collagen types I and III and TGF-β mRNA were decreased by hMSC treatment on day 13. CONCLUSION: The present results demonstrated that anti-inflammatory and immunomodulatory effects were involved in the mechanism of attenuating established experimental anti-GBM GN by hMSCs. These results suggest that hMSCs are a promising therapeutic candidate for the treatment of anti-GBM GN

FATE OF LIVER AND KIDNEY TRANSPLANT CANDIDATES BEFORE AND AFTER SIMULTANEOUS LIVER-KIDNEY TRANSPLANT ALLOCATION POLICY CHANGE

Background: The OPTN/UNOS policy for kidney allocation to liver transplant (LT) recipients was implemented on August 10th, 2017. We investigated the impact of the policy change on outcomes on simultaneous liver-kidney transplantation (SLK) candidates. Methods: Using OPTN/UNOS data, we analyzed adult SLK candidates between January 2015 and March 2019. We excluded patients registered for retransplant. Patients were classified into two cohorts; cohort 1: from January 1st, 2015 to July 31st, 2017 (pre-policy group), cohort 2: from September 1st, 2017 to March 30th, 2019 (post-policy group). Waitlist outcomes, including 90-day mortality, transplant probability, and type of transplant (SLK vs. LT alone [LTA]) were compared between the two cohorts using a Fine-Gray competing risk regression model. Post-transplant outcomes were compared according to transplant type using a Cox regression model. Results: Of the 4641 patients eligible for this study, 2975 and 1666 were registered in cohorts 1 and 2, respectively. The average number of waitlisted patients (daily) was significantly lower in cohort 2 compared to cohort 1 (2.89/day vs. 3.25/day; p=0.013). In patients with MELD score \u3e35, there was significantly higher 90-day transplant probability in cohort 2 (adjusted hazard ratio [aHR]:1.23, p=0.032); whereas no significant difference was observed in patients with MELD scores 30-34 or \u3c29. The patients in cohort 2 with MELD scores ≥35 trended towards a lower 90- day waitlist mortality compared to patients in cohort 1 (aHR: 0.69, p=0.06). Regarding transplant type, the proportion of LTA in SLK candidates was significantly higher in cohort 2 compared to cohort 1; both overall (7.9% vs. 3.0%, P\u3c0.001) and when stratified by MELD score (≤29, 30-34, ≥35; p=0.006, 0.008, 0.004, respectively) (Figure 1). Adjusted risk of 1-year graft loss was significantly higher in LTA compared to SLK (aHR 2.01, p=0.012) (Figure 2). Conclusion: The new SLK policy significantly decreased the number of SLK transplants while significantly improving waitlist outcomes, especially in patients with higher MELD scores. After the policy change, patients who were initially registered for SLK more frequently received LTA, likely due to more stringent criteria. Because LTA outcomes were significantly worse than SLK in SLK candidates, the decision on transplant type for this patient population needs careful assessment

PARADIGM CHANGE IN LIVER TRANSPLANT PRACTICE FOR PATIENTS WITH KIDNEY DYSFUNCTION AFTER THE IMPLEMENTATION OF THE NEW LIVER-KIDNEY ALLOCATION POLICY

Background: The new OPTN/UNOS policy regarding kidney allocation for liver transplant (LT) patients was implemented on Aug 10, 2017. Per the new policy, LT patients who developed kidney failure may be granted priority on the kidney transplant (KT) waitlist (Safety net). The aim of this study was to evaluate effects of the new policy on pre and post-transplant practice LT patients with kidney dysfunction. Methods: We analyzed adult primary LT alone (LTA) candidates who had kidney dysfunction at listing (Chronic kidney disease [CKD] stage 4 or higher) between January 2015 and March 2019 using data from the OPTN/UNOS. Impact of the new policy on the number of listings, waitlist outcomes, post-transplant outcomes, and KT listing after LTA were assessed. In post- LTA outcome analysis, patients were categorized according to kidney function at transplant (Group 1: CKD stage 4 without dialysis; Group 2: CKD stage 5 without dialysis; Group 3: dialysis requirement; Group 4: CKD stage 1-3 without dialysis). Results: A total of 3821 patients with CKD 4 or higher were registered for LTA. The daily number of patients on dialysis who were registered for LTA significantly increased in post- policy era compared with pre-policy era (1.21/day vs 0.95/ day, p \u3c0.001). 90-day LT waitlist mortality (HR 0.99, p=0.94) or transplant probability (HR 1.07, p=0.25) was not changed in post-policy era, compared to pre-policy era. One-year liver graft survival in Groups 1, 2, 3, and 4 were comparable between before and after the policy implementation (Table 1). Of all LTA patients, the patients in post-policy era had a higher risk for KT listing after LTA than those in pre-policy era (6.2% vs 3.9%, odds ratio = 3.30, p \u3c0.001), especially patients in Group 3, 8.4% vs 2.0% (odds ratio = 4.38, p \u3c0.001) (Table 2). Among the 65 patients who were listed for KT in post- policy era, one-year KT probability, waitlist mortality rate, and removal rate due to clinical improvement rate were 61.1%, 1.5%, and 2.7%, respectively. Conclusion: The new policy significantly increased the number of LTA candidates with dialysis, did not affect their post-transplant survival, and increased KT listing after LTA. The safety-net rule led to high KT probability and low waitlist mortality rate in patients who were listed for KT after LTA. These results suggest that the new policy successfully stratified patients with kidney dysfunction for LTA and provided KT opportunities to patients post-LT kidney failure

LIVER TRANSPLANTATION IN OLDER PATIENTS WITH ACUTE-ON-CHRONIC LIVER FAILURE: AN ANALYSIS OF UNOS REGISTRY

Background: Acute on chronic liver failure (ACLF) patients undergoing liver transplantation (LT) may require additional consideration in selection and management due to their severity of illness. We hypothesized that older recipient age might increase the risk of graft loss in ACLF patients. We aimed to identify risk factors for post-transplant mortality in patients with ACLF, focusing on recipient age. Methods: Using data from the UNOS registry, this study evaluated adult liver or liver and kidney transplant recipients between 2014 and 2019. Patients with status 1A, multi-organ, hepatocellular carcinoma, and re-transplant were excluded. We identified patients with ACLF using European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) criteria. One- year graft survival was compared between ACLF patients (ACLF grades 1, 2, 3) and those without ACLF for each age group (age\u3c50 \u3e[younger], 50-64 [mid], ≥65 [older]). Risk factors for 1-year graft survival were analyzed in ACLF patients using Cox regression models. A subgroup analysis in older ACLF patients was performed based on identified risk factors. Risk was adjusted by donor and recipient characteristics at LT. Results: Among 17,148 patients eligible for the study, 3,836 (22.4%), 3,050 (17.8%) and 2,084 (12.2%) had ACLF 1,2 and 3. 2983 (17.4%) patients were in the older group. In all age groups, ACLF 1, 2 and 3 groups showed significantly higher risk of 1-year graft loss than those without ACLF (Figure). In patients with ACLF, older recipient (≥65 years, aHR 1.56, P8 hours (aHR 1.21, P=0.038), and older donor (\u3e50 years: aHR 1.395, P Conclusion: Liver transplant outcomes were significantly worse in patients with ACLF compared to those without ACLF regardless of recipient age. Donor selection and shortening cold ischemia time may mitigate risk of graft loss in older patients with ACLF

EFFECTS OF AGING AND ACUTE-ON-CHRONIC LIVER FAILURE ON LIVER TRANSPLANT WAITLIST MORTALITY

Background: Acute-on-chronic liver failure (ACLF) is characterized by multiple organ failure with high short-term mortality. However, the effect of the severity of ACLF on waitlist outcomes in age groups has not been well elucidated. We hypothesized that the negative effect of ACLF may be different between age groups and older patients may increase the risk of waitlist mortality compared to younger population. The aim of this study is to investigate the effects of ACLF on waitlist mortality according to recipient age. Methods: This study used data from the UNOS registry and evaluated adult patients listed for liver-only or liver-kidney transplant between 2014 and 2019. Patients listed as status 1A, multi- organ transplant, hepatocellular carcinoma, and re-transplant were excluded. We identified patients with ACLF using the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) criteria. Ninety-day waitlist mortality was compared between ACLF grades 1, 2, and 3 in each age group at listing (age\u3c50 [younger], 50-64 [mid], ≥65 [older]). The risks of 90-day waitlist mortality were analyzed in ACLF patients using Fine-Gray competing risk regression model. Risk was adjusted by recipient characteristics at listing. Results: Among the 30,486 patients eligible for the study, 6,316 (20.7%), 1,995 (6.5%) and 1,653 (5.4%) had ACLF 1,2 and 3, respectively. 7733 (25.3%) were in younger group, 17462 (57.3%) were in mid group, 5291 (17.4%) were in older group. In all age groups, ACLF 1, 2 and 3 groups showed significantly higher adjusted risk of 90-day waitlist mortality than those without ACLF (Figure). The adverse impact of ACLF on waitlist mortality was most significant in the older group. In patients with ACLF, higher grade of ACLF (ACLF- 2: adjusted hazard ratio [aHR] 1.33, P\u3c0.001; ACLF-3: aHR 2.56, P\u3c0.001; ref: ACLF-1) and older recipient age (mid: aHR 1.57, P\u3c0.001: older: aHR 2.15, P\u3c0.001; ref younger) independently increased the risk of 90-day waitlist mortality. Conclusion: While ACLF negatively affected 90-day mortality for patients of all age groups on waitlist, this effect was more prominent in the older populations. Given this fact and the higher risk of waitlist mortality for those with ACLF, increased priority in liver allocation to these patients should be considered

Paradigm change in liver transplant practice after the implementation of the liver-kidney allocation policy

The OPTN/UNOS policy regarding kidney allocation for liver transplant (LT) patients was implemented in August 2017. This study aimed to evaluate the effects of the simultaneous liver-kidney transplant policy on outcomes in LT alone (LTA) patients with kidney dysfunction. We analyzed adult primary LTA patients with kidney dysfunction at listing (estimated glomerular filtration rate [eGFR] less than 30mL/min or dialysis requirement) between January 2015 and March 2019 using the OPTN/UNOS registry. Waitlist practice and kidney transplant (KT) listing after LTA were compared between pre- and post-policy groups. 3,821 LTA listings with eGFR\u3c30mL/min were included. The daily number of listings on dialysis was significantly higher in Era2 (post-policy group) than Era1 (pre-policy group) (1.21/day vs. 0.95/day, P\u3c0.001). Of these LTA listings, 90-day LT waitlist mortality, LTA probability, and one-year post-LTA survival were similar between eras. LTA recipients in Era2 had a higher probability for KT listing post-LTA than those in Era1 (6.2% vs. 3.9%, odds ratio=3.30, P\u3c0.001), especially those on dialysis (8.4% vs. 2.0%, odds ratio=4.38, P\u3c0.001). Under the safety-net rule, there was a higher KT probability after LTA (26.7% and 53% at 6 months in Eras 1 and 2, respectively, P=0.017). Conclusion: After the implementation of the policy, the number of LTA listings among patients on dialysis significantly increased. While their post-transplant survival was not changed, KT listing after LTA increased. The safety-net rule led to high KT probability and low waitlist mortality rate in patients who were listed for KT after LTA. These results suggest that the policy successfully achieved the goals, which did not compromise LTA waitlist or post-transplant outcomes in patients with kidney dysfunction, and provided KT opportunities if they developed kidney failure after LTA