A propensity score matched analysis of liver transplantation outcomes in the setting of preservation solution shortage.

The recent shortage of the University of Wisconsin (UW) solution prompted increased utilization of histidine-tryptophan-ketoglutarate (HTK) solution for liver graft preservation. This contemporary study analyzed deceased donor liver transplant outcomes following preservation with HTK vs UW. Patients receiving deceased donor liver transplantations between January 1, 2019, and June 30, 2022, were retrospectively identified utilizing the Organ Procurement and Transplant Network database, stratified by preservation with HTK vs UW, and a propensity score matching analysis was performed. Outcomes assessed included rates of primary nonfunction, graft survival, and patient survival. There were 4447 patients in each cohort. Primary nonfunction occurred in 60 (1.35%) patients in the HTK group vs 25 (0.54%) in the UW group (P < .001). HTK was associated with lower 90-day graft survival (94.39% vs 96.09%; P < .001) and 90-day patient survival (95.97% vs 97.38%; P = .001). Unmatched donation after cardiac death-specific analysis of HTK vs UW demonstrated respective rates of primary nonfunction of 1.63% vs 0.82% (P = .20), 90-day graft survival of 92.50% vs 95.29% (P = .069), and 90-day patient survival of 93.90% vs 96.35% (P = .077). These results suggest that HTK may not be an equivalent preservation solution for deceased donor liver transplantation.

Assessing Kidney Transplantation Using ECMO-Supported Donors Within a KDPI-Based Allocation System.

Background: Organ donors supported by extracorporeal membrane oxygenation (ECMO) have historically been considered high-risk and are judiciously utilized. This study examines transplant outcomes using renal allografts from donors supported on ECMO for nondonation purposes. Methods: Retrospective review of the Gift of Life (Pennsylvania, New Jersey, Delaware) organ procurement organization database, cross-referenced to the Organ Procurement and Transplantation Network database, assessed kidney transplants using donors supported on venoarterial (VA) and venovenous (VV) ECMO for nondonation purposes. Transplants using VA- and VV-ECMO donors were compared with Kidney Donor Profile Index (KDPI)-stratified non-ECMO donors. Regression modeling of the entire ECMO and non-ECMO populations assessed ECMO as predictive of graft survival. Additional regression of the ECMO population alone assessed for donor features associated with graft survival. Results: Seventy-eight ECMO donors yielded 128 kidney transplants (VA: 80, VV: 48). Comparing outcomes using these donors to kidney transplants using organs from KDPI-stratified non-ECMO donors, VA- and VV-ECMO donor grafts conferred similar rates of delayed graft function and posttransplant renal function to KDPI-matched non-ECMO counterparts. VA-ECMO kidneys demonstrated superior graft survival compared with the lowest-quality (KDPI 86%-100%) non-ECMO kidneys and similar graft survival to KDPI <85% non-ECMO kidneys. VV-ECMO showed inferior graft survival to all but the lowest-quality (KDPI 86%-100%) non-ECMO kidneys. VV-ECMO, but not VA-ECMO, was associated with increased risk of graft loss on multivariable regression (hazard ratios-VA: 1.02, VV: 2.18). Higher KDPI, advanced age, increased body mass index, hypertension, and diabetes were identified as high-risk features of ECMO donors. Conclusions: Kidney transplantation using appropriately selected ECMO donors can safely expand the donor pool. Ongoing studies are necessary to determine best practice patterns using kidneys from these donors.

Extracorporeal membrane oxygenation for cardiopulmonary failure in organ donation: Assessing liver transplant outcomes.

Liver transplantation continues to face significant organ shortages and efficient utilization of marginal donors is paramount. This study evaluates the practice patterns and outcomes in liver transplantation when utilizing allografts from marginal donors who required extracorporeal membrane oxygenation (ECMO) support. We performed a retrospective review of the Gift of Life (PA, NJ, DE) organ-procuring organization database for transplants performed using donors supported on ECMO for nondonation purposes. These were cross-referenced to the transplant recipients within the Organ Procurement and Transplantation Network database, and the outcomes of liver transplants using donors on ECMO support were compared with those not requiring ECMO. Organ use and nonuse patterns were then evaluated in ECMO-supported donors, identifying the factors associated with nonuse compared with the factors associated with graft failure. Thirty-nine of the 84 ECMO-supported donors contributing at least one intra-abdominal organ for transplant donated a liver. Graft survival and patient survival up to 5 years were comparable between transplants from ECMO and non-ECMO-supported donors, and no cases of primary nonfunction were seen in the ECMO group. ECMO support was not associated with 1-year graft failure on regression modeling. Additional regression analyses within the ECMO donor population identified bacteremia (HR: 19.81) and elevated total bilirubin at donation (HR: 2.44) as predictive of post-transplant graft failure. Livers from donors supported on ECMO before donation appear safe to use in select transplant settings. Better understanding of the impact of predonation ECMO on liver allograft function will help guide the optimal use of these scarcely used donors.

Reduced Rates of Post-Transplant Recurrent Hepatocellular Carcinoma in Non-Alcoholic Steatohepatitis: A Propensity Score Matched Analysis.

Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) has become the second leading cause of HCC-related liver transplantation in the United States. This study investigated post-transplant recurrence and survival for patients transplanted for NASH-related HCC compared to non-NASH HCC etiologies. Retrospective review of the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN) database identified 7,461 patients with HCC-1,405 with underlying NASH and 6,086 with non-NASH underlying diseases. After propensity score matching (PSM) to account for patient- and tumor-related confounders 1,175 remained in each group. Primary outcomes assessed were recurrence rate and recurrence-free survival. Recurrent malignancy at 5 years post-transplant was lower in NASH compared to non-NASH patients (5.80 vs. 9.41%, p = 0.01). Recurrence-free survival, however, was similar at 5 years between groups. Patients with NASH-related HCC were less likely to have post-transplant recurrence than their non-NASH counterparts, although recurrence-free survival was similar at 5 years.

Evaluating Outcomes Related to Donor and Recipient Metabolic Environment: Macrosteatotic Allografts and Nonalcoholic Steatohepatitis.

The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) affects both recipient and donor populations in liver transplantation. Presently, it is unclear whether transplantation of macrosteatotic allografts is affected by the metabolic milieu of liver transplant recipients. This study investigates fatty liver disease at the intersection of donor and recipient. A retrospective review of the Organ Procurement and Transplantation database identified 5167 NASH and 26,289 non-NASH transplant recipients who received transplants from January 1, 2004, to June 12, 2020. A total of 12,569 donors had allografts with no macrosteatosis (<5%), 16,140 had mild macrosteatosis (5%-29%), and 2747 had moderate to severe macrosteatosis (≥30%). Comparing recipients with NASH to propensity score-matched (PSM) recipients without NASH demonstrated noninferior graft and patient survival up to 10 years in patients with NASH. Similar trends were observed in subgroup analyses of transplants within each strata of allograft macrosteatosis. Assessing allograft macrosteatosis specifically in the NASH population demonstrated that allografts with ≥30% macrosteatosis were associated with reduced early graft survival (30 days, 93.32% versus 96.54% [P = 0.02]; 1 year, 84.53% versus 88.99% [P = 0.05]) compared with PSM grafts with <30% macrosteatosis. Long-term graft survival at 5 and 10 years, however, was similar. The use of carefully selected macrosteatotic allografts can be successful in both recipients with NASH and recipients without NASH. The metabolic environment of patients with NASH does not appear to adversely affect outcomes with regard to the allograft when controlled for numerous confounders. It is, however, important to remain cognizant of the potential for high-risk macrosteatotic allografts to negatively affect outcomes.

HCV-Positive Allograft Use in Heart Transplantation Is Associated With Increased Access to Overdose Donors and Reduced Waitlist Mortality Without Compromising Outcomes.

BACKGROUND: Because of ongoing shortages of donors for heart transplantation, the use of donor candidates whose availabilities are the result of drug overdoses (ODs) has become increasingly prevalent, even though these donors carry a high preponderance of the now curable hepatitis C virus (HCV). This study investigated temporal trends and regional variabilities in HVC-positive (HCV+) allograft use in heart transplantation and assessed the relationship between the use of HCV+ graft donors and the use of OD donors as well as assessing waitlist and post-transplant outcomes. METHODS AND RESULTS: A retrospective review of the United Network for Organ Sharing database assessed adults listed for heart transplantation. Patients were stratified both temporally into pre-HCV and HCV eras related to HCV+ graft use trends and regionally by degree of HCV+ allograft use. Regions of high HCV+ donor use were associated with an increase in OD donor access by 7.8% across eras compared to 0.4% in low HCV+ donor-use regions. One-year waitlist mortality decreased from 4.7% to 2.5% across eras in high HCV+ donor-use regions (P= 0.001) and remained roughly the same as before in low HCV+ donor-use regions (3.0% vs 2.4%; P= 0.244.). Post-transplant survival at 1 year remained similar across eras. CONCLUSIONS: HCV+ donor allograft use can help to optimize donor use, decreasing waitlist mortality without compromising early survival. Ongoing assessment is essential to ensure long-term safety and efficacy of using HCV+ donors.

Superoxide Dismutase-Loaded Nanoparticles Attenuate Myocardial Ischemia-Reperfusion Injury and Protect Against Chronic Adverse Ventricular Remodeling.

Early revascularization is critical to reduce morbidity after myocardial infarction, although reperfusion incites additional oxidative injury. Superoxide dismutase (SOD) is an antioxidant that scavenges reactive oxygen species (ROS) but has low endogenous expression and rapid myocardial washout when administered exogenously. This study utilizes a novel nanoparticle carrier to improve exogeneous SOD retention while preserving enzyme function. Its role is assessed in preserving cardiac function after myocardial ischemia-reperfusion (I/R) injury. Here, nanoparticle-encapsulated SOD (NP-SOD) exhibits similar enzyme activity as free SOD, measured by ferricytochrome-c assay. In an in vitro I/R model, free and NP-SOD reduce active ROS, preserve mitochondrial integrity and improve cell viability compared to controls. In a rat in vivo I/R injury model, NP-encapsulation of fluorescent-tagged SOD improves intramyocardial retention after direct injection. Intramyocardial NP-SOD administration in vivo improves left ventricular contractility at 3-hours post-reperfusion by echocardiography and 4-weeks by echocardiography and invasive pressure-volume catheter analysis. These findings suggest that NP-SOD mitigates ROS damage in cardiac I/R injury in vitro and maximizes retention in vivo. NP-SOD further attenuates acute injury and protects against myocyte loss and chronic adverse ventricular remodeling, demonstrating potential for translating NP-SOD as a therapy to mitigate myocardial I/R injury.

Organ allocation and procurement in cardiac transplantation.

PURPOSE OF REVIEW: There is a critical shortage of organs in cardiac transplantation. Recent advancements in both organ allocation and donor utilization have intended to address this shortage and optimally allocate allografts. This review evaluates several important aspects of recipient and donor management. For recipients, the focus is placed on the evolving mechanical circulatory support population and its bidirectional impact on organ allocation. From the donor standpoint, organ utilization is assessed with respect to increasing access to previously unused allografts. RECENT FINDINGS: Implementation of the new heart allocation system in the United States has better stratified waitlist candidates by illness acuity. Compared to the prior system, those requiring venoarterial extracorporeal membrane oxygenation support are less likely to die on the waitlist, although conflicting data exists whether this has improved their posttransplant survival. The use of pretransplant intra-aortic balloon pumps has markedly increased, whereas transplantation of patients with dischargeable left ventricular assist devices has decreased. Although some studies have reported inferior short- to mid-term posttransplant survival in the new system compared to its predecessor, others report similar outcomes.Several recent advancements in donor utilization have also been noted. Coinciding with the global increase in drug overdose deaths, efforts have been made to increase use of these donors who are frequently considered 'increased risk' and are hepatitis C-positive. Grafts from these donors appear safe to use. These, alongside donation after circulatory death donors, represent potentially underutilized populations that may effectively expand the donor pool. SUMMARY: Recent changes in organ allocation, alongside efforts to expand the donor pool, have attempted to improve cardiac allograft utilization and reduce the imbalance between organ supply and demand. Ongoing monitoring and continuous re-evaluation of these efforts will help guide future practice.

Simultaneous liver kidney allocation policy and the Safety Net: an early examination of utilization and outcomes in the United States.

Rates of simultaneous liver kidney (SLK) transplantation in the United States have progressively risen. On 8/10/17, the Organ Procurement and Transplantation Network implemented a policy defining criteria for SLK, with a "Safety Net" to prioritize kidney allocation to liver recipients with ongoing renal failure. We performed a retrospective review of the United Network for Organ Sharing (UNOS) database to evaluate policy impact on SLK, kidney after liver (KAL) and kidney transplant alone (KTA). Rates and outcomes of SLK and KAL transplants were compared, as was utilization of high-quality kidney allografts with Kidney Donor Profile Indices (KDPI) <35%. Here, SLK transplants comprised 9.0% and 4.5% of total postpolicy liver and kidney transplants compared to 10.2% and 5.5% prior. Policy enactment did not affect 1-year graft or patient survival for SLK and KAL populations. Less postpolicy SLK transplants utilized high-quality kidney allografts; in all transplant settings, outcomes using high-quality grafts remained stable. These findings suggest that policy implementation has reduced kidney allograft use in SLK transplantation, although both SLK and KAL rates have recently increased. Despite decreased high-quality kidney allograft use, SLK and KAL outcomes have remained stable. Additional studies and long-term follow-up will ensure optimal organ access and sharing.

Modulation of cytoskeletal dynamics by mammalian nucleoside diphosphate kinase (NDPK) proteins.

Nucleoside diphosphate kinase (NDPK) proteins comprise a family of ten human isoforms that participate in the regulation of multiple cellular processes via enzymatic and nonenzymatic functions. The major enzymatic function of NDPKs is the generation of nucleoside triphosphates, such as guanosine triphosphate (GTP). Mechanisms behind the nonenzymatic NDPK functions are not clear but likely involve context-dependent signaling roles of NDPK within multi-protein complexes. This is most evident for NDPK-A, which is encoded by the human NME1 gene, the first tumor metastasis suppressor gene to be identified. Understanding which protein interactions are most relevant for the biological and metastasis-related functions of NDPK will be important in the potential utilization of NDPK as a disease target. Accumulating evidence suggests that NDPK interacts with and affects various components and regulators of the cytoskeleton, including actin-binding proteins, intermediate filaments, and cytoskeletal attachment structures (adherens junctions, desmosomes, and focal adhesions). We review the existing literature on this topic and highlight outstanding questions and potential future directions that should clarify the impact of NDPK on the different cytoskeletal systems.

Alternative splicing of human NT5E in cirrhosis and hepatocellular carcinoma produces a negative regulator of ecto-5'-nucleotidase (CD73).

Ecto-5'-nucleotidase (CD73), encoded by NT5E, is the major enzymatic source of extracellular adenosine. CD73 controls numerous pathophysiological responses and is a potential disease target, but its regulation is poorly understood. We examined NT5E regulation by alternative splicing. Genomic database analysis of human transcripts led us to identify NT5E-2, a novel splice variant that was expressed at low abundance in normal human tissues but was significantly up-regulated in cirrhosis and hepatocellular carcinoma (HCC). NT5E-2 encodes a shorter CD73 isoform we named CD73S. The presence of CD73S protein, which lacks 50 amino acids, was detected in HCC using an isoform-specific antibody. A noncanonical mouse mRNA, similar to human CD73S, was observed, but the corresponding protein was undetectable. The two human isoforms exhibited functional differences, such that ectopic expression of canonical CD73 (CD73L) in human HepG2 cells was associated with decreased expression of the proliferation marker Ki67, whereas CD73S expression did not have an effect on Ki67 expression. CD73S was glycosylated, catalytically inactive, unable to dimerize, and complexed intracellularly with the endoplasmic reticulum chaperone calnexin. Furthermore, CD73S complexed with CD73L and promoted proteasome-dependent CD73L degradation. The findings reveal species-specific CD73 regulation, with potential significance to cancer, fibrosis, and other diseases characterized by changes in CD73 expression and function.