The Dynamic Organ Storage System (DOSS) is a portable device that delivers oxygenated perfusate at 10 °C and improves liver graft function compared with static cold storage. In this study, porcine donation after circulatory death (DCD) livers were preserved for 10 hours using DOSS with modified perfusate (M-DOSS) and compared with unmodified perfusate (U-DOSS) during normothermic machine perfusion (NMP). All M-DOSS livers met predefined viability criteria within 4 hours of NMP, whereas one U-DOSS liver failed due to impaired lactate clearance. At 4 hours of NMP, bile pH was significantly higher in the M-DOSS group (p = 0.002). Viable NMP was sustained for 36 ± 25 hours in M-DOSS livers. Histological injury was reduced after storage (M-DOSS: 2 ± 0.7, U-DOSS: 3 ± 0.4, p = 0.025), with greater regenerative activity reflected by higher Ki-67 positivity after storage (M-DOSS: 40 ± 4 cells/hpf, U-DOSS: 26 ± 10 cells/hpf, p = 0.016) and after 4 hours of NMP (M-DOSS: 33 ± 10 cells/hpf, U-DOSS: 17 ± 2 cells/hpf, p = 0.032). The Ki-67/TUNEL ratio—reflecting the balance between proliferative and apoptotic signals—was also significantly higher in M-DOSS livers after storage (4.5 ± 1.7 vs 1.3 ± 1.0, p = 0.008). These findings suggest that perfusate optimization is associated with favorable histological findings and warrants further investigation in transplantation models before clinical application.

Myostatin is a paracrine myokine that regulates muscle mass in a variety of species, including humans. In this work, we report a functional role for myostatin as an endocrine hormone that directly promotes pituitary follicle-stimulating hormone (FSH) synthesis and thereby ovarian function in mice. Previously, this FSH-stimulating role was attributed to other members of the transforming growth factor–β family, the activins. Our results both challenge activin’s eponymous role in FSH synthesis and establish an unexpected endocrine axis between skeletal muscle and the pituitary gland. Our data also suggest that efforts to antagonize myostatin to increase muscle mass may have unintended consequences on fertility.

In the United States, since 2019, liver transplant waitlist candidates who are approved for a model for end-stage liver disease exception are awarded points that vary based on geography. The number of points is based on the median model for end-stage liver disease score at transplant minus 3 (MMAT-3) of recipients within a specific area, which has changed over time. However, the median model for end-stage liver disease score at transplant (MMAT) is calculated based only on recipients ≥12 years of age transplanted with a liver from a donation after brain death donor located within 500 nautical miles of the transplant hospital. When the policy was first implemented, the restriction to only these donors had little impact, as they comprised the majority of deceased liver donors. However, with the broader use of donation after circulatory death donors, who represent nearly 40% of all deceased liver donors in the United States, the calculation of MMAT based only on donation after brain death donors has led to a marked difference in the calculated MMAT used for awarding exception points and the actual MMAT. In this viewpoint, we highlight the changes in exception policy, the growing difference between the policy-based MMAT and the actual MMAT, and propose policy changes to ensure allocation rules reflect current practice.

Donation after circulatory death (DCD) livers face increased risks of critical complications when preserved with static cold storage (SCS). Although machine perfusion (MP) may mitigate these risks, its cost and logistical complexity limit widespread application. We developed the Dynamic Organ Storage System (DOSS), which delivers oxygenated perfusate at 10°C with minimal electrical power requirement and allows real-time effluent sampling in a portable cooler. In a porcine DCD model, livers were preserved using DOSS or SCS for 10 hours and evaluated with 4 hours of normothermic MP, with n = 5 per group. After 4 hours of normothermic MP, the DOSS group demonstrated significantly lower perfusate lactate (p = 0.023), increased perfusate fibrinogen (p = 0.005), higher oxygen consumption (p = 0.018), greater bile production (p = 0.013), higher bile bicarbonate levels (p = 0.035) and bile/perfusate sodium ratio (p = 0.002), and lower hepatic arterial resistance after phenylephrine administration (p = 0.018). Histological analysis showed lower apoptotic markers in DOSS-preserved livers, with fewer cleaved caspase-3 (p = 0.039) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL; p = 0.009) positive cells. These findings suggest that DOSS can enhance DCD allograft function during transport, offering potential clinical benefits and contributing to the expansion of the donor pool.

The Liver Simulated Allocation Model (LSAM) is used to evaluate proposed organ allocation policies. Although LSAM has been shown to predict the directionality of changes in transplants and nonused organs, the magnitude is often overestimated. One reason is that policymakers and researchers using LSAM assume static levels of organ donation and center behavior because of challenges with predicting future behavior. We sought to assess the ability of LSAM to account for changes in organ donation and organ acceptance behavior using LSAM 2019. We ran 1-year simulations with the default model and then ran simulations changing donor arrival rates (ie, organ donation) and center acceptance behavior. Changing the donor arrival rate was associated with a progressive simulated increase in transplants, with corresponding simulated decreases in waitlist deaths. Changing parameters related to organ acceptance was associated with important changes in transplants, nonused organs, and waitlist deaths in the expected direction in data simulations, although to a much lesser degree than changing the donor arrival rate. Increasing the donor arrival rate was associated with a marked decrease in the travel distance of donor livers in simulations. In conclusion, we demonstrate that LSAM can account for changes in organ donation and organ acceptance in a manner aligned with historical precedent that can inform future policy analyses. As Scientific Registry of Transplant Recipients develops new simulation programs, the importance of considering changes in donation and center practice is critical to accurately estimate the impact of new allocation policies.

ImportanceA new liver allocation policy was implemented by United Network for Organ Sharing (UNOS) in February 2020 with the stated intent of improving access to liver transplant (LT). There are growing concerns nationally regarding the implications this new system may have on LT costs, as well as access to a chance for LT, which have not been captured at a multicenter level.ObjectiveTo characterize LT volume and cost changes across the US and within specific center groups and demographics after the policy implementation.Design, Setting, and ParticipantsThis cross-sectional study collected and reviewed LT volume from multiple centers across the US and cost data with attention to 8 specific center demographics. Two separate 12-month eras were compared, before and after the new UNOS allocation policy: March 4, 2019, to March 4, 2020, and March 5, 2020, to March 5, 2021. Data analysis was performed from May to December 2022.Main Outcomes and MeasuresCenter volume, changes in cost.ResultsA total of 22 of 68 centers responded comparing 1948 LTs before the policy change and 1837 LTs postpolicy, resulting in a 6% volume decrease. Transplants using local donations after brain death decreased 54% (P < .001) while imported donations after brain death increased 133% (P = .003). Imported fly-outs and dry runs increased 163% (median, 19; range, 1-75, vs 50, range, 2-91; P = .009) and 33% (median, 3; range, 0-16, vs 7, range, 0-24; P = .02). Overall hospital costs increased 10.9% to a total of $46 360 176 (P = .94) for participating centers. There was a 77% fly-out cost increase postpolicy ($10 600 234; P = .03). On subanalysis, centers with decreased LT volume postpolicy observed higher overall hospital costs ($41 720 365; P = .048), and specifically, a 122% cost increase for liver imports ($6 508 480; P = .002). Transplant centers from low-income states showed a significant increase in hospital (12%) and import (94%) costs. Centers serving populations with larger proportions of racial and ethnic minority candidates and specifically Black candidates significantly increased costs by more than 90% for imported livers, fly-outs, and dry runs despite lower LT volume. Similarly, costs increased significantly (>100%) for fly-outs and dry runs in centers from worse-performing health systems.Conclusions and RelevanceBased on this large multicenter effort and contrary to current assumptions, the new liver distribution system appears to place a disproportionate burden on populations of the current LT community who already experience disparities in health care. The continuous allocation policies being promoted by UNOS could make the situation even worse.

Background. A major change to deceased-donor kidney allocation in the United States, Kidney Allocation System 250 (KAS250), was implemented on March 15, 2021. Evaluating the consequences of this policy on critical system performance metrics is critical to determining its success. Methods. We performed a retrospective analysis of critical performance measures of the kidney transplant system by reviewing all organs procured during a 4-y period in the United States. To mitigate against possible effects of the COVID-19 pandemic, Scientific Registry of Transplant Recipients records were stratified into 2 pre- and 2 post-KAS250 eras: (1) 2019; (2) January 1, 2020-March14, 2021; (3) March 15, 2021-December 31, 2021; and (4) 2022. Between-era differences in rates of key metrics were analyzed using chi-square tests with pairwise z-tests. Multivariable logistic regression and analysis of variations methods were used to evaluate the effects of the policy on rural and urban centers. Results. Over the period examined, among kidneys recovered for transplant, nonuse increased from 19.7% to 26.4% (all between-era P < 0.05) and among all Kidney Donor Profile Index strata. Cold ischemia times increased (P < 0.001); however, the distance between donor and recipient hospitals decreased (P < 0.05). Kidneys from small-metropolitan or nonmetropolitan hospitals were more likely to not be used over all times (P < 0.05). Conclusions. Implementation of KAS250 was associated with increased nonuse rates across all Kidney Donor Profile Index strata, increased cold ischemic times, and shorter distance traveled.

Purpose Severe obesity is a barrier to listing for kidney transplantation due to concern for poor outcomes. This study aims to compare bariatric surgery with medical weight loss as a means of achieving weight loss and subsequent listing for renal transplant. We hypothesize that bariatric surgery will induce greater frequency of listing for transplant within 18 months of study initiation.Materials and Methods We performed a randomized study of metabolic bariatric surgery (MBS) vs medical weight loss (MM) in patients on dialysis with a body mass index (BMI) of 40-55 kg/m2. The primary outcome was suitability for renal transplant within 18 months of initiating treatment. Secondary outcomes included weight loss, mortality, and complications.Results Twenty patients enrolled, only 9 (5 MBS, 4 MM) received treatment. Treated groups did not differ in age, gender, or race (P >= .44). There was no statistically significant difference in the primary endpoint: 2 MBS (40%) and 1 MM (25%) listed for transplant <= 18 months (P = 1.00). With additional time, 100% MBS and 25% MM patients achieved listing status (P = .048); 100% of MBS and 0 MM received kidney transplants to date (P = .008). Weight, weight loss, and BMI trajectories differed between the groups (P <= .002). One death from COVID-19 occurred in the MM group, and 1 MBS patient had a myocardial infarction 3.75 years after baseline evaluation.Conclusion These results suggest MBS is superior to MM in achieving weight loss prior to listing for kidney transplantation. Larger studies are needed to ensure the safety profile is acceptable in patients with ESRD undergoing bariatric surgery.

ImportanceAvailability of organs inadequately addresses the need of patients waiting for a transplant.ObjectiveTo estimate the true number of donor patients in the United States and identify inefficiencies in the donation process as a way to guide system improvement.Design, Setting, and ParticipantsA retrospective cross-sectional analysis was performed of organ donation across 13 different hospitals in 2 donor service areas covered by 2 organ procurement organizations (OPOs) in 2017 and 2018 to compare donor potential to actual donors. More than 2000 complete medical records for decedents were reviewed as a sample of nearly 9000 deaths. Data were analyzed from January 1, 2017, to December 31, 2018.ExposureDeaths of causes consistent with donation according to medical record review, ventilated patient referrals, center acceptance practices, and actual deceased donors.Main Outcomes and MeasuresPotential donors by medical record review vs actual donors and OPO performance at specific hospitals.ResultsCompared with 242 actual donors, 931 potential donors were identified at these hospitals. This suggests a deceased donor potential of 3.85 times (95% CI, 4.23-5.32) the actual number of donors recovered. There was a surprisingly wide variability in conversion of potential donor patients into actual donors among the hospitals studied, from 0% to 51.0%. One OPO recovered 18.8% of the potential donors, whereas the second recovered 48.2%. The performance of the OPOs was moderately related to referrals of ventilated patients and not related to center acceptance practices.Conclusions and RelevanceIn this cross-sectional study of hospitals served by 2 OPOs, wide variation was found in the performance of the OPOs, especially at individual hospitals. Addressing this opportunity could greatly increase the organ supply, affirming the importance of recent efforts from the federal government to increase OPO accountability and transparency.

To the Editor: Glazier and Capron1 argue that normothermic regional perfusion (NRP) donation after circulatory death (DCD) protocols are not aligned with the Uniform Determination of Death Act (UDDA)2 and that the intention of physicians and patients is absent from the legal determination of death in the United States. This editorial provides a dangerously conservative interpretation of the UDDA that not only brings into question death in the setting of NRP DCD but also death in the setting of standard DCD protocols and perhaps any determination of death based on cardiopulmonary criteria. Glazier and Capron's contention that death can only be declared when circulation cannot and will not return regardless of intent ignores a critical portion of the UDDA—that the determination of death must be made in accordance with accepted medical standards. Accepted medical standards require intent to allow for natural death when the patient or family has made the decision to withdraw life-sustaining treatments and implemented a do not resuscitate order. If the legal determination of death requires that circulation cannot resume regardless of intention, this interpretation of the UDDA is problematic for all DCD organ procurements as well as the over 90% of hospitalized patients who are declared dead using cardiopulmonary criteria, as most could be resuscitated to the point of resumed cardio-pulmonary function with CPR, ECMO, or other interventions. Unlike the scenarios in which circulation is not resumed because resuscitative efforts are not made, Glazier and Capron have previously expressed concern that the resumption of circulatory function of the heart during NRP DCD procedures negates the prior declaration of death by invalidating the conditions under which death was declared.3 The resumption of the circulatory function of the heart is not exclusive to NRP DCD procedures. After super rapid recovery (SRR) DCD cardiac procurement, the donor's heart is restarted on an external perfusion device that connects into the heart. In NRP DCD procedures, the donor's heart is restarted in the body using an external perfusion device that is connected to the donor's blood vessels. While there is a difference in the location where the heart is restarted in NRP DCD and SRR DCD, there is no substantive difference in the fact that the circulatory function of the heart can be restarted after the declaration of death without negating that declaration. Ultimately, the legal definition of death must be in line with the standards of medical practice and respond to new medical technologies. NRP DCD procurements can utilize medical technology after death for organ preservation without negating medical standards for the declaration of death, and therefore remains consistent with the UDDA. Part of respecting the legacy of the decedent and providing family closure is to make organ donation an option, and to make organ transplantation as likely as possible when the choice has been made to donate. Adopting this conservative interpretation of the UDDA will lead not only to paralysis of DCD organ donation but also to the current practices of determining death using cardiopulmonary criteria.

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Cytokines are secreted soluble glycoproteins that regulate cellular growth, proliferation, and differentiation. Suppressors of cytokine signaling (SOCS) proteins negatively regulate cytokine signaling and form a classical negative feedback loop in the signaling pathways. There are eight members of the SOCS family. The SOCS proteins are all comprised of a loosely conserved N-terminal domain, a central Src homology 2 (SH2) domain, and a highly conserved SOCS box at the C-terminus. The role of SOCS proteins has been implicated in the regulation of cytokines and growth factors in liver diseases. The SOCS1 and SOCS3 proteins are involved in immune response and inhibit protective interferon signaling in viral hepatitis. A decreased expression of SOCS3 is associated with advanced stage and poor prognosis of patients with hepatocellular carcinoma (HCC). DNA methylations of SOCS1 and SOCS3 are found in HCC. Precise regulation of liver regeneration is influenced by stimulatory and inhibitory factors after partial hepatectomy (PH), in particular, SOCS2 and SOCS3 are induced at an early time point after PH. Evidence supporting the important role of SOCS signaling during liver regeneration also supports a role of SOCS signaling in HCC. Immuno-oncology drugs are now the first-line therapy for advanced HCC. The SOCS can be potential targets for HCC in terms of cell proliferation, cell differentiation, and immune response. In this literature review, we summarize recent findings of the SOCS family proteins related to HCC and liver diseases.