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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/m 2 . 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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., Competing Interests: Disclosure: Provisional patent for the Dynamic Organ Storage System (Reference No. VU033034) (Y.S., K.M.T., T.R.H., M.C., C.T.D., R.U., A.S.S., M.B.). The other authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

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., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Importance: A 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., Objective: To characterize LT volume and cost changes across the US and within specific center groups and demographics after the policy implementation., Design, Setting, and Participants: This 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 Measures: Center volume, changes in cost., Results: A 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 Relevance: Based 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.

Importance: Availability of organs inadequately addresses the need of patients waiting for a transplant., Objective: To 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 Participants: A 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., Exposure: Deaths of causes consistent with donation according to medical record review, ventilated patient referrals, center acceptance practices, and actual deceased donors., Main Outcomes and Measures: Potential donors by medical record review vs actual donors and OPO performance at specific hospitals., Results: Compared 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 Relevance: In 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.

Background: Societal factors that influence wait-listing for transplantation are complex and poorly understood. Social determinants of health (SDOH) affect rates of and outcomes after transplantation., Methods: This cross-sectional study investigated the impact of SDOH on additions to state-level, 2017-2018 kidney and liver wait-lists. Principal components analysis, starting with 127 variables among 3142 counties, was used to derive novel, comprehensive state-level composites, designated (1) health/economics and (2) community capital/urbanicity. Stepwise multivariate linear regression with backwards elimination (n = 51; 50 states and DC) tested the effects of these composites, Medicaid expansion, and center density on adult disease burden-adjusted wait-list additions., Results: SDOH related to increased community capital/urbanicity were independently associated with wait-listing (starting models: B = .40, P = .010 Kidney; B = .36, P = .038 Liver) (final models: B = .31, P = .027 Kidney, B = .34, P = .015 Liver). In contrast and surprisingly, no other covariates were associated with wait-listing (P ≥ .122)., Conclusions: These results suggest that deficits in community resources are important contributors to disparities in wait-list access. Our composite SDOH metrics may help identify at-risk communities, which can be the focus of local and national policy initiatives to improve access to organ transplantation., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

During the early wave of the COVID-19 pandemic, the Scientific Registry of Transplant Recipients (SRTR) designated a "black out" period between March 12, 2020, and June 12, 2020, for transplant outcomes reporting. We discuss the implications and potential bias it has introduced as it may selectively favor the outcomes for certain regions and harm other regions due to varied effects of different waves of COVID-19 infections across the United States., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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.

The novel approach of thoracic normothermic regional perfusion (TA-NRP) for in-situ preservation of organs prior to removal presents a new series of ethical questions about donation after circulatory determination of death (DCD) procedures. This manuscript describes the framework used for the analysis of ethical acceptability of DCD donation and analyzes the specific practice of TA-NRP DCD within that framework to demonstrate that TA-NRP DCD can be performed within the ethical boundaries of DCD donation. We argue that TA-NRP DCD organ procurements meet the ethical standards of informed consent, non-maleficence, adherence to the dead donor rule, and irreversibility, and as such, are ethically acceptable. We also describe the potential benefits of TA-NRP DCD procedures that result from higher organ yields and better recipient outcomes. Finally, we call for open and transparent support of TA-NRP DCD by professional organizations as a necessary cornerstone for the advancement of TA-NRP DCD procedures., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

To meet new Centers for Medicare and Medicaid Services (CMS) metrics, organ procurement organizations (OPOs) will benefit from understanding performance across decedent and hospital types. We sought to determine the utility of existing data-reporting structures for this purpose by reviewing Scientific Registry of Transplant Recipient (SRTR) OPO-Specific Reports (OSRs) from 2013 to 2019. OSRs contain both the Standardized donation rate ratio (SDRR) metric and OPO-reported numbers of "eligible deaths" and donors by hospital. Donor hospitals were characterized using information from Homeland Infrastructure Foundation-Level Data, Dartmouth Atlas Hospital Service Area data, and the US Census Bureau. Hospital data reported by OPOs showed 51% higher eligible death donors and 140% higher noneligible death donors per 100 inpatient beds in CMS ranked top versus bottom-quartile OPOs. Top-quartile OPOs by the CMS metric recovered 78% more donors than those in the bottom quartile, but were indistinguishable by SDRR rankings. These differences persisted across hospital sizes, trauma case mix, and area demographics. OPOs with divergent performance were indistinguishable over time by SDRR, but showed changes to hospital-level recovery patterns in SRTR data. Contemporaneous recognition of underperformance across hospitals may provide important and actionable data for regulators and OPOs for focused quality improvement projects., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Recent changes to organ procurement organization (OPO) performance metrics have highlighted the need to identify opportunities to increase organ donation in the United States. Using data from the Organ Procurement and Transplantation Network (OPTN), Scientific Registry of Transplant Recipients (SRTR), and Veteran Health Administration Informatics and Computing Infrastructure Clinical Data Warehouse (VINCI CDW), we sought to describe historical donation performance at Veteran Administration Medical Centers (VAMCs). We found that over the period 2010-2019, there were only 33 donors recovered from the 115 VAMCs with donor potential nationwide. VA donors had similar age-matched organ transplant yields to non-VA donors. Review of VAMC records showed a total of 8474 decedents with causes of death compatible with donation, of whom 5281 had no infectious or neoplastic comorbidities preclusive to donation. Relative to a single state comparison of adult non-VA inpatient deaths, VAMC deaths were 20 times less likely to be characterized as an eligible death by SRTR. The rate of conversion of inpatient donation-consistent deaths without preclusive comorbidities to actual donors at VAMCs was 5.9% that of adult inpatients at non-VA hospitals. Overall, these findings suggest significant opportunities for growth in donation at VAMCs., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Trauma patients may present with nonsurvivable injuries, which could be resuscitated for future organ transplantation. Trauma surgeons face an ethical dilemma of deciding whether, when, and how to resuscitate a patient who will not directly benefit from it. As there are no established guidelines to follow, we aimed to describe resuscitation practices for organ transplantation; we hypothesized that resuscitation practices vary regionally., Method: Over a 3-month period, we surveyed trauma surgeons practicing in Levels I and II trauma centers within a single state using an instrument to measure resuscitation attitudes and practices for organ preservation. Descriptive statistics were calculated for practice patterns., Results: The survey response rate was 51% (31/60). Many (81%) had experience with resuscitations where the primary goal was to preserve potential for organ transplantation. Many (90%) said they encountered this dilemma at least monthly. All respondents were willing to intubate; most were willing to start vasopressors (94%) and to transfuse blood (84%) (range, 1 unit to >10 units). Of respondents, 29% would resuscitate for ≥24 hours, and 6% would perform a resuscitative thoracotomy. Respect for patients' dying process and future organ quality were the factors most frequently considered very important or important when deciding to stop or forgo resuscitation, followed closely by concerns about excessive resource use., Conclusion: Trauma surgeons' regional resuscitation practices vary widely for this patient population. This variation implies a lack of professional consensus regarding initiation and extent of resuscitations in this setting. These data suggest this is a common clinical challenge, which would benefit from further study to determine national variability, areas of equipoise, and features amenable to practice guidelines., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Despite data showing equivalent outcomes between grafts from marginal versus standard criteria deceased liver donors, elevated donor transaminases constitute a frequent reason to decline potential livers. We assessed the effect of donor transaminase levels and other characteristics on graft survival., Materials and Methods: We performed a retrospective cohort analysis of adult first deceased donor liver transplant recipients with available transaminase levels registered in the Organ Procurement and Transplantation Network database (2008-2018). We used Cox proportional hazards regression to determine the effects of donor characteristics on graft survival., Results: Of 53 913 liver transplants, 52 158 were allografts from donors with low transaminases (≤ 500 U/L; group A) and 1755 were from donors with elevated transaminases (> 500 U/L; group B). Group A recipients were more likely to be hospitalized (P = .01) or in intensive care (P < .001) or to have mechanical assistance (P < .001), portal vein thrombosis (P = .01), diabetes mellitus (P = .003), or dialysis the week before liver transplant (P = .004). Multivariable analysis (controlling for recipient characteristics) showed donor risk factors of graft failure included diabetes mellitus (P < .001), donation after cardiac death (P < .001), total bilirubin > 3.5 mg/dL (P < .001), serum creatinine > 1.5 mg/dL (P = .01), and cold ischemia time > 6 hours (P < .001). Regional organ sharing showed lower risk of graft failure (P = .02). Donor transaminases > 500 U/L were not associated with graft failure (relative risk, 1.02; 95% CI, 0.91-1.14; P = .74)., Conclusions: Donor transaminases > 500 U/L should not preclude the use of liver grafts. Instead, donor total bilirubin > 3.5 mg/dL and serum creatinine > 1.5 mg/dL appear to be associated with higher likelihood of graft failure after liver transplant.

A unique and complex microstructure underlies the diverse functions of the liver. Breakdown of this organization, as occurs in fibrosis and cirrhosis, impairs liver function and leads to disease. The role of integrin β1 was examined both in establishing liver microstructure and recreating it after injury. Embryonic deletion of integrin β1 in the liver disrupts the normal development of hepatocyte polarity, specification of cell-cell junctions, and canalicular formation. This in turn leads to the expression of transforming growth factor β (TGF-β) and widespread fibrosis. Targeted deletion of integrin β1 in adult hepatocytes prevents recreation of normal hepatocyte architecture after liver injury, with resultant fibrosis. In vitro, integrin β1 is essential for canalicular formation and is needed to prevent stellate cell activation by modulating TGF-β. Taken together, these findings identify integrin β1 as a key determinant of liver architecture with a critical role as a regulator of TGF-β secretion. These results suggest that disrupting the hepatocyte-extracellular matrix interaction is sufficient to drive fibrosis., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: During the COVID-19 pandemic, health systems postponed non-essential medical procedures to accommodate surge of critically-ill patients. The long-term consequences of delaying procedures in response to COVID-19 remains unknown. We developed a high-throughput approach to understand the impact of delaying procedures on patient health outcomes using electronic health record (EHR) data., Materials and Methods: We used EHR data from Vanderbilt University Medical Center's (VUMC) Research and Synthetic Derivatives. Elective procedures and non-urgent visits were suspended at VUMC between March 18, 2020 and April 24, 2020. Surgical procedure data from this period were compared to a similar timeframe in 2019. Potential adverse impact of delay in cardiovascular and cancer-related procedures was evaluated using EHR data collected from January 1, 1993 to March 17, 2020. For surgical procedure delay, outcomes included length of hospitalization (days), mortality during hospitalization, and readmission within six months. For screening procedure delay, outcomes included 5-year survival and cancer stage at diagnosis., Results: We identified 416 surgical procedures that were negatively impacted during the COVID-19 pandemic compared to the same timeframe in 2019. Using retrospective data, we found 27 significant associations between procedure delay and adverse patient outcomes. Clinician review indicated that 88.9% of the significant associations were plausible and potentially clinically significant. Analytic pipelines for this study are available online., Conclusion: Our approach enables health systems to identify medical procedures affected by the COVID-19 pandemic and evaluate the effect of delay, enabling them to communicate effectively with patients and prioritize rescheduling to minimize adverse patient outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Living donor liver transplantation (LDLT) and donation after circulatory death (DCD) can expand the donor pool for cholestatic liver disease (CLD) patients. We sought to compare the outcomes of deceased donor liver transplant (DDLT) vs LDLT in CLD patients., Methods: Retrospective cohort analysis of adult CLD recipients registered in the OPTN database who received primary LT between 2002 and 2018. Cox proportional hazards regression models with mixed effects were used to determine the impact of graft type on patient and graft survival., Results: Five thousand, nine hundred ninety-nine DDLT (5730 donation after brain death [DBD], 269 DCD) and 912 LDLT recipients were identified. Ten-year patient/graft survival rates were DBD: 73.8%/67.9%, DCD: 74.7%/60.7%, and LDLT: 82.5%/73.9%. Higher rates of biliary complications as a cause of graft failure were seen in DCD (56.8%) than LDLT (30.5%) or DBD (18.7%) recipients. On multivariable analysis, graft type was not associated with patient mortality, while DCD was independently associated with graft failure (P = .046)., Conclusion: DBD, DCD, and LDLT were associated with comparable overall patient survival. No difference in the risk of graft failure could be observed between LDLT and DBD. DCD can be an acceptable alternative to DBD with equivalent patient survival, but inferior graft survival likely related to the high rate of biliary complications., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recipients of donation after circulatory death (DCD) LTs historically have an increased risk of graft failure. Antibody induction (AI) with antithymocyte globulin (ATG) or anti-interleukin 2 receptor (anti-IL2R) immunotherapy may decrease the incidence of graft failure by mitigating ischemia/reperfusion injury. A retrospective review of the United Network for Organ Sharing (UNOS) database for LTs between 2002 and 2015 was conducted to determine whether ATG or anti-IL2R AI was associated with graft survival in DCD. A secondary endpoint was postoperative renal function as measured by estimated glomerular filtration rate at 6 and 12 months. Among DCD recipients, ATG (hazard ratio [HR] = 0.71; P = 0.03), but not anti-IL2R (HR = 0.82; P = 0.10), was associated with a decrease in graft failure at 3 years when compared with recipients without AI. ATG (HR = 0.90; P = 0.02) and anti-IL2R (HR = 0.94; P = 0.03) were associated with a decreased risk of graft failure in donation after brain death (DBD) liver recipients at 3 years compared with no AI. When induction regimens were compared between DCD and DBD, only ATG (HR = 1.19; P = 0.19), and not anti-IL2R (HR = 1.49; P < 0.01) or no AI (HR = 1.77; P < 0.01), was associated with similar survival between DCD and DBD. In conclusion, AI therapy with ATG was associated with improved longterm liver allograft survival in DCD compared with no AI. ATG was associated with equivalent graft survival between DCD and DBD, suggesting a beneficial role of immune cell depletion in DCD outcomes., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Liver fibrosis is one of the risk factors for hepatocellular carcinoma (HCC) development. The staging of liver fibrosis can be evaluated only via a liver biopsy, which is an invasive procedure. Noninvasive methods for the diagnosis of liver fibrosis can be divided into morphological tests such as elastography and serum biochemical tests. Transient elastography is reported to have excellent performance in the diagnosis of liver fibrosis and has been accepted as a useful tool for the prediction of HCC development and other clinical outcomes. Two-dimensional shear wave elastography is a new technique and provides a real-time stiffness image. Serum fibrosis markers have been studied based on the mechanism of fibrogenesis and fibrolysis. In the healthy liver, homeostasis of the extracellular matrix is maintained directly by enzymes called matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs and TIMPs could be useful serum biomarkers for liver fibrosis and promising candidates for the treatment of liver fibrosis. Further studies are required to establish liver fibrosis-specific markers based on further clinical and molecular research. In this review, we summarize noninvasive fibrosis tests and molecular mechanism of liver fibrosis in current daily clinical practice.

Identifying and supporting specific organ procurement organizations (OPOs) with the greatest opportunity to increase donation rates could significantly increase the number of organs available for transplant. Accomplishing this is complicated by current Scientific Registry of Transplant Recipients/Centers for Medicare & Medicaid Services metrics of donation rates and OPO performance that rely on eligible deaths. These data are self-reported and unverifiable and have been shown to underestimate potential organ donors. We examine the limitations of current OPO performance/donation metrics to inform discussions related to strategies to increase donation. We propose changing to a simple, verifiable, and uniformly applied donation metric. This would allow the transplant community to (1) better understand inherent differences in donor availability based on geography and (2) identify underperforming areas that would benefit from systems improvement agreements to increase donation rates., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The transplant community has debated the necessity and merits of broader organ distribution for several years, but the debate has been fundamentally shaped by inaccurate assessments of donor supply and demand. The possible legal requirements of distribution must be balanced with (a) the moral and statutory imperatives to reduce inequities resulting from socioeconomic disparity, and (b) the shortcomings of MELD in predicting mortality risk in rural areas. In this viewpoint, we use the example of liver transplantation to discuss the drivers of geographic disparity as a direct consequence of donation rates, local organ use, wealth, and poverty. Seen in this light, strategies seeking to equalize MELD at transplant across the United States risk severely exacerbating existing inequalities in access to health care., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Database linkage is a common strategy to expand analytic possibilities. Our group recently completed a linkage between the SRTR and PHIS databases for pediatric heart transplant recipients. The aim of this project was to expand the linkage between SRTR and PHIS to include liver, kidney, lung, heart-lung, and small bowel transplants. All patients (<21 years) who underwent liver, kidney, lung, heart-lung, or small bowel transplant were identified from the PHIS database using APR-DRG codes (2002-2018). Linkage was performed in a stepwise approach using indirect identifiers. Hospital costs were estimated based on hospital charges and cost-to-charge ratios, inflated to 2018 dollars and described by transplant type. A total of 14 061 patients overlapped between databases. Of these, 13 388 (95.2%) were uniquely linked. Linkage success ranged from 92.6% to 97.8% by organ system. A total of 12 940 (92%) patients had complete cost data. Hospitalization costs were greatest for patients undergoing small bowel transplantation with a median cost of $734 454 (IQR $336 174 - $1 504 167), followed by heart $565 386 (IQR $352 813 - $999 216), heart-lung $471 573 (IQR $328 523 - 992 438), lung $303 536 (IQR $215 383 - $612 749), liver $200 448 (IQR $130 880 - $357 897), and kidney transplant $94 796 (IQR $73 157 -$131 040). We report a robust linkage between the SRTR and PHIS databases, providing an invaluable tool to assess resource utilization in solid organ transplant recipients. Our analysis provides contemporary cost data for pediatric solid organ transplantation from the largest US sample reported to date. It also provides a platform for expanded analyses in the pediatric transplant population., (© 2019 Wiley Periodicals, Inc.)

Allocation of scarce livers for transplantation seeks to balance competing ethical principles of autonomy, utility, and justice. Given the history and ongoing dependence of transplantation on public support for funding and organs, understanding and incorporating public attitudes into allocation decisions seems appropriate. In the context of the current controversy around liver allocation, we sought to determine public preferences about issues relevant to the debate. We performed multiple surveys of attitudes around donation and evaluated these using conjoint analysis and clarifying follow-up questions. We found little public support that allocation decisions should be based solely on risk of waiting-list mortality. Strong public sentiment supported maximizing outcomes after transplantation, prioritizing US citizens or residents, keeping organs local, and considering cost in allocation decisions. We then present a methodology for incorporating these preferences into the Model for End-Stage Liver Disease (or MELD) priority score. Taken together, these findings suggest that current allocation schemes do not accurately reflect public preferences and suggest a framework to better align allocation with the values of the public., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Allocation of livers for transplantation faces regulatory pressure to move toward broader sharing. A current proposal supported by the United Network for Organ Sharing Board of Directors relies on concentric circles, but its effect on socioeconomic inequities in access to transplant services is poorly understood. In this article, we offer a proposal that uses the state of donation as a unit of distribution, given that the state is a recognized unit of legal jurisdiction and socioeconomic health in many contexts. The Scientific Registry of Transplant Recipients liver simulated allocation model algorithm was used to generate comparative estimates of regional transplant volume and the impact of these considered changes with regard to vulnerable and high-risk patients on the waiting list and to disparities in wait-list access. State-based liver distribution outperforms the concentric circle models in overall system efficiency, reduced discards, and minimized flights for organs. Furthermore, the efflux of organs from areas of greater sociodemographic vulnerability and lesser wait-list access is more than 2-fold lower in a state-based model than in concentric circle alternatives. In summary, we propose that a state-based system offers a legally defensible, practical, and ethically sound alternative to geometric zones of organ distribution., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Objectives: Orthotopic liver transplantation (OLT) can require substantial usage of blood products. Higher rates of transfusion have been associated with increased length of hospital stay, higher rates of infection, graft failure, and mortality. This study was a retrospective analysis to assess the impact of quality improvement interventions in OLT., Methods: Data collection included demographics, preoperative and intraoperative data, blood utilization, and cost data. Statistical analysis was performed using R software., Results: Total blood product utilization was reduced by approximately 50%. Statistically significant decreases were noted in blood product usage in the intraoperative and first 48-hour postoperative utilization, the number of OLTs using fewer than five RBC units, length of hospital stay, and cost., Conclusions: This study showed successful implementation of quality improvement team interventions to reduce blood utilization during OLT. Reduced transfusion significantly correlated with decreased length of hospital stay and cost., (© American Society for Clinical Pathology, 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The United Network for Organ Sharing recently altered current liver allocation with the goal of decreasing Model for End-Stage Liver Disease (MELD) variance at transplant. Concerns over these and further planned revisions to policy include predicted decrease in total transplants, increased flying and logistical complexity, adverse impact on areas with poor quality health care, and minimal effect on high MELD donor service areas. To address these issues, we describe general approaches to equalize critical transplant metrics among regions and determine how they alter MELD variance at transplant and organ supply to underserved communities. We show an allocation system that increases minimum MELD for local allocation or preferentially directs organs into areas of need decreases MELD variance. Both models have minimal adverse effects on flying and total transplants, and do not disproportionately disadvantage already underserved communities. When combined together, these approaches decrease MELD variance by 28%, more than the recently adopted proposal. These models can be adapted for any measure of variance, can be combined with other proposals, and can be configured to automatically adjust to changes in disease incidence as is occurring with hepatitis C and nonalcoholic fatty liver disease., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Liver transplant recipients continue to have high perioperative resource utilization and prolonged length of stay despite improvements in perioperative care. Enhanced recovery pathways have been shown in other surgical populations to produce reductions in hospital resource utilization., Methods: A prospective, observational study was performed to examine the effect of an enhanced recovery pathway for postoperative care after liver transplantation. Outcomes from patients undergoing liver transplantation from November 1, 2013, to October 31, 2014, managed by the pathway were compared to transplant recipients from the year before pathway implementation. Multivariable regression analysis was used to assess the association of the clinical pathway on clinical outcomes., Results: The intervention and control groups included 141 and 106 patients, respectively. There were no demographic differences between the control and intervention group including no differences between the length of surgery and cold ischemic time. Median intensive care unit length of stay was reduced from 4.4 to 2.6 days (P < .001). The intervention group had a higher likelihood of earlier discharge (hazard ratio [95% CI], 2.01 [1.55-2.62]; P < .001), and a 69% and 65% lower odds of receiving a plasma (P < .001) or packed red blood cell (P < .001) transfusion. There was no significant effect on hospital mortality (P = .40), intensive care unit readmission rates (P = .75), or postoperative infections (urinary traction infections: P = .09; pneumonia: P = .27)., Conclusions: An enhanced recovery pathway focused on milestone-based elements of intensive care unit management and predetermined management triggers including hemodynamic goals, fluid therapy, perioperative antibiotics, glycemic control, and standardized transfusion triggers led to reductions in intensive care unit length of stay without an increase in perioperative complications.

A major challenge in developing blood-contacting medical devices is mitigating thrombogenicity of an intravascular device. Thrombi may interfere with device function or embolize from the device to occlude distant vascular beds with catastrophic consequences. Chemical interactions between plasma proteins and bioengineered surface occur at the nanometer scale; however, continuum models of blood predict local shear stresses that lead to platelet activation or aggregation and thrombosis. Here, an iterative approach to blood flow path design incorporating in silico, in vitro, and in vivo experiments predicted the occurrence and location of thrombi in an implantable hemofilter. Low wall shear stress (WSS) regions identified by computational fluid dynamics (CFD) predicted clot formation in vivo. Revised designs based on CFD demonstrated superior performance, illustrating the importance of a multipronged approach for a successful design process.

Background: Current Model for End-Stage Liver Disease (MELD) exception points provided to patients with hepatocellular cancer (HCC) are not based on outcome data and advantage these patients compared to those listed based on laboratory values (LABMELD). We sought to develop a data-based assignment for exception points for patients with HCC that equalizes outcomes among HCC and LABMELD patients., Methods: We used Scientific Registry of Transplant Recipients data to compare patients listed with HCC who received exception points versus patients listed with LABMELD. Nation- and region-specific data were examined for (1) a composite outcome for adverse events of death, delisting, or becoming ineligible for transplant; and (2) transplant rate. We also determined MELD progression rates for LABMELD patients. Candidates listed with LABMELD scores were compared with those listed with 22 exception points for HCC (HCC22) to determine the LABMELD for which statistical parity was achieved for our composite outcome., Results: HCC22 candidates time to adverse event were comparable to LABMELD scores of 16 (LABMELD16) candidates (range, 15-19), whereas time to transplant was comparable to LABMELD22 candidates (range, 21-23). LABMELD22 candidates had 2.1 times greater risk of adverse event compared with HCC22 (95% confidence interval, 1.9-2.4; range, 1.5-2.4). Progression among LABMELD16 candidates whose scores did not improve was similar across regions and averaged 0.94 points/month (95% confidence interval, 0.88-0.99, range 0.80-1.04)., Conclusions: To equalize the occurrence of an adverse outcome, the proper listing MELD for patients with HCC is 16, with approximately 1 additional point/month. These results provide a data-driven algorithm to increase fairness in listing priority.

Background: In the United States, 5% of adult liver transplant recipients receive a graft donation after circulatory determination of death (DCDD). Concerns for ischemic cholangiopathy (IC), a disease of diffuse intrahepatic stricturing limits broader DCDD use. Single-center reports demonstrate large variation in outcomes., Methods: Retrospective deidentified data collected between 2005 and 2013 were entered electronically by 10 centers via a Research Electronic Data Capture database. Our primary outcome was development of intrahepatic biliary strictures consistent with IC., Results: Within 6 months post-DCDD transplant, 162 (21.8%) patients developed a biliary stricture, of which 88 (11.8%) exhibited intrahepatic structuring consistent with IC. Unadjusted 6-month IC rate among the 10 centers varied significantly (P = 0.006) from 6.3% to 25.9%. The only factor associated with increased risk of IC within 6 months was Roux-en-Y hepaticojejunostomy (vs duct-to-duct) (odds ratio, 3.06; 95% confidence interval, 1.52-6.16; P = 0.002). Graft failure by 6 months was more than 3 times higher for DCDD recipients with IC (odds ratio for IC, 3.36; 95% confidence interval, 1.95-5.79)., Conclusions: This first report of the large combined experience with DCDD from the Improving DCDD Outcomes in Liver Transplant consortium demonstrates significant differences in IC among centers, the importance of biliary strictures as a risk factor for graft failure, and does not validate other risk factors for IC found in smaller studies.

Dicer processes microRNAs (miRs) into active forms in a wide variety of tissues, including the liver. To determine the role of Dicer in liver regeneration, we performed a series of in vivo and in vitro studies in a murine 2/3 hepatectomy model. Dicer was downregulated after 2/3 hepatectomy, and loss of Dicer inhibited liver regeneration associated with decreased cyclin A2 and miR-221, as well as increased levels of the cell cycle inhibitor p27. In vitro, miR-221 inhibited p27 production in primary hepatocytes and increased hepatocyte proliferation. Specific reconstitution of miR-221 in hepatocyte-specific Dicer-null mice inhibited p27 and restored liver regeneration. In wild type mice, targeted inhibition of miR-221 using a cholesterol-conjugated miR-221 inhibited hepatocyte proliferation after 2/3 hepatectomy. These results identify Dicer production of miR-221 as an essential component of a miRNA-dependent mechanism for suppression of p27 that controls the rate of hepatocyte proliferation after partial hepatectomy. NEW & NOTEWORTHY Our findings demonstrate a direct role for microRNAs in controlling the rate of liver regeneration after injury. By deleting Dicer, an enzyme responsible for processing microRNAs into mature forms, we determined miR-221 is a critical microRNA in the physiological process of restoration of liver mass after injury. miR-221 suppresses p27, releasing its inhibitory effects on hepatocyte proliferation. Pharmaceuticals based on miR-221 may be useful to modulate hepatocyte proliferation in the setting of liver injury., (Copyright © 2017 the American Physiological Society.)

Share 35 was implemented to provide improved access to organs for patients with Model for End-Stage Liver Disease (MELD) scores ≥ 35. However, little is known about the impact of Share 35 on organ offer acceptance rates. We evaluated all liver offers to adult patients who were ultimately transplanted between January 1, 2011 and December 31, 2015. The analyses focused on patients ranked in the top 5 positions of a given match run and used multilevel mixed-effects models, clustering on individual wait-list candidate and transplant center. There was a significant interaction between Share 35 era and MELD category (P < 0.001). Comparing offers to MELD score ≥ 35 patients, offers after Share 35 were 36% less likely to be accepted compared with offers to MELD score ≥ 35 patients before Share 35 (adjusted odds ratio, 0.64). There was no clinically meaningful difference in the donor risk index of livers that were declined for patients with an allocation MELD score ≥35 in the pre- versus post-Share 35 era. Organ offer acceptance rates for patients with an allocation MELD ≥ 35 decreased in every region after Share 35; the magnitude of these changes was bigger in regions 2, 3, 4, 5, 6, 7, and 11, compared with regions 8 and 9 that had regional sharing in place before Share 35. There were significant changes in organ offer acceptance rates at the center level before versus after Share 35, and these changes varied across centers (P < 0.001). In conclusion, in liver transplantation candidates achieving a MELD score ≥ 35, liver acceptance of offers declined significantly after implementation of Share 35. The alterations in behavior at the center level suggest that practice patterns changed as a direct result of Share 35. Changes in organ acceptance under even broader organ sharing (redistricting) would likely be even greater, posing major logistical and operational challenges, while potentially increasing discard rates, thus decreasing the total number of transplants nationally. Liver Transplantation 23 604-613 2017 AASLD., (© 2017 by the American Association for the Study of Liver Diseases.)

Purpose of Review: Over the last 2 years, the liver transplant community has been debating a proposal to redraw the maps of organ distribution. The basis for these proposed changes is reported disparities in severity of illness at transplantation across the USA - however, this is based on the allocation model for end-stage liver disease score. In this review, we provide a critical overview of the redistribution proposal, its flaws and how it may worsen outcomes and exacerbate disparities in liver transplantation., Recent Findings: The main findings we highlight are data questioning the disparity metric used to justify the redistribution. We also review data published in recent articles and presented at public forums questioning whether there truly are disparities in access to transplant care among the broader population with liver disease, and whether disparities even getting to the waitlist are important and not to be ignored., Summary: This review article highlights major methodological and policy flaws with the current redistribution proposal. We demonstrate how the waitlist disparities that the proposal is intended to fix are not as they seem. Furthermore, if this proposal is passed, outcomes of liver transplantation nationally may worsen, and disparities for those with limited access to healthcare will worsen.

An implantable hemofilter for the treatment of kidney failure depends critically on the transport characteristics of the membrane and the biocompatibility of the membrane, cartridge, and blood conduits. A novel membrane with slit-shaped pores optimizes the trade-off between permeability and selectivity, enabling implanted therapy. Sustained (3-8) day function of an implanted parallel-plate hemofilter with minimal anticoagulation was achieved by considering biocompatibility at the subnanometer scale of chemical interactions and the millimeter scale of blood fluid dynamics. A total of 400 nm-thick polysilicon flat sheet membranes with 5-8 nm × 2 micron slit-shaped pores were surface-modified with polyethylene glycol. Hemofilter cartridge geometries were refined based on computational fluid dynamics models of blood flow. In an uncontrolled pilot study, silicon filters were implanted in six class A dogs. Cartridges were connected to the cardiovascular system by anastamoses to the aorta and inferior vena cava and filtrate was drained to collection pouches positioned in the peritoneum. Pain medicine and acetylsalicylic acid were administered twice daily until the hemofilters were harvested on postoperative days 3 (n = 2), 4 (n = 2), 5 (n = 1), and 8 (n = 1). No hemofilters were thrombosed. Animals treated for 5 and 8 days had microscopic fractures in the silicon nanopore membranes and 20-50 ml of transudative (albumin sieving coefficient θalb ~ 0.5 - 0.7) fluid in the collection pouches at the time of explant. Shorter experimental durations (3-4 days) resulted in filtration volumes similar to predictions based on mean arterial pressures and membrane hydraulic permeability and (θalb ~ 0.2 - 0.3), similar to preimplantation measurements. In conclusion, a detailed mechanistic and materials science attention to blood-material interactions allows implanted hemofilters to resist thrombosis. Additional testing is needed to determine optimal membrane characteristics and identify limiting factors in long-term implantation.

After significant injury, the liver must maintain homeostasis during the regenerative process. We hypothesized the existence of mechanisms to limit hepatocyte proliferation after injury to maintain metabolic and synthetic function. A screen for candidates revealed suppressor of cytokine signaling 2 (SOCS2), an inhibitor of growth hormone (GH) signaling, was strongly induced after partial hepatectomy. Using genetic deletion and administration of various factors we investigated the role of SOCS2 during liver regeneration. SOCS2 preserves liver function by restraining the first round of hepatocyte proliferation after partial hepatectomy by preventing increases in growth hormone receptor (GHR) via ubiquitination, suppressing GH pathway activity. At later times, SOCS2 enhances hepatocyte proliferation by modulating a decrease in serum insulin-like growth factor 1 (IGF-1) that allows GH release from the pituitary. SOCS2, therefore, plays a dual role in modulating the rate of hepatocyte proliferation. In particular, this is the first demonstration of an endogenous mechanism to limit hepatocyte proliferation after injury., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)