BACKGROUND:In the US heart allocation system, when transplant centers submit applications for status exceptions to increase waitlist priority, patients obtain the requested status upgrades immediately while their applications are sent to the regional review boards (RRBs) and reviewed retrospectively. How often transplants occur during this period is unknown. METHODS:Using the Scientific Registry of Transplant Recipients, we identified all adult heart transplant candidates listed between October 18, 2018, and May 31, 2025, with submitted applications for status exceptions. We assessed (1) the time elapsed between submission of exception applications and their receipt by the RRBs and (2) the rate of heart transplantation during this travel time, stratified by whether the applications were eventually approved or denied. Additionally, we estimated how many listed patients were skipped by candidates who received transplants with exceptions that were ultimately denied. RESULTS:138 transplant centers submitted status exception requests on behalf of 11 508 adult candidates during the study period, of whom 913 (7.9%) received a denial at least once. The median time from obtaining status upgrades to application receipt by the RRBs was 3 days. Three thousand seven out of 11 508 (26.1%) patients received transplants before the RRBs even received their applications, with 174 (19.1%) among 913 with eventual denials and 2833 (26.7%) among 10 595 with approvals. The cumulative incidence of heart transplantation before application receipt for eventual denials was 19.1% (95% CI, 16.6%-21.7%), and that for approvals was 27.2% (95% CI, 26.4%-28.0%; P<0.001) at 2 weeks. Candidates who received transplants despite being denied exceptions bypassed more than 11 thousand potential transplant recipients. CONCLUSIONS:More than 25% of patients with status exception requests receive heart transplants before their applications are even received by their RRBs, raising significant concerns about the fairness of retrospective review of exception requests for the allocation of donor hearts.

BACKGROUND:After the 2018 heart allocation policy change, status 2 listings with temporary mechanical circulatory support (tMCS) have increased while listings with durable left ventricular assist devices (LVADs) have decreased. Treatment of cardiogenic shock varies geographically, but how often patients with status 2 are supported by inotropes before tMCS and receive durable LVADs is unknown. METHODS:Using the Scientific Registry of Transplant Recipients, we identified all adult heart transplant candidates who received an intra-aortic balloon pump (IABP) or percutaneous endovascular ventricular assist device (PEVAD) between October 18, 2018 and December 31, 2023 and subsequently obtained status 2. We assessed the rate of overall utilization and between-center variation in use of a priori inotropic support meeting status 3 criteria and durable LVAD implantation within 6 weeks after receiving status 2. RESULTS:During the study period, 6,010 patients with tMCS obtained status 2 (PEVADs: n = 1,957; IABPs: n = 4,053). Transplant centers reported use of inotropes meeting status 3 criteria in 7.2% of patients before IABP or PEVAD placement. The cumulative incidence of durable LVAD implantation within 6 weeks after obtaining status 2 was 2.7% (95% confidence interval [2.6%, 2.9%]). Reported rates of inotropic support before tMCS and durable LVAD implantation varied significantly by US transplant center (0%-38.8%, p < 0.001% and 0%-33.3%, p < 0.001, respectively). CONCLUSIONS:US heart transplant centers rarely report supporting candidates with inotropes meeting status 3 criteria before initiating tMCS and do not routinely transition patients with status 2 for tMCS to durable LVAD support.

Rationale & ObjectiveThe US Kidney Allocation System (KAS) prioritizes candidates with ≤20% Estimated Post-Transplant Survival (EPTS) for high longevity kidneys defined by a ≤20% Kidney Donor Profile Index (KDPI). Use of EPTS in the KAS deprioritizes candidates with older age, diabetes, and longer dialysis durations. We assessed whether this use also disadvantages racial-ethnic minority candidates, who are younger but more likely to have diabetes and longer durations of kidney failure requiring dialysis.Study DesignObservational cohort study.Setting& Participants: Adult candidates for and recipients of kidney transplantation represented in the Scientific Registry of Transplant Recipients from January 2015 through December 2020.ExposureRace and ethnicity.OutcomesAge-adjusted assignment to ≤20% EPTS, transplantation of a ≤20% KDPI kidney, and post-transplant survival in longevity matched recipients by racial-ethnicity.Analytic ApproachMultivariable logistic regression, Fine-Gray competing risks survival analysis, and Kaplan-Meier and Cox Proportional Hazards methods.ResultsThe cohort included 199,444 candidates (7% Asian, 29% Black, 19% Hispanic/Latino, 43% White) listed for deceased donor kidney transplantation. Non-White candidates had significantly higher rates of diabetes, longer dialysis duration, and were younger than White candidates. Adjusted for age, Asian, Black, and Hispanic/Latino candidates had significantly lower odds of having a ETPS score ≤20% (OR 0.86, [0.81, 0.91], 0.52 [0.50, 0.54], and 0.49, [0.47, 0.51]), and were less likely to receive a ≤20% KDPI kidney (subHR 0.70 [0.66, 0.75], 0.89 [0.87, 0.92], and 0.73 [0.71, 0.76]), compared to White candidates. Among recipients with ≤20% EPTS scores transplanted with a ≤20% KDPI deceased donor kidney, Asian and Hispanic recipients had lower post-transplant mortality (HR 0.45 [0.27, 0.77], and 0.63 [0.47, 0.86]) and Black recipients had higher but not statistically significant post-transplant mortality (HR 1.22 [0.99, 1.52]) compared to White recipients.LimitationsProvider reported race-ethnicity data and 5-year post transplant follow-up period.ConclusionsThe US kidney allocation system is less likely to identify racial-ethnic minority candidates as having a ≤20% EPTS score which triggers allocation of high longevity deceased donor kidneys. These findings should inform the OPTN about how to remedy racial/ethnic disparities introduced through KAS’s current approach of allocating allografts with longer predicted longevity to recipients with longer estimated post-transplant survival.

INTRODUCTION:Antibody-mediated rejection (ABMR) is dependent on complement activating donor-specific anti-HLA antibodies (DSA). This is commonly detected by C4d deposition in allografts. However, recent data define a C4d negative ABMR phenotype suggesting a role for complement-independent DSA injury, antibody-dependent cellular cytotoxicity (ADCC). METHODS:Here, we established an in vitro ADCC model that identified human ADCC-activated genes using microarray analysis. We subsequently interrogated renal allograft biopsies from patients with ABMR and controls for mRNA expression of the ADCC-activated gene set. RESULTS:We identified 13 ADCC-activated genes. Six gene expression assays including 8 of the 13 genes (CCL3, CCL4/CCL4L1/CCL4L2, CD160, IFNG, NR4A3 and XCL1/XCL2) were analyzed in 127 kidney biopsies obtained from HLA-sensitized (HS), non-HS patients and control individuals. Most ADCC-activated genes showed significantly higher expression in the transplant samples compared to the controls (p<0.0005). The gene expression levels were significantly higher in HS and non-HS transplant patients who developed ABMR compared to those who did not (p=0.04-0.002). There was no difference in the gene expression levels between C4d positive and negative ABMR (p=0.26-0.99). Samples from high PRA (>80%) or positive DSA patients showed higher gene expression levels for the ADCC-activated genes compared to low PRA (<80%) and negative DSA patients (p=0.04-0.001). CONCLUSION:ADCC pathways are active in transplant patients with ABMR, and likely mediate allograft injury, providing a potential mechanism for C4d negative ABMR.

Hemoglobin (Hb)-based oxygen carriers (HBOCs) are being developed as a potential therapy for increasing tissue oxygenation, yet they have not reached their full potential because of unwanted hemodynamic side effects (vasoconstriction, low cardiac output, and oxygen delivery) due in part to nitric oxide (NO) scavenging by cell-free Hb. It may be possible to overcome the NO scavenging effect by coinfusing S-nitrosylated (SNO) HBOC along with unmodified HBOC. SNO-HBOC, like free Hb, may act as an NO donor in low-oxygen conditions. We hypothesized that an unaltered HBOC, polymerized bovine Hb (PBvHb), coinfused with an SNO-PBvHb, would improve hemodynamics and oxygen delivery during hypoxia. Vascular oxygen content and hemodynamics were determined after euvolemic rats were infused (3 ml) with lactated Ringer's solution, PBvHb, SNO-PBvHb, or PBvHb plus SNO-PBvHb (1:10) during normoxia or acute hypoxia (fraction of inspired oxygen = 10%, 120 min). Hemodynamic side effects resulting from PBvHb infusion (vasoconstriction, elevated pulmonary blood pressure, and reduced cardiac output) were offset by SNO-PBvHb in acute hypoxic, but not normoxic, conditions. These data support the potential use of HBOC mixed with SNO-HBOC for the treatment of conditions in which acute hypoxia is present, such as tumor oxygenation, wound healing, hemorrhagic trauma, and sickle cell and hemolytic anemia.

Hemoglobin-based oxygen carriers (HBOC) have been primarily studied for blood loss treatment. More recently infusions of HBOC in euvolemic subjects have been proposed for a wide variety of potential therapies in which increased tissue oxygenation would be beneficial. However, compared with the exchange transfusion models to study blood loss, less is known about HBOC oxygen delivery and vasoacitvity when it is infused in euvolemic subjects. We hypothesized that HBOC [polymerized bovine hemoglobin (PBvHb)] infusion creating hypervolemia would increase oxygen delivery to tissues during acute global hypoxia. Vascular oxygen content and hemodynamics were determined after euvolemic rats were infused with 3 ml of either lactated Ringer or PBvHb solution (13 g/dl, 1.3 g/kg) during acute hypoxia (FIO 2 = 10%, 4 h) or normoxia (FIO 2 = 21%) exposure. Our data demonstrated that compared with Ringer-infused animals, in hypoxia and normoxia, PBvHb treatment improved oxygen content but raised mean arterial pressure, lowered stroke volume, heart rate, and cardiac index, which resulted in a net reduction in blood flow and oxygen delivery to the tissues. The PBvHb vasoactive effect was similar in magnitude and direction as to the Ringer-infused animals treated with a nitric oxide synthase inhibitor nitro-l-arginine, suggesting the PBvHb effect is mediated via nitric oxide scavenging. We conclude that infusion of PBvHb is not likely to be useful in treating global hypoxia under these conditions.

Objective. To determine if hemoglobin‐based oxygen carriers (HBOC) improves kidney oxygenation during global hypoxia at rest and exercise. Methods. Relative tissue oxygenation was assessed by determining hypoxia‐inducible transcription factor 1 (HIF‐1) DNA‐binding (ELISA) and metabolic profiles (magnetic resonance spectroscopy) in Sprague Dawley rat kidneys. Animals were exposed to 1600 (NX) or 5500 (HX) m for 4 h, after treatment (3 ml) with either lactated Ringer's solution or hemoglobin‐based oxygen carrier (HBOC, 1300 mg/kg), during rest or after run to exhaustion. Results. At rest, HX‐induced HIF‐1 DNA‐binding was significantly reduced with HBOC treatment. In accordance, kidneys of animals at rest during HX showed evidence of oxidative stress, high hydroxybutyerate and low phosphotidyl choline. Oxidative stress was not apparent in the kidneys of HBOC‐treated animals during HX. HBOC had no effect on HIF‐1 DNA‐binding during NX. Exercise during NX increased HIF‐1 DNA binding, but lowered it during HX. HBOC‐treatment during exercise had no effect on kidney HIF activity. Conclusion. Data indicate that HBOC lowered HIF‐1 activity in the kidneys of rats exposed to 5500 m, as did exercise, and may provide a therapeutic measure by which to improve tissue oxygenation during global hypoxia. Funded by the USA Defense Advanced Research Project Agency (DARPA) #BAA 06‐19‐F64.

Acute hypoxic pulmonary vascular leak (HPVL) is associated with increases in pulmonary artery pressure (Ppa) and endothelial permeability. Supplemental oxygen consistently prevents or ameliorates the potentially lethal symptoms related to HPVL. We hypothesized that hemoglobin‐based‐oxygen‐carrier (HBOC) treatment would decrease HPVL by controlling Ppa and/or plasma vascular endothelial growth factor concentration [VEGF] and prevent pulmonary leak despite an acute hypoxic insult. Conscious male Sprague Dawley rats were randomly treated with either Lactated Ringer's solution or HBOC solution and exposed to 4 hours of either normoxia (FiO2 = 21 %) or hypoxia (FiO2 = 10%). Only Ppa increased (p < 0.001) in response to the hypoxia. However, Ppa, pulmonary leak, and [VEGF], all, significantly increased (p = 0.026, 0.030, and 0.047, respectively) in response to HBOC treatment. We conclude that treatment with HBOC not only fails in prevention of HPVL but increases susceptibility by increasing Ppa and/or [VEGF]. Supported by the Defense Advanced Research Projects Agency (DARPA) and the Army Research Office (ARO) contract number W911NF‐06‐1‐0318.

Hemoglobin-based oxygen carriers (HBOC) may enhance oxygen carrying capacity of blood and potentially improve human performance at altitude. Oxygen delivery to exercising muscle may be enhanced with HBOC. PURPOSE: To determine, in the exercising rat model, if HBOC at altitude would increase exercise performance; and to investigate underlying hemodynamic determinants of oxygen delivery. METHODS: Study One: conscious male Sprague-Dawley rats rats were habituated to run on a treadmill for 4 days. On the study day, rats were randomly assigned to receive either a lactated Ringer's solution or an HBOC (Oxyglobin™, Biopure) via tail vein infusion. Rats were placed in a hypobaric chamber and the barometric pressure reduced to the equivalent of 13,500 ft (4,115 m) for a minimum of 20 min before running to exhaustion on the treadmill. Study Two: rats were acutely instrumented under anesthetic for BP, pulmonary artery pressure, and cardiac output (dye dilution). Animals were randomly assigned to a lactated Ringer's or HBOC group and infused via venous catheter. Following baseline measurements, conscious animals were exposed to either normoxia (FIO2 = 21 %) or hypoxia (FIO2 = 10%) for 4 hrs, with measurements at 2 and 4 hrs. RESULTS: Study One: rats running at altitude infused with lactated Ringer's averaged [mean (SEM)] 604 (142) sec vs. 307 (51) sec for HBOC treated (p=0.03, one-sided t-test). Study Two: HBOC animals both during normoxia and hypoxia had elevated arterial and pulmonary artery pressures, reduced cardiac output and decreased oxygen delivery (cardiac output times arterial oxygen content) [all p<0.05]. Cardiac output (ml/kg) was reduced from 224 (26) to 124 (14) at 4 hrs in normoxia, and from 242 (26) to 130 (12) in hypoxia. This corresponded to decreased oxygen delivery (ml O2/min/kg) from 40 (5) to 22 (2.5) in normoxia and from 23 (2.5) to 15.7 (1.6) in hypoxia, at 4 hrs. CONCLUSIONS: These studies suggest that HBOC reduces exercise performance at altitude because of its negative impact on cardiovascular function and oxygen delivery, despite increasing oxygen content. HBOC may alter cardiovascular function as a result of NO scavenging by the plasma borne hemoglobin (HBOC). Supported by the Defense Advanced Research Projects Agency (DARPA) and the Army Research Office (ARO) contract number W911NF-06-1-0318.