Effects of the March 2021 Allocation Policy Change on Key Deceased-donor Kidney Transplant Metrics.

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.

Multi-Site Optical Monitoring of Spinal Cord Ischemia during Spine Distraction.

Optimal surgical management of spine trauma will restore blood flow to the ischemic spinal cord. However, spine stabilization may also further exacerbate injury by inducing ischemia. Current electrophysiological technology is not capable of detecting acute changes in spinal cord blood flow or localizing ischemia. Further, alerts are delayed and unreliable. We developed an epidural optical device capable of directly measuring and immediately detecting changes in spinal cord blood flow using diffuse correlation spectroscopy (DCS). Herein we test the hypothesis that our device can continuously monitor blood flow during spine distraction. Additionally, we demonstrate the ability of our device to monitor multiple sites along the spinal cord and axially resolve changes in spinal cord blood flow. DCS-measured blood flow in the spinal cord was monitored at up to three spatial locations (cranial to, at, and caudal to the distraction site) during surgical distraction in a sheep model. Distraction was halted at 50% of baseline blood flow at the distraction site. We were able to monitor blood flow with DCS in multiple regions of the spinal cord simultaneously at ∼1 Hz. The distraction site had a greater decrement in flow than sites cranial to the injury (median -40 vs. -7%,). This pilot study demonstrated high temporal resolution and the capacity to axially resolve changes in spinal cord blood flow at and remote from the site of distraction. These early results suggest that this technology may assist in the surgical management of spine trauma and in corrective surgery of the spine.

Hyperoxia Injury in the Developing Lung Is Mediated by Mesenchymal Expression of Wnt5A.

Rationale: Bronchopulmonary dysplasia (BPD) is a leading complication of preterm birth that affects infants born in the saccular stage of lung development at <32 weeks of gestation. Although the mechanisms driving BPD remain uncertain, exposure to hyperoxia is thought to contribute to disease pathogenesis.Objectives: To determine the effects of hyperoxia on epithelial-mesenchymal interactions and to define the mediators of activated Wnt/ß-catenin signaling after hyperoxia injury.Methods: Three hyperoxia models were used: A three-dimensional organotypic coculture using primary human lung cells, precision-cut lung slices (PCLS), and a murine in vivo hyperoxia model. Comparisons of normoxia- and hyperoxia-exposed samples were made by real-time quantitative PCR, RNA in situ hybridization, quantitative confocal microscopy, and lung morphometry.Measurements and Main Results: Examination of an array of Wnt ligands in the three-dimensional organotypic coculture revealed increased mesenchymal expression of WNT5A. Inhibition of Wnt5A abrogated the BPD transcriptomic phenotype induced by hyperoxia. In the PCLS model, Wnt5A inhibition improved alveolarization following hyperoxia exposure, and treatment with recombinant Wnt5a reproduced features of the BPD phenotype in PCLS cultured in normoxic conditions. Chemical inhibition of NF-κB with BAY11-7082 reduced Wnt5a expression in the PCLS hyperoxia model and in vivo mouse hyperoxia model, with improved alveolarization in the PCLS model.Conclusions: Increased mesenchymal Wnt5A during saccular-stage hyperoxia injury contributes to the impaired alveolarization and septal thickening observed in BPD. Precise targeting of Wnt5A may represent a potential therapeutic strategy for the treatment of BPD.

Astrocyte HIF-2α supports learning in a passive avoidance paradigm under hypoxic stress.

BACKGROUND: The brain is extensively vascularized, uses20% of the body's oxygen, and is highly sensitive to changes in oxygen. While synaptic plasticity and memory are impaired in healthy individuals by exposure to mild hypoxia, aged individuals appear to be even more sensitive. Aging is associated with progressive failure in pulmonary and cardiovascular systems, exposing the aged to both chronic and superimposed acute hypoxia. The HIF proteins, the "master regulators" of the cellular response to hypoxia, are robustly expressed in neurons and astrocytes. Astrocytes support neurons and synaptic plasticity via complex metabolic and trophic mechanisms. The activity of HIF proteins in the brain is diminished with aging, and the increased exposure to chronic and acute hypoxia with aging combined with diminished HIF activity may impair synaptic plasticity. PURPOSE: Herein, we test the hypothesis that astrocyte HIF supports synaptic plasticity and learning upon hypoxia. MATERIALS AND METHODS: An Astrocyte-specific HIF loss-of-function model was employed, where knock-out of HIF-1α or HIF-2α in GFAP expressing cells was accomplished by cre-mediated recombination. Animals were tested for behavioral (open field and rotarod), learning (passive avoidance paradigm), and electrophysiological (long term potentiation) responses to mild hypoxic challenge. RESULTS: In an astrocyte-specific HIF loss-of-function model followed by mild hypoxia, we identified that the depletion of HIF-2α resulted in an impaired passive avoidance learning performance. This was accompanied by an attenuated response to induction in long-term potentiation (LTP), suggesting that the hippocampal circuitry was perturbed upon hypoxic exposure following HIF-2α loss in astrocytes, and not due to hippocampal cell death. We investigated HIF-regulated trophic and metabolic target genes and found that they were not regulated by HIF-2α, suggesting that these specific targets may not be involved in mediating the phenotypes observed. CONCLUSION: Together, these results point to a role for HIF-2α in the astrocyte's regulatory role in synaptic plasticity and learning under hypoxia and suggest that even mild, acute hypoxic challenges can impair cognitive performance in the aged population who harbor impaired HIF function.