Delineating the Metabolic Phenotype of Biopsy-Derived Kidney Cells.

Kidney transplantation is the optimal treatment for end-stage kidney disease; however, transplanted kidneys are often lost prematurely, with up to 50% graft loss at 10 years post-transplant. One of the major causes of premature graft loss is the injury sustained by the graft at the time of transplantation, known as ischemia-reperfusion injury (IRI). Delayed graft function (DGF), defined as the need for dialysis in the first week post-transplant, is a manifestation of severe IRI that shows functional and histologic features of acute kidney injury (AKI).

Health and economic benefits of energy, urban planning, and food interventions that lower greenhouse gas emissions.

Public health can be immediately and substantially improved by policies that also mitigate climate change over the longer term. However, implementation of these policies has been slowed at least in part by doubts and lack of awareness of these health co-benefits. To address this barrier to progress, we demonstrate how an illustrative set of interventions led to environmental, health, and economic benefits, in addition to mitigating climate change.

The neurorepellent SLIT2 inhibits LPS-induced proinflammatory signaling in macrophages.

Macrophages are important mediators of immune responses with critical roles in the recognition and clearance of pathogens, as well as in the resolution of inflammation and wound healing. The neuronal guidance cue SLIT2 has been widely studied for its effects on immune cell functions, most notably directional cell migration. Recently, SLIT2 has been shown to directly enhance bacterial killing by macrophages, but the effects of SLIT2 on inflammatory activation of macrophages are less known.

Normothermic ex vivo kidney perfusion preserves mitochondrial and graft function after warm ischemia and is further enhanced by AP39.

We previously reported that normothermic ex vivo kidney  perfusion (NEVKP) is superior in terms of organ protection compared to static cold storage (SCS), which is still the standard method of organ preservation, but the mechanisms are incompletely understood. We used a large animal kidney autotransplant model to evaluate mitochondrial function during organ preservation and after kidney transplantation, utilizing live cells extracted from fresh kidney tissue. Male porcine kidneys stored under normothermic perfusion showed preserved mitochondrial function and higher ATP levels compared to kidneys stored at 4 °C (SCS).

Bridging the gap between in vitro and in vivo models: a way forward to clinical translation of mitochondrial transplantation in acute disease states.

Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. To limit potential immune responses and rejection of donor mitochondria, current clinical applications have focused on delivery of autologous mitochondria. We recently convened a Mitochondrial Transplant Convergent Working Group (CWG), to explore three key issues that limit clinical translation: (1) storage of mitochondria, (2) biomaterials to enhance mitochondrial uptake, and (3) dynamic models to mimic the complex recipient tissue environment.

Adopting electric school buses in the United States: Health and climate benefits.

Electric school buses have been proposed as an alternative to reduce the health and climate impacts of the current U.S. school bus fleet, of which a substantial share are highly polluting old diesel vehicles.

The chemorepellent, SLIT2, bolsters innate immunity against .

Neutrophils are essential for host defense against (). The neuro-repellent, SLIT2, potently inhibits neutrophil chemotaxis, and might, therefore, be expected to impair antibacterial responses. We report here that, unexpectedly, neutrophils exposed to the N-terminal SLIT2 (N-SLIT2) fragment kill extracellular more efficiently.

Combining Oxygenated Cold Perfusion With Normothermic Ex Vivo Perfusion Improves the Outcome of Donation After Circulatory Death Porcine Kidney Transplantation.

Background: Ex vivo machine perfusion is a novel preservation technique for storing and assessing marginal kidney grafts. All ex vivo perfusion techniques have advantages and shortcomings. The current study analyzed whether a combination of oxygenated hypothermic machine perfusion (oxHMP) followed by a short period of normothermic ex vivo kidney perfusion (NEVKP) could combine the advantages of both techniques.

SLIT2/ROBO1 signaling suppresses mTORC1 for organelle control and bacterial killing.

SLIT/ROBO signaling impacts many aspects of tissue development and homeostasis, in part, through the regulation of cell growth and proliferation. Recent studies have also linked SLIT/ROBO signaling to the regulation of diverse phagocyte functions. However, the mechanisms by which SLIT/ROBO signaling acts at the nexus of cellular growth control and innate immunity remain enigmatic.

The loss of glycocalyx integrity impairs complement factor H binding and contributes to cyclosporine-induced endothelial cell injury.

Background: Calcineurin inhibitors (CNIs) are associated with nephrotoxicity, endothelial cell dysfunction, and thrombotic microangiopathy (TMA). Evolving evidence suggests an important role for complement dysregulation in the pathogenesis of CNI-induced TMA. However, the exact mechanism(s) of CNI-induced TMA remain(s) unknown.

The benefits and costs of U.S. employer COVID-19 vaccine mandates.

In 2021, the Biden Administration issued mandates requiring COVID-19 vaccinations for U.S. federal employees and contractors and for some healthcare and private sector workers.

Valuing COVID-19 Morbidity Risk Reductions.

Many economic analyses, including those that address the COVID-19 pandemic, focus on the value of averting deaths and do not include the value of averting nonfatal illnesses. Yet incorporating the value of averting nonfatal cases may change conclusions about the desirability of the policy. While per case values may be small, the number of nonfatal cases is often large, far outstripping the number of fatal cases.

The spectrin cytoskeleton integrates endothelial mechanoresponses.

Physiological blood flow induces the secretion of vasoactive compounds, notably nitric oxide, and promotes endothelial cell elongation and reorientation parallel to the direction of applied shear. How shear is sensed and relayed to intracellular effectors is incompletely understood. Here, we demonstrate that an apical spectrin network is essential to convey the force imposed by shear to endothelial mechanosensors.

Mutations in Are Not a Common Cause of Pediatric Idiopathic Hypercalciuria in Canada.

Background: Hypercalciuria is the most common risk factor for kidney stone formation, including in pediatric patients. However, the etiology is often unknown and children are frequently diagnosed with idiopathic hypercalciuria. Nearly 50% of children with hypercalciuria have a first-degree relative with kidney stones, suggesting a strong genetic basis for this disease.

Normothermic Ex Vivo Kidney Perfusion for Human Kidney Transplantation: First North American Results.

Background: Normothermic ex vivo kidney perfusion (NEVKP) has shown promising results for preservation, assessment, and reconditioning of kidney allografts in preclinical studies. Here, we report the first North American safety and feasibility study of deceased donor kidneys grafts transplanted following preservation with NEVKP.

Methods: Outcomes of 13 human kidney grafts that received 1 to 3 h of NEVKP after being transported in an anoxic hypothermic machine perfusion device were compared with a matched control group of 26 grafts that were preserved with anoxic hypothermic machine perfusion alone.

Prolonged Normothermic Ex Vivo Kidney Perfusion Is Superior to Cold Nonoxygenated and Oxygenated Machine Perfusion for the Preservation of DCD Porcine Kidney Grafts.

Unlabelled: The increased usage of marginal grafts has triggered interest in perfused kidney preservation to minimize graft injury. We used a donation after circulatory death (DCD) porcine kidney autotransplantation model to compare 3 of the most frequently used ex vivo kidney perfusion techniques: nonoxygenated hypothermic machine perfusion (non-oxHMP), oxygenated hypothermic machine perfusion (oxHMP), and normothermic ex vivo kidney perfusion (NEVKP).

Methods: Following 30 min of warm ischemia, grafts were retrieved and preserved with either 16 h of non-oxHMP, oxHMP, or NEVKP (n = 5 per group).

Prolonged warm ischemia time leads to severe renal dysfunction of donation-after-cardiac death kidney grafts.

Kidney transplantation with grafts procured after donation-after-cardiac death (DCD) has led to an increase in incidence of delayed graft function (DGF). It is thought that the warm ischemic (WI) insult encountered during DCD procurement is the cause of this finding, although few studies have been designed to definitely demonstrate this causation in a transplantation setting. Here, we use a large animal renal transplantation model to study the effects of prolonged WI during procurement on post-transplantation renal function.

Transcriptome Analysis of Kidney Grafts Subjected to Normothermic Ex Vivo Perfusion Demonstrates an Enrichment of Mitochondrial Metabolism Genes.

Unlabelled: Normothermic ex vivo kidney perfusion (NEVKP) has demonstrated superior outcomes for donation-after-cardiovascular death grafts compared with static cold storage (SCS). To determine the mechanisms responsible for this, we performed an unbiased genome-wide microarray analysis.

Methods: Kidneys from 30-kg Yorkshire pigs were subjected to 30 min of warm ischemia followed by 8 h of NEVKP or SCS, or no storage, before autotransplantation.

Identification of a Locus on the X Chromosome Linked to Familial Membranous Nephropathy.

Introduction: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis. Primary MN has a strong male predominance, accounting for approximately 65% of cases; yet, currently associated genetic loci are all located on autosomes. Previous reports of familial MN have suggested the existence of a potential X-linked susceptibility locus.

Role of the CXCL1-CXCR1 axis in renal disease.

Excessive infiltration of immune cells into the kidney is a key feature of acute and chronic kidney diseases. The family of chemokines comprises key drivers of this process. Fractalkine [chemokine (C-X3-C motif) ligand 1 (CXCL1)] is one of two unique chemokines synthesized as a transmembrane protein that undergoes proteolytic cleavage to generate a soluble species.

Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis.

Normothermic ex-vivo kidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of donation after circulatory death injury compared with static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at three time points from pig kidneys subjected to 30 min of warm ischemia, followed by 8 h of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (false discovery rate < 0.

Introduction to Special Issue on Risk Assessment, Economic Evaluation, and Decisions.

Integrating risk assessment, economic evaluation, and uncertainty to inform policy decisions is a core challenge to risk analysis. In September 2019, the Harvard Center for Risk Analysis, with support from the Society for Risk Analysis Economics and Benefits Analysis Specialty Group and others, convened a workshop to address this issue. The workshop built in part on the recommendations of the 2009 National Research Council report, Science and Decisions: Advancing Risk Assessment.