The cell motility modulator Slit2 is a potent inhibitor of platelet function.

Vascular injury and atherothrombosis involve vessel infiltration by inflammatory leukocytes, migration of medial vascular smooth muscle cells to the intimal layer, and ultimately acute thrombosis. A strategy to simultaneously target these pathological processes has yet to be identified. The secreted protein, Slit2, and its transmembrane receptor, Robo-1, repel neuronal migration in the developing central nervous system. More recently, it has been appreciated that Slit2 impairs chemotaxis of leukocytes and vascular smooth muscle cells toward diverse inflammatory attractants. The effects of Slit2 on platelet function and thrombus formation have never been explored. We detected Robo-1 expression in human and murine platelets and megakaryocytes and confirmed its presence via immunofluorescence microscopy and flow cytometry. In both static and shear microfluidic assays, Slit2 impaired platelet adhesion and spreading on diverse extracellular matrix substrates by suppressing activation of Akt. Slit2 also prevented platelet activation on exposure to ADP. In in vivo studies, Slit2 prolonged bleeding times in murine tail bleeding assays. Using intravital microscopy, we found that after mesenteric arteriolar and carotid artery injury, Slit2 delayed vessel occlusion time and prevented the stable formation of occlusive arteriolar thrombi. These data demonstrate that Slit2 is a powerful negative regulator of platelet function and thrombus formation. The ability to simultaneously block multiple events in vascular injury may allow Slit2 to effectively prevent and treat thrombotic disorders such as myocardial infarction and stroke

Slit2 prevents neutrophil recruitment and renal ischemia-reperfusion injury

Neutrophils recruited to the postischemic kidney contribute to the pathogenesis of ischemia-reperfusion injury (IRI), which is the most common cause of renal failure among hospitalized patients. The Slit family of secreted proteins inhibits chemotaxis of leukocytes by preventing activation of Rho-family GTPases, suggesting that members of this family might modulate the recruitment of neutrophils and the resulting IRI. Here, in static and microfluidic shear assays, Slit2 inhibited multiple steps required for the infiltration of neutrophils into tissue. Specifically, Slit2 blocked the capture and firm adhesion of human neutrophils to inflamed vascular endothelial barriers as well as their subsequent transmigration. To examine whether these observations were relevant to renal IRI, we administered Slit2 to mice before bilateral clamping of the renal pedicles. Assessed at 18 hours after reperfusion, Slit2 significantly inhibited renal tubular necrosis, neutrophil and macrophage infiltration, and rise in plasma creatinine. In vitro, Slit2 did not impair the protective functions of neutrophils, including phagocytosis and superoxide production, and did not inhibit neutrophils from killing the extracellular pathogen Staphylococcus aureus. In vivo, administration of Slit2 did not attenuate neutrophil recruitment or bacterial clearance in mice with ascending Escherichia coli urinary tract infections and did not increase the bacterial load in the livers of mice infected with the intracellular pathogen Listeriamonocytogenes. Collectively, these results suggest that Slit2 may hold promise as a strategy to combat renal IRI without compromising the protective innate immune response. Copyright © 2013 by the American Society of Nephrology

SLIT2 Prevents Renal Ischemia Reperfusion Injury in Mice

The Slit family of secreted proteins act as axonal repellents during embryogenesis. Slit2 via its receptor, Roundabout-1, also inhibits chemotaxis of multiple leukocyte subsets. Using static and microfluidic shear assays, we found that Slit2 inhibited multiple steps required to recruit circulating neutrophils. Slit2 blocked capture and firm adhesion of human neutrophils to and transmigration across inflamed primary vascular endothelial cells. To determine the response of Slit2 in renal ischemia reperfsuion injury, Slit2 was administered prior to bilateral renal pedicle clamping in mice. This led to significant decreases in both renal tubular necrosis score and neutrophil infiltration. Administration of Slit2 also prevented elevation of plasma creatinine following injury in a dose-dependent manner. Furthermore, administration of Slit2 did not increase hepatic bacterial load in mice infected with L.monocytogenes infection. Collectively, these data demonstrate Slit2 as an exciting therapeutic molecule to combat renal ischemia reperfusion injury without compromising protective host innate immune functions.MAS

Pediatric acute kidney injury and the subsequent risk for chronic kidney disease: is there cause for alarm?

Acute kidney injury (AKI) is characterized clinically as an abrupt decline in renal function marked by reduced excretion of waste products, disordered electrolytes, and disrupted fluid homeostasis. The recent development of a standardized AKI definition has transformed our understanding of AKI epidemiology and outcomes. We now know that in the short term, children with AKI experience greater morbidity and mortality; additionally, observational studies have established that chronic renal sequelae are far more common after AKI events than previously realized. Many of these studies suggest that patients who develop AKI are at greater risk for the subsequent development of chronic kidney disease (CKD). The goal of this review is to critically evaluate the data regarding the association between AKI and CKD in children. Additionally, we describe best practice approaches for future studies, including the use of consensus AKI criteria, the application of rigorous definitions for CKD and renal sequelae, and the inclusion of non-AKI comparator groups. Finally, based upon existing data, we suggest an archetypal approach to follow-up care for the AKI survivors who may be at greater CKD risk, including children with more severe AKI, those who endure repeated AKI episodes, patients who do not experience full recovery, and those with pre-existing CKD

Rising Incidence of End-Stage Kidney Disease and Poorer Access to Kidney Transplant Among Australian Aboriginal and Torres Strait Islander Children and Young Adults

Introduction: Details of the pediatric population with end-stage kidney disease (ESKD) in Australia and New Zealand have been published previously. There is, however, a paucity of studies exploring the trends in incidence, etiology, renal replacement therapy (RRT) modality, and transplant access among the Aboriginal and Torres Strait Islander children and young adults (ATCYAs) residing in Australia. Methods: An observational study was undertaken and data on Australian patients who commenced RRT at ≤24 years of age between 1963 and 2017 were extracted from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA). The incidence and prevalence rates were restricted from 1997 to 2017 because of the unavailability of Aboriginal– and Torres Strait Islander status–specific census data before 1997. Results: A total of 3629 children and young adults received RRT during the observation period, including 178 (4.9%) who identified as ATCYAs and 3451 (95.1%) other children and young adults (OCYAs). Compared with OCYAs, incident rates have risen among ATCYAs since 2000, with the biggest rise for young adults 20 to 24 years of age. Fewer ATCYAs received a kidney transplant compared with OCYAs (56.2% vs. 89.3%, P < 0.001). Pre-emptive kidney transplants were less common in ATCYAs compared with OCYAs (3.4% vs. 16.8%, P < 0.001). Living related donor transplants were less common among ATCYAs than OCYAs (10.7% vs. 35.9%, P < 0.001). Conclusions: Our study shows rising incident rates and poorer access to kidney transplantation among ATCYAs in Australia. The reasons for this health care disparity and barriers to transplantation need to be explored further and must be addressed

Pediatric acute kidney injury and the subsequent risk for chronic kidney disease: is there cause for alarm?

Acute kidney injury (AKI) is characterized clinically as an abrupt decline in renal function marked by reduced excretion of waste products, disordered electrolytes, and disrupted fluid homeostasis. The recent development of a standardized AKI definition has transformed our understanding of AKI epidemiology and outcomes. We now know that in the short term, children with AKI experience greater morbidity and mortality; additionally, observational studies have established that chronic renal sequelae are far more common after AKI events than previously realized. Many of these studies suggest that patients who develop AKI are at greater risk for the subsequent development of chronic kidney disease (CKD). The goal of this review is to critically evaluate the data regarding the association between AKI and CKD in children. Additionally, we describe best practice approaches for future studies, including the use of consensus AKI criteria, the application of rigorous definitions for CKD and renal sequelae, and the inclusion of non-AKI comparator groups. Finally, based upon existing data, we suggest an archetypal approach to follow-up care for the AKI survivors who may be at greater CKD risk, including children with more severe AKI, those who endure repeated AKI episodes, patients who do not experience full recovery, and those with pre-existing CKD

Metachronous B-cell and T-cell post-transplant lymphoproliferative disorders with features of chronic active Epstein-Barr virus infection

10.1002/ajh.24122AMERICAN JOURNAL OF HEMATOLOGY9010E204-E205United State

The cell motility modulator Slit2 is a potent inhibitor of platelet function

Background\u2014Vascular injury and atherothrombosis involve vessel infiltration by inflammatory leukocytes, migration of medial vascular smooth muscle cells to the intimal layer, and ultimately acute thrombosis. A strategy to simultaneously target these pathological processes has yet to be identified. The secreted protein, Slit2, and its transmembrane receptor, Robo-1, repel neuronal migration in the developing central nervous system. More recently, it has been appreciated that Slit2 impairs chemotaxis of leukocytes and vascular smooth muscle cells toward diverse inflammatory attractants. The effects of Slit2 on platelet function and thrombus formation have never been explored.Peer reviewed: YesNRC publication: Ye

Slit2 prevents neutrophil recruitment and renal ischemia-reperfusion injury.

Neutrophils recruited to the postischemic kidney contribute to the pathogenesis of ischemia-reperfusion injury (IRI), which is the most common cause of renal failure among hospitalized patients. The Slit family of secreted proteins inhibits chemotaxis of leukocytes by preventing activation of Rho-family GTPases, suggesting that members of this family might modulate the recruitment of neutrophils and the resulting IRI. Here, in static and microfluidic shear assays, Slit2 inhibited multiple steps required for the infiltration of neutrophils into tissue. Specifically, Slit2 blocked the capture and firm adhesion of human neutrophils to inflamed vascular endothelial barriers as well as their subsequent transmigration. To examine whether these observations were relevant to renal IRI, we administered Slit2 to mice before bilateral clamping of the renal pedicles. Assessed at 18 hours after reperfusion, Slit2 significantly inhibited renal tubular necrosis, neutrophil and macrophage infiltration, and rise in plasma creatinine. In vitro, Slit2 did not impair the protective functions of neutrophils, including phagocytosis and superoxide production, and did not inhibit neutrophils from killing the extracellular pathogen Staphylococcus aureus. In vivo, administration of Slit2 did not attenuate neutrophil recruitment or bacterial clearance in mice with ascending Escherichia coli urinary tract infections and did not increase the bacterial load in the livers of mice infected with the intracellular pathogen Listeria monocytogenes. Collectively, these results suggest that Slit2 may hold promise as a strategy to combat renal IRI without compromising the protective innate immune response