Role of increased neutrophil extracellular trap formation on acute kidney injury in COVID-19 patients

BackgroundA strong association between elevated neutrophil extracellular trap (NET) levels and poor clinical outcomes in patients with coronavirus infection 2019 (COVID-19) has been reported. However, while acute kidney injury (AKI) is a common complication of COVID-19, the role of NETs in COVID-19-associated AKI is unclear. We investigated the association between elevated NETs and AKI and the prognostic role of NETs in COVID-19 patients.MethodsTwo representative markers of NETs, circulating nucleosomes and myeloperoxidase-DNA, were measured in 115 hospitalized patients. Serum levels of interleukin [IL]-6, monocyte chemotactic protein-1 [MCP-1], plasma von Willebrand factor (vWF) and urinary biomarkers of renal tubular damage (β2-microglobulin [β2M] and kidney injury molecule 1 [KIM-1]) were measured.ResultsAKI was found in 43 patients (37.4%), and pre-existing chronic kidney disease (CKD) was a strong risk factor for AKI. Higher circulating NET levels were a significant predictor of increased risk of initial ICU admission, in-hospital mortality (adjusted HR 3.21, 95% CI 1.08–9.19) and AKI (OR 3.67, 95% CI 1.30-10.41), independent of age, diabetes, pre-existing CKD and IL-6 levels. There were strong correlations between circulating nucleosome levels and urinary KIM-1/creatinine (r=0.368, p=0.001) and β2M (r=0.218, p=0.049) levels. NETs were also strongly closely associated with serum vWF (r = 0.356, p<0.001), but not with IL-6 or MCP-1 levels.ConclusionsElevated NETs were closely associated with AKI, which was a strong predictor of mortality. The close association between NETs and vWF may suggest a role for NETs in COVID-19-associated vasculopathy leading to AKI

Neutrophil extracellular traps and heparin-induced antibodies contribute to vascular access thrombosis in hemodialysis patients

Background Anti-heparin/platelet factor 4 (PF4) antibodies may trigger severe thrombotic complications in hemodialysis (HD) patients. Tetrameric PF4 has a high affinity for extracellular DNA, which is a key component of neutrophil extracellular traps (NETs); therefore, the interactions between anti-heparin/PF4 antibodies and NETs can contribute to prothrombotic events. Methods Anti-heparin/PF4 antibody levels were measured by enzyme-linked immunosorbent assay and an optical density > 1.8 was regarded as clinically significant. We additionally measured serum nucleosome levels as representative markers of NETs, and the contributions of anti-heparin/PF4 and increased serum nucleosome levels to the primary functional patency loss of vascular access was assessed. Results The frequency of anti-heparin/PF4 antibodies was significantly higher in incident HD patients compared to prevalent HD patients (23.6% vs. 7.7%). Serum nucleosome levels, as well as the white blood cell counts, neutrophil counts, and high- sensitivity C-reactive protein levels, were significantly higher in anti-heparin/PF4 antibody-positive patients compared to the control. Platelet counts tended to be lower in the patients with anti-heparin/PF4 of >1.8 than in the controls. Relative risk calculations showed that the presence of anti-heparin/PF4 antibodies increased the risk of primary functional patency failure by 4.28-fold, and this risk increased further with higher nucleosome levels. Furthermore, in the anti-heparin/PF4 antibody-positive group, the time to first vascular intervention was much shorter, and the risk of repeated intervention was higher, compared to the controls. Conclusion In incident HD patients, the presence of anti-heparin/PF4 antibodies was associated with increased NET formation; this could be a strong predictor of vascular access complication