Significance of neutrophil extracellular traps and low-density granulocytes in advanced chronic kidney disease (stage 5D) cases with COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) affected billions of individuals globally, with symptoms ranging from isolated blood clotting to severe acute hypoxemic respiratory failure requiring intensive respiratory support ventilators. Those with advanced chronic kidney disease (CKD stage 5) were at high risk of severe disease faced a particularly heightened risk of severe illness. Inflammation and associated immune-thrombotic events in CKD stage 5 have attracted increasing attention, yet remain poorly understood. In this prospective cohort study, we examined and compared neutrophil extracellular traps (NETs) and low-density granulocytes (LDGs) in heathy controls (n = 15), CKD stage 5 patients without COVID-19 (n = 15), patients with COVID-19 (n = 15), and CKD stage 5 patients with COVID-19 (n = 90). Serum citrullinated histone H3 (CitH3) and related gene expression (PAD4, ERK1, PKC), NET complexes, platelet factor 4 (PF4), von Willebrand factor (vWF), RANTES, and specific cytokines were quantified. Proof-of-concept experiments were conducted to assess the role of lipopolysaccharide-LDG complexes in NETs detected in COVID-19 plasma. NETs complexes were significantly higher in COVID-19 cases, and more so in patients with CKD stage 5D, and those who died. Disease severity was directly correlated with NETs complex levels (p = 0.016). CitH3 and gene expression levels were not correlated with advanced CKD stage, while levels of components that initiate NETs formation were higher in patients with COVID-19 and in CKD stage 5 patients. In conclusion, NET activation could partially explain the thrombotic manifestations in patients with COVID-19 and in CKD stage 5 patients.