Neutrophil extracellular traps (NETs) are an essential component of the innate immune
system, designed to trap and neutralize invading pathogens. NETosis, the process by which
neutrophils release decondensed chromatin (DNA and histones) decorated with antimicrobial
proteins such as myeloperoxidase (MPO) and neutrophil elastase (NE), is a critical
mechanism in host defense. This process is induced by stimuli such as PMA, antibodies,
cytokines, chemokines, and sterile triggers, including high glucose, cholesterol, and
hypoxia. This stimulation activates the Raf-MEK-ERK pathway and NADPH oxidase-dependent
production of reactive oxygen species.1,2 An increase in cytosolic calcium cations
activates NADPH oxidases and acts as a cofactor for peptidylarginine deiminase 4 (PAD4).
PAD4 catalyzes citrullinated histone H3 (Cit-H3) inducing chromatin decondensation,
resulting in a cell extrusion of mixture of DNA and bactericidal proteins, including MPO
and NE, which all serves as a specific markers of NETosis.1,2 While beneficial in
infection settings, excessive or dysregulated NET formation can cause significant tissue
damage and organ dysfunction. NETs have been implicated in the pathogenesis of various
acute and chronic inflammatory diseases, including myocardial infarction,
atherosclerosis, autoimmune diseases, diabetes, and chronic kidney disease (CKD).
Elevated NETosis markers, including cell-free DNA (cfDNA) and Cit-H3, are commonly
observed in these conditions, underscoring their role in disease progression.3 Given the
dual nature of NETosis, understanding how different factors influence this process is
critical for developing targeted therapies. This study focuses on two key aspects:
evaluating the effects of antiglycemic medications on NETosis and investigating NETosis
across different stages of immune-mediated kidney disease before and after
immunosuppressive therapy.
(The hemodialysis part of this trial is not included in the current protocol)
Part 1: Evaluating the Effects of Antiglycemic Medications on NETosis Dysregulated
NETosis in diabetic and CKD patients contributes to systemic inflammation and organ
damage. Studies have shown elevated levels of NETosis markers, such as cfDNA and Cit-H3,
in these populations. While metformin has demonstrated the ability to reduce NET
formation in diabetic patients, the effects of newer glucose-lowering agents, including
SGLT2 inhibitors and GLP-1 receptor agonists, remain unexplored.4 Both SGLT2 inhibitors
and GLP-1 receptor agonists have demonstrated robust cardiovascular and renal protective
effects.5 This study aims to evaluate their impact on basal and stimulated NETosis in
diabetic and CKD patients with various etiologies. By analyzing NETosis markers before
and after treatment, this research will provide insights into whether these agents can
modulate NETosis, thereby offering additional anti-inflammatory benefits and reducing
disease-associated complications.
Part 2: Evaluating NETosis at Different Stages of Immune-Mediated Kidney Disease and
After Immunosuppressive Therapy Immune-mediated kidney diseases, such as ANCA-associated
vasculitis, involve heightened NETosis that contributes to kidney injury and systemic
inflammation.2 Chronic kidney disease resulting from these conditions often exhibits
elevated NET formation, exacerbating disease progression. This study seeks to investigate
the dynamics of NETosis at various stages of CKD caused by immune-mediated diseases.
In addition, the effects of immunosuppressive therapy on NETosis will be assessed.
Immunosuppressive medications, a cornerstone in the treatment of diseases like
ANCA-associated vasculitis, can influence neutrophil activity. By monitoring NETosis
markers, including cfDNA, Cit-H3, MPO, and NE, before and after initiating
immunosuppressive therapy, the study aims to identify patterns of response and the
potential therapeutic modulation of NETosis.
Conclusion This comprehensive investigation into the effects of antiglycemic medications
and immunosuppressive therapy on NETosis will provide critical insights into the
interplay between treatment, inflammation, and disease progression in diabetic and CKD
patients. These findings may help pave the way for targeted interventions aimed at
modulating NETosis and improving outcomes in high-risk populations.