Neutrophil Extracellular Traps and Lupus Nephritis

In recent years, growing evidence has emphasized the role of innate immune dysregulation in the pathogenesis of lupus nephritis, particularly the involvement of neutrophils and aberrant cell death pathways. Among these mechanisms, neutrophil extracellular traps (NETs) have emerged as key mediators of autoimmune-driven inflammation. NETs are extracellular chromatin networks composed of DNA, histones, and granular proteins released by activated neutrophils during NETosis. Although originally described as antimicrobial defense structures, excessive NET formation and impaired degradation have been strongly implicated in systemic autoimmunity.

In lupus nephritis, NETs contribute to renal injury through multiple mechanisms, including exposure of nuclear autoantigens, amplification of type I interferon signaling, activation of complement pathways, and direct cytotoxic effects on endothelial cells and podocytes. Moreover, impaired NET clearance has been demonstrated in SLE, further promoting persistent immune activation and renal inflammation. Recent studies have also suggested that circulating NETs levels are elevated in patients with renal involvement and may correlate with disease activity and outcomes.

However, most available data are cross-sectional, and limited evidence exists regarding the dynamic changes of NETs in response to therapy. Therefore, evaluating NETs before and after treatment may provide important insights into their role as predictive and prognostic biomarkers and potential therapeutic targets in lupus nephritis.

Inclusion criteria

for LN group:

• Adult patients (≥ 18 and > 60 years) of either sex.
• Fulfill the 2019 EULAR/ACR Classification Criteria for Systemic Lupus Erythematosus (SLE) [11].
• Diagnosis of active lupus nephritis requiring a renal biopsy as per standard clinical indications (e.g., proteinuria ≥ 0.5 g/24h, active urinary sediment, unexplained rise in serum creatinine).
• Availability of an adequate renal biopsy specimen for histopathological evaluation according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2018 classification.
• Patients planned to initiate standard induction therapy (e.g., mycophenolate mofetil or cyclophosphamide with corticosteroids).
• Provision of written informed consent.

Inclusion criteria

for Control Groups:

• SLE without nephritis: Patients meeting SLE criteria without any clinical or laboratory evidence of renal involvement (normal urinalysis, proteinuria < 0.3 g/24h, normal serum creatinine).

Exclusion criteria

• Participants will be excluded if ANY of the following criteria apply:

• Other Kidney Diseases:

• Presence of, or suspicion of, any other primary or significant secondary kidney disease unrelated to SLE (e.g., diabetic nephropathy, hypertensive nephrosclerosis, IgA nephropathy, significant drug-induced nephrotoxicity, rheumatoid arthritis, positive HBs antigen or HCV antibody).
• Confounding Clinical Conditions:

• Presence of an active or recent major infection (e.g., sepsis, pneumonia, UTI) at the time of enrollment, as infection can significantly alter immune markers.
• Presence of advanced chronic kidney disease (CKD Stage 4 or 5) predating the diagnosis of SLE.

3 · Pregnancy or lactation.

• Recent use (within the last 3 months) of biologic therapies that may affect neutrophil function or NET formation.

• Use of medications known to significantly alter neutrophil activity. 6. History of malignancy.