Neutrophil Extracellular Traps and Lupus Nephritis

Official title

Dynamic Changes of Neutrophil Extracellular Traps in Lupus Nephritis and Their Role in Predicting Treatment Response.

Overview

Lupus Nephritis is one of the most severe organ manifestations of systemic lupus erythematosus and represents a major cause of morbidity, chronic kidney disease, and long-term mortality. Despite significant advances in immunosuppressive therapies, a substantial proportion of patients fail to achieve sustained renal remission or progress to end-stage renal disease, highlighting the need for improved understanding of disease mechanisms and more reliable biomarkers for disease monitoring and therapeutic response

Detailed description

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.

Interventions

• Diagnostic test Serum Neutrophil Extracellular Traps
  Serum sample should be collected into a serum separator tube. After clotting for 2 hours at room temperature or overnight at 4°C, and then centrifuging at 1000 × g for 20 minutes. Assay freshly prepared serum immediately or store samples in aliquot at -20°C or -80°C for later use. Avoid repeated freeze-thaw cycles.

Primary outcome measures

• The primary outcome of the study is the change in circulating neutrophil extracellular traps (NETs) levels, in patients with Lupus Nephritis [Time frame: 2 years]

Eligibility criteria

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:

1\) 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.

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

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Study design

Observational model

Cohort

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Chen X, Gao D, Wang M, Wang L, Hu H, Wen C, Tang Y. Neutrophil Extracellular Traps in Systemic Lupus Erythematosus: Pathogenic Mechanisms, Crosstalk with Oxidative Stress, and Antioxidant Therapeutic Potential. Antioxidants (Basel). 2025 Dec 23;15(1):25. doi: 10.3390/antiox15010025. PMID 41596085
• Yu Y, Su K. Neutrophil Extracellular Traps and Systemic Lupus Erythematosus. J Clin Cell Immunol. 2013 Apr;4:139. doi: 10.4172/2155-9899.1000139. PMID 24244889
• Carmona-Rivera C, Zhao W, Yalavarthi S, Kaplan MJ. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann Rheum Dis. 2015 Jul;74(7):1417-24. doi: 10.1136/annrheumdis-2013-204837. Epub 2014 Feb 25. PMID 24570026
• Hakkim A, Furnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, Herrmann M, Voll RE, Zychlinsky A. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A. 2010 May 25;107(21):9813-8. doi: 10.1073/pnas.0909927107. Epub 2010 May 3. PMID 20439745
• Liu L, de Leeuw K, van Goor H, Doornbos-van der Meer B, Arends S, Westra J. Neutrophil extracellular traps and oxidative stress in systemic lupus erythematosus patients with and without renal involvement. Arthritis Res Ther. 2024 Dec 19;26(1):220. doi: 10.1186/s13075-024-03454-y. PMID 39702549
• Gupta S, Kaplan MJ. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat Rev Nephrol. 2016 Jul;12(7):402-13. doi: 10.1038/nrneph.2016.71. Epub 2016 May 31. PMID 27241241
• Mok CC, Teng YKO, Saxena R, Tanaka Y. Treatment of lupus nephritis: consensus, evidence and perspectives. Nat Rev Rheumatol. 2023 Apr;19(4):227-238. doi: 10.1038/s41584-023-00925-5. Epub 2023 Mar 2. PMID 36864291
• Lichtnekert J, Anders HJ. Lupus nephritis-related chronic kidney disease. Nat Rev Rheumatol. 2024 Nov;20(11):699-711. doi: 10.1038/s41584-024-01158-w. Epub 2024 Sep 24. PMID 39317803

Identifiers

NCT: NCT07721857 · DCNETLN

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗