Anti-alpha-actinin Antibodies and Lupus Nephritis Activity

Official title

Serum Anti-alpha-actinin Antibodies as an Early Biomarker for Histological Activity in Lupus Nephritis and Its Correlation With Other Conventional Serological Markers

Overview

Lupus nephritis (LN) develops in 30-60% of systemic lupus erythematosus (SLE) patients and remains a leading cause of morbidity, with 10-30% progressing to end-stage renal disease within 15 years. The International Society of Nephrology/Renal Pathology Society (ISN/RPS) classifies LN histologically, with proliferative forms (Classes III/IV) carrying the poorest prognosis.

Detailed description

Current monitoring tools have significant limitations. Conventional markers (anti-dsDNA, C3/C4) correlate imperfectly with renal activity, as 20-30% of active LN patients have normal anti-dsDNA levels. Renal biopsy remains the gold standard for assessing histological activity through the NIH activity index, but is invasive and cannot be repeated frequently.

Anti-alpha-actinin-4 antibodies have emerged as promising biomarkers. Alpha-actinin-4 is a podocyte cytoskeletal protein critical for glomerular filtration barrier integrity. A subset of anti-dsDNA antibodies cross-reacts with alpha-actinin, directly linking systemic autoimmunity to renal injury. These antibodies induce podocyte damage, complement activation, and correlate with proteinuria and histological activity.

However, comprehensive evaluation of their correlation with detailed histopathological activity indices remains limited, particularly in understudied populations. This study aims to assess the relationship between serum anti-alpha-actinin antibodies and the renal histopathological activity index in LN patients, comparing their performance with conventional serological markers.

Interventions

• Other renal biopsy
  Renal biopsy specimens will be evaluated by light microscopy and will be pathologically classified according to the 2003 International Society of Nephrology/ Renal Pathology Society classification (ISN/RPS Classification) as minimal mesangial (class I), mesangial proliferative LN (class II), focal LN (class III), diffuse LN (class IV), membranous LN (class V) and advanced sclerosis (class VI)
• Diagnostic test serum anti-alpha-actinin antibodies
  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.
• Diagnostic test CBC, serum creatinine and urea, estimated GFR, ESR, CRP, urine analysis, ANA, anti dsDNA, C3 & C4, serum albumin, 24-hrs urinary protein, and U. ACR
  Laboratory tests including, complete blood count (CBC, serum creatinine and urea and estimated GFR according to CKD-EPI and KDIGO;2024, urine analysis, C-reactive protein (CRP), Erythrocyte Sedimination Rate (ESR), anti-nuclear antibodies (ANA), serum albumin, serum complement (C3 and C4) ,anti-double stranded deoxyribonucleic acid (anti-dsDNA), 24-hrs urinary protein and urinary albumin:creatinine ratio (U. ACR).

Primary outcome measures

• evaluate associations between anti-alpha-actinin antibody levels and specific histological features of active LN [Time frame: 36 months]
• measure serum anti-alpha-actinin antibody levels in patients with biopsy-proven active lupus nephritis [Time frame: 36 months]

Eligibility criteria

Inclusion 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).
• 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.
• Renal biopsy performed within 3 months prior to enrollment, and patient has not received induction immunosuppressive therapy (cyclophosphamide, mycophenolate mofetil, or calcineurin inhibitors) in the period between biopsy and enrollment.
• Provision of written informed consent.

b)Inclusion Criteria for Control Groups:

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• 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).
• Healthy controls: Age- and sex-matched healthy individuals with no history of autoimmune disease, normal urinalysis, and negative autoantibodies (ANA, anti-dsDNA).

Exclusion criteria

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

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• 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.
• Pregnancy or lactation.
• Confounding Medications:

• Receipt of high-dose corticosteroids (> 20 mg/day of prednisone or equivalent) or any potent immunosuppressive agent (e.g., cyclophosphamide, mycophenolate mofetil, rituximab) within 4 weeks prior to the renal biopsy and blood sampling).

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

Healthy volunteers: Yes

Study design

Observational model

Other

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Deocharan B, Qing X, Lichauco J, Putterman C. Alpha-actinin is a cross-reactive renal target for pathogenic anti-DNA antibodies. J Immunol. 2002 Mar 15;168(6):3072-8. doi: 10.4049/jimmunol.168.6.3072. PMID 11884481
• Tsai CY, Li KJ, Shen CY, Lu CH, Lee HT, Wu TH, Ng YY, Tsao YP, Hsieh SC, Yu CL. Decipher the Immunopathological Mechanisms and Set Up Potential Therapeutic Strategies for Patients with Lupus Nephritis. Int J Mol Sci. 2023 Jun 13;24(12):10066. doi: 10.3390/ijms241210066. PMID 37373215
• He S, Zhang J, Wang X, Qi Z, Zhou Z, Wang Y, Xu S, Li D, Ye X, Liu Z, Hao X, Zhao Y, Wang R. Organoid Modeling and Single-Cell Profiling Reveal Smooth Muscle Cell Migration in Moyamoya Disease. Commun Biol. 2026 Jan 7;9(1):198. doi: 10.1038/s42003-025-09476-9. PMID 41501150
• Aringer M. EULAR/ACR classification criteria for SLE. Semin Arthritis Rheum. 2019 Dec;49(3S):S14-S17. doi: 10.1016/j.semarthrit.2019.09.009. PMID 31779843
• Alduraibi FK, Tsokos GC. Lupus Nephritis Biomarkers: A Critical Review. Int J Mol Sci. 2024 Jan 9;25(2):805. doi: 10.3390/ijms25020805. PMID 38255879
• Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002 Feb;29(2):288-91. PMID 11838846
• Almaani S, Meara A, Rovin BH. Update on Lupus Nephritis. Clin J Am Soc Nephrol. 2017 May 8;12(5):825-835. doi: 10.2215/CJN.05780616. Epub 2016 Nov 7. PMID 27821390

Identifiers

NCT: NCT07505576 · AAALN

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗