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.

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.

Inclusion Criteria:

1. Inclusion criteria for LN group:

   1. Adult patients (≥ 18 and > 60 years) of either sex.

   2. Fulfill the 2019 EULAR/ACR Classification Criteria for Systemic Lupus Erythematosus (SLE).

   3. 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).

   4. Availability of an adequate renal biopsy specimen for histopathological evaluation according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2018 classification.

   5. 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.

   6. Provision of written informed consent.

      b)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).

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

      Exclusion Criteria:

      -

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

   1. 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).

   2. 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.

   3. 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).

1. Inclusion criteria for LN group:

   1. Adult patients (≥ 18 and > 60 years) of either sex.
   2. Fulfill the 2019 EULAR/ACR Classification Criteria for Systemic Lupus Erythematosus (SLE) [11].
   3. 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).

2. Exclusion criteria:

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

1. 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).

2. 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.