Background: Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disorder characterized by immune dysregulation and autoantibody production. Renal involvement represents one of its most severe complications, significantly affecting prognosis. This study investigated the association between programmed cell death protein-1 (PD-1) and its ligand (PD-L1) immune checkpoint markers, immunological parameters, and renal involvement in SLE patients.

Methods: A case–control study enrolled 100 SLE patients and 100 age- and sex-matched healthy controls (December 2025–February 2026). Anti-nuclear antibodies (ANA) and anti-double stranded DNA (anti-dsDNA) were quantified by ELISA; complement factors C3 and C4 by nephelometry; thymosin β4 and vitamin D3 by ELISA; and renal biomarkers (cystatin C, urea, uric acid, creatinine) by standard biochemical methods. PD-1/PD-L1 expression was evaluated at the cellular level by flow cytometry and at the soluble serum level by ELISA.

Results: SLE patients exhibited significantly elevated ANA (147.31 ± 33.90 vs. 13.90 ± 3.70 IU/mL; p<0.001) and anti-dsDNA levels (109.73 ± 23.42 vs. 7.20 ± 3.51 IU/mL; p<0.001), with markedly reduced C3 (68.5 ± 12.20 vs. 110.3 ± 15.40 mg/dL) and C4 (12.4 ± 4.10 vs. 28.7 ± 5.20 mg/dL; p<0.001). Flow cytometry revealed significantly elevated PD-1+ T cells (34.50 ± 8.20% vs. 12.30 ± 4.10%) and PD-L1+ monocytes (28.70 ± 7.40% vs. 10.50 ± 3.50%), most pronounced in lupus nephritis (LN) subgroup. Soluble sPD-1 (3.42 ± 0.89 ng/mL) and sPD-L1 (2.97± 0.76 ng/mL) were significantly higher than controls. Thymosin β4 (15.30 ± 4.51 vs. 28.70 ± 5.10 ng/mL) and vitamin D3 (12.80 ± 3.23 vs. 31.20 ± 6.00 ng/mL) were markedly decreased. Cystatin C was found to be most correlated with PD-1 expression and severity of the disease (p<0.001).

Conclusion: PD-1/PD-L1 immune checkpoint dysregulation, in combination with conventional immunological and renal biomarkers, offers a holistic strategy of determining disease activity and renal involvement in SLE, with the potential of these biomarkers to serve as prognostic biomarkers and therapeutic targets.