Checkpoint Imbalance in Primary Glomerulopathies: Comparative Insights into IgA Nephropathy and Membranoproliferative...

Primary glomerulopathies are immune-driven kidney diseases. IgA nephropathy (IgAN) and membranoproliferative glomerulonephritis (MPGN) are prevalent entities with a risk of chronic progression. Immune checkpoints, such as PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200, regulate activation and tolerance in T, B, and NK cells, and also exist in soluble forms, reflecting systemic immune balance.

To compare immune checkpoint profiles in IgAN and MPGN versus healthy volunteers (HV) through surface expression, soluble serum levels, and PBMC transcripts, with attention to sex-related differences and diagnostic value assessed by ROC curves.

Ninety age-matched subjects were studied: IgAN (n = 30), MPGN (n = 30), HV (n = 30). Flow cytometry evaluated checkpoint expression on CD4+/CD8+ T cells, CD19+ B cells, and NK cells. ELISA quantified sPD-1, sPD-L1, sCTLA-4, sCD86, sCD200, sCD200R; PBMC transcript levels were assessed. Group comparisons, sex stratification, and ROC analyses were performed.

Lymphocyte distributions were preserved, but IgAN patients showed anemia and impaired renal function, while MPGN patients had greater proteinuria and dyslipidemia. GN patients displayed increased PD-1/PD-L1 and CD200R/CD200, with reduced CTLA-4/CD86, compared to HV. Serum analysis revealed elevated sPD-1, sPD-L1, sCD200, sCD200R and decreased sCTLA-4, sCD86. PBMC transcripts paralleled these trends, with PD-1/PD-L1 mainly increased in MPGN. Sex had minimal impact. ROC analyses showed strong GN vs. HV discrimination by CD19⁺CTLA-4⁺, PD-1/PD-L1, and CD200/CD200R, but limited ability to separate IgAN from MPGN.

IgAN and MPGN share a sex-independent checkpoint signature: PD-1/PD-L1 and CD200R/CD200 upregulation with CTLA-4/CD86 downregulation. CD19⁺, CTLA-4⁺, and soluble PD-1/PD-L1/CD200(R) emerge as promising biomarkers requiring further validation.