Single-Cell Transcriptomics Identifies CD8 T-Cell Differentiation Signatures in Early IgA Nephropathy

Objectives : IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide. Although still substantial proportion of patients progress to advanced kidney disease, its heterogeneous clinical course makes it difficult to identify patients at risk of progression, particularly during the early stage when kidney function remains relatively preserved. This study aimed to identify immune cell heterogeneity according to the different disease stages, with a particular focus on CD8⁺ T-cell differentiation signatures in early-stage IgAN.
Methods : Peripheral blood samples were obtained from 17 biopsy-proven IgAN patients and 9 healthy controls. Patients were classified into early- and late-stage groups based on estimated glomerular filtration rate and urine protein-to-creatinine ratio. Single-cell RNA sequencing was performed with peripheral blood mononuclear cells to characterize immune cell composition and CD8⁺ T-cell differentiation status. Differences according to the disease stages were evaluated using donor specific statistical modeling and pseudo-bulk analyses with covariate correction.
Results : Single-cell RNA sequencing revealed stage specific redistribution of CD8⁺ T-cell subsets (Figure 1). Early-stage IgAN was characterized by enrichment of IL-7Ra^high and IL-7Ra^med effector memory CD8⁺ T cells, whereas late-stage disease exhibited enrichment of IL-7Ra^low subsets. Branch-level differentiation demonstrated CD8⁺ T-cell commitment patterns according to the disease status (Figure 2). Although only a limited number of individual genes reached statistical significance after covariate adjustment, pathway analyses revealed coordinated transcriptional signatures associated with immune activation in early-stage disease and cytotoxic differentiation in advanced status. CD4⁺ T cells, B cells, and NK cells exhibited limited stage-specific alterations.
Conclusions : The present study showed stage specific redistribution of CD8⁺ T-cell subsets and pathway-level immune remodeling differentiation in early-stage IgAN. The results highlighted the insight into immune dynamics associated with disease progression and identified candidate pathways that warrant further investigation for risk stratification and precision-based management strategies.