Unveiling the immune landscape and microenvironmental architecture of IgA nephropathy using single-cell imaging mass cytometry.

Objective: The heterogeneity in the pathology of IgA nephropathy (IgAN) represents a significant gap in current research, emphasising the need for individualised treatment strategies. The role of the glomerular microenvironment in driving IgAN heterogeneity remains largely unknown. Methods: This study employed Imaging Mass Cytometry (IMC) to analyse 34 primary IgAN renal biopsies. A panel of 35 protein markers was used to identify and characterise 17 cell clusters. Results: Immune cells composed of 9.64% of the glomerular cell population, with macrophages being the predominant subset. While there was no significant difference in the overall percentage of immune cells across glomeruli exhibiting different pathological features, including mesangial proliferation, global sclerosis, segmental sclerosis and crescents, the infiltration pattern of these cells was distinct. Neighbourhood analysis revealed that the interaction mode of M1-like macrophages varied significantly among these four glomerular pathology types. Severe IgAN (Lee grades IV-V) was associated with a lower glomerular M1/M2-like macrophage infiltration ratio compared to mild IgAN (Lee grade III). The M1/M2-like macrophage ratio positively correlated with the estimated glomerular filtration rate (eGFR), while M2-like macrophages correlated with proteinuria, and T cells were associated with haematuria. Conclusions: Our study findings underscore that glomerular immune cell subtypes and their interaction patterns critically influence pathological and clinical outcomes, suggesting a new potential direction for molecular therapeutic strategies targeting the IgAN microenvironment.