TREM2⁺ macrophages accumulate in childhood IgA nephropathy and soluble TREM2 represents a reliable non‐invasive biomarker

IgA nephropathy (IgAN) is a common type of primary glomerulonephritis in children. The pathogenesis of childhood IgAN remains unclear, and there is a lack of effective non-invasive biomarkers for this disease. Single-cell RNA sequencing was performed in children with IgAN to delineate cellular and molecular compositions, and subcluster analysis for macrophages was conducted. Blood samples were collected from 38 children with IgAN to measure soluble TREM2 (sTREM2) and soluble CD163 (sCD163) levels and analyse their clinical significance. Single-cell RNA sequencing identified distinct cell clusters in both parenchymal and stromal compartments. Mesangial components were classified into vascular smooth muscle cells/pericytes, mesangial cells, fibroblasts and activated myofibroblasts. Patients with IgAN had a marked increase in myofibroblasts and immune cells in comparison to the control group. Remarkable infiltration of macrophages was observed in the kidneys of IgAN patients, and a subgroup of marcophages with high TREM2 expression was enriched. Children with IgAN exhibited significantly higher plasma sTREM2 levels than healthy individuals, and the sTREM2 level was correlated with sCD163 abundance. Importantly, an increased sTREM2 level was positively associated with the severity of proteinuria. Moreover, the elevation of sTREM2 was correlated with a more advanced pathological grading. In summary, we unveiled a remarkable remodelling of the stromal cellular landscape in childhood IgAN, and TREM2⁺ macrophages were found to accumulate. We identified that the plasma sTREM2 level was associated with clinical and pathological severity and therefore constituted a potential non-invasive biomarker for children with IgAN.