WCN26-2907 HIGH-SENSITIVITY ANTI-NEPHRIN AUTOANTIBODY ASSAY PREDICTS STEROID RESISTANCE AND GLOMERULONEPHRITIS IN CHILDHOOD IDIOPATHIC NEPHROTIC SYNDROME

by flow cytometry.B cell transcriptional signatures and clonality were evaluated by single-cell RNA-sequencing.Results: Anti-CRB2 autoantibodies were detected in all types of active idiopathic podocytopathies, with seropositivity significantly higher in adults (27/31 [87%] vs 23/51 [45%], P < 0.01) and titers significantly reduced in remission (51 vs 115 g/mL, P < 0.01).Double seropositivity for anti-CRB2 and anti-Nephrin was seen in 14/82 (17%) patients.IgG deposits colocalizing with CRB2 were identified in the glomeruli of anti-CRB2 seropositive patients.The expansion of extrafollicular T-bet+ CD21low atypical B cells, a population associated with autoimmunity, was seen in both children and adults.In children, both autoantibodies correlated with atypical B cell expansion.In adults, elevated frequencies of classical memory B cells indicated a greater degree of B cell dysregulation than in children.Further profiling in children using single-cell RNA-sequencing revealed a broadly dysregulated B cell pool poised for activation and the preferential accumulation of autoimmunity-prone VH4-39+ B cell clonotypes within the repertoire. Conclusion:We discovered that, despite being more frequent in adults, anti-CRB2 autoantibodies were seen in all types of idiopathic podocytopathies and could co-occur with anti-Nephrin autoantibodies.Moreover, we showed that children and adults had a dysregulated, autoimmunity prone B cell pool characterized by the expansion of extrafollicular atypical B cells.Altogether, these findings position anti-slit diaphragm autoimmunity as central to the pathogenesis of both childhood and adult idiopathic podocytopathies.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.