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The emerging technology of urinary proteomics has become an efficient biological approach for identifying biomarkers and characterizing pathogenesis in renal involvement. In this study, we attempted to elucidate the relationship between IgAN and HSPN in children, employing LC-MS/MS to perform urinary proteomic analyses using the DIA method. Early-morning spot urine was collected from patients with biopsy-proven IgAN (n = 19) and HSPN (n = 19) prior to treatment and renal biopsy in the Department of Pediatrics, Jinling Hospital, Nanjing, China, and did healthy volunteers (n = 14), from June 2018 to December 2019. Two hundred seventy-six urinary proteins and 125 urinary proteins were determined to be differentially expressed in children with IgAN (n = 4) and HSPN (n = 4), respectively, compared to the urinary proteins of healthy children (n = 4) (p < 0.05). GO analysis demonstrated that the differentially expressed proteins of the two groups, which were located in the extracellular matrix and cell membrane, were primarily involved in biological processes, including metabolic processes, immune system processes, cellular adhesion, cell proliferation, signaling, and biological regulation. KEGG analysis revealed that the differentially expressed proteins of the two groups were associated with cell adhesion molecules, ECM-receptor interactions, the PI3K-Akt signaling pathway, the complement and coagulation cascades, regulation of actin cytoskeleton, cholesterol metabolism, and platelet activation. The target proteins (alpha-1B-glycoprotein (A1BG) and afamin (AFM)), which participated in the complement and coagulation cascades and the regulation of complement activation, were further investigated in the independent validation cohort by ELISA. These proteins were significantly increased in children with IgAN (n = 15) and HSPN (n = 15) compared with the proteins observed in healthy controls (n = 10, P < 0.05). The validated results were consistent with the mass spectrometry results. IgAN and HSPN both result from the glomerular deposition of abnormally glycosylated IgA1 with mesangial proliferative changes, and both diseases are common glomerulopathies in the pediatric population that are believed to be correlated. Interestingly, our data, by combining urinary proteomic analyses, showed that several uniform enrichment pathways played an important role in the progression of IgAN and HSPN, suggesting that we might reduce the renal involvement of the two diseases in children through these pathways. The same urinary proteins along these pathways were observed to be differentially expressed in children with IgAN and HSPN, implying that these proteins may be potential biomarkers to identify the two diseases. Future studies examining larger cohorts are warranted to confirm the validity of our findings. Unlabelled Image • The biological relationship between IgAN and HSPN in children from urinary proteomics. • The differentially expressed proteins in children with IgAN and HSPN • Several common signaling pathways were associated with renal involvement. • Potential biomarkers along the pathways of IgAN and HSPN in children • The target proteins (A1BG and AFM) were chosen for validation by ELISA. [ABSTRACT FROM AUTHOR]