Multi-Omics Analysis Uncovers a Link Between Dysregulated Steroid Hormone Biosynthesis and Pediatric IgA Vasculitis Nephritis

Background: IgA vasculitis (IgAV) is a systemic vasculitis with variable clinical manifestations, ranging from self-limiting cutaneous purpura and joint pain to severe gastrointestinal and renal involvement. However, whether specific metabolites are associated with these heterogeneous clinical manifestations remains unclear. This study aimed to identify metabolic and proteomic signatures associated with distinct clinical manifestations of IgAV, particularly IgAV nephritis (IgAVN), and to identify molecular features potentially associated with disease pathogenesis. Methods: We performed liquid chromatography–tandem mass spectrometry (LC–MS/MS)-based metabolomic and exploratory proteomic analyses of plasma samples from patients with IgAV with isolated cutaneous purpura or additional joint, gastrointestinal, or renal involvement and from healthy controls. Results: Metabolomic analysis revealed significant differences between patients with IgAV, including those with IgAVN, and healthy controls. A total of 65 differentially abundant metabolites were identified, with the steroid hormone biosynthesis pathway among the most prominently altered pathways. Notably, patients with IgAVN exhibited a distinct metabolomic profile compared with patients without renal involvement. Levels of six steroids and steroid metabolites, including tetrahydrocorticosterone, tetrahydrocortisone, cortisone, aldosterone, androsterone glucuronide, and progesterone, decreased in patients with IgAVN compared with healthy controls. Proteomic profiling identified 50 upregulated and 12 downregulated proteins in patients with IgAV compared with healthy controls, with enrichment of pathways related to platelet activation and complement and coagulation cascades. Compared with healthy controls, 33 upregulated and 154 downregulated proteins were identified in the IgAVN group. Additionally, IgAVN was associated with a distinct proteomic signature involving the intestinal immune network, B cell receptor signaling, and cholesterol metabolism. Decreased levels of steroids and steroid metabolites were significantly associated with alterations in immunoglobulins and coagulation factors identified by exploratory proteomic analysis. Conclusions: Integrated metabolomic and proteomic analyses identified distinct molecular signatures associated with IgAV and IgAVN. Decreased levels of steroids and steroid metabolites and alterations in immune response, coagulation, and lipid metabolic pathways were particularly associated with IgAVN. These findings provide insights into the molecular features associated with IgAV and identify candidate biomarkers of disease severity and potential therapeutic targets that warrant further investigation.