Urinary Proteomics Identify Biomarkers for Predicting Complete Remission of Proteinuria in Pediatric IgA Nephropathy

Background: This study aimed to identify urinary biomarkers for predicting complete remission (CR) of proteinuria in pediatric IgAN. Methods: We enrolled pediatric patients with biopsy-proven IgAN from the Registry of IgA Nephropathy in Chinese Children (RACC, NCT03015974). Patients were divided into CR (defined as 24-hour urinary protein ≤200 mg/d or protein:creatinine ratio ≤200 mg/g) group and non-complete remission (NCR) group, according to whether they achieved CR within 6 months after the baseline. We profiled the proteome of baseline urine samples with data-independent acquisition mass spectrometry. Based on three machine-learning algorithms (including least absolute shrinkage and selection operator, random forest, and support vector machine), the biomarkers with the best ability to distinguish between CR group and NCR group were selected. The added value of these biomarkers on the clinical-pathological parameters were evaluated. The enrichment analysis for differentially expressed proteins were used to analyze the biological process associated with CR of proteinuria. Results: A total of 48 children were enrolled, including 34 children in the CR group and 14 children in the NCR group. The urine proteomics quantified a total of 1,721 proteins in baseline urine samples. The following four urinary biomarkers with the best predictive performance were identified: complement component C8 alpha chain, pigment epithelium-derived factor, tyrosine-protein kinase Yes and ribonuclease P protein subunit p38. Compared with clinical-pathological parameters alone, the addition of the new biomarkers on the clinical-pathological parameters significantly increased the predictive accuracy for CR of proteinuria (AUC from 0.819 to 0.969, P<0.001). The differentially expressed proteins between the two groups were mainly enriched in the complement coagulation pathway, regulation of actin cytoskeleton, regulation of apoptosis, and etc. Conclusion: The addition of the new urinary biomarkers identified by urine proteomics on the traditional clinical-pathological parameters could significantly improve the model fit for predicting CR of proteinuria in pediatric IgAN, thus helping achieve accurate prediction. Proteinuria remission might be associated with complement and coagulation pathway, regulation of actin cytoskeleton, regulation of apoptosis, and etc.