Integrative Transcriptomic Analysis Implicates Platelet Activation as a Potential Pathological Mechanism in IgA Nephropathy: Evidence from Multi-Dataset Analysis and Urinary Biomarker Validation

Background Immunoglobulin A nephropathy (IgAN) is the leading cause of end-stage kidney disease globally. Although platelet activation has been implicated in IgAN progression, comprehensive transcriptomic evidence and validated urinary biomarkers reflecting this process are lacking. This study aimed to identify platelet activation as a key pathological mechanism through integrative analysis of public microarray datasets and validate findings using a urinary biomarker. Methods Four Gene Expression Omnibus (GEO) datasets comprising 159 kidney samples (99 IgAN patients, 60 healthy controls) were reanalyzed. Differential expression analysis and KEGG/GO pathway enrichment were performed to identify dysregulated pathways. Findings were validated by measuring urinary soluble CD61 (sCD61) in 44 biopsy-confirmed IgAN patients and 20 healthy controls by ELISA. Results A total of 2,182 genes were differentially expressed in IgAN kidneys (1,302 upregulated, 880 downregulated). KEGG pathway analysis identified platelet activation as the most significantly enriched pathway (hsa04611, P = 2.1×10⁻⁹). GO enrichment analysis further revealed upregulation of actin cytoskeleton organization, cell adhesion, and inflammatory response terms. Consistent with transcriptomic findings, urinary sCD61 was significantly elevated in IgAN patients (340.47 ± 37.49 ng/g Cr) compared with healthy controls (257.35 ± 101.28 ng/g Cr, p < 0.001), and was associated with proteinuria and serum creatinine. Further analysis demonstrated that higher urinary sCD61 levels were associated with more severe Oxford classification histological lesions, particularly tubular atrophy/interstitial fibrosis (T1–T2) and cellular/fibrocellular crescents (C2). Conclusions Integrative transcriptomic analysis suggests that platelet activation may represent an important pathological mechanism in IgAN. Urinary sCD61 provides corroborating clinical evidence of platelet activation in IgAN patients, and may serve as a potential non-invasive biomarker for disease monitoring and risk stratification.