Multi-omics body-fluid biomarkers in immunoglobulin a nephropathy: Analytical Validation, standardization, and clinical chemistry translation of diagnostic and prognostic Analytes.

IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide. Although optimized supportive therapy is administered to these patients, a substantial proportion still progresses to end-stage kidney disease. The advancement of these noninvasive laboratory tools will complement renal biopsies. This review focuses on evaluating the multi-omics serum and urinary biomarkers that reflect the multi-hit pathogenesis of IgAN, such as abnormal O-glycosylation of immunoglobulin A1 (IgA1), autoantibody production, deposition of immune complexes in the mesangium, complement system activation, podocyte dysfunction, and tubulointerstitial fibrosis. Galactose-deficient IgA1 can be measured using various methodologies, including lectin-based enzyme-linked immunosorbent assay (ELISA), KM55 monoclonal antibody assays, site-resolved mass spectrometric glycoprofiling, nuclear magnetic resonance (NMR), and liquid chromatography-mass spectrometry (LC-MS)-based metabolite and lipid fingerprinting techniques. Additionally, peptide classifiers are generated using sequential window acquisition of all theoretical spectra (SWATH), data-independent acquisition (DIA), and aptamer-based proteomics techniques. Machine learning classifiers, such as artificial neural networks, XGBoost, and random survival forests, enable the integration of these analytes, facilitating individualized diagnosis, prognosis, and therapy monitoring within the framework of guideline-directed therapy. However, the clinical evaluation of these biomarkers is constrained by several factors, including preanalytical variation, incomplete interlaboratory standardization, absence of reference materials, ambiguous biomarker thresholds, and inconsistent sensitivity and specificity. Additionally, further validation is required across different ethnic groups and in both pediatric and adult populations. Therefore, traditional markers of urinary involvement such as albuminuria, proteinuria, hematuria, and estimated glomerular filtration rate (eGFR) may need to be combined with multi-omics markers for better prognostic classification. These biomarkers can only meaningfully complement renal biopsy in routine laboratory use if standardized International Federation of Clinical Chemistry (IFCC)-traceable assays are used and serial testing algorithms are harmonized.