Urinary ANGPTL3: A Novel Noninvasive Biomarker for Podocyte Injury in Pediatric Glomerular Diseases

Background: Podocyte injury is the pathological basis of various glomerular diseases, but noninvasive tools for assessing podocyte injury are still lacking at present. Angiopoietin-like protein 3 (ANGPTL3) has been proven to be pathologically elevated in glomerular diseases and associated with podocyte injury. The aim of this study was to evaluate the clinical utility of the urinary ANGPTL3-to-creatinine ratio (ANGPTL3/Cre) as a noninvasive biomarker for assessing podocyte injury in children with glomerular diseases. Methods: Renal ANGPTL3 expression was first examined in tissues from pediatric patients with podocyte injury (n=25) and controls (n=5), correlating it with established histological markers of podocyte injury and with urinary ANGPTL3 levels. Pediatric patients aged 1–18 years with glomerular diseases and healthy controls were subsequently enrolled and divided into a test set (n=346) and a validation set (n=150). ANGPTL3 levels in serum and urine were measured. Diagnostic performance was assessed using receiver operating characteristic (ROC) curves. Associations with podocyte injury and improvements in risk stratification were evaluated by logistic regression and reclassification improvement (NRI/IDI) analyses, respectively. Results: Renal ANGPTL3 expression correlated negatively with podocyte injury markers P57Kip2 ( r = -0.55, P = 0.002) and synaptopodin ( r = -0.37, P = 0.04) and positively with urinary ANGPTL3/Cre ( r = 0.64, P < 0.001). Urinary ANGPTL3/Cre was significantly elevated in patients with podocyte injury and served as an independent risk factor for this condition (OR = 7.66, 95% CI: 2.27-25.84, P = 0.001). It demonstrated superior diagnostic performance (area under the curve, AUC = 0.90 in both sets) compared to serum ANGPTL3 or traditional biomarkers. When combined with clinical variables, the AUC improved to 0.95 (95% CI: 0.93-0.97) with enhanced risk reclassification. High diagnostic efficacy (AUC = 0.88/0.86) was maintained even in patients with normal protein excretion. Conclusion: Urinary ANGPTL3/Cre is a reliable, noninvasive biomarker for podocyte injury in pediatric glomerular diseases. It effectively identifies subclinical injury in patients with normal protein excretion, showing strong potential for early screening and longitudinal monitoring.