Urinary ANGPTL3: a novel noninvasive biomarker for podocyte injury in pediatric glomerular diseases

Podocyte injury constitutes the pathological basis of various glomerular diseases; however noninvasive tools for assessing podocyte injury remain limited. Angiopoietin-like protein 3 (ANGPTL3) has been shown to be pathologically elevated in glomerular diseases and is associated with podocyte injury. This study aimed 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. Renal ANGPTL3 expression was first examined in tissue samples from pediatric patients with podocyte injury (n = 25) and controls (n = 5), and its associations with established histological markers of podocyte injury and urinary ANGPTL3 levels were analyzed. Subsequently, pediatric patients aged 1–18 years with glomerular diseases complicated with podocyte injury and healthy controls were 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 evaluated using receiver operating characteristic (ROC) curves. Associations with podocyte injury and improvements in risk stratification were assessed using logistic regression and reclassification improvement (NRI/IDI) analyses, respectively. Renal ANGPTL3 expression correlated negatively with the podocyte injury markers P57Kip2 (r = -0.55, P = 0.002) and Synaptopodin (r = -0.37, P = 0.04), while correlating 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 for podocyte injury. When combined with clinical variables, the AUC improved to 0.95 (95% CI: 0.93–0.97) with enhanced risk reclassification for podocyte injury. High diagnostic efficacy (AUC = 0.88/0.86) was maintained even in patients with normal protein excretion after clinical treatment. Urinary ANGPTL3/Cre is a reliable, noninvasive biomarker for podocyte injury in pediatric glomerular diseases. Notably, it may have potential value in identifying subclinical podocyte injury in patients with normal protein excretion, thereby supporting its robust potential for longitudinal monitoring and risk stratification in this patient population. • Urinary ANGPTL3 is a stable, noninvasive indicator closely associated with the severity of podocyte injury. • Urinary ANGPTL3 demonstrates superior diagnostic accuracy and improves risk stratification for podocyte injury compared with conventional biomarkers. • Urinary ANGPTL3 shows potential utility in identifying residual podocyte involvement in patients with normalized proteinuria.