Urinary nephrin and podocalyxin levels in preeclampsia: A systematic review and meta-analysis

Preeclampsia (PE) is a major hypertensive disorder characterized by systemic endothelial dysfunction and renal involvement. Although traditionally linked to glomerular endotheliosis, evidence suggests that podocyte injury is central to its pathophysiology. This systematic review and meta-analysis compares urinary levels of nephrin (NEP) and podocalyxin (PDC) between patients with PE and normotensive controls during the second half of gestation. Following PRISMA guidelines, 12 observational studies (421 PE cases and 415 controls) were included. A random-effects meta-analysis using Standardized Mean Differences (SMD) was performed to aggregate the heterogeneous biomarker metrics. Both urinary NEP and PDC were significantly elevated in patients with PE compared to normotensive controls during the second half of gestation, displaying robust pooled effect sizes (NEP: SMD = 2.38; 95% CI: 1.62-3.14; p < 0.00001; PDC: SMD = 3.07; 95% CI: 1.66-4.47; p < 0.0001). However, extreme statistical heterogeneity was observed (I² = 93% and I² = 95% for NEP and PDC, respectively), reflecting substantial pre-analytical and analytical diversity across commercial assays. Furthermore, diagnostic performance data remain scarce and controversial. While some studies report an Area Under the Curve (AUC) above 0.95, others report a specificity as low as 32%. This inconsistency, coupled with a lack of standardized cut-off points and Receiver Operating Characteristic (ROC) curves in most reports, makes it impossible to establish a universal diagnostic threshold. In conclusion, while urinary NEP and PDC confirm that PE involves significant podocytopathy, the current evidence is insufficient to support their use as reliable clinical tools. These findings underscore the urgent need for standardized laboratory protocols to determine their true diagnostic value.