Serum Cystatin C as an Early Predictive Biomarker for Acute Kidney Injury (AKI) in Neonates: A PRISMA-DTA Systematic Review

Background: Acute kidney injury (AKI) affects 12-40% of critically ill newborns which in-creases mortality risk significantly. Current diagnosis relies on serum creatinine, which rises only after substantial renal damage. Early biomarkers enabling timely intervention are urgently needed for this vulnerable population. Serum cystatin C (sCysC) is a candi-date since it is constantly produced by all nucleated cells. Aim: To investigate sCysC diag-nostic performance for early neonatal AKI detection. Methods: This systematic review fol-lowed PRISMA-DTA guidelines and is registered with PROSPERO (CRD420261302574). We searched four major databases for studies measuring sCysC in neonates (0-28 days) using validated assays, with creatinine-based AKI definitions as the reference standard. Studies were categorized by time-related design as either concurrent diagnostic or early predictive accuracy. The risk of bias was assessed using the QUADAS-2. Results: Fifteen studies involving 53,751 neonates were included. sCysC showed strong early predictive accuracy (AUC 0.670-1.000) and identified AKI 24 hours to 4 days earlier than serum cre-atinine. In the largest cohort (52,333 neonates), sCysC achieved 70% sensitivity and 65% specificity for early AKI detection. Other diagnostic studies reported 85-89% sensitivity and 62-75% specificity (AUC 0.844-0.849). Optimal sCysC cut-offs ranged from 1.25 to 2.87 mg/L. Fourteen studies (93%) had a high risk of bias in at least one domain. Conclusion: Serum cystatin C allows earlier detection of neonatal AKI, offering a 1-4-day advantage over current methods and supporting timely intervention. Implementing standardized as-says and population-specific thresholds is essential for clinical use. This time advantage marks a shift toward preventive neonatal nephrology.