Combined assessment of serum netrin-1 and GDF-15 across albuminuria stages in type 2 diabetes

Abstract

Objective: The urinary albumin-to-creatinine ratio (uACR) has limited sensitivity for early structural changes in diabetic kidney disease (DKD), prompting interest in novel circulating biomarkers. This cross-sectional study evaluated the combined diagnostic association of serum Netrin-1 and Growth Differentiation Factor-15 (GDF-15) across albuminuria stages in type 2 diabetes mellitus (T2DM).

Methods: Sixty T2DM patients (stratified by albuminuria: normo-, micro-, and macroalbuminuria, n=20 each) and 60 age- and BMI-matched healthy controls were enrolled. Serum Netrin-1 and GDF-15 were quantified by sandwich ELISA. Estimated glomerular filtration rate (eGFR) was calculated using the race-free CKD-EPI 2021 equation. ROC analysis and multivariable logistic regression were performed.

Results: Netrin-1 and GDF-15 were significantly elevated in T2DM versus controls (p=0.004 and p=0.001, respectively). Netrin-1 peaked in microalbuminuria (495.2±102.7 pg/mL) while GDF-15 was highest in macroalbuminuria (406.6±106.8 ng/L; ANOVA p=0.020 and p=0.041). Single-marker AUCs: Netrin-1 0.725 (95%CI:0.635-0.816), GDF-15 0.708 (95%CI:0.615-0.800); combined model AUC 0.743 (95%CI:0.655-0.831; p=0.032 vs GDF-15 alone). In adjusted analysis, only eGFR (aOR=0.945 per mL/min/1.73m², p<0.001) and BMI (aOR=1.195 per kg/m², p=0.023) independently predicted T2DM status; biomarker associations attenuated to non-significance.

Conclusion: Serum Netrin-1 and GDF-15 show stage-specific patterns across albuminuria in T2DM but provide only modest incremental diagnostic value over conventional renal indices. These findings are hypothesis-generating; longitudinal studies with hard renal endpoints are required to establish clinical utility.