Association of Serum Cystatin C with Creatinine-Defined Mildly Reduced eGFR: A Cross-Sectional Analysis of eGFR G2 Versus G1 Categories

Background: Mild reductions in renal function within the estimated glomerular filtration rate (eGFR) range of 60–89 mL/min/1.73 m2 may not be detected by routine creatinine-based screening, yet early recognition of subclinical nephropathy at this stage is essential for preventing irreversible renal damage. This study examined the association of serum cystatin C (CysC) with creatinine-defined mildly reduced eGFR and evaluated whether CysC improved discrimination between creatinine-based eGFR G2 and G1 categories.Methods: We analyzed 422 participants in a cross-sectional study. Participants were classified into an occult renal function decline group (eGFR 60–89 mL/min/1.73 m2, n = 218) and a healthy control group (eGFR ≥90 mL/min/1.73 m2, n = 204). A multivariable discrimination model was built by integrating CysC with conventional risk factors including age, sex, glucose, low-density lipoprotein cholesterol (LDL-C), and high-sensitivity C-reactive protein (hs-CRP). Restricted Cubic Splines (RCS), Net Reclassification Improvement (NRI), and Decision Curve Analysis were employed to assess the shape of the association and the added clinical value of CysC.Results: The Joint Model incorporating standardized CysC demonstrated superior discrimination (Area Under the Curve (AUC) 0.892, 95% CI 0.862–0.922) compared to the base model relying on traditional risk factors (AUC 0.725, 95% CI 0.677–0.773). RCS analysis suggested a non-linear inflection point at 1.03 mg/L. The addition of CysC yielded a substantial continuous NRI of 1.0691 (p < 0.001), improving reclassification between the two creatinine-defined eGFR categories. A nomogram was constructed to facilitate clinical translation.Conclusion: Serum CysC was strongly associated with creatinine-defined mildly reduced eGFR and improved discrimination between creatinine-based eGFR G2 and G1 categories, in this cross-sectional cohort. These findings should be interpreted as evidence of association and classification performance rather than proof that CysC independently predicts true occult renal function decline. Prospective studies using measured GFR and longitudinal renal outcomes are needed for confirmation.