Serum cystatin C as a biomarker for diabetic retinopathy and its role in diabetic retinopathy-diabetic kidney disease comorbidity

To investigate whether serum cystatin C (CysC) can serve as a biomarker for diabetic retinopathy (DR), and explore the comorbidity between DR and diabetic kidney disease (DKD). This study used a nested case-control design with Mendelian randomization (MR) analysis. A total of 128 type 2 diabetic patients were categorized into no DR (DM), non-proliferative DR (NPDR), and proliferative DR (PDR) groups with age- and sex- matched controls. Biochemical and renal biomarkers were assessed, including the absolute difference (abdiff) eGFR abdiff (eGFR CysC -eGFR Scr ) and relative difference (rediff) eGFR rediff (eGFR CysC /eGFR Scr ). Instrumental variables for renal function and DR subtypes were selected from the UK Biobank and FinnGen consortium. Genetic associations were primarily derived using the inverse-variance weighted approach, with sensitivity analyses and multivariable MR adjusting for confounders. Multivariable logistic analysis demonstrated that CysC levels were significantly associated with DM patients (OR=13.22, P =0.001) compared to healthy controls, and with NPDR patients ( P =0.016) compared to DM patients, after adjusting for confounding variables; while eGFR CysC was a protective factor for DM ( P DM vs. Normal =0.002); NPDR ( P NPDR vs. DM =0.025) and PDR ( P PDR vs. NPDR =0.013). Receiver operating characteristic (ROC) analysis confirmed the superior diagnostic efficacy of CysC and eGFR CysC for both DM and NPDR, eGFR rediff and urine Albumin-to-Creatinine Ratio (UACR) had superior predictive value for PDR compared to other renal biomarkers. Each standard deviation increases in serum CysC levels elevated the risks of DM ( P =0.011), NPDR ( P =0.00067), and PDR ( P =0.042) by MR analysis. The renal dysfunction biomarkers CysC and eGFR CysC were identified as key biomarkers for NPDR, while eGFR rediff and UACR were predictive for PDR. MR analyses confirmed CysC as a strong risk factor for DR susceptibility, particularly in the early stages.