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Background <p>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).</p> Methods <p>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<sub>abdiff</sub> (eGFR<sub>CysC</sub>-eGFR<sub>Scr</sub>) and relative difference (rediff) eGFR<sub>rediff</sub> (eGFR<sub>CysC</sub>/eGFR<sub>Scr</sub>). 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.</p> Results <p>Multivariable logistic analysis demonstrated that CysC levels were significantly associated with DM patients (OR=13.22, <i>P</i>=0.001) compared to healthy controls, and with NPDR patients (<i>P</i>=0.016) compared to DM patients, after adjusting for confounding variables; while eGFR<sub>CysC</sub> was a protective factor for DM (<i>P</i><sub><i>DM vs. Normal</i></sub>=0.002); NPDR (<i>P</i><sub><i>NPDR vs. DM</i></sub>=0.025) and PDR (<i>P</i><sub><i>PDR vs. NPDR</i></sub>=0.013). Receiver operating characteristic (ROC) analysis confirmed the superior diagnostic efficacy of CysC and eGFR<sub>CysC</sub> for both DM and NPDR, eGFR<sub>rediff</sub> 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 (<i>P</i>=0.011), NPDR (<i>P</i>=0.00067), and PDR (<i>P</i>=0.042) by MR analysis.</p> Conclusions <p>The renal dysfunction biomarkers CysC and eGFR<sub>CysC</sub> were identified as key biomarkers for NPDR, while eGFR<sub>rediff</sub> and UACR were predictive for PDR. MR analyses confirmed CysC as a strong risk factor for DR susceptibility, particularly in the early stages.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月12日

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  • Xiaosi Chen,
  • Weichen Yuan,
  • Yiyun Zeng,
  • Hanyu Wu,
  • Linghui Pi,
  • Yang Yang,
  • Xinming Gu,
  • Xinyuan Zhang

摘要

Background

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).

Methods

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) eGFRabdiff (eGFRCysC-eGFRScr) and relative difference (rediff) eGFRrediff (eGFRCysC/eGFRScr). 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.

Results

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 eGFRCysC was a protective factor for DM (PDM vs. Normal=0.002); NPDR (PNPDR vs. DM=0.025) and PDR (PPDR vs. NPDR=0.013). Receiver operating characteristic (ROC) analysis confirmed the superior diagnostic efficacy of CysC and eGFRCysC for both DM and NPDR, eGFRrediff 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.

Conclusions

The renal dysfunction biomarkers CysC and eGFRCysC were identified as key biomarkers for NPDR, while eGFRrediff and UACR were predictive for PDR. MR analyses confirmed CysC as a strong risk factor for DR susceptibility, particularly in the early stages.