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. 2026 Jan 12;24(1):161.
doi: 10.1186/s12967-025-07552-6.

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

Xiaosi Chen #  1   2 , Weichen Yuan #  1   2 , Yiyun Zeng  1   2 , Hanyu Wu  1   2 , Linghui Pi  1   2 , Yang Yang  1   2 , Xinming Gu  1   2 , Xinyuan Zhang  3   4
Affiliations

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

Xiaosi Chen et al. J Transl Med. .

Abstract

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.

Keywords: Biomarkers; Cystatin C; Diabetic Retinopathy; Diabetic kidney disease; Genetic Predisposition to Disease.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study protocol was approved by the Ethics Committee of Beijing Tongren Hospital, Capital Medical University (TRECKY2020-111), adhering to the Declaration of Helsinki, with written informed consent obtained from all participants. Consent for publication: Not applicable. Authors’ information: Not applicable. Footnotes: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of the study methodology. This study used a nested case-control design (a) with Mendelian randomization (MR) analysis (b). ACR urinary albumin-to-creatinine ratio, CKD chronic kidney disease, CysC cystatin C, eGFR estimated glomerular filtration rate (CKD-EPI 2021 equations using Scr, CysC, or both), eGFRabdiff absolute eGFR difference (eGFRCysC - eGFRScr), eGFRrediff relative eGFR difference (eGFRCysC/eGFRScr), GWAS genome-wide association study, IVW inverse variance weighted, MR Mendelian randomization, NC normal control, NPDR non-proliferative diabetic retinopathy, PDR proliferative diabetic retinopathy, ROC receiver operating characteristic, Scr serum creatinine, SNP single nucleotide polymorphism, T2DM type 2 diabetes mellitus, Ucr urinary creatinine, UK United Kingdom, UMA urinary microalbumin
Fig. 2
Fig. 2
ROC curve analysis of the renal biomarkers in normal, DM, NPDR, and PDR groups
Fig. 3
Fig. 3
Forest plot of mendelian randomization analyses for renal biomarkers in DM and DR cohorts. *statistically significant: p < 0.05. 95% ci 95% confidence interval, DM diabetes mellitus, DR diabetic retinopathy, eGFR estimated glomerular filtration rate (CKD-EPI 2021 equations using Scr or CysC), IVW-RE inverse-variance weighted random effects, NPDR non-proliferative diabetic retinopathy, or odds ratio, PDR proliferative diabetic retinopathy, SNPs single nucleotide polymorphisms, WMMR weighted median Mendelian randomization
Fig. 4
Fig. 4
CysC in the pathogenesis of diabetic retinopathy: exploring the renal-retinal axis. CysC cystatin C, DM diabetes mellitus, NPDR non-proliferative diabetic retinopathy, PDR proliferative diabetic retinopathy, DR diabetic retinopathy, eGFR estimated glomerular filtration rate, IBRB inner blood-retinal barrier, OBRB outer blood-retinal barrier, RPE retinal pigment epithelium, VEGF vascular endothelial growth factor
See this image and copyright information in PMC

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