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Updated: Aug 18, 2025

Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Mendelian randomization study supports the causal association between serum cystatin C and risk of diabetic
Baiyu Feng1, Yu Lu2, Lin Ye1
1Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China.
Insights
Cystatin C is a risk factor for diabetic nephropathy, independent of BMI and SBP. Targeting cystatin C may offer a potential therapy for diabetic kidney disease.
Area of Science:
- Biochemistry
- Genetics
- Nephrology
Background:
- Cystatin C, a cysteine protease inhibitor, is used to estimate glomerular filtration rate.
- The causal link between cystatin C and diabetic nephropathy is not fully understood.
Purpose of the Study:
- To investigate the causal effect of cystatin C on diabetic nephropathy using Mendelian randomization.
- To assess the mediation effects of BMI and SBP on this relationship.
Main Methods:
- Mendelian randomization (MR) analysis was employed.
- 234 genetic variants served as instrumental variables for cystatin C.
- Multivariable MR (MVMR) and two-step MR were used to assess stability and mediation.
Main Results:
- Cystatin C showed a causal association with diabetic nephropathy (IVW OR: 1.36).
- This causal effect persisted after adjusting for BMI and SBP (OR: 1.17).
- BMI was identified as a potential mediator.
Conclusions:
- Cystatin C is an independent risk factor for diabetic nephropathy in diabetic patients.
- Further research is needed to elucidate mechanisms and explore cystatin C-targeted therapies.
Aims:
Cystatin C, an inhibitor of cysteine protease, has been used as a biomarker for estimating glomerular filtration rate. However, the causal relation between cystatin C and diabetic nephropathy remains uncertain.
Methods:
We assessed the causal effect of cystatin C together with other five serum biomarkers including KIM-1, GDF-15, TBIL, uric acid, and Scr on diabetic nephropathy by Mendelian randomization (MR) analysis. 234 genetic variants were selected as instrumental variables to evaluate the causal effect of cystatin C (NGWAS=361194) on diabetic nephropathy (Ncase/Ncontrol up to 3283/210463). Multivariable MR (MVMR) was performed to assess the stability of cystatin C's causal relationship. Two-step MR was used to assess the mediation effect of BMI and SBP.
Results:
Among the six serum biomarkers, only cystatin C causally associated with diabetic nephropathy (IVW OR: 1.36, 95%CI [1.15, 1.61]). After adjusting for the potential confounders BMI and SBP, cystatin C maintained its causal effect on the DN (OR: 1.17, 95%CI [1.02, 1.33]), which means that the risk of DN increased by 17% with an approximate 1 standard deviation (SD) increment of serum cystatin C level. Two-step MR results indicated that BMI might mediate the causal effect of cystatin C on diabetic nephropathy.
Interpretation:
Our findings discovered that cystatin C was a risk factor for diabetic nephropathy independent of BMI and SBP in diabetes mellitus patients. Future research is required to illustrate the underlying mechanism and prove targeting circulating cystatin C could be a potential therapy method.
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