Author: Gao JieUnit: Shanxi Bethune Hospital Laboratory
Serum cystatin C (CysC), also known as cysteine protease inhibitor C, is a low molecular weight, non-glycosylated basic protein with a molecular weight of approximately 13kD. Almost all nucleated cells in the body’s tissues can continuously produce CysC at a constant rate.
CysC can freely pass through the glomerular filtration membrane, is completely reabsorbed in the proximal tubules, and is rapidly metabolized and decomposed. CysC does not form complexes with other proteins, and its serum concentration changes are not influenced by inflammation, infection, tumors, or liver function, nor are they related to gender, diet, body surface area, or muscle mass. It is an ideal endogenous marker reflecting changes in GFR.
In 2013, serum CysC was included in the international diagnostic guidelines for chronic kidney disease (CKD). In a landmark trial in 2012, the combined use of CysC and Scr was found to predict eGFR better than using any single biomarker alone. Based on this data, equations for eGFR based on creatinine, cystatin C, and the combination of creatinine-cystatin C were established as part of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)[1]. The formulas based on CysC are less accurate and have lower AUC, Youden index, and specificity compared to those based on Scr, suggesting that the CysC formula may have poor diagnostic efficacy for estimating GFR in adolescents aged 15-18 years[2].Since serum creatinine levels are affected by muscle mass, they decrease in patients with reduced muscle mass; however, serum CysC is not influenced by muscle mass. Based on these characteristics, muscle mass can be further predicted by the serum Scr/CysC levels.One study indicated that after adjusting for confounding factors, the Scr/CysC ratio is a biochemical predictor of skeletal muscle index and average skeletal muscle loss. Additionally, multiple stepwise linear regression analysis further demonstrated that Scr/CysC is an independent predictor of blood sugar levels at 120 minutes and 180 minutes[3].
Image source: LiteratureAdditionally, some scholars have indicated that Scr/Cys may serve as a predictive factor for sarcopenia complications in chronic obstructive pulmonary disease[4].
Image source: Literature
Research on CysC levels in patients with type 2 diabetes (T2DM) accompanied by lower extremity atherosclerotic occlusive disease (LEASOD) shows that higher serum CysC levels correlate with more severe lower limb atherosclerotic occlusion and can serve as an important serum indicator for monitoring the severity of T2DM combined with LEASOD. CysC may mediate atherosclerosis by modulating inflammatory factors and cytokine-induced inflammatory responses. Furthermore, CysC can inhibit low-density lipoprotein oxidation-induced vascular smooth muscle cell apoptosis, stabilize plaques, and consequently lead to lower extremity atherosclerotic occlusion[5].Moreover, studies on CysC levels in patients with coronary heart disease have found that as the number of coronary artery lesions increases, CysC levels also rise. CysC may participate in atherosclerosis by affecting extracellular matrix, vascular wall remodeling, inflammatory responses, and other processes[6]. High expression of CysC can affect the prognosis and survival of patients with chronic heart failure[7].
Image source: LiteratureDue to the similarity between the glomerular vascular network in the kidneys and small blood vessels in the brain, it is speculated that CysC plays a key role in various cerebrovascular diseases[8].The four main mechanisms of CysC in various cerebrovascular diseases include:
- CysC Leu-68-Gln(L68Q) variant and wild-type CysC protein co-aggregating with amyloid beta (Aβ)
- Disruption of the balance between CysC and related cysteine proteases
- Role of CysC as an inflammatory inducer
- CysC’s ability to induce autophagy
In summary, CysC can serve not only as a marker for chronic glomerular injury but also to predict the risk of vascular injury diseases.[References]
[1]Teaford HR, Barreto JN, Vollmer KJ, Rule AD, Barreto EF. Cystatin C: A Primer for Pharmacists. Pharmacy (Basel). 2020 Mar 9;8(1):35. doi: 10.3390/pharmacy8010035. PMID: 32182861; PMCID: PMC7151673.
[2]Kuan Qianhui, Gao Chunlin, Zhu Hong, et al. Comparison of Different Estimation Equations of Glomerular Filtration Rate in Children with Chronic Kidney Disease Aged 15 to 18 Years. Journal of Clinical Pediatrics, 2022, 40(12):905-911.
[3]Yang Q, Zhang M, Sun P, Li Y, Xu H, Wang K, Shen H, Ban B, Liu F. Cre/CysC ratio may predict muscle composition and is associated with glucose disposal ability and macrovascular disease in patients with type 2 diabetes. BMJ Open Diabetes Res Care. 2021 Nov;9(2):e002430. doi: 10.1136/bmjdrc-2021-002430. PMID: 34732398; PMCID: PMC8572382.
[4]Hirai K, Tanaka A, Homma T, Goto Y, Akimoto K, Uno T, Yoshitaka U, Miyata Y, Inoue H, Ohta S, Suzuki S, Sagara H. Serum creatinine/cystatin C ratio as a surrogate marker for sarcopenia in patients with chronic obstructive pulmonary disease. Clin Nutr. 2021 Mar;40(3):1274-1280. doi: 10.1016/j.clnu.2020.08.010. Epub 2020 Aug 19. PMID: 32863062.
[5]Feng F, Chen Y, Wang G, Huang P, Zhu Q, Zhou B. Correlation of Serum CysC, IMA, and LP-PLA2 Levels With Type 2 Diabetes Mellitus Patients With Lower Extremity Atherosclerotic Occlusive Disease. Front Surg. 2022 Mar 9;9:846470. doi: 10.3389/fsurg.2022.846470. PMID: 35356504; PMCID: PMC8959309.
[6]Shen C, Wang J, Tu S. Effects of Serum LDL-C, CysC, and D-D in Patients with Coronary Atherosclerotic Heart Disease. Comput Intell Neurosci. 2022 Jun 28;2022:5771960. doi: 10.1155/2022/5771960. PMID: 35800677; PMCID: PMC9256368.
[7]Ma Y, Zhu D, Chen X, Li B, Zhu J. Analysis of the Application Value of Echocardiography Combined with CK-MB, Alb, and CysC in the Prognosis Assessment of Patients with Chronic HF. Contrast Media Mol Imaging. 2022 Aug 30;2022:3986646. doi: 10.1155/2022/3986646. PMID: 36110978; PMCID: PMC9448626.
[8]Zhang Y, Sun L. Cystatin C in Cerebrovascular Disorders. Curr Neurovasc Res. 2017;14(4):406-414. doi: 10.2174/1567202614666171116102504. PMID: 29149834
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