Biomarkers of Kidney Function: Cystatin C

Optimal Takeaways

Cystatin C (cysC) is a small protein found in all body fluids and tissues; it belongs to the cystatin family of protease inhibitors. These inhibitors help prevent excessive proteolysis and tissue damage that can lead to chronic disease and help fight microbial infections. CysC is a reliable marker of kidney function, with elevated levels being associated with renal and cardiovascular disease risk. Levels of cysC are unaffected by protein intake, muscle mass, diet, gender, or inflammation, making it a preferred marker for detecting early changes in kidney function.

Elevated levels are associated with arterial stiffness, cardiovascular disease, stroke, neurodegenerative disease, kidney dysfunction, hyperthyroidism, lupus, and all-cause mortality. Lower levels may be seen with hypothyroidism.

Standard Range: 0.5 – 1.00 mg/L

The ODX Range: 0.62 – 0.90 mg/L

Low cystatin C may be seen with hypothyroidism (El-Metwally 2017) but are also suggestive of decreased risk of renal and cardiovascular disease.

High cystatin C is associated with preclinical renal dysfunction, cardiovascular disease (Pagana 2021), chronic kidney disease (Bevc 2019), oxidative stress with acute kidney injury (Dhama 2019), all-cause mortality (Shen 2019), acute cerebral infarction, large artery atherosclerosis (Dong 2019), vascular endothelial injury in active systemic lupus erythematosus (Gao 2018), early-stage atherosclerosis, arterial wall elasticity (Kaneko 2018), aortic arterial stiffness (Su 2018), heart failure, CVD mortality (Ho 2018), neurological and neurodegenerative disorders (Amin 2020), ischemic and hemorrhagic stroke (Shah 2009), venous thromboembolism (Brodin 2012), and hyperthyroidism (El-Metwally 2017).

Overview

Cystatin C (cysC) is a small protein found in all body fluids and tissues. It belongs to the cystatin family of protease inhibitors that prevent excess proteolysis caused by microbial proteases or endogenous proteases released by dying or diseased cells. Although associated with various pathological states, cystatins play a protective role by preventing irreversible tissue damage that can lead to chronic disease and inhibiting bacterial and viral replication. Cystatin C inhibits coronavirus replication and may help control metastases. Serum cysC is a marker of kidney function and elevated levels are associated with renal and cardiovascular disease risk (Shah 2009

Unlike creatinine, cysC is filtered out of the kidneys at a consistent rate and is unaffected by protein intake or muscle mass. An increase in circulating cysC suggests a decrease in glomerular filtration rate (GFR), the rate at which the kidney filters out metabolic waste products (Pagana 2021). Serum creatinine may not increase until renal function has declined by 50% or more (Kar 2018).

Circulating cysC is not significantly affected by gender, diet, inflammation, or liver disease either and may be a better marker of early renal dysfunction, i.e., when the estimated GFR is 60 ml/min/m2 or above, a level at which serum creatinine may not be a sensitive renal marker. However, once the eGFR falls below 60 and kidney disease advances, then serum creatinine and cysC should both be monitored closely (Pandey 2022).

All-cause mortality was significantly increased in a subset of 8,680 middle-aged and elderly subjects with elevated cysC and elevated hs-CRP. The association was evident with each biomarker independently but may be more predictive when combined. The lowest risk of all-cause mortality was observed with a cysC of 0.86 mg/L or below, and the highest risk was evident with a cysC of 1.13 mg/L or above. The hs-CRP level associated with the lowest all-cause mortality was 0.55 mg/L (5.24 nmol/L) or below, while the highest risk was with an hs-CRP of 2.19 mg/L (20.86 nmol/L) or above (Shen 2019).

Cystatin C appears to be a valuable marker for assessing early changes in kidney function in diabetics. A cross-sectional prospective study of 40 type 2 diabetics with a mean age of 52 found that cysC was able to identify a decline in renal function even in participants with normoalbuminuria and a GFR of 90 or above. Mean cysC levels were 0.65 mg/L in the control group; 0.74 in those with normoalbuminuria; 1.07 in those with microalbuminuria; and 3.25 mg/L in those with macroalbuminuria. It would be prudent to monitor cysC closely in those with type diabetes and a cysC level of 0.74 mg/L or above (Elsayed 2019).

CysC may also help detect early atherosclerosis in those with type 2 diabetes. A cross-sectional study of 180 individuals with T2DM and normal carotid intima thickness found that cysC of 0.86 mg/L was significantly associated with negative effects on arterial wall elasticity and early-stage atherosclerosis (Kaneko 2018). Another cross-sectional study of 170 T2DMs found that cysC was independently associated with arterial stiffness and that those with the greatest aortic arterial stiffness had significantly higher serum cysC, blood pressure, triglycerides, BUN, and creatinine. Cystatin C was 0.83 mg/dL in those with the lowest aortic stiffness and 0.99 in those with the highest. Risk increased by 1.369 for each 0.1 mg/dL increase in cysC (Su 2018).

Elevated cysC has also been observed in hyperthyroidism. In one study comprising 87 subjects, median CysC levels were 1.7 in clinical hyperthyroidism, 0.5 in clinical hypothyroidism, and 0.9 in controls (El-Metwally 2017).

References

Amin, Fakhra et al. “Mammalian cystatin and protagonists in brain diseases.” Journal of biomolecular structure & dynamics vol. 38,7 (2020): 2171-2196. doi:10.1080/07391102.2019.1620636

Bevc, Sebastjan et al. “Cystatin C as a predictor of mortality in elderly patients with chronic kidney disease.” The aging male : the official journal of the International Society for the Study of the Aging Male vol. 22,1 (2019): 62-67. doi:10.1080/13685538.2018.1479386

Brodin EE, Braekkan SK, Vik A, Brox J, Hansen JB. Cystatin C is associated with risk of venous thromboembolism in subjects with normal kidney function--the Tromso study. Haematologica. Jul 2012;97(7):1008-1013.

Dhama, Kuldeep et al. “Biomarkers in Stress Related Diseases/Disorders: Diagnostic, Prognostic, and Therapeutic Values.” Frontiers in molecular biosciences vol. 6 91. 18 Oct. 2019, doi:10.3389/fmolb.2019.00091

Dong, Xiaoyu, and Jianfei Nao. “Cystatin C as an index of acute cerebral infraction recurrence: one-year follow-up study.” The International journal of neuroscience vol. 129,1 (2019): 36-41. doi:10.1080/00207454.2018.1503180

El-Metwally, Elham Mohammad, et al. "Level of cystatin C in functional thyroid disorders and its relation to GFR." Comparative Clinical Pathology 26 (2017): 1141-1147.

Elsayed, Mohamed Shawky et al. “Serum cystatin C as an indicator for early detection of diabetic nephropathy in type 2 diabetes mellitus.” Diabetes & metabolic syndrome vol. 13,1 (2019): 374-381. doi:10.1016/j.dsx.2018.08.017

Fernando, Sanduni, and Kevan R Polkinghorne. “Cystatin C: not just a marker of kidney function.” Jornal brasileiro de nefrologia vol. 42,1 (2020): 6-7. doi:10.1590/2175-8239-JBN-2019-0240

Gao, Dong et al. “Correlations of serum cystatin C and hs-CRP with vascular endothelial cell injury in patients with systemic lupus erythematosus.” Panminerva medica vol. 60,4 (2018): 151-155. doi:10.23736/S0031-0808.18.03466-3

Ho, Jennifer E et al. “Protein Biomarkers of Cardiovascular Disease and Mortality in the Community.” Journal of the American Heart Association vol. 7,14 e008108. 13 Jul. 2018, doi:10.1161/JAHA.117.008108

Kaneko, Rei et al. “Serum cystatin C level is associated with carotid arterial wall elasticity in subjects with type 2 diabetes mellitus: A potential marker of early-stage atherosclerosis.” Diabetes research and clinical practice vol. 139 (2018): 43-51. doi:10.1016/j.diabres.2018.02.003

Kar, Sumit et al. “Cystatin C Is a More Reliable Biomarker for Determining eGFR to Support Drug Development Studies.” Journal of clinical pharmacology vol. 58,10 (2018): 1239-1247. doi:10.1002/jcph.1132

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Pandey, Vikas Kumar et al. “Study of Serum Cystatin C and Serum Creatinine in Different Stages of Chronic Kidney Disease Patients.” The Journal of the Association of Physicians of India vol. 70,4 (2022): 11-12.

Shah, Aaliya, and Bilqees Bano. “Cystatins in Health and Diseases.” International journal of peptide research and therapeutics vol. 15,1 (2009): 43. doi:10.1007/s10989-008-9160-1

Shen, Yueping et al. “High-sensitivity C-reactive protein and cystatin C independently and jointly predict all-cause mortality among the middle-aged and elderly Chinese population.” Clinical biochemistry vol. 65 (2019): 7-14. doi:10.1016/j.clinbiochem.2018.12.012

Su, I-Min et al. “Serum cystatin C is independently associated with aortic arterial stiffness in patients with type 2 diabetes.” Clinica chimica acta; international journal of clinical chemistry vol. 480 (2018): 114-118. doi:10.1016/j.cca.2018.02.007