Cystatin C: A Biomarker for Kidney Function Assessment
Cystatin C is a low molecular weight protein produced by all nucleated cells that serves as a superior biomarker for estimating glomerular filtration rate (GFR), particularly for detecting early renal impairment and in populations where creatinine-based measurements may be unreliable. 1
Definition and Biological Properties
- Cystatin C is a nonglycosylated basic protein belonging to the cystatin superfamily of cysteine proteinase inhibitors that is produced at a constant rate by all nucleated cells 1, 2
- It is freely filtered by the renal glomeruli and primarily catabolized in the tubules without being secreted or reabsorbed as an intact molecule 2
- Unlike creatinine, cystatin C concentration is independent of age, sex, and muscle mass, making it a more reliable marker of GFR 1, 3
- Normal adult values for cystatin C approach 0.51-0.98 mg/L by 1 year of age 3
Clinical Applications
Kidney Function Assessment
- Cystatin C is recommended for confirming the diagnosis of chronic kidney disease (CKD) in adults with borderline kidney function 3, 1
- The Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggest measuring cystatin C in adults with estimated GFR based on creatinine (eGFRcreat) of 45–59 mL/min/1.73 m² who do not have markers of kidney damage 3, 1
- Cystatin C can detect kidney dysfunction at earlier stages than creatinine, with levels starting to increase when GFR falls below 88 mL/min/1.73 m², whereas creatinine begins to increase only when GFR falls below 75 mL/min/1.73 m² 2
Specific Populations Where Cystatin C Is Particularly Valuable
- Pediatric patients: The revised Schwartz Formula or cystatin C should be used to estimate GFR in children with chronic liver disease 3
- Liver transplant recipients: Cystatin C-based equations have shown superior performance in estimating measured GFR compared to creatinine-based estimations 3
- Cancer patients: Cystatin C may improve dose individualization of cytotoxic drugs to achieve target AUC and reduce toxicity 3
- Patients with low muscle mass: Cystatin C provides more accurate GFR estimates in this population 1
Estimation Equations Using Cystatin C
- Three main equations are recommended by KDIGO 3:
- Cystatin C alone (eGFRcys)
- Creatinine alone (eGFRcreat)
- Combined equation using both markers (eGFRcreat-cys)
- The combined equation (eGFRcreat-cys) generally provides the most accurate GFR estimation 1, 4
- For drug dosing purposes in cancer patients, models incorporating both cystatin C and serum creatinine along with variables related to muscle mass have shown superior performance 3
Advantages Over Traditional Markers
- Greater sensitivity (93.4%) compared to serum creatinine (86.8%) for detecting impaired renal function 2
- Better correlation with adverse outcomes compared to creatinine 4
- More accurate in the "creatinine blind area" (early stages of kidney dysfunction) 5
- Not affected by muscle mass, making it valuable in elderly, pediatric patients, and those with muscle wasting 1, 5
- Provides a more accurate eGFR when used in combination with creatinine 4
Limitations and Considerations
- Cystatin C assays are not widely available in many countries, including the U.S. and Canada 1
- Certain conditions can affect cystatin C levels independently of renal function, including:
- Thyroid dysfunction
- Glucocorticoid use
- Malignancies 5
- Cost-effectiveness remains a concern for widespread implementation 1
- Requires standardized assay calibration traceable to international reference material 1
Future Directions
- National efforts are recommended to facilitate increased, routine, and timely use of cystatin C, especially to confirm eGFR in adults who are at risk for or have CKD 1, 4
- Further research is needed to better understand cystatin C's performance relative to creatinine-based eGFR in diverse populations 4
- Partnerships between clinical stakeholders and laboratories are necessary to promote cystatin C's clinical use and achieve widespread adoption 4