What is the role of serum cystatin C in assessing kidney function and managing impaired renal function?

Role of Serum Cystatin C in Assessing Kidney Function

Serum cystatin C is a superior biomarker for detecting early kidney dysfunction and provides more accurate glomerular filtration rate (GFR) estimation than serum creatinine, especially in patients with reduced muscle mass, making it valuable as a confirmatory test for chronic kidney disease (CKD) diagnosis. 1, 2

Advantages of Cystatin C as a Kidney Function Marker

• Cystatin C is a protein from the cystatin superfamily of cysteine proteinase inhibitors expressed in all nucleated cells, produced at a constant rate, not secreted, and catabolized in the tubules without returning to bloodstream 1
• Unlike creatinine, cystatin C is independent of age, sex, and muscle mass, making it particularly valuable in populations where creatinine may be unreliable 1, 2
• Cystatin C shows greater sensitivity (93.4%) than serum creatinine (86.8%) for detecting impaired renal function 2
• It can detect kidney dysfunction at earlier stages, with levels increasing when GFR falls below 88 mL/min/1.73m², while creatinine only increases when GFR falls below 75 mL/min/1.73m² 2
• Cystatin C may detect kidney dysfunction at an earlier stage than creatinine in people with diabetes 1

Clinical Applications and Recommendations

When to Use Cystatin C

• Recommended for confirmatory testing in specific circumstances when eGFR based on serum creatinine is less accurate, such as in individuals with low muscle mass 1
• Suggested for measuring in adults with eGFRcreat 45–59 mL/min/1.73m² who do not have markers of kidney damage if confirmation of CKD is required 1
• If eGFRcys/eGFRcreat-cys is ≥60 mL/min/1.73m², the diagnosis of CKD is not confirmed 1
• Particularly valuable for cancer patients receiving cytotoxic drugs, where cystatin C can improve dose individualization and reduce toxicity risk 1

Reporting and Interpretation

• Clinical laboratories should measure serum cystatin C using an assay with calibration traceable to the international standard reference material 1
• Cystatin C concentration should be reported rounded to the nearest 100th of a whole number when expressed as conventional units (mg/L) 1
• eGFRcys and eGFRcreat-cys should be reported and rounded to the nearest whole number relative to a body surface area of 1.73m² in adults 1
• eGFRcys and eGFRcreat-cys levels less than 60 mL/min/1.73m² should be reported as "decreased" 1

Limitations and Considerations

• Despite its advantages, cystatin C assays are not widely available in many countries, including the U.S. and Canada 1
• Some studies have potential weaknesses, including lack of assay standardization, inadequate sample sizes, and uncertain generalizability of data 1
• The biggest issue is lack of evidence of effectiveness (whether outcomes are improved by more accurate risk stratification) and cost-effectiveness 1
• In kidney transplant recipients, the KDIGO strategy using cystatin C as a confirmatory test for CKD diagnosis does not show added value compared to a strategy based on serum creatinine alone 1

Combined Use with Other Markers

• The National Kidney Foundation and American Society of Nephrology recommend combining filtration markers (creatinine and cystatin C) as this is more accurate and would support better clinical decisions than either marker alone 1
• A model incorporating both cystatin C and serum creatinine into the formula—along with variables related to muscle mass—was found superior to those utilizing either marker alone to predict clearance of carboplatin in cancer patients 1
• For topotecan, a cystatin C-based model was more predictive for drug clearance than creatinine-based models 1

Future Directions

• The 2021 CKD-EPI creatinine equation refit without the race variable is recommended for immediate implementation in all laboratories in the United States 1
• National efforts to facilitate increased, routine, and timely use of cystatin C are recommended, especially to confirm eGFR in adults who are at risk for or have CKD 1
• If ongoing evidence supports acceptable performance, the CKD-EPI eGFR-cystatin C and eGFR creatinine-cystatin C equations refit without race variables should be adopted 1

In clinical practice, while serum creatinine remains the standard first-line test for kidney function assessment, cystatin C provides valuable complementary information, particularly for early detection of kidney dysfunction and in populations where creatinine-based estimates may be inaccurate 3.