What is the role of Cystin C (Cystatin C) in assessing kidney function and estimating glomerular filtration rate (GFR)?

Role of Cystatin C in Assessing Kidney Function and Estimating GFR

Cystatin C is a valuable biomarker for kidney function assessment that provides more accurate GFR estimation than creatinine alone, especially in specific populations where creatinine may be unreliable, and should be used as a confirmatory test in patients with borderline kidney function. 1, 2

Characteristics of Cystatin C

• 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
• Serum cystatin C can detect kidney dysfunction at an earlier stage than creatinine, with studies showing it begins to increase when GFR falls below 88 mL/min/1.73m², while creatinine only increases when GFR falls below 75 mL/min/1.73m² 3

Clinical Applications

Confirmatory Testing

• KDIGO guidelines recommend measuring cystatin C in adults with eGFRcreat 45–59 mL/min/1.73m² who do not have markers of kidney damage if confirmation of CKD is required 2, 1
• If eGFRcys/eGFRcreat-cys is ≥60 mL/min/1.73m², the diagnosis of CKD is not confirmed 1
• GFR estimation using cystatin C alone or in combination with creatinine improves risk stratification for adverse outcomes 2

Combined Use with Creatinine

• The combination of creatinine and cystatin C (eGFRcr-cys) provides the most accurate GFR estimation and should be used when available 2, 1
• When cystatin C is measured, creatinine should be measured on the same sample to enable calculation of eGFRcr-cys 2
• A model incorporating both cystatin C and serum creatinine was found superior to those utilizing either marker alone to predict clearance of carboplatin in cancer patients 2

Special Populations

• Cystatin C is especially useful in patients with:
  • Low muscle mass or altered muscle metabolism 1
  • Obesity class III 2
  • Liver disease 1
  • Cancer patients receiving nephrotoxic medications 2
  • Children with chronic liver disease 1

Implementation Considerations

Laboratory Standards

• Clinical laboratories should measure serum cystatin C using an assay with calibration traceable to international standard reference materials 2
• Cystatin C concentration should be reported rounded to the nearest 100th of a whole number when expressed as conventional units (mg/L) 2
• Laboratories should ensure precise measurement (coefficient of variation <2.0% for cystatin C) with desirable bias (<3.2% for cystatin C) 2

Limitations

• Despite its advantages, cystatin C assays are not widely available in many countries 1
• Cystatin C testing is more expensive than creatinine, though costs are decreasing 2
• Non-GFR determinants that can affect cystatin C levels include:
  • Thyroid dysfunction 1
  • Inflammation 2
  • Some types of cancer 1

Algorithm for Clinical Use of Cystatin C

1. Initial Assessment: Use creatinine-based eGFR (eGFRcr) for routine screening of kidney function 2

2. When to Add Cystatin C:

   • eGFRcr 45-59 mL/min/1.73m² without albuminuria 2
   • Suspected inaccuracy of creatinine-based estimates (low muscle mass, obesity, etc.) 1
   • Need for more precise GFR estimation for medication dosing 2
   • Risk stratification for cardiovascular events or kidney failure 1

3. Interpretation:

   • If eGFRcys or eGFRcr-cys ≥60 mL/min/1.73m²: CKD not confirmed 1
   • If eGFRcys or eGFRcr-cys <60 mL/min/1.73m²: CKD confirmed 2
   • Discrepancy between eGFRcr and eGFRcys may provide clinical insights about non-GFR determinants 2

4. Follow-up: For confirmed CKD, either marker can be used for monitoring, though consistency in the method is recommended 2

Conclusion

Cystatin C provides significant advantages over creatinine alone for GFR estimation, particularly in specific populations and clinical scenarios. The combination of creatinine and cystatin C offers the most accurate assessment of kidney function and should be utilized when available and clinically indicated.