What is the significance of the cystatin C (Cysteine Proteinase Inhibitor C) lab test in assessing kidney function?

The Significance of Cystatin C in Assessing Kidney Function

Cystatin C is a valuable biomarker that provides more accurate assessment of kidney function than creatinine alone, particularly for early detection of kidney dysfunction and risk stratification for cardiovascular and kidney outcomes. 1, 2

Key Advantages 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 largely independent of age, sex, and muscle mass, making it particularly valuable in populations where creatinine may be unreliable (elderly, low muscle mass, children) 1, 3
• Cystatin C can detect kidney dysfunction at an earlier stage than creatinine in people with diabetes and other conditions 2, 1
• Large discrepancies between creatinine-based eGFR and cystatin C-based eGFR (eGFRdiff) are observed in at least 1 in 4 people, particularly among vulnerable populations 3

Clinical Applications in Kidney Function Assessment

• The 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
• Combining filtration markers (creatinine and cystatin C) provides more accurate GFR estimation and better clinical decisions than either marker alone 2, 1
• In a meta-analysis of 90,750 participants across 16 cohort studies, 23% of persons with eGFRcreat 60–74 ml/min/1.73 m² had eGFRcys <60 ml/min/1.73 m², indicating potential underdiagnosis of CKD when using creatinine alone 2

Risk Stratification and Prognostic Value

• Cystatin C markedly strengthens the association between eGFR and cardiovascular events, kidney failure, and death 2, 4
• Elevated cystatin C levels independently predict major cardiovascular events, development of chronic kidney disease, and cardiovascular and all-cause mortality 4
• Cystatin C has been found to be linearly associated with mortality, cardiovascular mortality, and heart failure risk, whereas creatinine predicted increased risk only in subjects with the worst kidney function 5
• A large eGFRdiff, where eGFRcys is lower than eGFRcr, is associated with medication-associated adverse events, acute kidney injury, cardiovascular disease, kidney failure and all-cause mortality 3

Practical Implementation

• Clinical laboratories should measure serum cystatin C using an assay with calibration traceable to the international standard reference material 1
• The National Kidney Foundation and American Society of Nephrology recommend national efforts to facilitate increased, routine, and timely use of cystatin C, especially to confirm eGFR in adults who are at risk for or have CKD 2
• The 2021 CKD-EPI creatinine equation refit without the race variable is recommended for immediate implementation in all laboratories in the United States 2
• Cystatin C may not be required for routine monitoring after the diagnosis of CKD is made 2

Limitations and Considerations

• Despite its advantages, cystatin C assays are not widely available in many countries, including the U.S. 2, 1
• The cost of testing is higher than creatinine, though the "triple marker" panel of serum creatinine, serum cystatin C, and urine albumin-to-creatinine ratio is considered affordable in high-income settings 2
• Thyroid dysfunction, smoking, and some types of cancer may affect cystatin C levels independently of renal function 1, 5
• In kidney transplant recipients, the KDIGO strategy using cystatin C (alone or combined with creatinine) as a confirmatory test for CKD diagnosis may not show added value compared to creatinine alone 2

Optimal Use Algorithm

1. Use creatinine-based eGFR (eGFRcr) for initial kidney function screening 2, 1
2. Add cystatin C measurement when:
   • eGFRcr is between 45-59 ml/min/1.73m² without albuminuria 2, 1
   • Patient has conditions affecting creatinine reliability (low muscle mass, extremes of age, etc.) 1, 3
   • More accurate risk stratification is needed for clinical decision-making 2, 4
3. Use combined creatinine-cystatin C equation (eGFRcr-cys) for most accurate GFR estimation 2, 1
4. Consider cystatin C for early detection of kidney dysfunction in high-risk populations like diabetes 2, 1