When should cystatin C be measured and how are its serum levels interpreted for estimating glomerular filtration rate?

Cystatin C Measurement and Interpretation for GFR Estimation

When to Measure Cystatin C

Measure cystatin C when creatinine-based eGFR is expected to be inaccurate or when critical clinical decisions require more precise kidney function assessment, using the combined creatinine-cystatin C equation (eGFRcr-cys) as it consistently outperforms either marker alone. 1, 2

Primary Clinical Algorithm

Start with creatinine-based eGFR (eGFRcr) as the initial test for all patients, then add cystatin C measurement in specific situations where eGFRcr is suspected to be inaccurate or when clinical decisions require greater accuracy. 2, 3

Specific Clinical Situations Requiring Cystatin C Measurement

• Extremes of muscle mass: Measure in patients with reduced muscle mass (elderly, malnutrition, muscle wasting diseases, amputees, paralysis) or increased muscle mass (bodybuilders, athletes). 2, 3

• Dietary factors affecting creatinine: Use in patients on low-protein diets, ketogenic diets, vegetarian diets, high-protein diets, or taking creatine supplements. 2, 3

• Chronic illness states: Measure in patients with cirrhosis, where both creatinine and cystatin C non-GFR determinants are affected. 1, 2

• Obesity class III: Consider measurement in patients with BMI >40 or >35 kg/m² depending on regional definitions. 1, 3

• Confirmatory testing for borderline CKD: Measure cystatin C in adults with eGFRcr 45-59 mL/min/1.73 m² who lack markers of kidney damage to confirm whether CKD is truly present. 1, 2, 3

Critical Clinical Decisions Requiring Cystatin C

• CKD diagnosis and staging 2, 3
• Medication dosing decisions 2, 3
• Timing of dialysis initiation 2
• Preemptive kidney transplant listing 2
• Risk stratification for cardiovascular events 2, 4

How to Interpret Serum Cystatin C Levels

Use the Combined Equation (eGFRcr-cys)

Always calculate eGFRcr-cys (combined creatinine-cystatin C equation) rather than using cystatin C alone, as it demonstrates the highest accuracy across all patient populations with improved precision, better risk stratification for mortality and cardiovascular events, and more accurate medication dosing decisions. 2, 3, 4

The combined equation has correct GFR classification rates of 62% compared to 38% for eGFRcr alone and 45% for eGFRcys alone. 3

Laboratory Reporting Standards

• Serum cystatin C concentration should be reported rounded to the nearest 0.01 mg/L. 1, 2

• eGFRcys and eGFRcr-cys should be reported rounded to the nearest whole number in mL/min/1.73 m². 1, 3

• Assays must use calibration traceable to international standard reference materials with coefficient of variation <2.0% for cystatin C and desirable bias <3.2% compared with reference methodology. 1

• Measure creatinine on the same sample when cystatin C is measured to enable calculation of eGFRcr-cys. 1

Interpretation of Cystatin C Values

• Higher cystatin C levels indicate lower GFR: Decreased GFR is associated with higher levels of cystatin C, as this low-molecular-weight protein is normally removed by glomerular filtration. 1, 5

• Early detection advantage: Serum cystatin C levels start to increase when GFR falls to 88 mL/min/1.73 m², whereas serum creatinine begins to increase only when GFR reaches 75 mL/min/1.73 m². 5

• Diagnostic accuracy: Cystatin C has 90% diagnostic accuracy in discriminating normal from reduced GFR, significantly exceeding creatinine's 77% accuracy. 2, 3

Confirmatory Testing Interpretation

• If eGFRcys or eGFRcr-cys ≥60 mL/min/1.73 m² in a patient with eGFRcr 45-59 mL/min/1.73 m² without markers of kidney damage, CKD diagnosis is not confirmed. 2, 3

• Repeat both creatinine and cystatin C in 3 months to confirm stability and recalculate eGFRcr-cys, as CKD diagnosis requires persistence of reduced eGFR for ≥3 months. 3

Important Limitations and Non-GFR Determinants

Factors That Affect Cystatin C Independent of GFR

• Thyroid dysfunction: Hypothyroidism increases cystatin C levels; hyperthyroidism decreases them. 3, 4, 6

• Inflammation: High levels of inflammation can elevate cystatin C levels. 1, 3, 4

• Exogenous steroid use: Glucocorticoids can affect cystatin C levels. 1, 3, 6

• Malignancies: Some types of cancer can influence cystatin C levels. 4, 6

• High catabolic states: Conditions like tuberculosis, AIDS, hematologic malignancies, and severe skin diseases may affect levels. 1

When eGFRcr-cys May Be Inaccurate

Be aware that eGFRcr-cys may be inaccurate in patients with very low muscle mass, very high levels of inflammation, high catabolic states, or exogenous steroid use. 2, 3

Managing Discordant eGFR Values

When eGFRcys Differs from eGFRcr

• Use the combined equation: When there is discordance between creatinine and cystatin C estimates, use eGFRcr-cys as it demonstrates superior performance. 3

• When eGFRcys is higher than eGFRcr: The creatinine-based estimate is typically underestimating true kidney function, often due to reduced muscle mass, malnutrition, or other non-GFR determinants of creatinine. 3

• For medication dosing: Use the combined eGFRcr-cys value for all medication dosing decisions, as the creatinine-based eGFR may underestimate true kidney function, leading to potential underdosing of renally-cleared medications. 3

Key Advantages of Cystatin C

• Independent of muscle mass, age, sex, and diet. 2, 4, 5

• Fewer non-GFR determinants than creatinine. 2, 3

• Detects early kidney dysfunction earlier than creatinine. 2, 5

• Produced at a constant rate by all nucleated cells. 3, 5, 7

• More accurate estimation of GFR when combined with creatinine in a meta-analysis of patients with cirrhosis. 1