Why is a cystatin (Cystatin C) lab ordered with an estimated Glomerular Filtration Rate (eGFR)?

Why Cystatin C is Ordered with Estimated GFR

Cystatin C is ordered alongside eGFR to improve accuracy when creatinine-based eGFR is expected to be inaccurate due to non-GFR factors affecting creatinine levels, such as altered muscle mass, extreme body composition, or certain medications—the combined creatinine-cystatin C equation (eGFRcr-cys) provides superior precision and accuracy compared to either marker alone. 1

Primary Clinical Rationale

The KDIGO 2024 guidelines establish a clear algorithmic approach: start with creatinine-based eGFR (eGFRcr) as the initial test, then measure cystatin C when eGFRcr is thought to be inaccurate or when more accurate GFR assessment is needed for critical clinical decisions like CKD diagnosis, staging, or drug dosing. 1

When Creatinine-Based eGFR is Unreliable

Cystatin C should be measured in the following specific situations where creatinine is known to be inaccurate: 1

Body Composition Issues:

• Extremes of muscle mass (very low in malnutrition, sarcopenia, amputation; very high in bodybuilders or athletes) 1
• Obesity class III (BMI >40 kg/m²) 1
• Muscle wasting diseases 1

Dietary Factors:

• Low-protein diets 1
• Ketogenic diets 1
• Vegetarian diets 1
• High-protein diets and creatine supplements 1

Chronic Illness:

• Malnutrition 1
• Cancer 1
• Heart failure 1
• Cirrhosis 1
• Catabolic consuming diseases 1

Medication Effects:

• Drugs that decrease tubular secretion of creatinine 1
• Broad-spectrum antibiotics that decrease extrarenal elimination 1
• Anabolic steroids 1

Superior Performance of Combined Equations

The combined creatinine-cystatin C equation (eGFRcr-cys) consistently outperforms either marker alone. 1 In validation studies, eGFRcr-cys demonstrated:

• Improved precision: interquartile range of difference from measured GFR was 13.4 ml/min/1.73 m² versus 15.4 for creatinine alone and 16.4 for cystatin C alone 2
• Better accuracy: only 8.5% of estimates were >30% different from measured GFR, compared to 12.8% for creatinine and 14.1% for cystatin C 2
• Improved reclassification: in patients with eGFRcr 45-74 ml/min/1.73 m², the combined equation correctly reclassified 16.9% of those initially estimated at 45-59 ml/min/1.73 m² as actually having GFR ≥60 ml/min/1.73 m² 2

Confirmatory Testing Strategy

The KDIGO 2024 guidelines recommend using eGFRcr-cys specifically as a confirmatory test when clinical decision-making depends on accurate GFR assessment. 1 This is particularly important for:

• CKD diagnosis and staging 1
• Drug dosing decisions 1
• Evaluating patients with eGFRcr 45-59 ml/min/1.73 m² without albuminuria 1

The KDOQI commentary emphasizes that when cystatin C is ordered, both eGFRcys and eGFRcr-cys should be reported to give clinicians both values for decision-making. 1

Advantages of Cystatin C Over Creatinine Alone

Cystatin C has fewer non-GFR determinants compared to creatinine: 3, 4

• Independent of muscle mass, age, sex, and diet 1, 5
• Produced at constant rate by all nucleated cells 1
• Not secreted by renal tubules (unlike creatinine which has tubular secretion) 1
• Detects kidney dysfunction earlier than creatinine, particularly in diabetes 5
• Stronger association with mortality and cardiovascular events 3, 4

Important Caveats and Limitations

Sources of error in eGFRcr-cys include: 1

• Very low muscle mass
• Very high levels of inflammation
• High catabolic states
• Exogenous steroid use

Cystatin C can be affected by: 5

• Thyroid dysfunction
• Smoking
• Some types of cancer

Practical considerations: 1, 5

• Cost is higher than creatinine (though increasingly affordable)
• Not widely available in all settings
• Requires assays traceable to international reference standards 1

Clinical Decision Algorithm

Based on KDIGO 2024 guidelines, follow this approach: 1

1. Initial assessment: Use eGFRcr for all patients
2. Consider cystatin C if:
   • eGFRcr expected to be inaccurate (see conditions above)
   • More accurate GFR needed for clinical decisions
   • eGFRcr 45-59 ml/min/1.73 m² without albuminuria
3. Use eGFRcr-cys (not eGFRcys alone) when cystatin C is measured, as it provides the most accurate estimate 1, 6
4. Consider eGFRcys alone only in otherwise healthy populations with isolated muscle mass abnormalities and no comorbid illness 1
5. If even more accuracy needed: Proceed to measured GFR using exogenous filtration markers 1

The combined equation is recommended over cystatin C alone in most clinical scenarios because it leverages the complementary strengths of both biomarkers. 1, 6