When should cystatin C (Cystatin C) be used instead of estimated Glomerular Filtration Rate (eGFR) to assess kidney function?

When to Use Cystatin C Instead of eGFR

Use cystatin C-based eGFR (eGFRcr-cys) when creatinine-based eGFR is expected to be inaccurate or when more precise kidney function assessment is needed for critical clinical decisions such as CKD diagnosis, staging, or drug dosing. 1

Primary Clinical Algorithm

The KDIGO 2024 guidelines establish a stepwise approach 1:

• Start with creatinine-based eGFR (eGFRcr) as the initial test for all patients 1
• Add cystatin C measurement when eGFRcr is suspected to be inaccurate or when clinical decisions require greater accuracy 1
• Calculate eGFRcr-cys (combined creatinine-cystatin C equation) as it consistently outperforms either marker alone 1, 2

Specific Clinical Situations Requiring Cystatin C

Extremes of Muscle Mass

• Reduced muscle mass: Elderly patients, malnutrition, muscle wasting diseases, amputees, paralysis 1
• Increased muscle mass: Bodybuilders, athletes 1
• In these populations without comorbid illness, eGFRcys alone may be appropriate; with comorbid illness, use eGFRcr-cys 1

Dietary Factors Affecting Creatinine

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

Chronic Illness States

Use eGFRcr-cys in patients with 1:

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

These conditions affect both creatinine and cystatin C non-GFR determinants, making the combined equation most accurate 1.

Medication Effects

• Drugs decreasing tubular secretion (trimethoprim, cimetidine, cobicistat) 1
• Broad-spectrum antibiotics that decrease extrarenal creatinine elimination 1
• Anabolic steroids or hormone therapy (effect on cystatin C unknown) 1

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:

• If eGFRcys or eGFRcr-cys ≥60 mL/min/1.73 m², CKD diagnosis is not confirmed 1, 2
• This prevents misclassification in the borderline range where creatinine-based estimates are least accurate 2

Why the Combined Equation (eGFRcr-cys) is Superior

The combined creatinine-cystatin C equation demonstrates the highest accuracy across all patient populations 1, 2:

• Improved precision compared to either marker alone 2
• Better risk stratification for mortality and cardiovascular events 3, 4
• More accurate for medication dosing decisions 1, 2

Key Advantages of Cystatin C Over Creatinine

• Independent of muscle mass, age, sex, and diet 2, 3
• Produced at constant rate by all nucleated cells 5
• Fewer non-GFR determinants than creatinine 3
• Detects early kidney dysfunction earlier: cystatin C rises when GFR falls to 88 mL/min/1.73 m², while creatinine doesn't rise until GFR reaches 75 mL/min/1.73 m² 5
• Diagnostic accuracy of 90% for discriminating normal from reduced GFR, compared to 77% for creatinine 2

Important Limitations and Caveats

Sources of Error in Cystatin C-Based Estimates

Be aware that eGFRcr-cys may be inaccurate in 1, 2:

• Very low muscle mass (consider eGFRcys alone instead) 1
• Very high levels of inflammation 1, 2
• High catabolic states 1
• Exogenous steroid use 1, 2
• Thyroid dysfunction: hypothyroidism increases cystatin C; hyperthyroidism decreases it 2

When to Use eGFRcys Alone vs. eGFRcr-cys

Use eGFRcys alone (without creatinine) in otherwise healthy individuals with 1:

• Isolated reduction in muscle mass
• Isolated increase in muscle mass
• Medications affecting creatinine secretion or extrarenal elimination

Use eGFRcr-cys (combined equation) when 1:

• Comorbid illnesses are present
• Most accurate assessment is needed
• Clinical decision-making requires highest precision

Practical Implementation

Laboratory Standards

• Cystatin C assays must use calibration traceable to international standard reference material 1
• Report serum cystatin C rounded to nearest 0.01 mg/L 1
• Report eGFRcys and eGFRcr-cys rounded to nearest whole number in mL/min/1.73 m² 1

Clinical Decision Points

Use cystatin C for critical decisions involving 1, 2:

• CKD diagnosis and staging
• Medication dosing (especially nephrotoxic drugs)
• Timing of dialysis initiation
• Preemptive kidney transplant listing
• Risk stratification for cardiovascular events

Cost-Effectiveness Consideration

While the Canadian Society of Nephrology noted in 2015 that widespread cystatin C use lacked cost-effectiveness data 1, the KDIGO 2024 guidelines now strongly recommend its use in specific clinical situations where accuracy impacts outcomes 1. The key is selective, not universal, application in populations where creatinine-based estimates are known to be unreliable 1.

Common Pitfalls to Avoid

• Don't rely on cystatin C concentration alone—always use it in an eGFR equation 1
• Don't ignore clinical context—consider inflammation, thyroid disease, and steroid use when interpreting results 2
• Don't use creatinine-based eGFR for medication dosing in patients with altered muscle mass—use eGFRcr-cys instead 2
• Don't assume CKD is present with borderline eGFRcr without confirmatory cystatin C testing 1, 2