When is ordering cystatin (Cystatin C) GFR (Glomerular Filtration Rate) recommended?

When to Order Cystatin C GFR

Order cystatin C when creatinine-based eGFR is expected to be inaccurate and accurate GFR assessment will impact clinical decision-making, particularly in patients with extremes of muscle mass, obesity class III, malnutrition, or when confirming CKD in patients with eGFRcr 45-59 mL/min/1.73 m² without proteinuria. 1

Primary Clinical Indications

Use the combined creatinine-cystatin C equation (eGFRcr-cys) as confirmatory testing when:

• eGFRcr is 45-59 mL/min/1.73 m² without markers of kidney damage to confirm or exclude CKD diagnosis (if eGFRcr-cys ≥60, CKD is not confirmed) 1
• Critical clinical decisions depend on accurate GFR, including drug dosing (especially nephrotoxic or kidney-cleared chemotherapy), CKD staging, or determining timing for renal replacement therapy 1
• Creatinine-based estimates are unreliable due to non-GFR determinants affecting creatinine generation or secretion 1

Specific Clinical Situations Where Cystatin C Improves Accuracy

Extremes of Muscle Mass

• Very low muscle mass: malnutrition, muscle wasting diseases, elderly patients, amputees 1, 2
• Very high muscle mass: bodybuilders, athletes 1
• In these populations, eGFRcr-cys consistently outperforms creatinine alone 1, 3

Body Composition Abnormalities

• Obesity class III (BMI >40 kg/m²) where creatinine generation is altered 1, 2
• Extreme body sizes where standard equations perform poorly 4

Dietary Factors

• Low-protein diets or ketogenic diets that reduce creatinine generation 1
• Vegetarian diets with minimal meat intake 1
• High-protein diets or creatine supplementation that increase creatinine independent of GFR 1

Chronic Illness States

• Cancer (particularly with high cell turnover) 1, 5
• HIV infection 5
• Heart failure 1
• Cirrhosis (though performance may be variable) 1, 5
• Severe malnutrition 1

Medication Effects

• Drugs that block tubular creatinine secretion (trimethoprim, cimetidine, cobicistat) 1
• Broad-spectrum antibiotics that decrease extrarenal creatinine elimination 1

Algorithmic Approach to GFR Assessment

Step 1: Start with creatinine-based eGFR (eGFRcr) for initial assessment 1

Step 2: Assess whether clinical context suggests eGFRcr inaccuracy:

• Review muscle mass, body composition, diet, medications, and comorbid illness 1
• Consider if eGFRcr is borderline (45-59 mL/min/1.73 m²) without proteinuria 1

Step 3: If eGFRcr expected to be inaccurate AND accurate GFR affects clinical decisions:

• Order cystatin C and calculate eGFRcr-cys 1
• The combined equation provides 89% of estimates within 30% of measured GFR, superior to either marker alone 3

Step 4: If eGFRcr-cys still expected to be inaccurate (very high inflammation, high catabolism, exogenous steroids):

• Consider measured GFR using exogenous filtration markers (iothalamate, iohexol, EDTA) 1

Key Advantages of Cystatin C

• Independent of muscle mass, age, sex, and diet (though small effects of these variables exist) 2, 3
• Superior diagnostic accuracy (90%) compared to creatinine alone (77%) for detecting reduced GFR 2, 6
• Particularly sensitive for detecting mild GFR reduction in early CKD 6, 7
• Fewer non-GFR determinants than creatinine 2

Critical Limitations and Pitfalls

Conditions That Affect Cystatin C Accuracy

• Thyroid dysfunction: hypothyroidism increases cystatin C; hyperthyroidism decreases it 2
• High inflammation states (sepsis, severe infection, autoimmune disease) 1, 2
• High catabolic states (advanced cancer with high turnover) 1
• Exogenous corticosteroid use 1, 2

Common Pitfalls to Avoid

• Do not rely on cystatin C concentration alone—always use a validated eGFR equation 1
• Ensure laboratory uses standardized assays traceable to international reference material 1
• Recognize that even eGFRcr-cys has limitations in extreme clinical states (advanced cirrhosis, critical illness) 1, 5
• Do not assume cystatin C is always superior—in patients without confounding factors, creatinine-based eGFR is adequate and more cost-effective 1, 4

Laboratory Standards

Clinical laboratories measuring cystatin C must: 1

• Use assays calibrated to international standard reference material
• Report eGFR from cystatin C (not just the concentration)
• Specify which equation was used
• Round cystatin C to nearest 0.01 mg/L
• Round eGFR to nearest whole number in mL/min/1.73 m²
• Flag values <60 mL/min/1.73 m² as "decreased"

When NOT to Order Cystatin C

• Routine screening in healthy populations without risk factors 1
• When eGFRcr is clearly normal (>90 mL/min/1.73 m²) and no clinical concerns exist 4
• When results will not change management regardless of the value 1
• In settings with known high inflammation or steroid use where cystatin C will also be inaccurate—proceed directly to measured GFR if precision is critical 1