Is cystatin C (Cystatin C) a better estimate of estimated Glomerular Filtration Rate (eGFR) than creatinine?

Is Cystatin C a Better eGFR Estimate Than Creatinine?

The combined creatinine-cystatin C equation (eGFRcr-cys) provides the most accurate GFR estimation and should be the preferred approach when cystatin C is available, while cystatin C alone (eGFRcys) offers minimal advantage over creatinine alone for most clinical purposes. 1, 2

Primary Recommendation: Use Combined Equations

The 2024 KDIGO guidelines establish that combining both filtration markers yields superior accuracy compared to either marker alone, with the combined equation achieving 89% of estimates within 30% of measured GFR versus 85% for creatinine alone and 83% for cystatin C alone 3. When cystatin C is measured, always calculate eGFRcr-cys rather than relying on cystatin C alone. 1, 4

Strategic Use of Cystatin C: A Confirmatory Test, Not a Replacement

The most recent KDIGO 2024 guidelines recommend a stepwise approach rather than routine cystatin C use 1:

• Start with creatinine-based eGFR (eGFRcr) for initial assessment in all patients 1, 2
• Measure cystatin C as a confirmatory test only in specific circumstances when eGFRcr is likely inaccurate 1, 2
• The primary indication is adults with eGFRcr 45-59 mL/min/1.73 m² who lack other markers of kidney damage (no albuminuria, no imaging abnormalities) 1, 2, 5

Why Cystatin C Alone Is Not Superior

A critical 2015 study in kidney transplant recipients demonstrated that cystatin C-based strategies provided no added value for CKD detection compared to creatinine alone, with similar misclassification rates (21% vs 23%) 1. This challenges the notion that cystatin C is universally better, emphasizing that statistical accuracy does not always translate to improved clinical decision-making 1.

More importantly, research shows that while cystatin C improves GFR estimation accuracy, it actually performs worse than creatinine for evaluating CKD risk factors because cystatin C associates with obesity, inflammation, and metabolic factors along non-GFR pathways 6. This means cystatin C can be influenced by factors unrelated to kidney function, potentially leading to misleading results 6.

Specific Clinical Scenarios Where Cystatin C Adds Value

Cystatin C measurement is justified when creatinine-based estimates are unreliable due to altered muscle mass 1, 2:

• Extremes of muscle mass: eating disorders, muscle wasting diseases, amputations, spinal cord injury with paralysis 1, 2
• Extreme athletes or bodybuilders with significantly increased muscle mass 1, 2
• Class III obesity (though combined eGFRcr-cys is required, not cystatin C alone) 1, 2
• Dietary extremes: low-protein, ketogenic, or vegetarian diets that alter creatinine production 1, 2

In these populations, use eGFRcys when no comorbidities exist, but prefer eGFRcr-cys when comorbid illness is present 1, 2.

Important Limitations and Caveats

Cystatin C has its own non-GFR determinants that can compromise accuracy 1, 7:

• Thyroid dysfunction (hypothyroidism increases levels, hyperthyroidism decreases them) 7, 5
• High levels of inflammation and C-reactive protein 6
• Exogenous corticosteroid use 5
• Smoking 1
• Certain malignancies with high cell turnover 2

The Canadian Society of Nephrology explicitly does not recommend widespread cystatin C use, citing lack of evidence for improved outcomes and cost-effectiveness 1. The biggest barrier is not just cost, but the absence of data showing that more accurate GFR estimation actually improves patient outcomes 1.

Practical Implementation Algorithm

1. Initial assessment: Use eGFRcr for all patients 1, 2

2. Consider cystatin C measurement if:

   • eGFRcr is 45-59 mL/min/1.73 m² AND no albuminuria or other kidney damage markers 1, 2, 5
   • Extreme alterations in muscle mass make creatinine unreliable 1, 2
   • Critical treatment decisions require maximum GFR accuracy (nephrotoxic drug dosing, chemotherapy) 2

3. When cystatin C is measured:

   • Always calculate eGFRcr-cys (combined equation) 1, 4
   • If eGFRcr-cys ≥60 mL/min/1.73 m², CKD is not confirmed 2, 5
   • Use assays calibrated to international reference standards 1, 7

4. Do not use cystatin C:

   • For routine CKD monitoring after diagnosis is established 2
   • When cost or availability is limited 1
   • In populations where outcomes data are lacking 1

The Bottom Line

Cystatin C is not categorically "better" than creatinine—it serves a specific confirmatory role in select populations where creatinine-based estimates are unreliable. 1 The combined creatinine-cystatin C equation represents the optimal approach when both markers are available, but routine cystatin C measurement for all patients is not supported by current evidence 1. The 2024 KDIGO guidelines reflect a nuanced, targeted strategy rather than wholesale replacement of creatinine with cystatin C 1.