What is cystatin C (Cystatin C) estimated glomerular filtration rate (eGFR)?

What is Cystatin C eGFR?

Cystatin C eGFR is an estimated glomerular filtration rate calculated using serum cystatin C levels—a protein marker that provides more accurate kidney function assessment than creatinine alone, particularly in populations where creatinine-based estimates are unreliable due to altered muscle mass, extreme body composition, or other non-GFR factors. 1, 2

Core Concept and Clinical Purpose

Cystatin C is a low-molecular-weight protein produced at a constant rate by all nucleated cells in the body. 2 Unlike creatinine, it is independent of muscle mass, age, sex, and diet, making it particularly valuable when creatinine-based estimates may be inaccurate. 1, 2 The protein is freely filtered by the glomerulus and serves as an endogenous filtration marker to estimate kidney function. 3

The primary clinical rationale for using cystatin C is to overcome the significant limitations of creatinine-based eGFR, which is heavily influenced by muscle mass and other non-GFR determinants that are not adequately accounted for in standard equations. 3

Three Types of Cystatin C-Based eGFR Equations

When cystatin C is measured, three different eGFR values can be calculated:

• eGFRcys: Uses cystatin C alone 3, 1
• eGFRcr-cys: Combines both creatinine and cystatin C (the combined equation) 3, 1
• eGFRcr: The standard creatinine-based estimate for comparison 3

The combined creatinine-cystatin C equation (eGFRcr-cys) consistently outperforms either marker alone, with improved precision and accuracy, and represents the most accurate GFR estimation method available without direct measurement. 1, 2

When to Use Cystatin C eGFR: The KDIGO Algorithm

The KDIGO 2024 guidelines establish a clear stepwise approach: 1

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

Step 2: Measure cystatin C in these specific situations:

• Confirmatory testing: Adults with eGFRcr 45-59 mL/min/1.73 m² without albuminuria to confirm whether CKD is truly present 3, 1, 2
• When creatinine is unreliable: Extremes of muscle mass, obesity class III, muscle wasting diseases, low-protein diets, ketogenic diets, vegetarian diets, high-protein diets 1, 2
• Critical clinical decisions: When accurate GFR assessment is needed for CKD diagnosis and staging, drug dosing decisions, or evaluating living kidney donors 1

Step 3: Interpret the results:

• If eGFRcys or eGFRcr-cys is also <60 mL/min/1.73 m², CKD diagnosis is confirmed 3
• If eGFRcys or eGFRcr-cys is ≥60 mL/min/1.73 m², CKD diagnosis is not confirmed 3, 1

Performance Characteristics

Cystatin C demonstrates superior diagnostic accuracy compared to creatinine alone, with 90% accuracy in discriminating normal from reduced GFR versus 77% for creatinine. 1 In patients with advanced kidney disease (GFR <30 mL/min/1.73 m²), cystatin C-based estimates show strong correlation with measured GFR (r=0.88), with no patients showing differences exceeding 50% from measured values. 4

In routine clinical practice, discordances between eGFRcys and eGFRcr are common, with eGFRcys being lower than eGFRcr in 65% of cases—and patients with eGFRcys >27% lower than eGFRcr have significantly higher risk of adverse outcomes including acute kidney injury (HR 2.6), kidney failure (HR 1.4), cardiovascular disease (HR 1.4), heart failure (HR 2.0), and death (HR 2.6). 5

Critical Limitations and Sources of Error

Important caveat: Cystatin C is not perfect and has its own non-GFR determinants that must be considered: 1, 2

• Thyroid dysfunction: Hypothyroidism increases cystatin C levels; hyperthyroidism decreases them 1, 6
• Inflammation: High inflammatory states artificially elevate cystatin C 1, 6
• Exogenous corticosteroids: Steroid use significantly affects cystatin C levels 7, 6
• Very low muscle mass: Can still impact accuracy 1
• High catabolic states: May alter cystatin C production 1

In patients receiving corticosteroids, the KDIGO 2024 guidelines explicitly recommend against using cystatin C-based estimates, as steroids artificially elevate cystatin C levels and will lead to falsely low eGFR estimates. 7 In these patients, creatinine-based eGFR or measured GFR using exogenous filtration markers should be used instead. 7

Laboratory Reporting Standards

For accurate and standardized results: 1, 2

• Laboratories must use assays with calibration traceable to international standard reference materials 1, 2
• Cystatin C concentration should be reported rounded to the nearest 0.01 mg/L 2
• eGFRcys and eGFRcr-cys should be reported rounded to the nearest whole number relative to 1.73 m² body surface area 1
• Both eGFRcys and eGFRcr-cys should be reported whenever cystatin C is ordered, giving clinicians both values for decision-making 3

Clinical Advantages Over Creatinine Alone

The key advantages that make cystatin C valuable in clinical practice include: 2, 8, 9

• Does not differ by race, making it valuable for race-neutral GFR estimation 9
• Correlates better with adverse outcomes compared to creatinine 9
• May detect kidney dysfunction at an earlier stage than creatinine in people with diabetes 1
• Particularly useful in cancer patients receiving nephrotoxic medications, patients with liver disease, and children with chronic liver disease 2