Cystatin C for eGFR Estimation
Cystatin C should be used as a confirmatory test when creatinine-based eGFR is unreliable or when accurate GFR assessment is critical for clinical decisions, with the combined creatinine-cystatin C equation (eGFRcr-cys) providing the most accurate kidney function assessment. 1
Primary Clinical Algorithm
Start with creatinine-based eGFR for initial assessment, then measure cystatin C in specific circumstances where creatinine is known to be inaccurate. 2, 1 The KDIGO 2024 guidelines establish this stepwise approach with high-quality evidence. 1
When to Measure Cystatin C
Measure cystatin C in the following situations:
- Adults with eGFRcreat 45-59 mL/min/1.73 m² without markers of kidney damage to confirm whether CKD is truly present 2, 3
- Extremes of muscle mass (very low or very high), including muscle wasting diseases 1, 3
- Obesity class III 1, 3
- Dietary extremes: low-protein, ketogenic, vegetarian, or high-protein diets 1
- Elderly patients where age-associated decline in muscle mass makes creatinine unreliable 3, 4
- Cancer patients receiving nephrotoxic medications 3
- Liver disease and cirrhosis 3, 5
- When accurate GFR is needed for critical drug dosing decisions 1, 6
Performance Characteristics
Superiority of Combined Equations
The combined creatinine-cystatin C equation (eGFRcr-cys) consistently outperforms either marker alone with improved precision and accuracy. 1, 3 This combined approach should be used when available for the most accurate GFR estimation. 3
Advantages Over Creatinine Alone
Cystatin C offers several key advantages:
- Independent of muscle mass, age, sex, and diet 1, 3
- Produced at a constant rate by all nucleated cells 1
- Fewer non-GFR determinants compared to creatinine 1, 6
- Diagnostic accuracy of 90% in discriminating normal from reduced GFR, significantly exceeding creatinine's 77% 1
- More strongly associated with all-cause mortality and cardiovascular events 6
- May detect kidney dysfunction at an earlier stage than creatinine in people with diabetes 2
Critical Caveats and Limitations
Non-GFR Factors That Affect Cystatin C
Be aware of these confounding factors:
- Thyroid dysfunction: hypothyroidism increases cystatin C levels; hyperthyroidism decreases them 1, 3
- High levels of inflammation can elevate cystatin C 1, 3
- Exogenous steroid use influences cystatin C levels 1, 3
- High catabolic states may affect accuracy 1
- Some types of cancer can alter cystatin C levels 3
Current Implementation Challenges
The biggest limitation is lack of widespread availability and standardization across laboratories. 2 While cystatin C reference ranges exist, standardization of calibration across laboratories in Canada and the U.S. remains incomplete, though work is in progress. 2 The 2021 National Kidney Foundation and American Society of Nephrology Task Force recommended national efforts to facilitate increased, routine, and timely use of cystatin C. 2
Laboratory Reporting Standards
When cystatin C is measured, laboratories should:
- Use assays with calibration traceable to international standard reference materials 2, 3
- Report serum cystatin C concentration rounded to the nearest 100th when expressed as mg/L 2, 3
- Report eGFRcys and eGFRcr-cys rounded to the nearest whole number relative to body surface area of 1.73 m² 2
- Report values <60 mL/min/1.73 m² as "decreased" 2
- Specify the equation used whenever reporting eGFR from cystatin C 2
Clinical Decision-Making
Confirming CKD Diagnosis
If eGFRcys or eGFRcr-cys is ≥60 mL/min/1.73 m², the diagnosis of CKD is not confirmed in patients with borderline creatinine-based estimates. 2 This is particularly important in the eGFRcreat 45-59 mL/min/1.73 m² range where creatinine-based estimates are prone to misclassification. 1
Race-Neutral Equations
The 2021 CKD-EPI creatinine equation refit without race variables should be used for initial assessment. 2 Adding cystatin C to serum creatinine improves the accuracy of race-neutral eGFR equations, addressing inequities that occur with race-based calculations. 2 Race is a social construct, not a biologic one, and should not be included in GFR estimation. 2
When More Accurate GFR Measurement is Needed
Consider measuring GFR using an exogenous filtration marker when more accurate ascertainment will impact treatment decisions, though this is rarely needed in routine practice. 2 This represents the gold standard but is complex and not widely available. 2
Special Populations
Diabetes
In patients with type 2 diabetes, cystatin C-based equations detect eGFR decline earlier than creatinine-based equations. 4 Plasma glucose and glycated hemoglobin are associated with increased risk of eGFR decline and negatively correlate with eGFR. 4 Exercise and total cholesterol are independently associated with eGFR in diabetic patients. 4
Elderly Patients
Cystatin C is particularly valuable in elderly patients where age-associated decline in muscle mass makes creatinine unreliable. 3, 4 Recent research in older hospitalized patients found that cystatin C-based formulae predicted lower kidney function than creatinine, with more than 20% receiving a new diagnosis of CKD that may require drug dose adjustment. 7
Pediatric Considerations
In younger children, delay measured GFR evaluations at least 2 weeks after any intercurrent illnesses, as acute illness can affect GFR measurements. 2