Why Check Cystatin C with GFR
Cystatin C should be measured alongside creatinine-based eGFR as a confirmatory test when creatinine-based estimates are likely inaccurate or when critical clinical decisions depend on precise kidney function assessment. 1, 2
Primary Clinical Rationale
The KDIGO 2024 guidelines establish a clear algorithmic approach: start with creatinine-based eGFR, then measure cystatin C when you need confirmation or greater accuracy. 2 This two-step strategy exists because creatinine alone can be misleading in many common clinical scenarios, while cystatin C provides independent information that improves diagnostic precision. 1, 2
When Creatinine-Based eGFR Is Unreliable
Measure cystatin C in these specific situations where creatinine is known to be inaccurate: 2
- Extremes of muscle mass (sarcopenia, bodybuilders, amputees) 1, 2
- Obesity class III 1
- Muscle wasting diseases 2
- Dietary extremes (low-protein, ketogenic, vegetarian, or high-protein diets) 2
- Liver disease 1
- Cancer patients receiving nephrotoxic medications 1
- Certain medications that affect creatinine secretion 2
The fundamental advantage is that cystatin C is independent of age, sex, and muscle mass, making it particularly valuable when creatinine's muscle-dependence creates uncertainty. 1, 3
Confirmatory Testing for Borderline Kidney Function
KDIGO specifically recommends measuring cystatin C in adults with eGFRcreat 45-59 mL/min/1.73m² who lack markers of kidney damage when you need to confirm whether CKD is truly present. 1, 2 This borderline range is where creatinine-based estimates are most prone to misclassification, and the clinical stakes are high for accurate diagnosis. 4
Superior Accuracy with Combined Equations
The combined creatinine-cystatin C equation (eGFRcr-cys) consistently outperforms either marker alone and provides the most accurate GFR estimation available without direct measurement. 1, 2 Research demonstrates that cystatin C shows stronger correlation with measured GFR (r = 0.84) compared to creatinine alone (r = 0.65). 5
Key performance advantages include: 1, 2
- Improved precision and accuracy for CKD diagnosis and staging
- Better risk stratification for adverse outcomes including mortality and cardiovascular events
- Enhanced reliability for drug dosing decisions
Earlier Detection of Kidney Dysfunction
Cystatin C begins rising when GFR falls to 88 mL/min/1.73m², whereas creatinine doesn't increase until GFR drops to 75 mL/min/1.73m². 3 This earlier signal makes cystatin C particularly valuable for detecting mild reductions in kidney function when early intervention matters most. 3 The diagnostic accuracy of cystatin C (90%) significantly exceeds that of creatinine (77%) in discriminating normal from reduced GFR. 5
Important Caveats
Non-GFR factors that can affect cystatin C levels include: 1, 2, 6
- Thyroid dysfunction (hypothyroidism increases levels, hyperthyroidism decreases them)
- High levels of inflammation
- Exogenous steroid use
- Some types of cancer
- High catabolic states
Despite these limitations, cystatin C has fewer non-GFR determinants overall compared to creatinine, since it's produced at a constant rate by all nucleated cells and is independent of dietary protein and muscle metabolism. 2, 7
Practical Implementation
Clinical laboratories should measure cystatin C using assays with calibration traceable to international standard reference materials. 1 The Canadian Society of Nephrology notes that while standardization is still evolving, the bigger issue is demonstrating cost-effectiveness in routine practice. 4 However, the 2024 KDIGO guidelines now provide clear clinical scenarios where the added accuracy justifies the cost. 2
The bottom line: Don't check cystatin C on everyone—use it strategically when creatinine-based eGFR is expected to be inaccurate or when clinical decisions require the most accurate kidney function assessment possible. 2