Estimating Glomerular Filtration Rate with Cystatin C

Introduction to Cystatin C

• The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend using cystatin C alongside creatinine-based estimated glomerular filtration rate (eGFR) to improve accuracy in certain populations, such as those with altered muscle mass or extreme body composition 1, 2

Primary Clinical Rationale

• The KDIGO 2024 guidelines establish a clear algorithmic approach, starting with creatinine-based eGFR and then measuring cystatin C when eGFR is thought to be inaccurate or when more accurate GFR assessment is needed for critical clinical decisions, with a strength of evidence level of high 1, 3, 4

When Creatinine-Based eGFR is Unreliable

• Cystatin C should be measured in specific situations where creatinine is known to be inaccurate, including extremes of muscle mass, obesity class III, muscle wasting diseases, low-protein diets, ketogenic diets, vegetarian diets, high-protein diets, and certain medications, with a moderate level of evidence 1, 2

Superior Performance of Combined Equations

• The combined creatinine-cystatin C equation (eGFRcr-cys) consistently outperforms either marker alone, with improved precision and accuracy, and is recommended for use in clinical practice, with a high level of evidence 1, 2, 5

Confirmatory Testing Strategy

• The KDIGO 2024 guidelines recommend using eGFRcr-cys as a confirmatory test when clinical decision-making depends on accurate GFR assessment, particularly for CKD diagnosis and staging, drug dosing decisions, and evaluating patients with eGFRcr 45-59 ml/min/1.73 m² without albuminuria, with a high level of evidence 1, 3, 6

Advantages of Cystatin C Over Creatinine Alone

• Cystatin C has fewer non-GFR determinants compared to creatinine, is independent of muscle mass, age, sex, and diet, and is produced at a constant rate by all nucleated cells, with a moderate level of evidence 7, 6

Important Caveats and Limitations

• Sources of error in eGFRcr-cys include very low muscle mass, very high levels of inflammation, high catabolic states, and exogenous steroid use, with a low level of evidence 1, 2, 6

Clinical Decision Algorithm

• The KDIGO 2024 guidelines recommend a step-wise approach to estimating GFR, starting with eGFRcr and then considering cystatin C if eGFRcr is expected to be inaccurate or if more accurate GFR assessment is needed, with a high level of evidence 1, 3, 4

Cystatin C Measurement in Kidney Function Assessment

Confirmatory Testing and Accuracy

• The American Journal of Kidney Diseases recommends measuring cystatin C in adults with eGFRcreat 45-59 mL/min/1.73m² who lack markers of kidney damage to confirm whether CKD is truly present, as creatinine-based estimates are prone to misclassification in this range 8
• Thyroid dysfunction, such as hypothyroidism, which increases cystatin C levels, and hyperthyroidism, which decreases them, can affect cystatin C levels 8
• High levels of inflammation can also impact cystatin C levels, making it essential to consider these factors when interpreting results 8
• Exogenous steroid use can influence cystatin C levels, highlighting the need for careful patient assessment 8

Non-GFR Factors and Diagnostic Accuracy

• Cystatin C has a diagnostic accuracy of 90% in discriminating normal from reduced GFR, significantly exceeding that of creatinine (77%), although non-GFR factors like thyroid dysfunction, inflammation, and exogenous steroid use can affect its levels 8

Cystatin C for eGFR Estimation

Primary Clinical Algorithm

• The KDIGO guidelines establish a stepwise approach for using cystatin C as a confirmatory test when creatinine-based eGFR is unreliable, with high-quality evidence 9
• Adults with eGFRcreat 45-59 mL/min/1.73 m² without markers of kidney damage should have cystatin C measured to confirm whether CKD is truly present, as recommended by the American Journal of Kidney Diseases 9, 10

Performance Characteristics

• The combined creatinine-cystatin C equation (eGFRcr-cys) provides more accurate kidney function assessment than either marker alone, according to the American Journal of Kidney Diseases 9
• Cystatin C may detect kidney dysfunction at an earlier stage than creatinine in people with diabetes, as reported in Diabetes Care 11

Laboratory Reporting Standards

• Laboratories should use assays with calibration traceable to international standard reference materials when measuring cystatin C, as recommended by the American Journal of Kidney Diseases 10
• Serum cystatin C concentration should be reported rounded to the nearest 100th when expressed as mg/L, and eGFRcys and eGFRcr-cys should be reported rounded to the nearest whole number relative to body surface area of 1.73 m², according to the American Journal of Kidney Diseases 10

Clinical Decision-Making

• 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, as stated in the American Journal of Kidney Diseases 10
• The 2021 CKD-EPI creatinine equation refit without race variables should be used for initial assessment, and adding cystatin C to serum creatinine improves the accuracy of race-neutral eGFR equations, as reported in Diabetes Care 11

Special Populations

• In younger children, measured GFR evaluations should be delayed at least 2 weeks after any intercurrent illnesses, as recommended by the American Journal of Kidney Diseases 9

Management of Discordant eGFR Values

Understanding the Discordance

• When eGFRcys is higher than eGFRcr, the creatinine-based estimate is typically underestimating true kidney function, often due to reduced muscle mass, malnutrition, or other non-GFR determinants of creatinine, as recommended by the KDIGO guidelines 12

The Combined Equation is Superior in Discordance

• The KDIGO 2024 guidelines explicitly recommend using eGFRcr-cys when there is discordance between creatinine and cystatin C estimates, with the combined equation demonstrating superior performance across various patient populations 12

Clinical Implications and Risk Stratification

• The combined eGFRcr-cys of approximately 64 mL/min/1.73 m² places the patient in Stage 3a CKD, which requires appropriate CKD management, according to the KDIGO guidelines 12

Medication Dosing Considerations

• The combined eGFRcr-cys value should be used for all medication dosing decisions, as the creatinine-based eGFR may underestimate true kidney function, leading to potential underdosing of renally-cleared medications 12

Ongoing Management Algorithm

• Confirm CKD Stage 3a diagnosis using eGFRcr-cys ≈64 mL/min/1.73 m², and investigate causes of discordance, including muscle mass, dietary factors, and medications affecting creatinine secretion, as recommended by the KDIGO guidelines 12
• Repeat both creatinine and cystatin C in 3 months to confirm stability and recalculate eGFRcr-cys, and monitor for CKD progression with serial eGFRcr-cys measurements 12

Interpretation of Discordant eGFR Values

Understanding the Discordance and Clinical Implications

• The KDIGO 2024 guidelines recommend using the combined creatinine-cystatin C equation (eGFRcr-cys) when there is discordance between creatinine and cystatin C estimates, as it demonstrates superior performance across various patient populations 13
• The combined eGFRcr-cys equation is significantly more accurate than either marker alone, with correct GFR classification rates of 62% compared to 38% for eGFRcr alone and 45% for eGFRcys alone, although the exact strength of evidence is not provided 13
• Low muscle mass is a common cause of discordance between eGFRcys and eGFRcr, resulting in lower creatinine generation independent of kidney function, and the combined equation helps to accurately estimate kidney function in such cases 13
• The American College of Cardiology and other guideline societies may recommend using the combined eGFRcr-cys equation for medication dosing decisions, as it provides a more accurate estimate of kidney function, although the specific recommendation is not provided in the article 13

Medication Dosing and Ongoing Management

• The combined eGFRcr-cys value should be used for all medication dosing decisions, as the creatinine-based eGFR may underestimate true kidney function, potentially leading to inappropriate dose reductions, and the strength of evidence for this recommendation is based on the KDIGO 2024 guidelines 13
• Repeat both creatinine and cystatin C in 3 months to confirm stability and recalculate eGFRcr-cys, as CKD diagnosis requires persistence of reduced eGFR for ≥3 months, and this approach is recommended by the KDIGO 2024 guidelines 13
• Monitor for CKD progression with serial eGFRcr-cys measurements rather than relying on creatinine alone, as the combined equation provides more accurate tracking of kidney function changes, and this approach is supported by the available evidence 13
• Assess for albuminuria if not already done, as this would provide additional confirmation of kidney damage and help guide prognosis and treatment intensity, and the KDIGO 2024 guidelines recommend this approach 13