Is Cystatin C with eGFR a More Reliable Tool for Assessing Kidney Function?

Understanding eGFR

The glomerular filtration rate (GFR) measures how much blood is filtered by the kidneys each minute. It is considered the best overall indicator of kidney function, as it reflects how efficiently the kidneys are clearing waste products from the blood. Because measuring GFR directly requires complex procedures, clinicians estimate it (eGFR) using biomarkers present in the blood.

Traditionally, eGFR has been calculated using serum creatinine. Creatinine is a breakdown product of muscle metabolism that is filtered by the kidneys. Equations such as the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations use creatinine levels, along with factors like age and sex, to estimate GFR.

However, creatinine-based eGFR has limitations. Since creatinine is influenced by muscle mass, diet, and certain medications, it can underestimate or overestimate kidney function in people who are elderly, malnourished, obese, or have chronic illnesses. This is where cystatin C offers a significant advantage.

Why Cystatin C Matters

Cystatin C is a small protein produced by all nucleated cells at a steady rate, freely filtered by the kidneys, and not significantly affected by muscle mass, diet, or gender. This makes it an appealing biomarker for estimating GFR, particularly in patients where creatinine-based measures may be misleading.

Comparing Cystatin C and Creatinine in eGFR Estimation

Several studies have compared cystatin C-based eGFR (eGFRcys) to creatinine-based eGFR (eGFRcr) across various clinical contexts:

• In kidney transplant recipients, eGFRcys values differed significantly from eGFRcr, particularly in advanced stages of kidney disease, suggesting cystatin C may reclassify patients into more accurate CKD stages.
• Among live kidney donors, cystatin C-based eGFR provided the highest specificity (90.3%) for predicting future chronic kidney disease compared to creatinine-based estimates.
• In patients with peripheral artery disease, eGFRcys outperformed eGFRcr as an independent predictor of adverse cardiovascular outcomes, with a significantly stronger predictive value.

Prognostic Value of Cystatin C-Based eGFR

Beyond simply estimating renal function, cystatin C has demonstrated superior prognostic value:

• In atrial fibrillation patients, eGFRcys was a better predictor of cardioembolic stroke risk than eGFRcr.
• In a large Chinese cohort, eGFRcys using the CKD-EPI equation was strongly associated with both cardiovascular disease incidence and all-cause mortality, whereas newer equations showed weaker predictive value.
• Discrepancies where eGFRcys is lower than eGFRcr have been linked to worse outcomes, including higher risks of kidney failure and mortality, reinforcing the importance of cystatin C as a risk stratification tool.

Populations Where Cystatin C Shines

• HIV patients on antiretroviral therapy: Cystatin C-based eGFR showed high specificity and diagnostic accuracy, making it a reliable confirmatory test for kidney disease.
• Sickle cell anemia patients: Cystatin C equations more effectively identified patients with reduced kidney function compared to creatinine alone.
• Advanced kidney disease: In patients with GFR below 30 mL/min/1.73 m², cystatin C-based eGFR correlated more strongly with the gold standard iohexol clearance than creatinine-based estimates.

Limitations of Cystatin C

Despite its strengths, cystatin C is not flawless. Certain conditions can alter its production, such as thyroid dysfunction and corticosteroid use. Additionally, studies in Indigenous Australian populations with high chronic inflammation found that cystatin C-based eGFR performed worse than creatinine-based equations.

What To Do If Your eGFR is Abnormal

An abnormal eGFR can indicate reduced kidney function, but interpretation depends on context:

• Mild reductions (eGFR 60–89 mL/min/1.73 m²): May be normal in older adults, but can also reflect early kidney disease if albuminuria or structural abnormalities are present.
• Moderate to severe reductions (eGFR <60): Suggest chronic kidney disease (CKD) and usually warrant further evaluation.
• Rapid decline over time: Even if absolute values are not critically low, a fast decline in eGFR suggests active kidney injury.

Possible reasons for an abnormal eGFR include chronic conditions (diabetes, hypertension), acute injury (dehydration, medication toxicity), or systemic diseases (autoimmune disorders). If results are abnormal, clinicians often confirm with repeat testing, urinalysis for protein, imaging, or referral to nephrology.

The Power of Combining Creatinine and Cystatin C

The future of kidney function testing may not be about replacing creatinine with cystatin C, but using them together. Each biomarker has its limitations: creatinine can be influenced by muscle mass and diet, while cystatin C may be affected by thyroid function or inflammation. When combined, however, they balance each other’s weaknesses and create a more accurate picture of kidney health.

The combined equation for creatinine and cystatin C has been shown to improve accuracy and reduce misclassification, especially in patients whose kidney function lies near important clinical thresholds. This approach also provides reassurance in practice. If both markers point in the same direction, clinicians can be confident in the result. If they differ, the combined estimate often highlights the more reliable assessment and signals patients who may need closer monitoring.