What Cystatin C (Cysteine proteinase inhibitor) level is required to rule out Chronic Kidney Disease (CKD)?

Cystatin C Threshold to Rule Out CKD

To rule out CKD, the cystatin C-based eGFR must be ≥60 mL/min/1.73 m² when used as a confirmatory test in patients with creatinine-based eGFR of 45-59 mL/min/1.73 m² who lack other markers of kidney damage. 1, 2

KDIGO Guideline Framework

The KDIGO guidelines provide a specific algorithmic approach for using cystatin C to confirm or rule out CKD 1:

• Measure cystatin C in adults with creatinine-based eGFR 45-59 mL/min/1.73 m² who do not have markers of kidney damage (such as albuminuria >300 mg/day) 1

• If eGFR based on cystatin C (eGFRcys) OR combined creatinine-cystatin C equation (eGFRcreat-cys) is ≥60 mL/min/1.73 m², the diagnosis of CKD is NOT confirmed 1, 3, 4

• If eGFRcys or eGFRcreat-cys is <60 mL/min/1.73 m², the diagnosis of CKD IS confirmed 1, 2, 4

Interpretation of the Threshold

The 60 mL/min/1.73 m² cutoff is the critical decision point 1:

• Cystatin C-based eGFR ≥60 mL/min/1.73 m² indicates that the reduced creatinine-based eGFR likely reflects factors other than true kidney disease (such as reduced muscle mass, dietary factors, or medication effects) rather than actual kidney dysfunction 3, 4

• Research shows that approximately 23% of patients with creatinine-based eGFR 45-59 mL/min/1.73 m² actually have normal kidney function when confirmed with cystatin C 4

• The combined creatinine-cystatin C equation demonstrates the highest accuracy (94.9% within 30% of measured GFR) and should guide clinical decisions 2

Clinical Application Algorithm

Step 1: Patient has creatinine-based eGFR 45-59 mL/min/1.73 m² without albuminuria or other kidney damage markers 1

Step 2: Order cystatin C measurement (note: requires specialized laboratory equipment and may take several days for results) 4

Step 3: Calculate eGFRcys or eGFRcreat-cys using CKD-EPI equations 1, 2

Step 4: Apply the threshold:

• ≥60 mL/min/1.73 m² = CKD ruled out 1, 3, 4
• <60 mL/min/1.73 m² = CKD confirmed 1, 2, 4

Important Caveats and Limitations

Misclassification rates exist: Even with cystatin C, studies show 21-30% misclassification rates in certain populations, particularly kidney transplant recipients and those with eGFR 30-45 mL/min/1.73 m² 1, 3

Variable muscle mass scenarios: Cystatin C is particularly valuable in patients with conditions affecting muscle mass (eating disorders, extreme exercise, amputations, spinal cord injuries), where creatinine-based estimates are unreliable 2

Laboratory considerations: Cystatin C assays must be calibrated to international standard reference materials (IFCC-traceable), and not all laboratories perform this testing on-site 4

Prognostic implications: Patients with CKD confirmed by both creatinine AND cystatin C have significantly higher risks for mortality (HR 1.74-1.93), cardiovascular events, and ESRD compared to those with CKD by creatinine alone (HR 0.80-1.09) 5