What is the use of cystatin C (Cysteine Proteinase Inhibitor C) in assessing kidney function?

How Cystatin C is Used in Assessing Kidney Function

Cystatin C is primarily used as a confirmatory test to verify chronic kidney disease (CKD) diagnosis in adults with borderline creatinine-based eGFR (45-59 mL/min/1.73m²) who lack other markers of kidney damage, and should always be combined with creatinine in the eGFRcr-cys equation for maximum accuracy. 1

Primary Clinical Algorithm for Cystatin C Use

The KDIGO guidelines establish a stepwise approach that prioritizes strategic rather than universal use: 2

• Step 1: Begin with creatinine-based eGFR (eGFRcr) for initial kidney function assessment in all patients 2, 3
• Step 2: Measure cystatin C only in specific circumstances when eGFRcr is likely inaccurate or when confirmation is needed 1
• Step 3: When cystatin C is measured, always calculate the combined equation (eGFRcr-cys) rather than using cystatin C alone 2, 3

Specific Indications for Measuring Cystatin C

Confirmatory Testing for CKD Diagnosis

The most evidence-based indication is confirming CKD in adults with eGFRcr 45-59 mL/min/1.73m² without albuminuria or other kidney damage markers. 1 In this borderline range, creatinine-based estimates are prone to misclassification, and cystatin C helps determine if true kidney disease exists. 2

• If eGFRcys or eGFRcr-cys is also <60 mL/min/1.73m², CKD diagnosis is confirmed 1
• If eGFRcys or eGFRcr-cys is ≥60 mL/min/1.73m², CKD diagnosis is not confirmed 1

When Creatinine-Based Estimates Are Unreliable

Cystatin C should be measured when altered muscle mass makes creatinine unreliable: 2, 3

• Extremes of low muscle mass: malnutrition, eating disorders, neuromuscular diseases, amputations, spinal cord injury 2
• Extremes of high muscle mass: extreme athletes, bodybuilders 2
• Class III obesity: both creatinine and cystatin C have non-GFR determinants, but combined equation is most accurate 2
• Dietary extremes: low-protein diets, ketogenic diets, vegetarian diets, high-protein diets, creatine supplementation 2

Critical Clinical Decision-Making

Measure cystatin C when accurate GFR assessment directly impacts treatment decisions: 2, 3

• Cancer patients: superior for predicting carboplatin and topotecan clearance, improving dose individualization and reducing toxicity 2
• Heart failure patients: eGFRcr-cys should be used for routine evaluation 2
• Liver disease/cirrhosis: eGFRcys is less biased than creatinine alone 2
• Liver transplant recipients: cystatin C-based equations are recommended 2

Why the Combined Equation (eGFRcr-cys) is Superior

The combined creatinine-cystatin C equation consistently outperforms either marker alone and should always be used when both markers are available. 2, 3 The combined equation achieves 89% of estimates within 30% of measured GFR, compared to lower accuracy with either marker alone. 3

The superiority stems from: 2, 4

• Creatinine and cystatin C have different non-GFR determinants that partially cancel out when combined
• Better classification of CKD stages and risk stratification
• Stronger associations with cardiovascular events, kidney failure, and mortality

Laboratory Reporting Standards

Clinical laboratories must adhere to specific standards when measuring cystatin C: 1

• Use assays with calibration traceable to international standard reference materials 1
• Report serum cystatin C concentration rounded to the nearest 0.01 mg/L 1
• Report eGFRcys and eGFRcr-cys rounded to the nearest whole number relative to 1.73 m² body surface area 1
• Specify the equation used when reporting eGFR values 1
• Report eGFR values <60 mL/min/1.73m² as "decreased" 1

Key Advantages of Cystatin C

Cystatin C offers specific advantages over creatinine alone: 2, 5

• Independent of muscle mass, age, and sex: makes it particularly valuable in populations where creatinine is unreliable 2, 5
• Earlier detection: may detect kidney dysfunction at an earlier stage than creatinine, especially in diabetes 2
• Better risk stratification: elevated cystatin C strongly predicts cardiovascular events, CKD progression, and mortality even when creatinine-based eGFR appears normal 6
• Constant production rate: produced at a steady rate by all nucleated cells, freely filtered, and completely catabolized in tubules 2

Important Limitations and Non-GFR Determinants

Common pitfall: Cystatin C can be affected by factors unrelated to kidney function, which must be considered when interpreting results: 2, 3

• Thyroid dysfunction: hypothyroidism increases cystatin C; hyperthyroidism decreases it 3, 5
• Inflammation: high inflammatory states can elevate cystatin C 2, 3
• Exogenous steroid use: can influence cystatin C levels 3
• Obesity: cystatin C has non-GFR determinants in class III obesity 2
• Active smoking: affects cystatin C independent of GFR 2
• Some cancers: particularly those with high cell turnover 2

When NOT to Use Cystatin C

Critical caveat: Despite its advantages, cystatin C is not recommended for: 2

• Routine CKD monitoring after diagnosis is established 2
• Universal screening in all patients (lack of cost-effectiveness evidence) 2
• Settings with limited resources where creatinine-based estimates are adequate 1

The Canadian Society of Nephrology explicitly does not recommend widespread cystatin C use, citing lack of evidence that more accurate GFR estimation actually improves patient outcomes. 2 The biggest barrier is not cost, but absence of data showing improved clinical outcomes. 2

Practical Clinical Implementation

For optimal use in practice: 2, 3

1. Initial assessment: Use eGFRcr for all patients as the first-line test 2
2. Selective cystatin C measurement: Order cystatin C only when eGFRcr is 45-59 mL/min/1.73m² without other CKD markers, OR when extreme muscle mass alterations make creatinine unreliable 2
3. Always calculate combined equation: When cystatin C is measured, use eGFRcr-cys for clinical decisions 2, 3
4. Medication dosing: Use the combined eGFRcr-cys value for all drug dosing decisions when available 3
5. Avoid cystatin C alone: Do not rely on cystatin C concentration or eGFRcys alone; always use the combined equation 1

Special Populations

In kidney transplant recipients, cystatin C-based or combined equations show better accuracy than creatinine alone (81-86% vs 75% within 30% of measured GFR), supporting its use in this population. 1

In elderly persons without CKD by creatinine criteria, elevated cystatin C (≥1.0 mg/L) identifies a "preclinical" state of kidney dysfunction with 4-fold increased risk of progressing to CKD and significantly increased cardiovascular mortality. 6