When is Cystatin C (Cysteine Proteinase Inhibitor) indicated in a renal function work-up?

Indications for Cystatin C in Renal Function Work-Up

Cystatin C should be measured when serum creatinine-based eGFR estimates are unreliable due to altered muscle mass, in patients with eGFR 45-59 mL/min/1.73m² requiring CKD confirmation, and when accurate GFR assessment is critical for treatment decisions involving nephrotoxic drugs or dose adjustments. 1

Primary Indications Based on Body Habitus and Muscle Mass Alterations

The KDIGO 2024 guidelines provide specific clinical scenarios where cystatin C overcomes the limitations of creatinine-based estimates:

Conditions with Reduced Muscle Mass

• Eating disorders: Use eGFRcys when no comorbid illness exists beyond muscle mass reduction 1
• Above-knee amputation: eGFRcys appropriate without comorbidities; use combined eGFRcr-cys if comorbid illness present 1
• Spinal cord injury (paraplegia/quadriplegia): eGFRcys for patients without comorbidities; eGFRcr-cys with comorbid conditions 1
• Neuromuscular diseases: Creatinine-based equations overestimate GFR by 22-60 mL/min/1.73m², with cystatin C showing lowest bias 2

Conditions with Increased Muscle Mass

• Extreme athletes/bodybuilders: eGFRcys appropriate when increased muscle mass is the only abnormality 1

Obesity

• Class III obesity: Combined eGFRcr-cys demonstrated to be most accurate, as both creatinine and cystatin C have non-GFR determinants in this population 1

Confirmatory Testing for CKD Diagnosis

Measure cystatin C in adults with eGFRcreat 45-59 mL/min/1.73m² who lack other markers of kidney damage when CKD confirmation is required. 1, 3

• If eGFRcys or eGFRcr-cys is ≥60 mL/min/1.73m², CKD diagnosis is not confirmed 3
• In a meta-analysis of 90,750 participants, 23% with eGFRcreat 60-74 mL/min/1.73m² had eGFRcys <60 mL/min/1.73m², indicating potential underdiagnosis with creatinine alone 3

Chronic Illness Requiring Accurate GFR Assessment

Cancer Patients

• Combined eGFRcr-cys most accurate in studied populations, though accuracy decreases in frail patients or high cell turnover cancers 1
• Superior for predicting carboplatin and topotecan clearance, improving dose individualization and reducing toxicity risk 1
• Consider measured GFR (mGFR) for treatment decisions when precise dosing is critical 1

Heart Failure

• eGFRcys shows less bias though all equations have low accuracy 1
• Use eGFRcr-cys or eGFRcys for routine evaluation; consider mGFR for treatment decisions 1

Cirrhosis

• eGFRcys less biased but accuracy remains limited 1
• Use eGFRcr-cys or eGFRcys routinely; mGFR recommended for treatment decisions 1

Malnutrition

• Both creatinine and cystatin C affected by chronic illness and inflammation 1
• eGFRcr-cys may be less accurate; strongly consider mGFR for treatment decisions 1

Dietary and Lifestyle Factors

When Cystatin C is Preferred

• Low-protein diets: Creatinine production reduced 1
• Ketogenic diets: Limited data, but creatinine affected 1
• Vegetarian diets: Creatinine production altered 1

When Creatinine May Be Preferred

• Active smoking: Cystatin C has non-GFR determinants; use eGFRcr if no changes to creatinine determinants 1
• High-protein diets/creatine supplements: Creatinine elevated independent of GFR 1

Early Detection of Renal Impairment

Cystatin C detects mild GFR reductions earlier than creatinine, with sensitivity of 93.4% versus 86.8% for creatinine. 4

• Cystatin C begins rising when GFR falls to 88 mL/min/1.73m², while creatinine rises only at 75 mL/min/1.73m² 4
• Particularly valuable in diabetes for earlier detection of kidney dysfunction 3

Special Populations

Liver Transplant Recipients

• Cystatin C-based equations recommended for estimating GFR 1, 3
• Non-creatinine biomarkers needed to detect early renal injury before GFR decline 1

Elderly Patients

• Both Cockcroft-Gault and MDRD formulas less accurate in elderly populations 1
• Cystatin C independent of age, making it more reliable 1, 3

Critical Caveats and Limitations

When NOT to Use Cystatin C Alone

• Thyroid dysfunction: Affects cystatin C levels independent of renal function 3
• Severe malnutrition with inflammation: Both markers unreliable; use mGFR 1

Practical Considerations

• Availability: Not widely available in many countries including U.S. and Canada 3
• Cost: Higher than creatinine, though "triple marker" panel (creatinine, cystatin C, urine albumin-to-creatinine ratio) considered affordable in high-income settings 3
• Not required for routine monitoring after CKD diagnosis established 3

Optimal Testing Strategy

The combined creatinine-cystatin C equation (eGFRcr-cys) provides the most accurate GFR estimation and should be used when both markers are available, as it outperforms either marker alone. 1, 3

• Use 2012 CKD-EPI combined equation for maximum accuracy 1
• Laboratories should use assays with calibration traceable to international standard reference material 3
• Report cystatin C rounded to nearest hundredth (mg/L) 3