What are the implications and management strategies for elevated cystatin C (Cystatin C) levels indicating potential kidney dysfunction?

Cystatin C: Implications and Management for Kidney Dysfunction

Cystatin C should be measured in adults with eGFR 45-59 ml/min/1.73 m² who do not have other markers of kidney damage when confirmation of chronic kidney disease is required, as it provides a more accurate assessment of kidney function and helps identify patients at higher risk for mortality, cardiovascular disease, and end-stage renal disease. 1

Understanding Cystatin C

Cystatin C is a low-molecular-weight protein produced at a constant rate by all nucleated cells, freely filtered by the glomeruli, and not secreted by renal tubules. Unlike creatinine, cystatin C is:

• Independent of muscle mass, gender, and age
• More sensitive for detecting early kidney dysfunction
• Particularly valuable when creatinine-based eGFR may be inaccurate 2

Clinical Significance of Elevated Cystatin C

Diagnostic Value

• Elevated cystatin C levels can identify kidney dysfunction even when albuminuria and creatinine-based eGFR do not yet reflect CKD 3
• In patients without established CKD (eGFR ≥60 ml/min/1.73 m²), elevated cystatin C identifies a "preclinical" state of kidney dysfunction not detected by serum creatinine 4
• Cystatin C can detect acute kidney injury 1.5 ± 0.6 days earlier than creatinine 5

Prognostic Value

• Elevated cystatin C strongly predicts:
  • All-cause mortality (HR 1.33 per SD increase)
  • Cardiovascular death (HR 1.42 per SD increase)
  • Heart failure (HR 1.28 per SD increase)
  • Stroke (HR 1.22 per SD increase)
  • Myocardial infarction (HR 1.20 per SD increase) 4
• Patients with elevated cystatin C have a 4-fold increased risk of progressing to CKD within 4 years 4

When to Measure Cystatin C

1. Primary Indication: Adults with eGFRcreat 45-59 ml/min/1.73 m² who do not have albuminuria or other markers of kidney damage 1

2. Other Clinical Scenarios:

   • When creatinine-based eGFR is less accurate and GFR affects clinical decision-making 1
   • Patients with altered muscle mass (elderly, cachectic, amputees)
   • Monitoring for medication nephrotoxicity
   • Early detection of diabetic kidney disease in normoalbuminuric patients 3

Interpreting Cystatin C Results

Recommended Approach

1. Request both eGFRcys (cystatin C-based) and eGFRcr-cys (combined creatinine and cystatin C) for comprehensive assessment 1, 2

2. Use the CKD-EPI cystatin C equation for GFR estimation 1

3. Interpretation algorithm:

   • If eGFRcys <60 ml/min/1.73 m² confirms eGFRcreat <60 ml/min/1.73 m²: Diagnosis of CKD is confirmed
   • If eGFRcys ≥60 ml/min/1.73 m² despite eGFRcreat <60 ml/min/1.73 m²: CKD is less likely 1
   • Understand the implications of differences between eGFRcr and eGFRcys, as these may be informative 1

Clinical Implications

• Two-thirds of persons with eGFRcreat <60 ml/min/1.73 m² have CKD confirmed by eGFRcys <60 ml/min/1.73 m² 1
• These patients have markedly elevated risks for death, cardiovascular disease, and end-stage renal disease compared with those with eGFRcys ≥60 ml/min/1.73 m² 1

Management Strategies for Elevated Cystatin C

1. Confirm CKD Diagnosis:

   • Use combined creatinine and cystatin C-based eGFR (eGFRcr-cys) for most accurate assessment 1
   • Assess albuminuria using albumin-to-creatinine ratio (ACR) 1

2. Monitor Progression:

   • Assess albuminuria and GFR at least annually in people with confirmed CKD 1
   • More frequent monitoring for those at higher risk of progression 1
   • A change in eGFR >20% on subsequent testing exceeds expected variability and warrants evaluation 1

3. Implement Risk Reduction Strategies:

   • Blood pressure control with RAS inhibitors
   • For patients with diabetes and CKD: Consider SGLT2 inhibitors if eGFR ≥30 ml/min/1.73 m² 1
   • Address cardiovascular risk factors aggressively given the strong association between cystatin C and cardiovascular outcomes 4

Practical Considerations and Limitations

• Cystatin C testing may have limited availability and higher cost than creatinine testing 1, 2
• Factors that may affect cystatin C levels independent of GFR include:
  • Smoking
  • Inflammation (elevated C-reactive protein)
  • Certain medications (high-dose glucocorticoids)
  • Thyroid dysfunction 6, 5
• Ensure the laboratory uses standardized assays traceable to international reference materials for accurate results 7

By incorporating cystatin C into clinical practice, particularly for patients with borderline kidney function, clinicians can more accurately identify kidney dysfunction, stratify risk, and implement appropriate management strategies to improve outcomes.