What is the role of Cystatin C (Cysteine Proteinase Inhibitor) in estimating Glomerular Filtration Rate (eGFR) and managing Impaired Renal Function?

Role of Cystatin C in Estimating GFR and Managing Impaired Renal Function

Cystatin C should be used as a confirmatory test for GFR estimation when creatinine-based eGFR is expected to be inaccurate or when more precise GFR assessment is needed for critical clinical decision-making. 1, 2

When to Use Cystatin C

Primary Indications

• When creatinine-based eGFR (eGFRcr) is suspected to be inaccurate 1
• When more accurate GFR assessment is needed for clinical decisions such as:
  • Diagnosis or staging of chronic kidney disease
  • Drug dosing decisions
  • Transplantation evaluation 1, 2

Specific Patient Populations Benefiting from Cystatin C Testing

• Patients with altered muscle mass:

  • Extreme athletes
  • Individuals with eating disorders
  • Amputees
  • Spinal cord injury
  • Class III obesity 2

• Patients with specific dietary patterns:

  • Low-protein diet
  • Ketogenic diets
  • Vegetarian diet
  • High-protein diets and creatine supplements 1, 2

• Patients with chronic illnesses affecting non-GFR determinants:

  • Malnutrition
  • Cancer
  • Heart failure
  • Cirrhosis
  • Catabolic consuming diseases 1, 2

• Patients with eGFRcr of 45-59 mL/min/1.73 m² without albuminuria 1, 2

Advantages of Cystatin C Over Creatinine

1. Less influenced by non-renal factors:

   • Muscle mass
   • Gender
   • Age
   • Dietary factors 2, 3

2. Provides race-neutral GFR estimation:

   • Eliminates need for race-based adjustments required with creatinine
   • Helps reduce healthcare inequalities 2

3. Earlier detection of kidney dysfunction:

   • Serum cystatin C levels begin to increase when GFR falls below 88 mL/min/1.73 m²
   • Serum creatinine typically increases only when GFR falls below 75 mL/min/1.73 m² 4

4. Better prognostic value:

   • More strongly associated with all-cause mortality and cardiovascular events 3

Recommended Approach to GFR Evaluation

1. Initial assessment: Use serum creatinine and an estimating equation (eGFRcr) 1

2. If eGFRcr is suspected to be inaccurate OR more accurate assessment is needed:

   • Measure cystatin C
   • Calculate eGFRcr-cys (combined creatinine-cystatin C equation) 1

3. If eGFRcr-cys is suspected to be inaccurate OR even more accurate assessment is needed:

   • Consider direct GFR measurement using exogenous filtration markers 1

4. Special consideration: In patients with reduced muscle mass but no other comorbidities, consider using eGFRcys rather than eGFRcr-cys 1

Equations and Accuracy

• The combined creatinine-cystatin C equation (CKD-EPI-Cr-CystC) provides the most accurate GFR estimation 2, 5
• Percentage of estimated GFR within 30% of measured GFR:
  • eGFRcys alone: 81%
  • eGFRcys with age, sex, race: 83%
  • eGFRcr with age, sex, race: 85%
  • eGFRcr-cys with age, sex, race: 89% 5

Laboratory Considerations

• Laboratories should measure cystatin C using assays with calibration traceable to international standard reference materials 2
• Both eGFRcys and eGFRcr-cys should be reported in addition to serum cystatin C concentration 1, 2
• eGFRcys and eGFRcr-cys levels less than 60 mL/min/1.73 m² should be reported as "decreased" 1

Clinical Pitfalls and Limitations

1. Cystatin C is not completely free of non-GFR determinants:

   • Very high levels of inflammation
   • High catabolic states
   • Exogenous steroid use can affect levels 1

2. Limited availability and higher cost compared to creatinine testing 6

3. Standardization of cystatin C assays is still evolving, though improving 6

4. May underestimate measured GFR by approximately 12%, particularly in low GFR groups 2

By incorporating cystatin C into clinical practice according to these guidelines, clinicians can achieve more accurate GFR estimation, especially in patients where creatinine-based estimates are unreliable, leading to improved diagnosis, staging, and management of kidney disease.