What is the role of Cystatin C (Cysteine Proteinase Inhibitor) in assessing kidney function, particularly in elderly patients or those with a history of Diabetes Mellitus (DM), Hypertension (HTN), or Cardiovascular Disease (CVD)?

Cystatin C in Kidney Function Assessment

Primary Recommendation

Measure cystatin C in adults with creatinine-based eGFR 45-59 mL/min/1.73 m² who lack albuminuria or other markers of kidney damage to confirm whether chronic kidney disease is truly present, and always use the combined creatinine-cystatin C equation (eGFRcr-cys) when both markers are available, as this provides superior accuracy compared to either marker alone. 1

Clinical Algorithm for Cystatin C Use

Step 1: Initial Assessment

• Begin with creatinine-based eGFR (eGFRcr) using the CKD-EPI equation for all patients as the initial screening tool 1, 2
• Check urine albumin-to-creatinine ratio (ACR) simultaneously, as albuminuria confirms kidney damage independent of GFR 1

Step 2: Identify When Cystatin C is Indicated

Measure cystatin C in the following specific scenarios:

• Borderline eGFR without albuminuria: eGFRcr 45-59 mL/min/1.73 m² AND ACR <30 mg/g (no albuminuria) 1

  • This represents 3.6% of the U.S. population and 41% of persons labeled with CKD based on creatinine alone 1
  • Two-thirds of these patients will have CKD confirmed by eGFRcys <60 mL/min/1.73 m², who then have markedly elevated risks for death, cardiovascular disease, and end-stage renal disease 1

• Altered muscle mass conditions where creatinine is unreliable 2, 3:

  • Extremes of low muscle mass: malnutrition, eating disorders, amputation, spinal cord injury, neuromuscular diseases 3
  • Extremes of high muscle mass: extreme athletes, bodybuilders 3
  • Class III obesity (both markers affected, use combined equation) 3

• Dietary factors affecting creatinine 3:

  • Low-protein diets, ketogenic diets, vegetarian diets (creatinine reduced)
  • High-protein diets or creatine supplementation (creatinine elevated)

• Critical clinical decisions requiring accurate GFR 2, 3:

  • Nephrotoxic drug dosing (chemotherapy, especially carboplatin) 3
  • Evaluation for kidney donation 2
  • Medication dose adjustments in elderly patients 4

Step 3: Calculate and Interpret Combined Equation

• Always calculate eGFRcr-cys (combined creatinine-cystatin C equation) when both markers are available 2, 4, 3
• The combined equation achieves 89-95% of estimates within 30% of measured GFR, superior to either marker alone 2, 3
• If eGFRcys or eGFRcr-cys is ≥60 mL/min/1.73 m², CKD diagnosis is not confirmed in patients with borderline creatinine-based estimates 2, 3

Special Population Considerations

Elderly Patients

• Creatinine-based eGFR systematically overestimates kidney function due to reduced muscle mass 4
• Use eGFRcr-cys for all medication dosing decisions in elderly patients, not creatinine alone 4
• Monitor every 3-6 months using both creatinine and cystatin C to calculate eGFRcr-cys for accurate longitudinal assessment 4

Patients with Diabetes, Hypertension, or Cardiovascular Disease

• Cystatin C may detect kidney dysfunction at an earlier stage than creatinine in people with diabetes 2, 3
• Elevated cystatin C levels are independently associated with increased risk of major cardiovascular events, development of CKD, and cardiovascular and all-cause mortality 3, 5
• In the general population, elevated cystatin C is independently associated with diabetes (OR=5.37), male sex (OR=4.91), and decreased glomerular filtration 5

Managing Discordant Results

When eGFRcys differs significantly from eGFRcr:

• Use the combined eGFRcr-cys value for all clinical decisions, as it demonstrates superior performance across patient populations 2, 4
• If eGFRcys is higher than eGFRcr: creatinine is underestimating true kidney function (typically due to reduced muscle mass, malnutrition) 2
• If eGFRcys is lower than eGFRcr: seen in 1 in 4 people, more common in older adults, females, non-White individuals, and those with multiple medical conditions 6
• Large discrepancies where eGFRcys is lower are associated with medication-associated adverse events, acute kidney injury, cardiovascular disease, kidney failure, and all-cause mortality 6

Laboratory Reporting Standards

• Laboratories should use assays with calibration traceable to international standard reference materials 2, 3
• Report serum cystatin C concentration rounded to the nearest 0.01 mg/L 2, 3
• Report eGFRcys and eGFRcr-cys rounded to the nearest whole number relative to body surface area of 1.73 m² 2

Critical Pitfalls to Avoid

Do NOT rely on creatinine alone in:

• Elderly patients (systematically overestimates function) 4
• Patients with extremes of muscle mass 2, 3
• Patients with eGFRcr 45-59 mL/min/1.73 m² without albuminuria 1

Factors that affect cystatin C independent of GFR:

• Thyroid dysfunction: hypothyroidism increases cystatin C, hyperthyroidism decreases it 2, 3
• High inflammation states and high catabolic states 2
• Exogenous steroid use 2
• Active smoking (cystatin C has non-GFR determinants) 3
• Obesity and metabolic factors 3

When NOT to use cystatin C:

• Routine CKD monitoring after diagnosis is established 3
• When cost or availability is severely limited and creatinine-based estimates are adequate 3
• As a standalone marker—always use the combined equation when both markers are available 2, 3

Advantages of Cystatin C Over Creatinine Alone

• Independent of muscle mass, age, sex, and diet 2, 3, 7
• Produced at a constant rate by all nucleated cells 3
• Fewer non-GFR determinants compared to creatinine 2, 7
• More strongly associated with all-cause mortality and cardiovascular events 7
• Diagnostic accuracy of 90% in discriminating normal from reduced GFR, compared to 77% for creatinine 2

Monitoring Strategy After CKD Confirmation

• Repeat both creatinine and cystatin C in 3 months to confirm stability, as CKD diagnosis requires persistence of reduced eGFR for ≥3 months 2, 4
• Use serial eGFRcr-cys measurements for tracking kidney function changes, not creatinine alone 2, 4
• Assess for albuminuria if not already done, as this provides additional confirmation of kidney damage and guides prognosis 2, 4
• Consider nephrology referral if eGFRcr-cys confirms Stage 3b CKD (30-44 mL/min/1.73 m²) or worse, if albuminuria is present, or if difficulty managing complications 4