What are the reasons for falsely elevated cystatin C (Cystatin C) levels?

Causes of Falsely Elevated Cystatin C Levels

Cystatin C levels can be falsely elevated due to various non-renal factors including inflammatory states, high-dose steroid use, thyroid dysfunction, smoking, and certain chronic illnesses, necessitating careful interpretation when using it for GFR estimation. 1

Physiological and Pathological Factors

Inflammatory Conditions

• Serious infections and inflammatory states can increase cystatin C production independent of kidney function 1
• Elevated C-reactive protein (CRP) levels are independently associated with higher serum cystatin C levels 2

Metabolic and Endocrine Factors

• Thyroid dysfunction:
  • Hyperthyroidism significantly increases cystatin C levels (62% of hyperthyroid patients show elevated values) 3
  • Hypothyroidism decreases cystatin C levels 3
  • Normalization of thyroid function restores normal cystatin C concentrations 3
• Obesity class III (BMI >40 or >35 kg/m²) affects non-GFR determinants of cystatin C 1

Medication Effects

• High-dose steroid use (anabolic or hormone) can alter cystatin C levels 1
• Gender-affirming hormone therapy may affect cystatin C-based equations 1

Demographic and Lifestyle Factors

• Older age is independently associated with higher cystatin C levels 2
• Male gender is associated with higher cystatin C levels after adjusting for creatinine clearance 2
• Current cigarette smoking increases cystatin C levels 2
• Greater weight and height are associated with higher cystatin C levels 2

Disease States Affecting Cystatin C

High Cell Turnover Conditions

• Cancer with high cell turnover rates can increase cystatin C production 1
• Hematologic malignancies may affect cystatin C levels 1

Chronic Illnesses

• Advanced cirrhosis affects non-GFR determinants of cystatin C 1
• Heart failure (especially advanced) can alter cystatin C levels 1
• Catabolic states including:
  • Tuberculosis
  • AIDS
  • Severe skin diseases 1
• Muscle-wasting diseases show large bias for cystatin C-based GFR estimates 1

Clinical Implications

When to Suspect False Elevation

• When there's a discrepancy between cystatin C-based GFR and clinical presentation
• In patients with known inflammatory conditions but stable kidney function
• When cystatin C levels change rapidly without corresponding changes in kidney function

Alternative Approaches

• For patients with factors that may falsely elevate cystatin C:
  • Use combined creatinine and cystatin C-based estimated GFR (eGFRcr-cys) for routine evaluation 1
  • Consider measured GFR (mGFR) using exogenous filtration markers for critical treatment decisions 1
  • In very frail patients or those with serious comorbidities, measured GFR may be necessary 1

Practical Considerations

• The 2024 KDIGO guidelines recommend using eGFRcr-cys in clinical situations when eGFRcr is less accurate and GFR affects clinical decision-making 1
• For transgender and gender-diverse individuals on hormone therapy, cystatin C may be preferred as it is less dependent on muscle mass, though factors like smoking and obesity still influence results 1
• When more accurate GFR assessment will impact treatment decisions (e.g., oncology drug dosing, kidney donor eligibility), measured GFR is recommended 1

Remember that while cystatin C is often considered superior to creatinine for GFR estimation, it is still influenced by non-renal factors that must be considered for accurate interpretation of kidney function.