Non-Renal Factors Affecting Cystatin C Levels
Cystatin C levels are influenced by older age, obesity, cigarette smoking, inflammation (elevated CRP), diabetes, thyroid dysfunction, male sex, higher lean body mass, lower serum albumin, and higher white blood cell count—all independent of kidney function. 1, 2, 3, 4
Demographic and Anthropometric Factors
Age
- Cystatin C increases with advancing age independent of GFR, with levels rising approximately 0.004 mg/L per year after adjusting for vascular risk factors 5
- After adjustment for measured GFR, cystatin C is 4.3% lower for every 20 years of younger age 3
- The age effect is more pronounced in men than women 5
Sex and Gender
- Female sex is associated with 9.2% lower cystatin C levels after adjusting for measured GFR 3
- Male sex independently increases cystatin C levels beyond the effect of kidney function 4, 5
Race
- Black race is associated with only 1.9% lower cystatin C levels after GFR adjustment, a much smaller effect than seen with creatinine 3
Body Composition
- Lean body mass is a previously unrecognized but important factor affecting cystatin C levels, with greater lean mass associated with higher levels independent of GFR 6
- Greater weight and height are independently associated with higher cystatin C levels after adjusting for creatinine clearance 4
- Class III obesity affects cystatin C through non-GFR determinants, making the combined creatinine-cystatin C equation most accurate in this population 2
Lifestyle and Behavioral Factors
Smoking
- Current cigarette smoking is independently associated with higher serum cystatin C levels after adjusting for creatinine clearance 4, 5
- Cystatin C has non-GFR determinants in active smokers, and creatinine-based eGFR may be preferred if no changes to creatinine determinants are present 2
Dietary Factors
- Unlike creatinine, cystatin C is less dependent on dietary intake, making it advantageous for GFR estimation 1
- However, this does not mean cystatin C is completely unaffected by nutritional status 2
Medical Conditions
Diabetes
- Diabetes is associated with 8.5% higher cystatin C levels after adjustment for measured GFR 3
Thyroid Dysfunction
- Thyroid dysfunction can affect cystatin C levels independently of renal function 2
Inflammation and Acute Illness
- Higher C-reactive protein (CRP) levels are independently associated with higher cystatin C levels after adjusting for GFR 3, 4
- Higher white blood cell count is associated with higher cystatin C levels 3
- Lower serum albumin is associated with higher cystatin C levels 3
- Chronic illness and inflammation affect both creatinine and cystatin C in patients with malnutrition 2
Cancer
- High cell turnover cancers can affect cystatin C levels, reducing accuracy in frail cancer patients 2
Cardiovascular Disease
- Higher diastolic blood pressure is associated with higher cystatin C levels 5
- Lower HDL cholesterol is associated with higher cystatin C levels 5
Liver Disease
- Cystatin C can be affected in patients with chronic liver disease, though it remains more reliable than creatinine in this population 2
Clinical Implications
When to Exercise Caution
- Be cautious interpreting cystatin C in patients with older age, obesity, active smoking, elevated inflammatory markers, or thyroid dysfunction, as these factors can elevate levels independent of true kidney function 1, 2
Optimal Testing Strategy
- The combined creatinine-cystatin C equation (eGFRcr-cys) provides the most accurate GFR estimation because it accounts for the different non-GFR determinants affecting each marker 2
- When both markers are affected by non-GFR factors, the combined equation achieves 89% of estimates within 30% of measured GFR 2