What is Cystatin C?
Cystatin C is a low molecular weight protein (13 kDa) from the cystatin superfamily of cysteine proteinase inhibitors that is produced at a constant rate by all nucleated cells and serves as an endogenous marker of glomerular filtration rate (GFR). 1
Biochemical Properties
Cystatin C is a non-glycosylated protein consisting of 120 amino acid residues with a molecular mass of approximately 13,343-13,359 Da. 2 The protein exhibits several key characteristics that make it valuable for assessing kidney function:
- Constant production rate: All nucleated cells produce cystatin C at a steady rate, independent of external factors. 1, 3
- Free glomerular filtration: The protein is freely filtered at the glomerulus without restriction. 4
- Tubular handling: After filtration, cystatin C is reabsorbed by proximal tubular epithelial cells and completely catabolized, so it does not return to the bloodstream. 1
- Independence from demographic factors: Unlike creatinine, cystatin C levels are not significantly affected by age (in individuals 1-50 years), sex, or muscle mass. 1, 3
Clinical Advantages Over Creatinine
Cystatin C addresses several critical limitations of serum creatinine as a kidney function marker:
- Earlier detection of renal impairment: Cystatin C begins to rise when GFR falls to 88 mL/min/1.73 m², whereas creatinine only increases when GFR drops to 75 mL/min/1.73 m². 4
- Higher sensitivity: Studies demonstrate 93.4% sensitivity for cystatin C compared to 86.8% for creatinine in detecting impaired renal function. 4
- Superior accuracy in specific populations: Cystatin C is particularly valuable in elderly patients, those with low muscle mass, malnutrition, liver disease, and cancer patients receiving nephrotoxic drugs. 1, 5
Clinical Applications and Guidelines
The KDIGO guidelines recommend measuring cystatin C in adults with eGFRcreat 45-59 mL/min/1.73 m² who do not have markers of kidney damage if confirmation of chronic kidney disease is required. 6, 5
GFR Estimation Equations
Three main approaches exist for using cystatin C to estimate GFR:
- eGFRcys: Uses cystatin C alone
- eGFRcreat: Uses creatinine alone
- eGFRcreat-cys: Combines both markers (most accurate approach) 6, 5
The combined creatinine-cystatin C equation (eGFRcreat-cys) provides superior accuracy compared to either marker alone and should be used when available. 6, 5 In liver transplant recipients specifically, cystatin C-based equations demonstrate the most accurate estimation of measured GFR (r²=0.78-0.83) compared to creatinine-based formulas (r²=0.76-0.77). 1
Specific Clinical Scenarios
In cancer patients receiving cytotoxic drugs, cystatin C improves dose individualization to achieve target drug exposure and reduces toxicity risk. 1 Models incorporating both cystatin C and serum creatinine were superior to single-marker models for predicting carboplatin clearance. 1
For elderly cancer patients, cystatin C showed no difference from creatinine-based equations except in patients with severe malnutrition and/or inflammation. 1
Important Limitations and Caveats
Despite its advantages, several factors can affect cystatin C levels independent of renal function:
- Thyroid dysfunction: Both hypo- and hyperthyroidism alter cystatin C levels. 1, 5
- Inflammation and malignancy: These conditions may elevate cystatin C. 1, 5
- Glucocorticoid use: Corticosteroids can influence cystatin C production. 7
Practical Implementation Barriers
- Limited availability: Cystatin C assays are not widely available in many countries, including the United States and Canada. 6
- Higher cost: Testing costs more than creatinine, though the "triple marker" panel (creatinine, cystatin C, and urine albumin-to-creatinine ratio) is considered affordable in high-income settings. 6
- Lack of effectiveness data: The biggest implementation barrier is insufficient evidence of cost-effectiveness. 6
Laboratory Considerations
Clinical laboratories should measure serum cystatin C using assays with calibration traceable to international standard reference materials. 6, 5 Results should be reported rounded to the nearest hundredth (0.01 mg/L). 6, 5
Prognostic Value Beyond GFR
Cystatin C provides additional prognostic information beyond kidney function assessment:
- Cardiovascular risk: Elevated cystatin C levels associate with increased risk of major cardiovascular events and mortality. 6
- Risk stratification: In the general population, individuals with eGFRcys <60 mL/min/1.73 m² face higher risk for death and cardiovascular disease, even when eGFRcreat >60 mL/min/1.73 m². 1
However, the prognostic superiority of cystatin C over creatinine remains controversial in some populations, particularly kidney transplant recipients. 1