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, freely filtered by the glomerulus, and completely reabsorbed and catabolized by proximal tubular cells without returning to the bloodstream—making it an endogenous marker of kidney function that is independent of age, sex, and muscle mass. 1, 2, 3
Biochemical Characteristics
Cystatin C is a 120 amino acid peptide chain protein belonging to the family of papain-like cysteine protease inhibitors, with its main biological role being the extracellular inhibition of cathepsins 4, 5
The protein is produced at a constant rate by all nucleated cells throughout ages 1 to 50 years, making its production rate highly stable 6, 7
Due to its low molecular weight and positive isoelectric point (pI), cystatin C is freely filtered at the glomerular membrane 5, 7
After glomerular filtration, it is completely reabsorbed by proximal renal tubular cells where it undergoes full catabolism, with no secretion or reabsorption as an intact molecule back into the bloodstream 1, 8
Advantages Over Creatinine
Cystatin C is independent of age, sex, and muscle mass—the major confounders that limit creatinine's accuracy as a kidney function marker 1, 2, 3
It is not affected by nutritional status, gender, muscle mass, or malignancy, unlike serum creatinine 6
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, making cystatin C superior for detecting early renal impairment 8
In one study, cystatin C showed 93.4% sensitivity compared to 86.8% for creatinine, with 100% of patients with impaired renal function showing elevated cystatin C versus 92.15% for creatinine 8
Clinical Applications
The KDIGO guidelines recommend measuring cystatin C in adults with creatinine-based eGFR of 45-59 mL/min/1.73 m² who lack other markers of kidney damage when CKD confirmation is required 2, 3
Combining both creatinine and cystatin C in the eGFRcr-cys equation provides the most accurate GFR estimation, superior to either marker alone 2, 3
In cancer patients receiving nephrotoxic drugs like carboplatin and topotecan, cystatin C improves dose individualization to achieve target drug exposure and reduces toxicity risk 1
Cystatin C is particularly valuable in populations where creatinine is unreliable: patients with extremes of muscle mass, class III obesity, liver disease, malnutrition, and those on unusual diets 2
In cirrhosis patients, the combination of serum cystatin C and creatinine has the least bias in estimating GFR, though applicability to patients with ascites or on transplant waiting lists requires caution 1
Measurement and Reporting
Clinical laboratories must measure serum cystatin C using assays with calibration traceable to international standard reference materials 2, 3
Cystatin C concentration should be reported rounded to the nearest hundredth (0.01) when expressed in conventional units (mg/L) 2
The assay has improved precision compared to creatinine, which can display interassay variability as high as 25% at low concentrations 1
Important Limitations
Cystatin C levels can be affected by thyroid dysfunction, inflammation, smoking, and some types of cancer—factors unrelated to kidney function 2, 3
Despite its advantages, cystatin C assays are not widely available in many countries including the United States and Canada 2
The cost of cystatin C testing is higher than creatinine, though the combined panel remains affordable in high-income settings 2
The biggest barrier to widespread adoption is the lack of evidence demonstrating that more accurate GFR estimation with cystatin C actually improves patient outcomes or is cost-effective 2
Role in Risk Stratification
Elevated cystatin C levels are associated with increased risk of major cardiovascular events, development of chronic kidney disease, and cardiovascular and all-cause mortality 2, 4
Cystatin C markedly strengthens the association between eGFR and cardiovascular events, kidney failure, and death 2
Throughout the spectrum of cardiovascular disease (peripheral arterial disease, stroke, heart failure, coronary artery disease), high plasma cystatin C levels correlate with adverse outcomes 4