Cystatin C is relatively new for general practice, but is already a well-studied marker of kidney function. For people with a lot of muscle mass who take creatine or follow a protein diet, it often gives a more accurate picture than regular creatinine. The editors tell what kind of protein it is, how the analysis works and in which situations an athlete should take it.
What is cystatin C
Cystatin C is a small protein with a mass of about 13 kilodaltons that belongs to the family of cysteine protease inhibitors. Its physiological role is to regulate the activity of enzymes that break down proteins inside and outside cells. For laboratory diagnostics, it is not the function of the protein that is important, but the features of its formation and excretion.
Cystatin C is synthesized by almost all cells of the body that have a nucleus, and at a relatively constant rate. Unlike creatinine, its formation is almost not related to muscle mass. It is this property that makes protein an attractive marker for people with atypical physiques - both very thin and very muscular.
Due to its small size, cystatin C is freely filtered through the kidney glomerular filter. Next, the cells of the proximal tubules completely capture and split it, so the protein practically does not enter the urine, and it does not return to the blood. Therefore, the concentration of cystatin C in the blood is determined mainly by the rate of glomerular filtration.
Due to such an "exchange scheme", the clearance of cystatin C in urine cannot be measured - it can only be estimated by its concentration in the serum with subsequent calculation of GFR using special equations.
How the analysis works and what it shows
Cystatin C is determined in blood serum by the immunoturbidimetric or immunonephelometric method. The result is expressed in milligrams per liter. The reference intervals depend on the method and the calibrator: in most laboratories, the upper limit for adults is about 1.0 mg/L, for the elderly it is slightly higher. It is important that the laboratory uses a method standardized to an international reference material.
On its own, cystatin C concentration is interpreted in the same way as creatinine: the higher the value, the lower the filtration. But the main value of the analysis is in the calculation of eGFR. For this, there are CKD-EPI equations based on cystatin C, as well as combined equations that take into account both creatinine and cystatin C at the same time.
A study by Inker et al. (2012) showed that the combined equation is more accurate than each marker separately. Later, the same group (2021) developed updated equations without the race factor, and it was the combined version that showed the best fit to measured GFR.
| Characteristics | Creatinine | Cystatin C |
|---|---|---|
| Source | Muscles (creatine), food | All nucleated cells |
| Dependence on muscle mass | Strong | Minimal |
| Effect of creatine and meat | Yes | Practically none |
| Tubular secretion | Small | None |
| What else does it react to | Some drugs that block secretion | Thyroid function, glucocorticoids, inflammation |
| Cost and availability | Low, everywhere | Higher, not in every laboratory |
Cystatin C also has prognostic value. A meta-analysis by Shlipak et al (2013) in the New England Journal of Medicine found that eGFR by cystatin C was more strongly associated with risk of death, cardiovascular events, and end-stage renal disease than eGFR by creatinine.
Why it is important for an athlete
In sports medicine, the main problem of creatinine is its dependence on muscles. A muscular athlete using creatine and plenty of protein can have a creatinine above normal and an eGFR in the "gray zone" with perfectly healthy kidneys. Cystatin C allows you to check if filtration is really reduced.
A study by Baxmann et al. (2008) compared markers in people with different muscle mass and activity level. Serum creatinine was correlated with muscle mass, while cystatin C had practically no such dependence. This makes cystatin C a logical "second test" for athletes.
Another situation is athletes who lose weight or have low muscle mass, for example in aesthetic or weight sports. In them, creatinine can be "deceptively normal" with a real decrease in GFR. Cystatin C helps not to miss the problem.
Finally, cystatin C is useful for people who use potentially nephrotoxic substances and want creatine-independent control, so that every dose of creatine will not distort the picture.
When the analysis is recommended by the guidelines
International KDIGO guidelines recommend using creatinine as the primary test and cystatin C as a confirmatory test when the accuracy of eGFR by creatinine is in doubt. This is exactly what happens in people with unusual muscle mass, with significant changes in diet, in vegans or people who take creatine.
The guidelines also advise determining cystatin C to confirm the diagnosis of chronic kidney disease in people with a creatinine eGFR in the range of 45–59 ml/min/1.73 m² without other signs of kidney damage. If cystatin eGFR or combined eGFR is greater than 60, the diagnosis is not confirmed.
- Athletes with large muscle mass and creatinine above normal.
- Persons who take creatine and do not wish to interrupt the intake before the examination.
- People with very low muscle mass, vegetarians and vegans.
- Patients requiring accurate GFR for medication dosing.
- Contradictory results: high creatinine without albuminuria and other changes.
At the same time, cystatin C does not replace urine tests. Albuminuria remains an independent marker of kidney damage, and only together with GFR does it provide a complete picture of stage and risk.
Restrictions and preparation for analysis
Despite its muscle independence, cystatin C is not perfect. Its level increases with hyperthyroidism and decreases with hypothyroidism, increases against the background of taking glucocorticoids in high doses, with systemic inflammation, obesity, and in smokers. The doctor takes these factors into account during interpretation.
For athletes who use hormonal drugs, it is worth remembering: drugs that affect the thyroid gland or contain corticosteroids can change the level of cystatin C regardless of kidney function. Therefore, during the examination, the doctor needs to know the full list of drugs.
The short-term effects of exercise on cystatin C are less well studied than on creatinine, but dehydration and strenuous exercise potentially alter any filtration markers. It is logical to take the test under standard conditions: in the morning, on an empty stomach, after 1-2 days without heavy training and with normal hydration.
Since the methods of determination may differ, it is worth using the same laboratory for observation in dynamics. It is preferable to combine the assay with creatinine in the same sample so that the laboratory or physician can calculate the combined eGFR.
Editorial conclusion
Cystatin C is a marker of glomerular filtration rate, which is almost independent of muscle mass, creatine and meat diet. That is why it is especially useful for athletes whose creatinine often "lies".
The combined eGFR based on creatinine and cystatin C provides the most accurate assessment of kidney function. The analysis does not replace a urine test and has its own limitations — the influence of the thyroid gland, glucocorticoids, and inflammation.
The editors also recommend reading "Cystatin C above or below the norm: causes in athletes and what to do", "Creatinine: what the analysis shows and why it is important for the athlete" and our material on health control against the background of a high-protein diet.
References
- Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117âS314.
- Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20â29.
- Inker LA, Eneanya ND, Coresh J, et al. New creatinine- and cystatin Câbased equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737â1749.
- Shlipak MG, Matsushita K, Ãrnlöv J, et al. Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med. 2013;369(10):932â943.
- Baxmann AC, Ahmed MS, Marques NC, et al. Influence of muscle mass and physical activity on serum and urinary creatinine and serum cystatin C. Clin J Am Soc Nephrol. 2008;3(2):348â354.
- Fricker M, Wiesli P, Brändle M, et al. Impact of thyroid dysfunction on serum cystatin C. Kidney Int. 2003;63(5):1944â1947.
