Cystatin C Testing: What It Shows and Why It Matters for Athletes
Every year, plenty of healthy, muscular athletes get an unsettling note on their blood work: "eGFR low, possible kidney disease." In many cases the kidneys are fine and the culprit is the test itself. Creatinine, the standard marker, depends heavily on muscle mass. Cystatin C offers a second, largely muscle-independent way to estimate kidney function. Here is how it works and when it is worth requesting.
The creatinine problem in athletes
Creatinine is a breakdown product of creatine phosphate in muscle. It is filtered by the kidneys, so its blood level rises when kidney function falls. Labs plug creatinine, age and sex into an equation to calculate the estimated glomerular filtration rate (eGFR), reported in mL/min/1.73 m².
The equation assumes an average amount of muscle for a person's age and sex. Someone with substantially more muscle produces more creatinine, so their blood level is higher even with perfectly healthy kidneys. The calculated eGFR then appears lower than the true filtration rate.
Diet and supplements make it worse. Creatine supplements are converted into creatinine; a large portion of cooked meat a few hours before testing can temporarily raise levels; and intense exercise the day before can push values up as well. Baxmann and colleagues showed that muscle mass and physical activity strongly influenced serum creatinine but had little effect on cystatin C.
The result is a common clinical scenario: a bodybuilder or strength athlete with an eGFR in the 60s, which by number alone could suggest stage 2 or 3 chronic kidney disease, but whose kidneys are entirely normal.
What cystatin C is
Cystatin C is a small protein produced at a relatively constant rate by virtually all nucleated cells in the body. It is freely filtered by the glomeruli, then reabsorbed and broken down by the tubules, so it does not return to the blood. Its blood concentration therefore reflects how well the kidneys filter.
Because it does not come mainly from muscle, cystatin C is much less affected by muscle mass, diet or creatine supplementation. That makes it particularly useful for people at the extremes of body composition: very muscular athletes, as well as frail older adults and people with amputations or muscle-wasting diseases.
Results are reported in milligrams per liter (mg/L). Reference intervals vary by laboratory and assay, but in healthy younger adults values typically fall below about 1.0 mg/L. Labs standardized to the international reference material allow eGFR to be calculated from cystatin C alone or combined with creatinine.
Cystatin C has also been shown to predict cardiovascular events and mortality. Shlipak and colleagues found that eGFR based on cystatin C, alone or with creatinine, improved risk classification compared with creatinine alone across large cohorts.
Equations and what the numbers mean
Inker and colleagues showed in 2012 that the equation combining creatinine and cystatin C estimated GFR more accurately than either marker alone. In 2021, the same research group published updated CKD-EPI equations that do not include race, and the National Kidney Foundation and American Society of Nephrology task force recommended their adoption in the US, encouraging wider use of cystatin C.
| Approach | Strengths | Limitations |
|---|---|---|
| eGFR from creatinine | Cheap, universally available | Underestimates function in muscular people |
| eGFR from cystatin C | Largely independent of muscle mass | Affected by thyroid status, steroids, inflammation |
| eGFR from creatinine + cystatin C | Most accurate estimate in most groups | Costlier, not always ordered routinely |
| Measured GFR (e.g., iohexol clearance) | Reference standard | Specialist test, rarely needed |
KDIGO guidelines suggest measuring cystatin C in adults with a creatinine-based eGFR between 45 and 59 who have no other markers of kidney damage, to confirm whether chronic kidney disease is truly present. That recommendation fits the athletic scenario well.
If both creatinine and cystatin C estimates are low, kidney function is likely genuinely reduced. If cystatin C is normal while creatinine suggests a problem, muscle mass is the probable explanation, though other findings such as urine albumin still need review.
Factors that affect cystatin C
Cystatin C is not perfect. Several conditions change its production independent of kidney function, and these need to be considered when interpreting results:
- Thyroid function: hyperthyroidism raises cystatin C; hypothyroidism lowers it. This includes people misusing thyroid hormone for fat loss.
- Corticosteroids: high-dose glucocorticoids increase cystatin C.
- Inflammation and obesity: both are associated with higher levels.
- Smoking: associated with modestly higher values.
- Some cancers and HIV: may raise cystatin C.
Anabolic steroid use poses its own interpretation challenges. It increases muscle mass and therefore creatinine, but, more importantly, high doses have been associated in case reports with genuine kidney injury, including focal segmental glomerulosclerosis. In such cases, cystatin C can help distinguish real damage from a muscle-mass artifact.
Anyone with abnormal results should also have a urine albumin-to-creatinine ratio, urinalysis and blood pressure checked, since these reveal kidney damage that eGFR alone can miss.
Practical tips for athletes
To get a reliable picture of kidney function, preparation matters. Avoid heavy training for 24 to 48 hours before a blood draw, stay well hydrated and skip a large meat meal the evening before. If you take creatine, tell your physician, as it will raise creatinine but not cystatin C.
If your report flags a low creatinine-based eGFR, ask whether a cystatin C test is appropriate rather than accepting a diagnosis based on a single value. Many US labs offer it, and insurers increasingly cover it when clinically justified.
Keep copies of your results over time. Trends are often more informative than a single value, and a stable baseline helps your doctor recognize a meaningful change.
Finally, do not use a normal cystatin C result as a reason to ignore other warning signs such as high blood pressure, foamy urine or swelling.
Conclusions of the Editorial Team
Creatinine-based eGFR can underestimate kidney function in muscular athletes, sometimes leading to a mistaken diagnosis of kidney disease. Cystatin C, largely independent of muscle mass, provides a valuable cross-check.
The combined creatinine–cystatin C equation is the most accurate routine estimate. Cystatin C has its own confounders, including thyroid status and steroid medications, so results always need clinical interpretation.
For more on this topic, see our articles on creatine and kidney markers, how training affects liver enzyme tests and blood pressure monitoring for strength athletes.
References
- 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):20–29.
- Inker LA, Eneanya ND, Coresh J, et al. New creatinine- and cystatin C–based equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737–1749.
- Delgado C, Baweja M, Crews DC, et al. A unifying approach for GFR estimation: recommendations of the NKF-ASN Task Force on reassessing the inclusion of race in diagnosing kidney disease. Am J Kidney Dis. 2022;79(2):268–288.
- Shlipak MG, Matsushita K, Ärnlöv J, et al. Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med. 2013;369(10):932–943.
- 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):348–354.
- Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3(1):1–150.
