Cystatin C vs Creatinine: Which Test Measures Kidney Function Better?

Creatinine is produced in skeletal muscle: creatine and phosphocreatine slowly and non-enzymatically convert to creatinine at a roughly constant rate proportional to muscle mass. It enters the blood, is freely filtered in the kidney glomeruli, and a part is additionally secreted by the tubules. Its blood level is therefore the result of three things: production (muscle, diet), filtration (kidneys) and tubular secretion. That is why we reach true glomerular filtration rate (GFR) only indirectly, through an equation that accounts for age and sex and assumes an 'average' muscle mass.

Cystatin C is a small protein (about 13 kDa) produced at a roughly constant rate by virtually all nucleated cells in the body. It is freely filtered in the glomeruli and then almost completely taken up and broken down in the proximal tubules, so it does not return to the blood and does not appear in the urine of a healthy person. This means its blood level mainly reflects glomerular filtration and does not depend directly on muscle or on meat in the diet.

The difference has practical consequences. A creatinine result reported in mg/dl (or µmol/l; the conversion is 88.4 µmol/l per 1 mg/dl) changes after a large meat meal, after hard exercise and with dehydration. Cystatin C, usually reported in mg/l, reacts less to such factors, although, as we will see, it has its own sources of interference. Reference ranges for both markers differ between laboratories and assay methods, so always interpret a result against the range printed on your own lab report rather than a 'universal' number from the internet.

Laboratories usually report, next to creatinine, a calculated eGFR (estimated glomerular filtration rate, in ml/min/1.73 m²). The current standard is the 2021 CKD-EPI equations, without a race term, in three versions: creatinine only (eGFRcr), cystatin C only (eGFRcys) and combined (eGFRcr-cys). The combined equation uses both markers at once, so the errors of each partly cancel out because they have different non-kidney determinants.

This is important: eGFR is still an estimate, not a measurement. True GFR is measured with clearance methods (for example using iohexol), which are costly and used mainly in special situations such as kidney donor evaluation. In everyday practice, choosing between eGFRcr, eGFRcys and eGFRcr-cys is a choice about how much we want to reduce the chance of a wrong call in a particular person.

What does this mean for an individual? First, cystatin C can sort people better by risk: someone whose eGFR rises after cystatin C is added statistically has a lower risk than creatinine alone suggested, and someone whose eGFR falls has a higher one. Second, the higher share of people below an eGFR of 60 with cystatin C does not mean there are suddenly more sick people, only that some people previously 'hidden' behind high muscle mass or other non-kidney factors are classified more accurately.

eGFRcr equations assume an average muscle mass for age and sex. If yours is clearly different, the result shifts one way or the other. High muscle mass (bodybuilders, people who strength-train) raises creatinine and lowers the calculated eGFR even though the kidneys may be working very well. Conversely, low muscle mass (sarcopenia in older people, prolonged immobilisation, malnutrition, amputations, advanced liver disease) lowers creatinine and can mask truly reduced filtration: the result looks 'nice' simply because there is little creatinine.

Practical takeaway: in older people the eGFR from creatinine is often noticeably higher than the eGFR from cystatin C, not because either result is 'wrong' but because creatinine partly reflects how little muscle is left. In young, well-built athletes the relationship is the opposite. A broader discussion of how large muscle mass affects creatinine is in our knowledge-base entry on creatinine and eGFR.

In addition, creatinine responds to freshly cooked meat eaten before the test (cooking converts creatine in meat into creatinine) and to creatine supplementation. These are usually small, reversible swings, but in someone whose result sits right at a threshold they can decide whether the calculated eGFR falls below 60. That is why, before a follow-up creatinine test, it is worth following the instructions about the last meal and supplements, which we describe in separate articles on meat before the test and on stopping creatine.

Cystatin C is not perfect. A large population study from Groningen (8,058 people) found that, after adjusting for creatinine clearance, higher cystatin C was independently associated with older age, male sex, greater weight and height, cigarette smoking and higher CRP. The authors concluded that cystatin C depends on factors other than the kidneys and that they found no evidence that multivariable models based on cystatin C were superior to those based on creatinine.

Thyroid function is particularly relevant. In a cross-sectional study of 8,126 men, cystatin C was significantly raised and eGFR from cystatin C lowered in both subclinical hypothyroidism and subclinical hyperthyroidism, while creatinine behaved differently. The authors advise against assessing the kidneys with cystatin C alone in people with thyroid dysfunction. So if your TSH is uncontrolled, the cystatin C-based eGFR may be understated without real kidney damage; more on interpreting TSH is in our entry on thyroid hormones.

The KDIGO 2024 guideline on chronic kidney disease recommends using eGFRcr-cys where the creatinine-based eGFR is less reliable or when confirmation of the diagnosis is needed. This does not mean everyone should test cystatin C 'just in case'. Reasonable situations are mainly those where muscle mass differs greatly from average or the creatinine result does not fit the rest of the picture.

In Poland, cystatin C is usually an add-on test, and availability, price and funding depend on the laboratory and the referral, so it is worth asking in advance. The blood draw needs no special preparation beyond what applies to creatinine: avoid heavy exercise the day before, keep normal hydration and do not eat freshly cooked meat right before the test.

When the two values are similar, it is simple: the picture is consistent and there is no reason for further analysis. When they diverge, the question is which marker is distorted by a non-kidney factor. If eGFRcys is clearly lower than eGFRcr, possible causes are low muscle mass (creatinine overstates filtration), inflammation, obesity, smoking, thyroid disorders, or genuinely reduced filtration hidden behind a 'nice' creatinine. If eGFRcr is clearly lower than eGFRcys, the usual suspects are high muscle mass, creatine supplementation, fresh meat in the diet, or drugs that inhibit tubular secretion of creatinine.

Limitations: the studies described mainly involve Western populations, and the 2021 CKD-EPI equations were validated in selected cohorts, so accuracy may be lower in people with unusual body composition, in pregnancy, at very high body weight or in children. Cystatin C is also not a screening test for people without risk factors: overusing it leads to finding minor deviations of no clinical significance. Reference ranges and units differ between laboratories, so always discuss the result with a doctor against the whole clinical picture: blood pressure, glycaemia, urine test and coexisting conditions.

The good news is that the question 'creatinine or cystatin C' is rarely an either-or. Large analyses show the two markers carry complementary information, and their mismatch is a useful diagnostic signal, not a measurement error. If you are physically active, carry a lot of muscle or take creatine, before you worry about a raised creatinine ask your doctor for cystatin C and an albuminuria test. If you are older and your creatinine looks excellent, do not treat that as a guarantee; that is exactly when cystatin C tends to be most informative.