Why do labs need a marker in addition to creatinine to estimate glomerular filtration rate (GFR)?

A: Creatinine is a byproduct of muscle metabolism that is freely filtered by the kidney, the blood concentration of which reflects GFR. However, because muscle mass varies depending on age, sex, race, and level of fitness, the serum concentration of creatinine can still differ between individuals with the same level of kidney function.

The most recent equations for estimating GFR get around this issue to some extent by adjusting for age, sex, and race, which account for much of the inter-individual variability in muscle mass. The equations do not account for other factors that might be important, though, such as chronic illness, malnutrition, or even a larger-than-average muscle mass.

What are the advantages of cystatin C versus creatinine?

Cystatin C is made by all nucleated cells, not just muscle. As a result, cystatin C production varies less than creatinine production between individuals, and blood concentrations of cystatin C are fairly similar between individuals who have the same GFR. However, cystatin C has other potential confounders. For example, chronic inflammation seems to increase cystatin C blood concentrations slightly. Perhaps for this reason, relatively higher blood cystatin C concentrations seem to be a poor prognostic marker.

Overall, when modern equations are used creatinine and cystatin C are, on average, fairly comparable tools for estimating GFR. However, in certain patient populations one may be better than the other, as my research group recently found (Clin Chem 2015;61:1265–72).

How do different assays for cystatin C compare with each other?

Over the last 15 years clinical laboratories and manufacturers have strived to standardize serum creatinine measurement across virtually all platforms. They are in the early phases of a similar process with cystatin C. An international reference material for cystatin C (ERM-DA471/IFCC) was released in June 2010 and certain assays are traceable to this material. As of 2016, though, biases might still exist between commercially available cystatin C assays.

Should cystatin C be used by itself or with other markers?

With modern estimating equations, serum creatinine can be used to obtain an estimated GFR (eGFR) for most individuals that can adequately guide clinical decision making. However, cystatin C is a helpful adjunct in certain subsets of patients. Importantly, cystatin C can be useful when a healthcare provider suspects that a patient’s muscle mass differs from average for his or her age and sex.

Another important setting where cystatin C might have an advantage is among hospitalized patients. In acutely ill individuals GFR often changes rapidly, and cystatin C tends to track this more accurately due to its shorter blood half-life. Muscle mass can also decline rather abruptly in the hospital, further confounding the relationship between GFR and creatinine. Overall, the optimal use of cystatin C among acutely hospitalized patients is an area ripe for further research.

A third approach is applying the combined Chronic Kidney Disease Epidemiology Collaboration equation that uses both cystatin C and creatinine. In effect this averages together the errors of each biomarker alone, since the confounders differ between the two. Personally, I favor using both biomarkers and eGFR equations separately, since differences in the respective eGFRs can provide helpful insights.

How can cystatin C and creatinine be used together to identify and stage patients with chronic kidney disease (CKD)?

I find cystatin C a very useful tool for evaluating CKD patients. If the cystatin C eGFR is greater than the creatinine eGFR, this is usually reassuring. On the other hand, if the cystatin C eGFR is lower than the creatinine eGFR, such individuals appear to have a worse prognosis. This group might benefit the most from intensive efforts to reduce CKD risk factors to the greatest extent possible.

John C. Lieske, MD, is professor of medicine and medical director of the Renal Testing Laboratory at Mayo Clinic, Rochester, Minnesota. +Email: Lieske.John@mayo.edu