Use of cystatin C to estimate GFR
Cystatin C is a 13,347 Dalton protein consisting of 120 amino acid residues. It is expressed in all nucleated cells and is reported to be produced at a relatively constant rate.14
Circulating cystatin C levels were originally considered to have minimal non-GFR determinants, but it is now recognized that there is some variation in generation among and within people. Serum cystatin C concentrations are higher in men and in younger individuals compared with older people.
Levels are increased with high-dose glucocorticoid therapy and hyperthyroidism. Higher blood cystatin C levels have also been reported in smokers and in association with high C-reactive protein levels and greater fat mass. There appears to be extra-renal elimination at lower levels of GFR. These factors may affect the accuracy of estimating equations based on cystatin C (Table 1).
The CKD-EPI group developed and evaluated equations using cystatin C alone and in combination with creatinine in a diverse population.15 The CKD-EPI cystatin C equation (eGFRcys) also includes age and sex, although of smaller magnitude than for the creatinine equation, but importantly does not include a term for race.
In the combined creatinine and cystatin C equation (eGFRcr-cys), the coefficients for serum creatinine and cystatin C are approximately half the magnitude of the coefficients in equations with the creatinine and cystatin C equations, and the age, sex, and race coefficients are intermediate between the creatinine and cystatin C equations.
Evaluation in the validation populations separate from which the equations were developed showed similar accuracy of eGFRcys and eGFRcr but higher accuracy of eGFRcr-cys.
There were few African Americans in the validation population, and the lack of a race term in the cystatin C estimating equation will therefore require further evaluation. Performance in other subgroups showed uniform higher accuracy of eGFRcr-cys over eGFRcr and eGFRcys, with a greater accuracy of eGFRcys over eGFRcr for subgroups with lower BMI, and lesser accuracy at higher BMI.16 The lesser accuracy of eGFRcys at higher levels of BMI is thought to be secondary to the relationship of fat mass to cystatin C generation.
There were small differences in accuracy in people according to diabetes status. Based on a small number of studies, the performance of the CKD-EPI cystatin C equation is better than the CKD-EPI creatinine equation in regions outside North America, Europe, and Australia, and requires less or no modification by a local coefficient.17,18
Other studies have confirmed the findings that eGFRcr-cys is more precise than eGFRcr or eGFRcys and that eGFRcys may not require a local coefficient for racial or ethnic groups.19-22 In addition, other investigations, including a large meta-analysis, have demonstrated that eGFRcys and eGFRcr-cys provide better estimates of risk than eGFRcr.23
The gold standard for the measurement of GFR is urinary clearance of an ideal filtration marker, defined as a substance that is freely filtered at the glomerulus, neither reabsorbed, secreted, synthesized, or metabolized by the tubules, and does not alter the function of the kidney. Inulin, a 5,200-dalton, inert, uncharged polymer of fructose, is the only known ideal filtration marker.
However, inulin is difficult to handle and the procedures are invasive. Because of these disadvantages, we use alterative clearance methods and filtration markers. Below is a brief description of methods that could be used in clinical practice in the U.S. at this time.
The details of the comparisons of the accuracy of these methods are beyond the scope of this article and have been reviewed elsewhere.24,25