Why might cystatin C be preferred over creatinine in some people?

Cystatin C production is less dependent on muscle mass, so it can give a more reliable estimate of glomerular filtration rate in people whose muscle mass is unusually high or low and in whom creatinine would mislead.

Is cystatin C a perfect filtration marker?

No. Although it depends mainly on filtration, its level can be affected by factors such as inflammation and thyroid status, so like creatinine it has non-GFR determinants, which is one reason combined equations are used.

Cystatin C as Alternative GFR Marker

Cystatin C is a small, freely filtered protein used as an alternative or complementary marker of glomerular filtration rate. As a low-molecular-weight cysteine-protease inhibitor produced by nearly all nucleated cells at a fairly constant rate, its blood level is largely determined by filtration and is less dependent on muscle mass than creatinine.

Definition

Cystatin C is a 13-kilodalton cysteine-protease inhibitor produced by nucleated cells at a relatively constant rate, freely filtered at the glomerulus and reabsorbed and catabolised by the proximal tubule, whose serum concentration is used to estimate glomerular filtration rate.

Scope

This topic covers the biochemistry of cystatin C, the basis for using it to estimate glomerular filtration rate, and how it complements creatinine-based estimation, including combined equations. It treats cystatin C as a clinical-biochemistry marker and does not provide diagnostic thresholds or treatment guidance.

Key concepts

Low-molecular-weight protein freely filtered at the glomerulus
Near-constant production by nucleated cells
Proximal-tubular reabsorption and catabolism (not returned to blood)
Reduced dependence on muscle mass relative to creatinine
Combined creatinine-and-cystatin-C estimating equations
Non-GFR determinants (e.g. inflammation, thyroid status)
Assay standardisation against a reference material

Mechanisms

Cystatin C is synthesised by essentially all nucleated cells and released into blood at a relatively stable rate that is largely independent of muscle mass, sex, and diet. Because of its small size and lack of significant plasma-protein binding, it is freely filtered at the glomerulus; the filtered protein is then almost completely reabsorbed and catabolised by proximal tubular cells rather than returned to the circulation. Its serum concentration therefore depends mainly on glomerular filtration rate, making it a useful endogenous filtration marker whose determinants differ from those of creatinine. Estimating equations use cystatin C alone or combined with creatinine, and the combined equation can improve accuracy by averaging out the non-GFR errors specific to each marker. Cystatin C levels can nonetheless be influenced by factors such as inflammation and thyroid function, so it is not entirely free of non-GFR determinants.

Clinical relevance

Cystatin C provides an alternative filtration marker that is useful when creatinine-based estimates are unreliable, such as in people with atypical muscle mass, and combined creatinine-cystatin C equations can refine the estimate of glomerular filtration rate. The topic describes what the marker measures and its determinants for interpretation and appraisal; it is not a basis for individual diagnosis or treatment.

History

Cystatin C was identified as a candidate GFR marker because its production is more stable across body composition than creatinine generation. Equations to estimate GFR from cystatin C, and especially the combined creatinine-cystatin C equation reported by Inker and colleagues in 2012, established its role as a complementary marker that improves accuracy when added to creatinine, supported by assay standardisation against a common reference material.

Debates

When should cystatin C be used instead of, or together with, creatinine?: Cystatin C is less affected by muscle mass but is influenced by other non-GFR factors such as inflammation; whether to use it alone, combined with creatinine, or as a confirmatory test depends on the clinical context and on the trade-off between the different error sources of each marker.

Key figures

Lesley A. Inker
Andrew S. Levey
Josef Coresh

Seminal works

inker-2012

Frequently asked questions

Why might cystatin C be preferred over creatinine in some people?: Cystatin C production is less dependent on muscle mass, so it can give a more reliable estimate of glomerular filtration rate in people whose muscle mass is unusually high or low and in whom creatinine would mislead.
Is cystatin C a perfect filtration marker?: No. Although it depends mainly on filtration, its level can be affected by factors such as inflammation and thyroid status, so like creatinine it has non-GFR determinants, which is one reason combined equations are used.