Cystatin C

Cystatin C or cystatin 3 (formerly gamma trace, post-gamma-globulin or neuroendocrine basic polypeptide), a is_associated_with::protein encoded by the CST3 is_associated_with::gene, is mainly used as a is_associated_with::biomarker of is_associated_with::kidney function. Recently, it has been studied for its role in predicting new-onset or deteriorating is_associated_with::cardiovascular disease. It also seems to play a role in brain disorders involving is_associated_with::amyloid (a specific type of protein deposition), such as is_associated_with::Alzheimer's disease. In humans, all cells with a nucleus (cell core containing the is_associated_with::DNA) produce cystatin C as a chain of 120 is_associated_with::amino acids. It is found in virtually all tissues and body fluids. It is a potent inhibitor of lysosomal is_associated_with::proteinases (is_associated_with::enzymes from a special subunit of the cell that break down proteins) and probably one of the most important is_associated_with::extracellular inhibitors of is_associated_with::cysteine proteases (it prevents the breakdown of proteins outside the cell by a specific type of protein degrading enzymes). Cystatin C belongs to the type 2 is_associated_with::cystatin is_associated_with::gene family.

Kidney function
Glomerular filtration rate (GFR), a marker of kidney health, is best measured by injecting compounds such as is_associated_with::inulin, is_associated_with::radioisotopes such as 51chromium-is_associated_with::EDTA, 125I-iothalamate, 99mTc-is_associated_with::DTPA or is_associated_with::radiocontrast agents such as is_associated_with::iohexol, but these techniques are complicated, costly, time-consuming and have potential side-effects. Creatinine is the most widely used is_associated_with::biomarker of kidney function. It is inaccurate at detecting mild renal impairment, and levels can vary with muscle mass and protein intake. Formulas such as the Cockcroft and Gault formula and the MDRD formula (see is_associated_with::Renal function) try to adjust for these variables.

Cystatin C has a low is_associated_with::molecular weight (approximately 13.3 is_associated_with::kilodaltons), and it is removed from the bloodstream by is_associated_with::glomerular filtration in the kidneys. If kidney function and glomerular filtration rate decline, the blood levels of cystatin C rise. Serum levels of cystatin C are a more precise test of kidney function (as represented by the is_associated_with::glomerular filtration rate, GFR) than serum is_associated_with::creatinine levels. This finding is based mainly on cross-sectional studies (on a single point in time). Longitudinal studies (that follow cystatin C over time) are scarcer; some studies show promising results. Cystatin C levels are less dependent on age, sex, race and muscle mass compared to creatinine. Cystatin C measurements alone have not been shown to be superior to formula-adjusted estimations of kidney function. As opposed to previous claims, cystatin C has been found to be influenced by body composition. It has been suggested that cystatin C might predict the risk of developing is_associated_with::chronic kidney disease, thereby signaling a state of 'preclinical' kidney dysfunction.

Studies have also investigated cystatin C as a marker of kidney function in the adjustment of medication dosages.

Cystatin C levels have been reported to be altered in patients with cancer,  (even subtle) thyroid dysfunction   and glucocorticoid therapy in some  but not all situations. Other reports have found that levels are influenced by is_associated_with::cigarette smoking and levels of is_associated_with::C-reactive protein. Levels seem to be increased in is_associated_with::HIV infection, which might or might not reflect actual renal dysfunction. The role of cystatin C to monitor GFR during pregnancy remains controversial. Like creatinine, the elimination of cystatin C via routes other than the kidney increase with worsening GFR.

Death and cardiovascular disease
Kidney dysfunction increases the risk of death and cardiovascular disease. Several studies have found that increased levels of cystatin C are associated with the risk of death, several types of cardiovascular disease (including is_associated_with::myocardial infarction, is_associated_with::stroke, is_associated_with::heart failure, is_associated_with::peripheral arterial disease and is_associated_with::metabolic syndrome) and healthy aging. Some studies have found cystatin C to be better in this regard than serum creatinine or creatinine-based GFR equations. Because the association of cystatin C with long term outcomes has appeared stronger than what could be expected for GFR, it has been hypothesized that cystatin C might also be linked to mortality in a way independent of kidney function. In keeping with its is_associated_with::housekeeping gene properties, it has been suggested that cystatin C might be influenced by the is_associated_with::basal metabolic rate.

Neurologic disorders
is_associated_with::Mutations in the cystatin 3 is_associated_with::gene are responsible for the is_associated_with::Icelandic type of hereditary is_associated_with::cerebral amyloid angiopathy, a condition predisposing to is_associated_with::intracerebral haemorrhage, is_associated_with::stroke and is_associated_with::dementia. The condition is inherited in a dominant fashion.

Since cystatin 3 also binds is_associated_with::amyloid β and reduces its aggregation and deposition, it is a potential target in is_associated_with::Alzheimer's disease. Although not all studies have confirmed this, the overall evidence is in favor of are role for CST3 as a susceptibility gene for Alzheimer's disease. Cystatin C levels have been reported to be higher in subjects with Alzheimer's disease.

The role of cystatin C in is_associated_with::multiple sclerosis and other is_associated_with::demyelinating diseases (characterized by a loss of the myelin nerve sheath) remains controversial.

Other roles
Cystatin C levels are decreased in atherosclerotic (so-called 'hardening' of the arteries) and is_associated_with::aneurysmal (saccular bulging) lesions of the is_associated_with::aorta. Genetic and prognostic studies also suggest a role for cystatin C. Breakdown of parts of the vessel wall in these conditions is thought to result from an imbalance between proteinases (is_associated_with::cysteine proteases and is_associated_with::matrix metalloproteinases, increased) and their inhibitors (such as cystatin C, decreased).

A few studies have looked at the role of cystatin C or the CST3 gene in is_associated_with::age-related macular degeneration. Cystatin C has also been investigated as a prognostic marker in several forms of cancer. Its role in is_associated_with::pre-eclampsia remains to be confirmed.

Laboratory measurement
Cystatin C can be measured in a random sample of serum (the fluid in is_associated_with::blood from which the is_associated_with::red blood cells and is_associated_with::clotting factors have been removed) using is_associated_with::immunoassays such as is_associated_with::nephelometry or particle-enhanced is_associated_with::turbidimetry. It is a more expensive test than serum creatinine (around $2 or $3, compared to $0.02 to $0.15), which can be measured with a Jaffé reaction.

Reference values differ in many populations and with sex and age. Across different studies, the mean reference interval (as defined by the 5th and 95th is_associated_with::percentile) was between 0.52 and 0.98 mg/L. For women, the average reference interval is 0.52 to 0.90 mg/L with a mean of 0.71 mg/L. For men, the average reference interval is 0.56 to 0.98 mg/L with a mean of 0.77 mg/L. The normal values decrease until the first year of life, remaining relatively stable before they increase again, especially beyond age 50. Creatinine levels increase until puberty and differ according to gender from then on, making their interpretation problematic for pediatric patients.

In a large study from the United States is_associated_with::National Health and Nutrition Examination Survey, the reference interval (as defined by the 1st and 99th is_associated_with::percentile) was between 0.57 and 1.12 mg/L. This interval was 0.55 - 1.18 for women and 0.60 - 1.11 for men. Non-Hispanic blacks and Mexican Americans had lower normal cystatin C levels. Other studies have found that in patients with an impaired renal function, women have lower and blacks have higher cystatin C levels for the same GFR. For example, the cut-off values of cystatin C for is_associated_with::chronic kidney disease for a 60-year-old white women would be 1.12 mg/L and 1.27 mg/L in a black man (a 13% increase). For serum creatinine values adjusted with the MDRD equation, these values would be 0.95 mg/dL to 1.46 mg/dL (a 54% increase).

Based on a threshold level of 1.09 mg/L (the 99th percentile in a population of 20 to 39-year-olds without hypertension, diabetes, is_associated_with::microalbuminuria or macroalbuminuria or higher than stage 3 chronic kidney disease), the is_associated_with::prevalence of increased levels of cystatin C in the United States was 9.6% in subjects of normal weight, increasing in is_associated_with::overweight and is_associated_with::obese individuals. In Americans aged 60 and 80 and older, serum cystatin is increased in 41% and more than 50%.

Molecular biology
The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (is_associated_with::stefins), type 2 cystatins and the is_associated_with::kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on the short arm of is_associated_with::chromosome 20 contains the majority of the type 2 cystatin genes and is_associated_with::pseudogenes.

The CST3 gene is located in the cystatin locus and comprises 3 is_associated_with::exons (coding regions, as opposed to is_associated_with::introns, non-coding regions within a gene), spanning 4.3 is_associated_with::kilo-base pairs. It encodes the most abundant extracellular inhibitor of cysteine proteases. It is found in high concentrations in biological fluids and is expressed in virtually all organs of the body (CST3 is a is_associated_with::housekeeping gene). The highest levels are found in is_associated_with::semen, followed by is_associated_with::breastmilk, is_associated_with::tears and is_associated_with::saliva. The is_associated_with::hydrophobic leader sequence indicates that the protein is normally secreted. There are three polymorphisms in the promoter region of the gene, resulting in two common variants. Several is_associated_with::single nucleotide polymorphisms have been associated with altered cystatin C levels.

Cystatin C is a non-glycosylated, basic protein (is_associated_with::isoelectric point at is_associated_with::pH 9.3). The crystal structure of cystatin C is characterized by a short is_associated_with::alpha helix and a long alpha helix which lies across a large antiparallel, five-stranded is_associated_with::beta sheet. Like other type 2 cystatins, it has two is_associated_with::disulfide bonds. Around 50% of the molecules carry a hydroxylated proline. Cystatin C forms dimers (molecule pairs) by exchanging subdomains; in the paired state, each half is made up of the long alpha helix and one beta strand of one partner, and four beta strands of the other partner.

History
Cystatin C was first described as 'gamma-trace' in 1961 as a trace protein together with other ones (such as beta-trace) in the is_associated_with::cerebrospinal fluid and in the is_associated_with::urine of patients with is_associated_with::renal failure. Grubb and Löfberg first reported its amino acid sequence. They noticed it was increased in patients with advanced is_associated_with::renal failure. It was first proposed as a measure of glomerular filtration rate by Grubb and coworkers in 1985.

Use of serum creatinine and cystatin C was found very effective in accurately reflecting the GFR in a study reported in the July 5, 2012 issue of the New England Journal of Medicine.