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Cystatin C orcystatin 3 (formerly gamma trace, post-gamma-globulin or neuroendocrine basicpolypeptide), a proteinencoded by the CST3 gene, is mainly used as a biomarkerofkidney function. Recently, it has been studied for its role in predictingnew-onset or deteriorating cardiovascular disease. It also seems to play a rolein brain disorders involving amyloid(a specific type of protein deposition),such as Alzheimer's disease. In humans, all cells with a nucleus (cell corecontaining the DNA) produce cystatin C as a chain of 120 amino acids. It isfound in virtually all tissues and body fluids. It is a potent inhibitor oflysosomal proteinases (enzymes from a special subunit of the cell that breakdown proteins) and probably one of the most important extracellular inhibitorsofcysteine proteases (it prevents the breakdown of proteins outside the cell bya specific type of protein degrading enzymes). Cystatin C belongs to the type 2cystatin gene family.
Glomerularfiltration rate (GFR), a marker of kidney health, is best measured by injectingcompounds such as inulin,radioisotopes such as 51chromium-EDTA,125I-iothalamate, 99mTc-DTPA or radiocontrast agents such as iohexol, but thesetechniques are complicated, costly, time-consuming and have potentialside-effects. Creatinine is the most widely usedbiomarker of kidney function.It is inaccurate at detecting mild renal impairment, and levels can vary withmuscle mass and protein intake. Formulas such as the Cockcroft and Gaultformula and the MDRD formula (see Renal function) try to adjust for thesevariables.
Cystatin C has alow molecular weight (approximately 13.3kilodaltons), and it is removed fromthe bloodstream byglomerular filtration in the kidneys. If kidney function andglomerular filtration rate decline, the blood levels of cystatin C rise. Serumlevels of cystatin C are a more precise test of kidney function (as representedby the glomerular filtration rate, GFR) than serum creatinine levels. Thisfinding is based mainly on cross-sectional studies (on a single point in time).Longitudinal studies (that follow cystatin C over time) are scarcer; somestudies show promising results.Cystatin C levels are less dependent on age,sex, race and muscle mass compared to creatinine. Cystatin C measurements alonehave not been shown to be superior to formula-adjusted estimations of kidneyfunction. As opposed to previous claims, cystatin C has been found to beinfluenced by body composition. It has been suggested that cystatin C mightpredict the risk of developing chronic kidney disease, thereby signaling astate of 'preclinical' kidney dysfunction.
Studies havealso investigated cystatin C as a marker of kidney function in the adjustmentof medication dosages.
Cystatin Clevels 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 cigarette smoking andlevels of C-reactive protein. Levels seem to be increased in HIV infection,which might or might not reflect actual renal dysfunction. The role of cystatinC to monitor GFR during pregnancy remains controversial. Like creatinine, theelimination of cystatin C via routes other than the kidney increase withworsening GFR.
Death and cardiovascular disease
Kidneydysfunction increases the risk of death and cardiovascular disease. Severalstudies have found that increased levels of cystatin C are associated with therisk of death, several types of cardiovascular disease (including myocardialinfarction, stroke, heart failure, peripheral arterial disease and metabolicsyndrome) and healthy aging. Some studies have found cystatin C to be better inthis regard than serum creatinine or creatinine-based GFR equations. Becausethe association of cystatin C with long term outcomes has appeared strongerthan what could be expected for GFR, it has been hypothesized that cystatin Cmight also be linked to mortality in a way independent of kidney function. Inkeeping with its housekeeping gene properties, it has been suggested thatcystatin C might be influenced by thebasal metabolic rate.
Mutations in thecystatin 3 gene are responsible for the Icelandic type of hereditary cerebralamyloid angiopathy, a condition predisposing to intracerebral haemorrhage,stroke and dementia. The condition is inherited in a dominant fashion.
Since cystatin 3also binds amyloid β and reduces its aggregation and deposition, it is apotential target inAlzheimer's disease. Although not all studies have confirmedthis, the overall evidence is in favor of are role for CST3 as a susceptibilitygene for Alzheimer's disease. Cystatin C levels have been reported to be higherin subjects with Alzheimer's disease.
The role ofcystatin C in multiple sclerosis and other demyelinating diseases(characterized by a loss of the myelin nerve sheath) remains controversial.
Cystatin C levelsare decreased in atherosclerotic (so-called 'hardening' of the arteries) andaneurysmal(saccular bulging) lesions of the aorta. Genetic and prognosticstudies also suggest a role for cystatin C. Breakdown of parts of the vesselwall in these conditions is thought to result from an imbalance betweenproteinases (cysteine proteases and matrix metalloproteinases, increased) andtheir inhibitors (such as cystatin C, decreased).
A few studieshave looked at the role of cystatin C or the CST3 gene in age-related maculardegeneration. Cystatin C has also been investigated as a prognostic marker inseveral forms of cancer. Its role in pre-eclampsia remains to be confirmed.
Cystatin C canbe measured in a random sample of serum (the fluid in blood from which the redblood cells andclotting factors have been removed) using immunoassays such asnephelometry or particle-enhancedturbidimetry. It is a more expensive test thanserum creatinine (around $2 or $3, compared to $0.02 to $0.15), which can bemeasured with a Jaffé reaction.
Reference valuesdiffer in many populations and with sex and age. Across different studies, themean reference interval (as defined by the 5th and 95th percentile) was between0.52 and 0.98 mg/L. For women, the average reference interval is 0.52 to 0.90mg/L with a mean of 0.71 mg/L. For men, the average reference interval is 0.56to 0.98 mg/L with a mean of 0.77 mg/L. The normal values decrease until thefirst year of life, remaining relatively stable before they increase again,especially beyond age 50. Creatinine levels increase until puberty and differaccording to gender from then on, making their interpretation problematic forpediatric patients.
In a large studyfrom the United States National Health and Nutrition Examination Survey, thereference interval (as defined by the 1st and 99th percentile) was between 0.57and 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. Forexample, the cut-off values of cystatin C forchronic kidney disease for a60-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, thesevalues would be 0.95 mg/dL to 1.46 mg/dL (a 54% increase).
Based on athreshold level of 1.09 mg/L (the 99th percentile in a population of 20 to39-year-olds without hypertension, diabetes, microalbuminuria ormacroalbuminuria or higher than stage 3 chronic kidney disease), the prevalenceof increased levels of cystatin C in the United States was 9.6% in subjects ofnormal weight, increasing in overweight and obese individuals. In Americansaged 60 and 80 and older, serum cystatin is increased in 41% and more than 50%.
The cystatinsuperfamily encompasses proteins that contain multiple cystatin-like sequences.Some of the members are active cysteine protease inhibitors, while others havelost or perhaps never acquired this inhibitory activity. There are threeinhibitory families in the superfamily, including the type 1 cystatins(stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteinsare a class of cysteine proteinase inhibitors found in a variety of humanfluids and secretions, where they appear to provide protective functions. Thecystatin locus on the short arm of chromosome 20 contains the majority of thetype 2 cystatin genes and pseudogenes.
The CST3 gene islocated in the cystatin locus and comprises 3 exons (coding regions, as opposedto introns, non-coding regions within a gene), spanning 4.3 kilo-base pairs. Itencodes the most abundant extracellular inhibitor of cysteine proteases. It isfound in high concentrations in biological fluids and is expressed in virtuallyall organs of the body (CST3 is a housekeeping gene). The highest levels arefound in semen, followed by breastmilk, tears and saliva. The hydrophobicleader sequence indicates that the protein is normally secreted. There arethree polymorphisms in the promoter region of the gene, resulting in two commonvariants. Several single nucleotide polymorphisms have been associated withaltered cystatin C levels.
Cystatin C is anon-glycosylated, basic protein (isoelectric point at pH 9.3). The crystalstructure of cystatin C is characterized by a short alpha helix and a longalpha helix which lies across a large antiparallel, five-stranded beta sheet.Like other type 2 cystatins, it has two disulfide bonds. Around 50% of themolecules carry a hydroxylated proline. Cystatin C forms dimers (moleculepairs) by exchanging subdomains; in the paired state, each half is made up ofthe long alpha helix and one beta strand of one partner, and four beta strandsof the other partner.