Cystatin C: Difference between revisions

CST3
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1G96, 1R4C, 1TIJ, 3GAX, 3NX0, 3PS8, 3QRD, 3S67, 3SVA
Identifiers
Aliases	CST3, ARMD11, HEL-S-2, cystatin C
External IDs	OMIM: 604312; MGI: 102519; HomoloGene: 78; GeneCards: CST3; OMA:CST3 - orthologs
Gene location (Human)
Chr.	Chromosome 20 (human)
End	23,638,473 bp
Gene location (Mouse)
Chr.	Chromosome 2 (mouse)
End	148,717,612 bp
RNA expression pattern
	Top expressed in
	right frontal lobe; ; Amygdala; ; right testis; ; left testis; ; nucleus accumbens; ; retinal pigment epithelium; ; apex of heart; ; right coronary artery; ; right hemisphere of cerebellum; ; Descending thoracic aorta;
	Top expressed in
	skin of external ear; ; arcuate nucleus; ; globus pallidus; ; entorhinal cortex; ; median eminence; ; perirhinal cortex; ; superior frontal gyrus; ; CA3 field; ; retinal pigment epithelium; ; nucleus accumbens;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	peptidase inhibitor activity; cysteine-type endopeptidase inhibitor activity; amyloid-beta binding; protein binding; identical protein binding; endopeptidase inhibitor activity; protease binding;
Cellular component	extracellular region; extracellular exosome; tertiary granule lumen; ficolin-1-rich granule lumen; basement membrane; extracellular space; cytoplasm; lysosome; multivesicular body; endoplasmic reticulum; endoplasmic reticulum lumen; axon; nuclear membrane; vesicle; cell projection; soma; contractile fiber; perinuclear region of cytoplasm; Golgi apparatus; plasma membrane;
Biological process	negative regulation of proteolysis; defense response; negative regulation of peptidase activity; negative regulation of extracellular matrix disassembly; regulation of tissue remodeling; negative regulation of blood vessel remodeling; negative regulation of elastin catabolic process; negative regulation of collagen catabolic process; neutrophil degranulation; supramolecular fiber organization; eye development; response to hypoxia; cell activation; apoptotic process; response to oxidative stress; brain development; salivary gland development; embryo implantation; positive regulation of cell population proliferation; male gonad development; response to toxic substance; response to carbohydrate; response to inorganic substance; response to organic cyclic compound; response to nutrient levels; response to estradiol; cellular response to oxidative stress; circadian sleep/wake cycle, REM sleep; regulation of programmed cell death; post-translational protein modification; positive regulation of DNA replication; response to axon injury; Sertoli cell development; negative regulation of cell death; cellular response to hydrogen peroxide; negative regulation of cysteine-type endopeptidase activity; negative regulation of endopeptidase activity;
	Sources:Amigo / QuickGO
Orthologs
	1471
	13010
	ENSG00000101439
	ENSMUSG00000027447
	P01034
	P21460
	NM_001288614; NM_000099
	NM_009976
	NP_000090; NP_001275543
	NP_034106
	Wikidata
View/Edit Human	View/Edit Mouse

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Latest revision as of 04:55, 11 November 2024

Cystatin C or cystatin 3 (formerly gamma trace, post-gamma-globulin, or neuroendocrine basic polypeptide),^[5] a protein encoded by the CST3 gene, is mainly used as a biomarker of kidney function. Recently, it has been studied for its role in predicting new-onset or deteriorating cardiovascular disease. It also seems to play a role in brain disorders involving amyloid (a specific type of protein deposition), such as Alzheimer's disease. In humans, all cells with a nucleus (cell core containing the DNA) produce cystatin C as a chain of 120 amino acids. It is found in virtually all tissues and body fluids. It is a potent inhibitor of lysosomal proteinases (enzymes from a special subunit of the cell that break down proteins) and probably one of the most important extracellular inhibitors of 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 cystatin gene family.

Role in medicine

Kidney function

Glomerular filtration rate (GFR), a marker of kidney health, is most accurately measured by injecting compounds such as inulin, radioisotopes such as ⁵¹chromium-EDTA, ¹²⁵I-iothalamate, ^99mTc-DTPA or radiocontrast agents such as iohexol, but these techniques are complicated, costly, time-consuming and have potential side-effects.^[6]^[7] Creatinine is the most widely used biomarker of kidney function. It is inaccurate at detecting mild renal impairment, and levels can vary with muscle mass but not with protein intake. Urea levels might change with protein intake.^[8] Formulas such as the Cockcroft and Gault formula and the MDRD formula (see Renal function) try to adjust for these variables.

Cystatin C has a low molecular weight (approximately 13.3 kilodaltons), and it is removed from the bloodstream by glomerular filtration in the kidneys. If kidney function and glomerular filtration rate decline, the blood levels of cystatin C rise. Cross-sectional studies (based on a single point in time) suggest that serum levels of cystatin C are a more precise test of kidney function (as represented by the glomerular filtration rate, GFR) than serum creatinine levels.^[7]^[9] Longitudinal studies (following cystatin C over time) are sparse, but some show promising results.^[10]^[11]^[12] Although studies are somewhat divergent, most studies find that cystatin C levels are less dependent on age, gender, ethnicity, diet, and muscle mass compared to creatinine,^[13]^[14] and that cystatin C is equal or superior to the other available biomarkers in a range of different patient populations, including diabetic patients, in chronic kidney disease (CKD), and after kidney transplant.^[15] It has been suggested that cystatin C might predict the risk of developing CKD, thereby signaling a state of 'preclinical' kidney dysfunction.^[16] Additionally, the age-related rise in serum cystatin C is a powerful predictor of adverse age-related health outcomes, including all-cause mortality, death from cardiovascular disease, multimorbidity, and declining physical and cognitive function.^[17] The UK's National Institute for Health and Care Excellence (NICE) guideline for the assessment and management of CKD in adults concluded that using serum cystatin C to estimate GFR is more specific for important disease outcomes than use of serum creatinine, and may reduce overdiagnosis in patients with a borderline diagnosis, reducing unnecessary appointments, patient worries, and the overall burden of CKD in the population.^[18]

Studies have also investigated cystatin C as a marker of kidney function in the adjustment of medication dosages.^[19]^[20]

Cystatin C levels have been reported to be altered in patients with cancer,^[21]^[22]^[23] (even subtle) thyroid dysfunction^[24]^[25]^[26] and glucocorticoid therapy in some^[27]^[28] but not all^[29] situations. Other reports have found that levels are influenced by cigarette smoking and levels of C-reactive protein.^[30] However, inflammation does not cause an increase in the production of cystatin C, since elective surgical procedures, producing a strong inflammatory response in patients, do not change the plasma concentration of cystatin C.^{[medical citation needed]} Levels seem to be increased in HIV infection, which might or might not reflect actual renal dysfunction.^[31]^[32]^[33] The role of cystatin C to monitor GFR during pregnancy remains controversial.^[34]^[35] Like creatinine, the elimination of cystatin C via routes other than the kidney increases with worsening GFR.^[36]

Death and cardiovascular disease

Kidney dysfunction increases the risk of death and cardiovascular disease.^[37]^[38] Several studies have found that increased levels of cystatin C are associated with the risk of death, several types of cardiovascular disease (including myocardial infarction, stroke, heart failure, peripheral arterial disease and metabolic syndrome) and healthy aging.^{[citation needed]}^{[clarification needed]} Some studies have found cystatin C to be better in this regard than serum creatinine or creatinine-based GFR equations.^[39]^[40]^[41]^[42]^[43]^[44]^[45]^[46]^[47]^[48]^[49]^[50] 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.^[51] In keeping with its housekeeping gene properties, it has been suggested that cystatin C might be influenced by the basal metabolic rate.^[52]

Proposed shrunken pore syndrome

The glomerular sieving coefficients for 10–30 kDa plasma proteins in the human kidney are relatively high with coefficients between 0.9 and 0.07.^{[medical citation needed]}^[53] These relatively high sieving coefficients, combined with the high production of ultrafiltrate in health, means that proteins less than or equal to 30 kDa in plasma normally are mainly cleared by the kidneys and at least 85% of the clearance of cystatin C occurs in the kidney.^{[medical citation needed]}^[54] If the pores of the glomerular membrane shrink, the filtration of bigger molecules, e.g. cystatin C, will decrease, whereas the filtration of small molecules, like water and creatinine, will be less affected. In this case, cystatin C-based estimates of GFR, eGFR_{cystatin C}, will be lower than creatinine-based estimates eGFR_creatinine, so that a hypothesized condition, named shrunken pore syndrome, is identified by a low eGFR_{cystatin C}/eGFR_creatinine-ratio.^{[medical citation needed]}^[55] This syndrome is associated with a very strong increase in mortality.^[56]

Neurologic disorders

Mutations in the cystatin 3 gene are responsible for the Icelandic type of hereditary cerebral amyloid angiopathy, a condition predisposing to intracerebral haemorrhage, stroke and dementia.^[57]^[58] The condition is inherited in a dominant fashion. The monomeric cystatin C forms dimers and oligomers by domain swapping^[59] and the structures of both the dimers^[60] and oligomers^[61] have been determined.

Since cystatin 3 also binds amyloid β and reduces its aggregation and deposition, it is a potential target in Alzheimer's disease.^[62]^[63] Although not all studies have confirmed this, the overall evidence is in favor of a role for CST3 as a susceptibility gene for Alzheimer's disease.^[64] Cystatin C levels have been reported to be higher in subjects with Alzheimer's disease.^[65]

The role of cystatin C in multiple sclerosis and other demyelinating diseases (characterized by a loss of the myelin nerve sheath) remains controversial.^[66]

Other roles

Cystatin C levels are decreased in atherosclerotic (so-called 'hardening' of the arteries) and aneurysmal (saccular bulging) lesions of the aorta.^[67]^[68]^[69]^[70] Genetic and prognostic studies also suggest a role for cystatin C.^[71]^[72] Breakdown of parts of the vessel wall in these conditions is thought to result from an imbalance between proteinases (cysteine proteases and 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 age-related macular degeneration.^[73]^[74] Cystatin C has also been investigated as a prognostic marker in several forms of cancer.^[75]^[76] Its role in pre-eclampsia remains to be confirmed.^[77]^[78]^[79]^[80]

Laboratory measurement

Cystatin C can be measured in a random sample of serum (the fluid in blood from which the red blood cells and clotting factors have been removed) using immunoassays such as nephelometry or particle-enhanced turbidimetry.^[81] 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 Jaffe reaction.^[82]^[83]^[84]

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 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.^[81] The normal values decrease until the first year of life, remaining relatively stable before they increase again, especially beyond age 50.^[85]^[86]^[87] Creatinine levels increase until puberty and differ according to gender from then on, making their interpretation problematic for pediatric patients.^[86]^[88]

In a large study from the United States National Health and Nutrition Examination Survey, the reference interval (as defined by the 1st and 99th 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.^[85] 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.^[89] For example, the cut-off values of cystatin C for CKD 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).^[90]

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, microalbuminuria or macroalbuminuria or higher than stage 3 chronic kidney disease), the prevalence of increased levels of cystatin C in the United States was 9.6% in subjects of normal weight, increasing in overweight and obese individuals.^[91] In Americans aged 60 and 80 and older, serum cystatin is increased in 41% and more than 50%.^[85]

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 (stefins), type 2 cystatins and the 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 chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes.

The CST3 gene is located in the cystatin locus and comprises 3 exons (coding regions, as opposed to introns, non-coding regions within a gene), spanning 4.3 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 housekeeping gene). The highest levels are found in semen, followed by breastmilk, tears and saliva. The 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.^[92] Several single nucleotide polymorphisms have been associated with altered cystatin C levels.^[93]

Cystatin C is a non-glycosylated, basic protein (isoelectric point at pH 9.3). The crystal structure of cystatin C is characterized by a short alpha helix and a long alpha helix which lies across a large antiparallel, five-stranded beta sheet. Like other type 2 cystatins, it has two 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.^[94]

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 cerebrospinal fluid and in the urine of people with kidney failure.^[95] Grubb and Löfberg first reported its amino acid sequence.^[95] They noticed it was increased in patients with advanced kidney failure.^[96] It was first proposed as a measure of glomerular filtration rate by Grubb and coworkers in 1985.^[97]^[98]

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.^[99]

References

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External links

The MEROPS online database for peptidases and their inhibitors: I25.004 Archived 2016-01-20 at the Wayback Machine
Overview of all the structural information available in the PDB for UniProt: P01034 (Cystatin-C) at the PDBe-KB.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000101439 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000027447 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

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@@ Line 1: / Line 1: @@
+{{Short description|Protein used as a biomarker of kidney function}}
 {{Infobox_gene}}
 '''Cystatin C''' or '''cystatin 3''' (formerly '''gamma trace''', post-gamma-globulin, or neuroendocrine basic polypeptide),<ref name="Alzforum">{{cite web |url=http://www.alzforum.org/res/com/gen/alzgene/geneoverview.asp?geneid=66 |title=Alzforum: AlzGene |url-status=dead |archive-url=https://web.archive.org/web/20041227020557/http://www.alzforum.org/res/com/gen/alzgene/geneoverview.asp?geneid=66 |archive-date=2004-12-27 }}</ref> a [[protein]] encoded by the '''CST3''' [[gene]], is mainly used as a [[biomarker]] of [[kidney function]]. Recently, it has been studied for its role in predicting new-onset or deteriorating [[cardiovascular disease]]. It also seems to play a role in brain disorders involving [[amyloid]] (a specific type of protein deposition), such as [[Alzheimer's disease]].
 In humans, all [[Cell (biology)|cells]] with a [[Cell nucleus|nucleus]] (cell core containing the [[DNA]]) produce cystatin C as a [[polypeptide|chain]] of 120 [[amino acid]]s. It is found in virtually all tissues and body fluids. It is a potent [[enzyme inhibitor|inhibitor]] of [[lysosome|lysosomal]] [[proteinase]]s ([[enzyme]]s from a special [[organelle|subunit of the cell]] that break down proteins) and probably one of the most important [[extracellular]] inhibitors of [[cysteine protease]]s (it prevents the breakdown of proteins outside the cell by a specific type of protein degrading enzymes). Cystatin C belongs to the type 2 [[cystatin]] [[gene family]].
@@ Line 9: / Line 10: @@
 [[Renal function|Glomerular filtration rate]] (GFR), a marker of kidney health, is most accurately measured by injecting compounds such as [[inulin]], [[radioisotope]]s such as <sup>51</sup>chromium-[[EDTA]], <sup>125</sup>I-iothalamate, <sup>99m</sup>Tc-[[DTPA]] or [[radiocontrast agent]]s such as [[iohexol]], but these techniques are complicated, costly, time-consuming and have potential side-effects.<ref name="pmid17361076">{{cite journal | vauthors = Zahran A, El-Husseini A, Shoker A | s2cid = 25523216 | title = Can cystatin C replace creatinine to estimate glomerular filtration rate? A literature review | journal = American Journal of Nephrology | volume = 27 | issue = 2 | pages = 197–205 | year = 2007 | pmid = 17361076 | doi = 10.1159/000100907 | url = https://www.karger.com/Article/PDF/000100907 }}</ref><ref name="pmid17316593"/>
-Creatinine is the most widely used [[biomarker]] of kidney function. It is inaccurate at detecting mild renal impairment, and levels can vary with muscle mass but not with protein intake. Urea levels might change with protein intake.<ref name="pmid8329667">{{cite journal | vauthors = King AJ, Levey AS | title = Dietary protein and renal function | journal = Journal of the American Society of Nephrology | volume = 3 | issue = 11 | pages = 1723–37 | date = May 1993 | pmid = 8329667 | doi =  | url = http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=8329667 }}</ref>
+[[Creatinine]] is the most widely used [[biomarker]] of kidney function. It is inaccurate at detecting mild renal impairment, and levels can vary with muscle mass but not with protein intake. Urea levels might change with protein intake.<ref name="pmid8329667">{{cite journal | vauthors = King AJ, Levey AS | title = Dietary protein and renal function | journal = Journal of the American Society of Nephrology | volume = 3 | issue = 11 | pages = 1723–37 | date = May 1993 | doi = 10.1681/ASN.V3111723 | pmid = 8329667 | url = http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=8329667 | doi-access = free }}</ref>
 Formulas such as the Cockcroft and Gault formula and the MDRD formula (see [[Renal function]]) try to adjust for these variables.
-Cystatin C has a low [[molecular weight]] (approximately 13.3 [[kilodalton]]s), and it is removed from the bloodstream by [[glomerular filtration]] in the kidneys. If kidney function and glomerular filtration rate decline, the blood levels of cystatin C rise. [[Cross-sectional study|Cross-sectional studies]] (based on a single point in time) suggest that serum levels of cystatin C are a more precise test of kidney function (as represented by the [[glomerular filtration rate]], GFR) than serum [[creatinine]] levels.<ref name="pmid17316593">{{cite journal | vauthors = Roos JF, Doust J, Tett SE, Kirkpatrick CM | title = Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children--a meta-analysis | journal = Clinical Biochemistry | volume = 40 | issue = 5–6 | pages = 383–91 | date = March 2007 | pmid = 17316593 | doi = 10.1016/j.clinbiochem.2006.10.026 }}</ref><ref name="pmid12148093">{{cite journal | vauthors = Dharnidharka VR, Kwon C, Stevens G | title = Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis | journal = American Journal of Kidney Diseases | volume = 40 | issue = 2 | pages = 221–6 | date = August 2002 | pmid = 12148093 | doi = 10.1053/ajkd.2002.34487 }}</ref>. [[Longitudinal study|Longitudinal studies]] (following cystatin C over time) are sparse, but some show promising results.<ref name="pmid18319326">{{cite journal | vauthors = Premaratne E, MacIsaac RJ, Finch S, Panagiotopoulos S, Ekinci E, Jerums G | title = Serial measurements of cystatin C are more accurate than creatinine-based methods in detecting declining renal function in type 1 diabetes | journal = Diabetes Care | volume = 31 | issue = 5 | pages = 971–3 | date = May 2008 | pmid = 18319326 | doi = 10.2337/dc07-1588 | url = http://care.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=18319326 | doi-access = free }}</ref><ref name="pmid15788478">{{cite journal | vauthors = Perkins BA, Nelson RG, Ostrander BE, Blouch KL, Krolewski AS, Myers BD, Warram JH | title = Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study | journal = Journal of the American Society of Nephrology | volume = 16 | issue = 5 | pages = 1404–12 | date = May 2005 | pmid = 15788478 | pmc = 2429917 | doi = 10.1681/ASN.2004100854 | url = http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=15788478 }}</ref><ref name="pmid16406933">{{cite journal | vauthors = Corrao AM, Lisi G, Di Pasqua G, Guizzardi M, Marino N, Ballone E, Chiesa PL | title = Serum cystatin C as a reliable marker of changes in glomerular filtration rate in children with urinary tract malformations | journal = The Journal of Urology | volume = 175 | issue = 1 | pages = 303–9 | date = January 2006 | pmid = 16406933 | doi = 10.1016/S0022-5347(05)00015-7 }}</ref>
+Cystatin C has a low [[molecular weight]] (approximately 13.3 [[kilodalton]]s), and it is removed from the bloodstream by [[glomerular filtration]] in the kidneys. If kidney function and glomerular filtration rate decline, the blood levels of cystatin C rise. [[Cross-sectional study|Cross-sectional studies]] (based on a single point in time) suggest that serum levels of cystatin C are a more precise test of kidney function (as represented by the [[glomerular filtration rate]], GFR) than serum creatinine levels.<ref name="pmid17316593">{{cite journal | vauthors = Roos JF, Doust J, Tett SE, Kirkpatrick CM | title = Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children--a meta-analysis | journal = Clinical Biochemistry | volume = 40 | issue = 5–6 | pages = 383–91 | date = March 2007 | pmid = 17316593 | doi = 10.1016/j.clinbiochem.2006.10.026 }}</ref><ref name="pmid12148093">{{cite journal | vauthors = Dharnidharka VR, Kwon C, Stevens G | title = Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis | journal = American Journal of Kidney Diseases | volume = 40 | issue = 2 | pages = 221–6 | date = August 2002 | pmid = 12148093 | doi = 10.1053/ajkd.2002.34487 }}</ref> [[Longitudinal study|Longitudinal studies]] (following cystatin C over time) are sparse, but some show promising results.<ref name="pmid18319326">{{cite journal | vauthors = Premaratne E, MacIsaac RJ, Finch S, Panagiotopoulos S, Ekinci E, Jerums G | title = Serial measurements of cystatin C are more accurate than creatinine-based methods in detecting declining renal function in type 1 diabetes | journal = Diabetes Care | volume = 31 | issue = 5 | pages = 971–3 | date = May 2008 | pmid = 18319326 | doi = 10.2337/dc07-1588 | url = http://care.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=18319326 | doi-access = free }}</ref><ref name="pmid15788478">{{cite journal | vauthors = Perkins BA, Nelson RG, Ostrander BE, Blouch KL, Krolewski AS, Myers BD, Warram JH | title = Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study | journal = Journal of the American Society of Nephrology | volume = 16 | issue = 5 | pages = 1404–12 | date = May 2005 | pmid = 15788478 | pmc = 2429917 | doi = 10.1681/ASN.2004100854 }}</ref><ref name="pmid16406933">{{cite journal | vauthors = Corrao AM, Lisi G, Di Pasqua G, Guizzardi M, Marino N, Ballone E, Chiesa PL | title = Serum cystatin C as a reliable marker of changes in glomerular filtration rate in children with urinary tract malformations | journal = The Journal of Urology | volume = 175 | issue = 1 | pages = 303–9 | date = January 2006 | pmid = 16406933 | doi = 10.1016/S0022-5347(05)00015-7 }}</ref> Although studies are somewhat divergent, most studies find that cystatin C levels are less dependent on age, gender, ethnicity, diet, and muscle mass compared to creatinine,<ref name="Onopiuk">{{cite journal |vauthors=Onopiuk A, Tokarzewicz A, Gorodkiewicz E |title=Cystatin C: a kidney function biomarker |journal=Adv Clin Chem |date=2015 |volume=68 |pages=57–69 |doi=10.1016/bs.acc.2014.11.007 |pmid=25858868}}</ref><ref name="Ferguson2015">{{cite journal |vauthors=Ferguson TW, Komenda P, Tangri N |title=Cystatin C as a biomarker for estimating glomerular filtration rate |journal=Curr Opin Nephrol Hypertens |date=May 2015 |volume=24 |issue=3 |pages=295–300|doi=10.1097/MNH.0000000000000115 |pmid=26066476|s2cid=27385 |doi-access=free }}</ref> and that cystatin C is equal or superior to the other available biomarkers in a range of different patient populations, including diabetic patients, in [[chronic kidney disease]] (CKD), and after kidney transplant.<ref name="Porto2017">{{cite journal |vauthors=Porto JR, Gomes KB, Fernandes AP, Domingueti CP |title=Cystatin C: a promising biomarker to evaluate renal function |journal=Revista Brasileira de Analises Clinicas |date=January 1, 2017 |volume=49 |issue=3 |doi=10.21877/2448-3877.201600446 |url=http://www.rbac.org.br/artigos/cystatin-c-promising-biomarker-to-evaluate-renal-function/ |accessdate=18 November 2020}}</ref> It has been suggested that cystatin C might predict the risk of developing CKD, thereby signaling a state of 'preclinical' kidney dysfunction.<ref name="pmid16908914">{{cite journal | vauthors = Shlipak MG, Katz R, Sarnak MJ, Fried LF, Newman AB, Stehman-Breen C, Seliger SL, Kestenbaum B, Psaty B, Tracy RP, Siscovick DS | s2cid = 24679098 | display-authors = 6 | title = Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease | journal = Annals of Internal Medicine | volume = 145 | issue = 4 | pages = 237–46 | date = August 2006 | pmid = 16908914 | doi = 10.7326/0003-4819-145-4-200608150-00003 | url = http://www.annals.org/cgi/pmidlookup?view=reprint&pmid=16908914 }}</ref> Additionally, the age-related rise in serum cystatin C is a powerful predictor of adverse age-related health outcomes, including all-cause mortality, death from cardiovascular disease, [[multimorbidity]], and declining physical and cognitive function.<ref name="Justice2018">{{cite journal |vauthors=Justice JN, Ferrucci L, Newman AB, Aroda VR, Bahnson JL, Divers J, Espeland MA, Marcovina S, Pollak MN, Kritchevsky SB, Barzilai N, Kuchel GA |title=A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup |journal=[[Geroscience (journal)|Geroscience]] |date=December 2018 |volume=40 |issue=5–6 |pages=419–436 |doi=10.1007/s11357-018-0042-y |pmid=30151729 |pmc=6294728}}</ref> The UK's [[National Institute for Health and Care Excellence]] (NICE) guideline for the assessment and management of CKD in adults concluded that using serum cystatin C to estimate GFR is more specific for important disease outcomes than use of serum creatinine, and may reduce overdiagnosis in patients with a borderline diagnosis, reducing unnecessary appointments, patient worries, and the overall burden of CKD in the population.<ref name="NICECKD">{{cite web |title=Chronic kidney disease in adults: assessment and management |url=https://www.nice.org.uk/guidance/cg182/chapter/implementation-getting-started |website=[[National Institute for Health and Care Excellence]] (NICE) |date=23 July 2014 |accessdate=18 November 2020}}</ref>
-Cystatin C levels are less dependent on age, gender, ethnicity and muscle mass compared to creatinine. Cystatin C measurements alone have not been shown to be superior to formula-adjusted estimations of kidney function.<ref name="Stevens2008">{{cite journal | vauthors = Stevens LA, Coresh J, Schmid CH, Feldman HI, Froissart M, Kusek J, Rossert J, Van Lente F, Bruce RD, Zhang YL, Greene T, Levey AS | display-authors = 6 | title = Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD | journal = American Journal of Kidney Diseases | volume = 51 | issue = 3 | pages = 395–406 | date = March 2008 | pmid = 18295055 | pmc = 2390827 | doi = 10.1053/j.ajkd.2007.11.018 }}</ref> As opposed to previous claims, cystatin C has been found to be influenced by body composition.<ref name="pmid17290239">{{cite journal | vauthors = Shlipak MG | s2cid = 26913766 | title = Cystatin C as a marker of glomerular filtration rate in chronic kidney disease: influence of body composition | journal = Nature Clinical Practice. Nephrology | volume = 3 | issue = 4 | pages = 188–9 | date = April 2007 | pmid = 17290239 | doi = 10.1038/ncpneph0404 }}</ref><ref name="pmid17059990">{{cite journal | vauthors = Macdonald J, Marcora S, Jibani M, Roberts G, Kumwenda M, Glover R, Barron J, Lemmey A | display-authors = 6 | title = GFR estimation using cystatin C is not independent of body composition | journal = American Journal of Kidney Diseases | volume = 48 | issue = 5 | pages = 712–9 | date = November 2006 | pmid = 17059990 | doi = 10.1053/j.ajkd.2006.07.001 }}</ref>
-It has been suggested that cystatin C might predict the risk of developing [[chronic kidney disease]], thereby signaling a state of 'preclinical' kidney dysfunction.<ref name="pmid16908914">{{cite journal | vauthors = Shlipak MG, Katz R, Sarnak MJ, Fried LF, Newman AB, Stehman-Breen C, Seliger SL, Kestenbaum B, Psaty B, Tracy RP, Siscovick DS | s2cid = 24679098 | display-authors = 6 | title = Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease | journal = Annals of Internal Medicine | volume = 145 | issue = 4 | pages = 237–46 | date = August 2006 | pmid = 16908914 | doi = 10.7326/0003-4819-145-4-200608150-00003 | url = http://www.annals.org/cgi/pmidlookup?view=reprint&pmid=16908914 }}</ref>
 Studies have also investigated cystatin C as a marker of kidney function in the adjustment of medication dosages.<ref name="pmid16778715">{{cite journal | vauthors = Hermida J, Tutor JC | s2cid = 27219789 | title = Serum cystatin C for the prediction of glomerular filtration rate with regard to the dose adjustment of amikacin, gentamicin, tobramycin, and vancomycin | journal = Therapeutic Drug Monitoring | volume = 28 | issue = 3 | pages = 326–31 | date = June 2006 | pmid = 16778715 | doi = 10.1097/01.ftd.0000211805.89440.3d }}</ref><ref name="pmid15180169">{{cite journal | vauthors = Schück O, Teplan V, Sibová J, Stollová M | title = Predicting the glomerular filtration rate from serum creatinine, serum cystatin C and the Cockcroft and Gault formula with regard to drug dosage adjustment | journal = International Journal of Clinical Pharmacology and Therapeutics | volume = 42 | issue = 2 | pages = 93–7 | date = February 2004 | pmid = 15180169 | doi = 10.5414/cpp42093 }}</ref>
-Cystatin C levels have been reported to be altered in patients with cancer,<ref name="pmid16337174">{{cite journal | vauthors = Demirtaş S, Akan O, Can M, Elmali E, Akan H | title = Cystatin C can be affected by nonrenal factors: a preliminary study on leukemia | journal = Clinical Biochemistry | volume = 39 | issue = 2 | pages = 115–8 | date = February 2006 | pmid = 16337174 | doi = 10.1016/j.clinbiochem.2005.10.009 }}</ref><ref name="pmid18317874">{{cite journal | vauthors = Nakai K, Kikuchi M, Fujimoto K, Kaneko Y, Omori S, Nakai K, Suwabe A | s2cid = 19326312 | title = Serum levels of cystatin C in patients with malignancy | journal = Clinical and Experimental Nephrology | volume = 12 | issue = 2 | pages = 132–139 | date = April 2008 | pmid = 18317874 | doi = 10.1007/s10157-008-0043-8 }}</ref><ref name="pmid9836733">{{cite journal | vauthors = Kos J, Stabuc B, Cimerman N, Brünner N | title = Serum cystatin C, a new marker of glomerular filtration rate, is increased during malignant progression | journal = Clinical Chemistry | volume = 44 | issue = 12 | pages = 2556–7 | date = December 1998 | pmid = 9836733 | doi = 10.1093/clinchem/44.12.2556 | url = http://www.clinchem.org/cgi/pmidlookup?view=long&pmid=9836733 }}{{Dead link|date=August 2020 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> (even subtle) thyroid dysfunction<ref name="pmid12675875">{{cite journal | vauthors = Fricker M, Wiesli P, Brändle M, Schwegler B, Schmid C | title = Impact of thyroid dysfunction on serum cystatin C | journal = Kidney International | volume = 63 | issue = 5 | pages = 1944–7 | date = May 2003 | pmid = 12675875 | doi = 10.1046/j.1523-1755.2003.00925.x }}</ref><ref name="pmid15966508">{{cite journal | vauthors = Manetti L, Pardini E, Genovesi M, Campomori A, Grasso L, Morselli LL, Lupi I, Pellegrini G, Bartalena L, Bogazzi F, Martino E | display-authors = 6 | title = Thyroid function differently affects serum cystatin C and creatinine concentrations | journal = Journal of Endocrinological Investigation | volume = 28 | issue = 4 | pages = 346–9 | date = April 2005 | pmid = 15966508 | doi = 10.1007/bf03347201 | url = http://www.kurtis.it/abs/index.cfm?id_articolo_numero=3109 | url-status = dead | archive-url = https://web.archive.org/web/20080608033357/http://www.kurtis.it/abs/index.cfm?id_articolo_numero=3109 | archive-date = 2008-06-08 }}</ref><ref name="pmid14637271">{{cite journal | vauthors = Wiesli P, Schwegler B, Spinas GA, Schmid C | title = Serum cystatin C is sensitive to small changes in thyroid function | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 338 | issue = 1–2 | pages = 87–90 | date = December 2003 | pmid = 14637271 | doi = 10.1016/j.cccn.2003.07.022 }}</ref> and glucocorticoid therapy in some<ref name="pmid11673383">{{cite journal | vauthors = Risch L, Herklotz R, Blumberg A, Huber AR | title = Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients | journal = Clinical Chemistry | volume = 47 | issue = 11 | pages = 2055–9 | date = November 2001 | pmid = 11673383 | doi = 10.1093/clinchem/47.11.2055 | url = http://www.clinchem.org/cgi/pmidlookup?view=long&pmid=11673383 }}{{Dead link|date=August 2020 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="pmid10958865">{{cite journal | vauthors = Cimerman N, Brguljan PM, Krasovec M, Suskovic S, Kos J | title = Serum cystatin C, a potent inhibitor of cysteine proteinases, is elevated in asthmatic patients | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 300 | issue = 1–2 | pages = 83–95 | date = October 2000 | pmid = 10958865 | doi = 10.1016/S0009-8981(00)00298-9 }}</ref> but not all<ref name="pmid12089191">{{cite journal | vauthors = Bökenkamp A, van Wijk JA, Lentze MJ, Stoffel-Wagner B | title = Effect of corticosteroid therapy on serum cystatin C and beta2-microglobulin concentrations | journal = Clinical Chemistry | volume = 48 | issue = 7 | pages = 1123–6 | date = July 2002 | pmid = 12089191 | doi = 10.1093/clinchem/48.7.1123 | url = http://www.clinchem.org/cgi/pmidlookup?view=long&pmid=12089191 }}{{Dead link|date=August 2020 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> situations. Other reports have found that levels are influenced by [[cigarette smoking]] and levels of [[C-reactive protein]].<ref name="pmid15086483">{{cite journal | vauthors = Knight EL, Verhave JC, Spiegelman D, Hillege HL, de Zeeuw D, Curhan GC, de Jong PE | title = Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement | journal = Kidney International | volume = 65 | issue = 4 | pages = 1416–21 | date = April 2004 | pmid = 15086483 | doi = 10.1111/j.1523-1755.2004.00517.x }}</ref> However, inflammation does not cause an increase in the production of cystatin C, since elective surgical procedures, producing a strong inflammatory response in patients, do not change the plasma concentration of cystatin C. <ref>{{cite journal | vauthors = Akerfeldt T, Helmersson J, Larsson A | title = Postsurgical inflammatory response is not associated with increased serum cystatin C values | journal = Clinical Biochemistry | volume = 43 | issue = 13–14 | pages = 1138–40 | date = September 2010 | pmid = 20627098 | doi = 10.1016/j.clinbiochem.2010.07.004 }}</ref><ref>{{cite journal | vauthors = Grubb A, Björk J, Nyman U, Pollak J, Bengzon J, Ostner G, Lindström V | title = Cystatin C, a marker for successful aging and glomerular filtration rate, is not influenced by inflammation | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 71 | issue = 2 | pages = 145–9 | date = April 2011 | pmid = 21198422 | doi = 10.3109/00365513.2010.546879 | pmc = 3072693 }}</ref> Levels seem to be increased in [[HIV]] infection, which might or might not reflect actual renal dysfunction.<ref name="pmid17998494">{{cite journal | vauthors = Odden MC, Scherzer R, Bacchetti P, Szczech LA, Sidney S, Grunfeld C, Shlipak MG | title = Cystatin C level as a marker of kidney function in human immunodeficiency virus infection: the FRAM study | journal = Archives of Internal Medicine | volume = 167 | issue = 20 | pages = 2213–9 | date = November 2007 | pmid = 17998494 | pmc = 3189482 | doi = 10.1001/archinte.167.20.2213 | url = http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=17998494 | url-status = dead | archive-url = https://archive.today/20080607214011/http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=17998494 | archive-date = 2008-06-07 }}</ref><ref name="pmid1569212">{{cite journal | vauthors = Collé A, Tavera C, Prévot D, Leung-Tack J, Thomas Y, Manuel Y, Benveniste J, Leibowitch J | display-authors = 6 | title = Cystatin C levels in sera of patients with human immunodeficiency virus infection. A new avidin-biotin ELISA assay for its measurement | journal = Journal of Immunoassay | volume = 13 | issue = 1 | pages = 47–60 | year = 1992 | pmid = 1569212 | doi = 10.1080/15321819208019824 }}</ref><ref name="pmid16964834">{{cite journal | vauthors = Jaroszewicz J, Wiercinska-Drapalo A, Lapinski TW, Prokopowicz D, Rogalska M, Parfieniuk A | title = Does HAART improve renal function? An association between serum cystatin C concentration, HIV viral load and HAART duration | journal = Antiviral Therapy | volume = 11 | issue = 5 | pages = 641–5 | year = 2006 | pmid = 16964834 | doi =  }}</ref> The role of cystatin C to monitor GFR during pregnancy remains controversial.<ref name="pmid12004930">{{cite journal | vauthors = Strevens H, Wide-Swensson D, Torffvit O, Grubb A | s2cid = 25382382 | title = Serum cystatin C for assessment of glomerular filtration rate in pregnant and non-pregnant women. Indications of altered filtration process in pregnancy | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 62 | issue = 2 | pages = 141–7 | year = 2002 | pmid = 12004930 | doi = 10.1080/003655102753611771 }}</ref><ref name="pmid15842279">{{cite journal | vauthors = Akbari A, Lepage N, Keely E, Clark HD, Jaffey J, MacKinnon M, Filler G | title = Cystatin-C and beta trace protein as markers of renal function in pregnancy | journal = BJOG | volume = 112 | issue = 5 | pages = 575–8 | date = May 2005 | pmid = 15842279 | doi = 10.1111/j.1471-0528.2004.00492.x }}</ref> Like creatinine, the elimination of cystatin C via routes other than the kidney increase with worsening GFR.<ref name="pmid16025834">{{cite journal | vauthors = Sjöström P, Tidman M, Jones I | s2cid = 41336736 | title = Determination of the production rate and non-renal clearance of cystatin C and estimation of the glomerular filtration rate from the serum concentration of cystatin C in humans | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 65 | issue = 2 | pages = 111–24 | year = 2005 | pmid = 16025834 | doi = 10.1080/00365510510013523 }}</ref>
+Cystatin C levels have been reported to be altered in patients with cancer,<ref name="pmid16337174">{{cite journal | vauthors = Demirtaş S, Akan O, Can M, Elmali E, Akan H | title = Cystatin C can be affected by nonrenal factors: a preliminary study on leukemia | journal = Clinical Biochemistry | volume = 39 | issue = 2 | pages = 115–8 | date = February 2006 | pmid = 16337174 | doi = 10.1016/j.clinbiochem.2005.10.009 }}</ref><ref name="pmid18317874">{{cite journal | vauthors = Nakai K, Kikuchi M, Fujimoto K, Kaneko Y, Omori S, Nakai K, Suwabe A | s2cid = 19326312 | title = Serum levels of cystatin C in patients with malignancy | journal = Clinical and Experimental Nephrology | volume = 12 | issue = 2 | pages = 132–139 | date = April 2008 | pmid = 18317874 | doi = 10.1007/s10157-008-0043-8 }}</ref><ref name="pmid9836733">{{cite journal | vauthors = Kos J, Stabuc B, Cimerman N, Brünner N | title = Serum cystatin C, a new marker of glomerular filtration rate, is increased during malignant progression | journal = Clinical Chemistry | volume = 44 | issue = 12 | pages = 2556–7 | date = December 1998 | pmid = 9836733 | doi = 10.1093/clinchem/44.12.2556 | doi-access = free }}</ref> (even subtle) thyroid dysfunction<ref name="pmid12675875">{{cite journal | vauthors = Fricker M, Wiesli P, Brändle M, Schwegler B, Schmid C | title = Impact of thyroid dysfunction on serum cystatin C | journal = Kidney International | volume = 63 | issue = 5 | pages = 1944–7 | date = May 2003 | pmid = 12675875 | doi = 10.1046/j.1523-1755.2003.00925.x | doi-access = free }}</ref><ref name="pmid15966508">{{cite journal | vauthors = Manetti L, Pardini E, Genovesi M, Campomori A, Grasso L, Morselli LL, Lupi I, Pellegrini G, Bartalena L, Bogazzi F, Martino E | display-authors = 6 | title = Thyroid function differently affects serum cystatin C and creatinine concentrations | journal = Journal of Endocrinological Investigation | volume = 28 | issue = 4 | pages = 346–9 | date = April 2005 | pmid = 15966508 | doi = 10.1007/bf03347201 | s2cid = 26777752 | url = http://www.kurtis.it/abs/index.cfm?id_articolo_numero=3109 | url-status = dead | archive-url = https://web.archive.org/web/20080608033357/http://www.kurtis.it/abs/index.cfm?id_articolo_numero=3109 | archive-date = 2008-06-08 }}</ref><ref name="pmid14637271">{{cite journal | vauthors = Wiesli P, Schwegler B, Spinas GA, Schmid C | title = Serum cystatin C is sensitive to small changes in thyroid function | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 338 | issue = 1–2 | pages = 87–90 | date = December 2003 | pmid = 14637271 | doi = 10.1016/j.cccn.2003.07.022 }}</ref> and glucocorticoid therapy in some<ref name="pmid11673383">{{cite journal | vauthors = Risch L, Herklotz R, Blumberg A, Huber AR | title = Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients | journal = Clinical Chemistry | volume = 47 | issue = 11 | pages = 2055–9 | date = November 2001 | pmid = 11673383 | doi = 10.1093/clinchem/47.11.2055 | doi-access = free }}</ref><ref name="pmid10958865">{{cite journal | vauthors = Cimerman N, Brguljan PM, Krasovec M, Suskovic S, Kos J | title = Serum cystatin C, a potent inhibitor of cysteine proteinases, is elevated in asthmatic patients | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 300 | issue = 1–2 | pages = 83–95 | date = October 2000 | pmid = 10958865 | doi = 10.1016/S0009-8981(00)00298-9 }}</ref> but not all<ref name="pmid12089191">{{cite journal | vauthors = Bökenkamp A, van Wijk JA, Lentze MJ, Stoffel-Wagner B | title = Effect of corticosteroid therapy on serum cystatin C and beta2-microglobulin concentrations | journal = Clinical Chemistry | volume = 48 | issue = 7 | pages = 1123–6 | date = July 2002 | pmid = 12089191 | doi = 10.1093/clinchem/48.7.1123 | doi-access = free }}</ref> situations. Other reports have found that levels are influenced by [[cigarette smoking]] and levels of [[C-reactive protein]].<ref name="pmid15086483">{{cite journal | vauthors = Knight EL, Verhave JC, Spiegelman D, Hillege HL, de Zeeuw D, Curhan GC, de Jong PE | title = Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement | journal = Kidney International | volume = 65 | issue = 4 | pages = 1416–21 | date = April 2004 | pmid = 15086483 | doi = 10.1111/j.1523-1755.2004.00517.x | doi-access = free }}</ref> However, inflammation does not cause an increase in the production of cystatin C, since elective surgical procedures, producing a strong inflammatory response in patients, do not change the plasma concentration of cystatin C.{{medcn|date=August 2020}} Levels seem to be increased in [[HIV]] infection, which might or might not reflect actual renal dysfunction.<ref name="pmid17998494">{{cite journal | vauthors = Odden MC, Scherzer R, Bacchetti P, Szczech LA, Sidney S, Grunfeld C, Shlipak MG | title = Cystatin C level as a marker of kidney function in human immunodeficiency virus infection: the FRAM study | journal = Archives of Internal Medicine | volume = 167 | issue = 20 | pages = 2213–9 | date = November 2007 | pmid = 17998494 | pmc = 3189482 | doi = 10.1001/archinte.167.20.2213 | url = http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=17998494 | url-status = dead | archive-url = https://archive.today/20080607214011/http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=17998494 | archive-date = 2008-06-07 }}</ref><ref name="pmid1569212">{{cite journal | vauthors = Collé A, Tavera C, Prévot D, Leung-Tack J, Thomas Y, Manuel Y, Benveniste J, Leibowitch J | display-authors = 6 | title = Cystatin C levels in sera of patients with human immunodeficiency virus infection. A new avidin-biotin ELISA assay for its measurement | journal = Journal of Immunoassay | volume = 13 | issue = 1 | pages = 47–60 | year = 1992 | pmid = 1569212 | doi = 10.1080/15321819208019824 }}</ref><ref name="pmid16964834">{{cite journal | vauthors = Jaroszewicz J, Wiercinska-Drapalo A, Lapinski TW, Prokopowicz D, Rogalska M, Parfieniuk A | title = Does HAART improve renal function? An association between serum cystatin C concentration, HIV viral load and HAART duration | journal = Antiviral Therapy | volume = 11 | issue = 5 | pages = 641–5 | year = 2006 | doi = 10.1177/135965350601100502 | pmid = 16964834 | s2cid = 33722022 | doi-access = free }}</ref> The role of cystatin C to monitor GFR during pregnancy remains controversial.<ref name="pmid12004930">{{cite journal | vauthors = Strevens H, Wide-Swensson D, Torffvit O, Grubb A | s2cid = 25382382 | title = Serum cystatin C for assessment of glomerular filtration rate in pregnant and non-pregnant women. Indications of altered filtration process in pregnancy | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 62 | issue = 2 | pages = 141–7 | year = 2002 | pmid = 12004930 | doi = 10.1080/003655102753611771 }}</ref><ref name="pmid15842279">{{cite journal | vauthors = Akbari A, Lepage N, Keely E, Clark HD, Jaffey J, MacKinnon M, Filler G | title = Cystatin-C and beta trace protein as markers of renal function in pregnancy | journal = BJOG | volume = 112 | issue = 5 | pages = 575–8 | date = May 2005 | pmid = 15842279 | doi = 10.1111/j.1471-0528.2004.00492.x | s2cid = 1851149 }}</ref> Like creatinine, the elimination of cystatin C via routes other than the kidney increases with worsening GFR.<ref name="pmid16025834">{{cite journal | vauthors = Sjöström P, Tidman M, Jones I | s2cid = 41336736 | title = Determination of the production rate and non-renal clearance of cystatin C and estimation of the glomerular filtration rate from the serum concentration of cystatin C in humans | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 65 | issue = 2 | pages = 111–24 | year = 2005 | pmid = 16025834 | doi = 10.1080/00365510510013523 }}</ref>
 ===Death and cardiovascular disease===
-Kidney dysfunction increases the risk of death and cardiovascular disease.<ref name="pmid16738019">{{cite journal | vauthors = Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, McAlister F, Garg AX | display-authors = 6 | title = Chronic kidney disease and mortality risk: a systematic review | journal = Journal of the American Society of Nephrology | volume = 17 | issue = 7 | pages = 2034–47 | date = July 2006 | pmid = 16738019 | doi = 10.1681/ASN.2005101085 | url = http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=16738019 | doi-access = free }}</ref><ref name="pmid15385656">{{cite journal | vauthors = Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY | title = Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization | journal = The New England Journal of Medicine | volume = 351 | issue = 13 | pages = 1296–305 | date = September 2004 | pmid = 15385656 | doi = 10.1056/NEJMoa041031 }}</ref>
+Kidney dysfunction increases the risk of death and cardiovascular disease.<ref name="pmid16738019">{{cite journal | vauthors = Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, McAlister F, Garg AX | display-authors = 6 | title = Chronic kidney disease and mortality risk: a systematic review | journal = Journal of the American Society of Nephrology | volume = 17 | issue = 7 | pages = 2034–47 | date = July 2006 | pmid = 16738019 | doi = 10.1681/ASN.2005101085 | url = http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=16738019 | doi-access = free }}</ref><ref name="pmid15385656">{{cite journal | vauthors = Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY | title = Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization | journal = The New England Journal of Medicine | volume = 351 | issue = 13 | pages = 1296–305 | date = September 2004 | pmid = 15385656 | doi = 10.1056/NEJMoa041031 | doi-access = free }}</ref>
-Several studies have found that increased levels of cystatin C are associated with the risk of death, several types of cardiovascular disease (including [[myocardial infarction]], [[stroke]], [[heart failure]], [[peripheral arterial disease]] and [[metabolic syndrome]]) and healthy aging.{{citation needed|date=February 2014}}{{clarify|date=February 2014}} Some studies have found cystatin C to be better in this regard than serum creatinine or creatinine-based GFR equations.<ref name="pmid18480203">{{cite journal | vauthors = Zethelius B, Berglund L, Sundström J, Ingelsson E, Basu S, Larsson A, Venge P, Arnlöv J | display-authors = 6 | title = Use of multiple biomarkers to improve the prediction of death from cardiovascular causes | journal = The New England Journal of Medicine | volume = 358 | issue = 20 | pages = 2107–16 | date = May 2008 | pmid = 18480203 | doi = 10.1056/NEJMoa0707064 }}</ref><ref name="pmid15901858">{{cite journal | vauthors = Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, Siscovick DS, Stehman-Breen C | display-authors = 6 | title = Cystatin C and the risk of death and cardiovascular events among elderly persons | journal = The New England Journal of Medicine | volume = 352 | issue = 20 | pages = 2049–60 | date = May 2005 | pmid = 15901858 | doi = 10.1056/NEJMoa043161 }}</ref><ref name="pmid17190862">{{cite journal | vauthors = Ix JH, Shlipak MG, Chertow GM, Whooley MA | title = Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart disease: data from the Heart and Soul Study | journal = Circulation | volume = 115 | issue = 2 | pages = 173–9 | date = January 2007 | pmid = 17190862 | pmc = 2771187 | doi = 10.1161/CIRCULATIONAHA.106.644286 | url = http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=17190862 }}</ref><ref name="pmid18082491">{{cite journal | vauthors = Deo R, Fyr CL, Fried LF, Newman AB, Harris TB, Angleman S, Green C, Kritchevsky SB, Chertow GM, Cummings SR, Shlipak MG | display-authors = 6 | title = Kidney dysfunction and fatal cardiovascular disease--an association independent of atherosclerotic events: results from the Health, Aging, and Body Composition (Health ABC) study | journal = American Heart Journal | volume = 155 | issue = 1 | pages = 62–8 | date = January 2008 | pmid = 18082491 | doi = 10.1016/j.ahj.2007.08.012 }}</ref><ref name="pmid15563478">{{cite journal | vauthors = Koenig W, Twardella D, Brenner H, Rothenbacher D | title = Plasma concentrations of cystatin C in patients with coronary heart disease and risk for secondary cardiovascular events: more than simply a marker of glomerular filtration rate | journal = Clinical Chemistry | volume = 51 | issue = 2 | pages = 321–7 | date = February 2005 | pmid = 15563478 | doi = 10.1373/clinchem.2004.041889 | doi-access = free }}</ref><ref name="pmid15477399">{{cite journal | vauthors = Jernberg T, Lindahl B, James S, Larsson A, Hansson LO, Wallentin L | title = Cystatin C: a novel predictor of outcome in suspected or confirmed non-ST-elevation acute coronary syndrome | journal = Circulation | volume = 110 | issue = 16 | pages = 2342–8 | date = October 2004 | pmid = 15477399 | doi = 10.1161/01.CIR.0000145166.44942.E0 | url = http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=15477399 | doi-access = free }}</ref><ref name="pmid16046222">{{cite journal | vauthors = Luc G, Bard JM, Lesueur C, Arveiler D, Evans A, Amouyel P, Ferrieres J, Juhan-Vague I, Fruchart JC, Ducimetiere P | display-authors = 6 | title = Plasma cystatin-C and development of coronary heart disease: The PRIME Study | journal = Atherosclerosis | volume = 185 | issue = 2 | pages = 375–80 | date = April 2006 | pmid = 16046222 | doi = 10.1016/j.atherosclerosis.2005.06.017 | url = https://pure.qub.ac.uk/ws/files/496612/Plasma%20cystatin-C%20and%20development%20of%20coronary%20heart%20disease%20-%20The%20PRIME%20Study%20-%20Atherosclerosis%202006%20-%20Evans%20AE%20-%20(Yarnell%20JW,%20Kee%20F,%20members).pdf }}</ref><ref name="pmid18456039">{{cite journal | vauthors = Servais A, Giral P, Bernard M, Bruckert E, Deray G, Isnard Bagnis C | title = Is serum cystatin-C a reliable marker for metabolic syndrome? | journal = The American Journal of Medicine | volume = 121 | issue = 5 | pages = 426–32 | date = May 2008 | pmid = 18456039 | doi = 10.1016/j.amjmed.2008.01.040 }}</ref><ref name="pmid17606957">{{cite journal | vauthors = Menon V, Shlipak MG, Wang X, Coresh J, Greene T, Stevens L, Kusek JW, Beck GJ, Collins AJ, Levey AS, Sarnak MJ | s2cid = 31964826 | display-authors = 6 | title = Cystatin C as a risk factor for outcomes in chronic kidney disease | journal = Annals of Internal Medicine | volume = 147 | issue = 1 | pages = 19–27 | date = July 2007 | pmid = 17606957 | doi = 10.7326/0003-4819-147-1-200707030-00004 | url = http://www.annals.org/cgi/pmidlookup?view=reprint&pmid=17606957 }}</ref><ref name="pmid18227360">{{cite journal | vauthors = Sarnak MJ, Katz R, Fried LF, Siscovick D, Kestenbaum B, Seliger S, Rifkin D, Tracy R, Newman AB, Shlipak MG | display-authors = 6 | title = Cystatin C and aging success | journal = Archives of Internal Medicine | volume = 168 | issue = 2 | pages = 147–53 | date = January 2008 | pmid = 18227360 | pmc = 2871318 | doi = 10.1001/archinternmed.2007.40 | url = http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=18227360 | url-status = dead | archive-url = https://archive.today/20080607214016/http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=18227360 | archive-date = 2008-06-07 }}</ref><ref name="pmid18082494">{{cite journal | vauthors = Djoussé L, Kurth T, Gaziano JM | title = Cystatin C and risk of heart failure in the Physicians' Health Study (PHS) | journal = American Heart Journal | volume = 155 | issue = 1 | pages = 82–6 | date = January 2008 | pmid = 18082494 | pmc = 2179893 | doi = 10.1016/j.ahj.2007.08.023 }}</ref><ref name="pmid16344426">{{cite journal | vauthors = O'Hare AM, Newman AB, Katz R, Fried LF, Stehman-Breen CO, Seliger SL, Siscovick DS, Shlipak MG | display-authors = 6 | title = Cystatin C and incident peripheral arterial disease events in the elderly: results from the Cardiovascular Health Study | journal = Archives of Internal Medicine | volume = 165 | issue = 22 | pages = 2666–70 | year = 2005 | pmid = 16344426 | doi = 10.1001/archinte.165.22.2666 | doi-access = free }}</ref>
+Several studies have found that increased levels of cystatin C are associated with the risk of death, several types of cardiovascular disease (including [[myocardial infarction]], [[stroke]], [[heart failure]], [[peripheral arterial disease]] and [[metabolic syndrome]]) and healthy aging.{{citation needed|date=February 2014}}{{clarify|date=February 2014}} Some studies have found cystatin C to be better in this regard than serum creatinine or creatinine-based GFR equations.<ref name="pmid18480203">{{cite journal | vauthors = Zethelius B, Berglund L, Sundström J, Ingelsson E, Basu S, Larsson A, Venge P, Arnlöv J | display-authors = 6 | title = Use of multiple biomarkers to improve the prediction of death from cardiovascular causes | journal = The New England Journal of Medicine | volume = 358 | issue = 20 | pages = 2107–16 | date = May 2008 | pmid = 18480203 | doi = 10.1056/NEJMoa0707064 | doi-access = free }}</ref><ref name="pmid15901858">{{cite journal | vauthors = Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, Siscovick DS, Stehman-Breen C | display-authors = 6 | title = Cystatin C and the risk of death and cardiovascular events among elderly persons | journal = The New England Journal of Medicine | volume = 352 | issue = 20 | pages = 2049–60 | date = May 2005 | pmid = 15901858 | doi = 10.1056/NEJMoa043161 | doi-access = free }}</ref><ref name="pmid17190862">{{cite journal | vauthors = Ix JH, Shlipak MG, Chertow GM, Whooley MA | title = Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart disease: data from the Heart and Soul Study | journal = Circulation | volume = 115 | issue = 2 | pages = 173–9 | date = January 2007 | pmid = 17190862 | pmc = 2771187 | doi = 10.1161/CIRCULATIONAHA.106.644286 | url = http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=17190862 }}</ref><ref name="pmid18082491">{{cite journal | vauthors = Deo R, Fyr CL, Fried LF, Newman AB, Harris TB, Angleman S, Green C, Kritchevsky SB, Chertow GM, Cummings SR, Shlipak MG | display-authors = 6 | title = Kidney dysfunction and fatal cardiovascular disease--an association independent of atherosclerotic events: results from the Health, Aging, and Body Composition (Health ABC) study | journal = American Heart Journal | volume = 155 | issue = 1 | pages = 62–8 | date = January 2008 | pmid = 18082491 | doi = 10.1016/j.ahj.2007.08.012 }}</ref><ref name="pmid15563478">{{cite journal | vauthors = Koenig W, Twardella D, Brenner H, Rothenbacher D | title = Plasma concentrations of cystatin C in patients with coronary heart disease and risk for secondary cardiovascular events: more than simply a marker of glomerular filtration rate | journal = Clinical Chemistry | volume = 51 | issue = 2 | pages = 321–7 | date = February 2005 | pmid = 15563478 | doi = 10.1373/clinchem.2004.041889 | doi-access = free }}</ref><ref name="pmid15477399">{{cite journal | vauthors = Jernberg T, Lindahl B, James S, Larsson A, Hansson LO, Wallentin L | title = Cystatin C: a novel predictor of outcome in suspected or confirmed non-ST-elevation acute coronary syndrome | journal = Circulation | volume = 110 | issue = 16 | pages = 2342–8 | date = October 2004 | pmid = 15477399 | doi = 10.1161/01.CIR.0000145166.44942.E0 | url = http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=15477399 | doi-access = free }}</ref><ref name="pmid16046222">{{cite journal | vauthors = Luc G, Bard JM, Lesueur C, Arveiler D, Evans A, Amouyel P, Ferrieres J, Juhan-Vague I, Fruchart JC, Ducimetiere P | display-authors = 6 | title = Plasma cystatin-C and development of coronary heart disease: The PRIME Study | journal = Atherosclerosis | volume = 185 | issue = 2 | pages = 375–80 | date = April 2006 | pmid = 16046222 | doi = 10.1016/j.atherosclerosis.2005.06.017 | s2cid = 40221090 | url = https://pure.qub.ac.uk/ws/files/496612/Plasma%20cystatin-C%20and%20development%20of%20coronary%20heart%20disease%20-%20The%20PRIME%20Study%20-%20Atherosclerosis%202006%20-%20Evans%20AE%20-%20(Yarnell%20JW,%20Kee%20F,%20members).pdf }}</ref><ref name="pmid18456039">{{cite journal | vauthors = Servais A, Giral P, Bernard M, Bruckert E, Deray G, Isnard Bagnis C | title = Is serum cystatin-C a reliable marker for metabolic syndrome? | journal = The American Journal of Medicine | volume = 121 | issue = 5 | pages = 426–32 | date = May 2008 | pmid = 18456039 | doi = 10.1016/j.amjmed.2008.01.040 }}</ref><ref name="pmid17606957">{{cite journal | vauthors = Menon V, Shlipak MG, Wang X, Coresh J, Greene T, Stevens L, Kusek JW, Beck GJ, Collins AJ, Levey AS, Sarnak MJ | s2cid = 31964826 | display-authors = 6 | title = Cystatin C as a risk factor for outcomes in chronic kidney disease | journal = Annals of Internal Medicine | volume = 147 | issue = 1 | pages = 19–27 | date = July 2007 | pmid = 17606957 | doi = 10.7326/0003-4819-147-1-200707030-00004 | url = http://www.annals.org/cgi/pmidlookup?view=reprint&pmid=17606957 }}</ref><ref name="pmid18227360">{{cite journal | vauthors = Sarnak MJ, Katz R, Fried LF, Siscovick D, Kestenbaum B, Seliger S, Rifkin D, Tracy R, Newman AB, Shlipak MG | display-authors = 6 | title = Cystatin C and aging success | journal = Archives of Internal Medicine | volume = 168 | issue = 2 | pages = 147–53 | date = January 2008 | pmid = 18227360 | pmc = 2871318 | doi = 10.1001/archinternmed.2007.40 | url = http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=18227360 | url-status = dead | archive-url = https://archive.today/20080607214016/http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=18227360 | archive-date = 2008-06-07 }}</ref><ref name="pmid18082494">{{cite journal | vauthors = Djoussé L, Kurth T, Gaziano JM | title = Cystatin C and risk of heart failure in the Physicians' Health Study (PHS) | journal = American Heart Journal | volume = 155 | issue = 1 | pages = 82–6 | date = January 2008 | pmid = 18082494 | pmc = 2179893 | doi = 10.1016/j.ahj.2007.08.023 }}</ref><ref name="pmid16344426">{{cite journal | vauthors = O'Hare AM, Newman AB, Katz R, Fried LF, Stehman-Breen CO, Seliger SL, Siscovick DS, Shlipak MG | display-authors = 6 | title = Cystatin C and incident peripheral arterial disease events in the elderly: results from the Cardiovascular Health Study | journal = Archives of Internal Medicine | volume = 165 | issue = 22 | pages = 2666–70 | year = 2005 | pmid = 16344426 | doi = 10.1001/archinte.165.22.2666 | doi-access = free }}</ref>
-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.<ref name="pmid15901867">{{cite journal | vauthors = Stevens LA, Levey AS | title = Chronic kidney disease in the elderly--how to assess risk | journal = The New England Journal of Medicine | volume = 352 | issue = 20 | pages = 2122–4 | date = May 2005 | pmid = 15901867 | doi = 10.1056/NEJMe058035 }}</ref> In keeping with its [[housekeeping gene]] properties, it has been suggested that cystatin C might be influenced by the [[basal metabolic rate]].<ref name="pmid18283218">{{cite journal | vauthors = Delanaye P, Cavalier E, Krzesinski JM | title = Cystatin C, renal function, and cardiovascular risk | journal = Annals of Internal Medicine | volume = 148 | issue = 4 | pages = 323 | date = February 2008 | pmid = 18283218 | doi = 10.7326/0003-4819-148-4-200802190-00023 | url = http://orbi.ulg.ac.be/handle/2268/4787 }}</ref>
+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.<ref name="pmid15901867">{{cite journal | vauthors = Stevens LA, Levey AS | title = Chronic kidney disease in the elderly--how to assess risk | journal = The New England Journal of Medicine | volume = 352 | issue = 20 | pages = 2122–4 | date = May 2005 | pmid = 15901867 | doi = 10.1056/NEJMe058035 }}</ref> In keeping with its [[housekeeping gene]] properties, it has been suggested that cystatin C might be influenced by the [[basal metabolic rate]].<ref name="pmid18283218">{{cite journal | vauthors = Delanaye P, Cavalier E, Krzesinski JM | title = Cystatin C, renal function, and cardiovascular risk | journal = Annals of Internal Medicine | volume = 148 | issue = 4 | pages = 323 | date = February 2008 | pmid = 18283218 | doi = 10.7326/0003-4819-148-4-200802190-00023 | hdl = 2268/4787 | url = http://orbi.ulg.ac.be/handle/2268/4787 | hdl-access = free }}</ref>
-===Cystatin C, Shrunken pore syndrome and mortality===
+===Proposed shrunken pore syndrome===
-The glomerular sieving coefficients for 10–30 kDa plasma proteins in the human kidney are relatively high with coefficients between 0.9 and 0.07. <ref>{{cite journal | vauthors = Norden AG, Lapsley M, Lee PJ, Pusey CD, Scheinman SJ, Tam FW, Thakker RV, Unwin RJ, Wrong O | display-authors = 6 | title = Glomerular protein sieving and implications for renal failure in Fanconi syndrome | journal = Kidney International | volume = 60 | issue = 5 | pages = 1885–92 | date = November 2001 | pmid = 11703607 | doi = 10.1046/j.1523-1755.2001.00016.x }}</ref> These relatively high sieving coefficients, combined with the high production of ultrafiltrate in health, means that proteins ≤ 30 kDa in plasma normally are mainly cleared by the kidneys and at least 85% of the clearance of cystatin C occurs in the kidney. <ref>{{cite journal | vauthors = Tenstad O, Roald AB, Grubb A, Aukland K | title = Renal handling of radiolabelled human cystatin C in the rat | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 56 | issue = 5 | pages = 409–14 | date = August 1996 | pmid = 8869663 | doi = 10.3109/00365519609088795 }}</ref> If the pores of the glomerular membrane shrink, the filtration of bigger molecules, e.g. cystatin C,  will decrease, whereas the filtration of small molecules, like water and creatinine, will be less affected. In this case, cystatin C-based estimates of GFR, eGFR<sub>cystatin C</sub>, will be lower than creatinine-based estimates eGFR<sub>creatinine</sub>, so that this condition, named [[shrunken pore syndrome]] can be identified by a low  eGFR<sub>cystatin C</sub>/eGFR<sub>creatinine</sub>-ratio. <ref>{{cite journal | vauthors = Grubb A, Lindström V, Jonsson M, Bäck SE, Åhlund T, Rippe B, Christensson A | title = Reduction in glomerular pore size is not restricted to pregnant women. Evidence for a new syndrome: 'Shrunken pore syndrome' | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 75 | issue = 4 | pages = 333–40 | date = July 2015 | pmid = 25919022 | doi = 10.3109/00365513.2015.1025427 | pmc = 4487590 }}</ref> This syndrome is associated with a very strong increase in mortality. <ref>{{cite journal | vauthors = Dardashti A, Nozohoor S, Grubb A, Bjursten H | title = Shrunken Pore Syndrome is associated with a sharp rise in mortality in patients undergoing elective coronary artery bypass grafting | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 76 | issue = 1 | pages = 74–81 | year = 2016 | pmid = 26647957 | doi = 10.3109/00365513.2015.1099724 | pmc = 4720044 }}</ref><ref>{{cite journal | vauthors = Åkesson A, Lindström V, Nyman U, Jonsson M, Abrahamson M, Christensson A, Björk J, Grubb A | display-authors = 6 | title = Shrunken pore syndrome]] and mortality: a cohort study of patients with measured GFR and known comorbidities | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = Online ahead of print | pages = 1–12 | date = May 2020 | pmid = 32459111 | doi = 10.1080/00365513.2020.1759139 }}</ref><ref name=”foo”>{{cite journal | vauthors = Grubb A | title = Shrunken pore syndrome - a common kidney disorder with high mortality. Diagnosis, prevalence, pathophysiology and treatment options | journal = Clinical Biochemistry | volume = Online ahead of print | date = June 2020 | pmid = 32544475 | doi = 10.1016/j.clinbiochem.2020.06.002 }}</ref> The capacity of cystatin C to identify this syndrome might therefore explain the marked superiority of eGFR<sub>cystatin C</sub>, or cystatin C, over eGFR<sub>creatinine</sub>, or creatinine, in predicting end-stage renal disease, cardiovascular manifestations, hospitalisation or death. <ref name=”foo”/>
+The glomerular sieving coefficients for 10–30 kDa plasma proteins in the human kidney are relatively high with coefficients between 0.9 and 0.07.{{medcn|date=August 2020}}<ref> {{primary source inline|date=August 2020}} {{cite journal | vauthors = Norden AG, Lapsley M, Lee PJ, Pusey CD, Scheinman SJ, Tam FW, Thakker RV, Unwin RJ, Wrong O | display-authors = 6 | title = Glomerular protein sieving and implications for renal failure in Fanconi syndrome | journal = Kidney International | volume = 60 | issue = 5 | pages = 1885–92 | date = November 2001 | pmid = 11703607 | doi = 10.1046/j.1523-1755.2001.00016.x | doi-access = free }}</ref> These relatively high sieving coefficients, combined with the high production of ultrafiltrate in health, means that proteins less than or equal to 30 kDa in plasma normally are mainly cleared by the kidneys and at least 85% of the clearance of cystatin C occurs in the kidney.{{medcn|date=August 2020}}<ref> {{primary source inline|date=August 2020}} {{cite journal | vauthors = Tenstad O, Roald AB, Grubb A, Aukland K | title = Renal handling of radiolabelled human cystatin C in the rat | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 56 | issue = 5 | pages = 409–14 | date = August 1996 | pmid = 8869663 | doi = 10.3109/00365519609088795 }}</ref> If the pores of the glomerular membrane shrink, the filtration of bigger molecules, e.g. cystatin C,  will decrease, whereas the filtration of small molecules, like water and creatinine, will be less affected. In this case, cystatin C-based estimates of GFR, eGFR<sub>cystatin C</sub>, will be lower than creatinine-based estimates eGFR<sub>creatinine</sub>, so that a hypothesized condition, named [[shrunken pore syndrome]], is identified by a low  eGFR<sub>cystatin C</sub>/eGFR<sub>creatinine</sub>-ratio.{{medcn|date=August 2020}}<ref> {{primary source inline|date=August 2020}} {{cite journal | vauthors = Grubb A, Lindström V, Jonsson M, Bäck SE, Åhlund T, Rippe B, Christensson A | title = Reduction in glomerular pore size is not restricted to pregnant women. Evidence for a new syndrome: 'Shrunken pore syndrome' | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 75 | issue = 4 | pages = 333–40 | date = July 2015 | pmid = 25919022 | doi = 10.3109/00365513.2015.1025427 | pmc = 4487590 }}</ref> This syndrome is associated with a very strong increase in mortality.<ref name=Grubb2020>{{cite journal | vauthors = Grubb A | title = Shrunken pore syndrome - a common kidney disorder with high mortality. Diagnosis, prevalence, pathophysiology and treatment options | journal = Clinical Biochemistry | volume = Online ahead of print | date = June 2020 | pages = 12–20 | pmid = 32544475 | doi = 10.1016/j.clinbiochem.2020.06.002 | doi-access = free }}</ref>
 ===Neurologic disorders===
-[[Mutation]]s in the cystatin 3 [[gene]] are responsible for the [[Iceland]]ic type of hereditary [[cerebral amyloid angiopathy]], a condition predisposing to [[intracerebral haemorrhage]], [[stroke]] and [[dementia]].<ref name="pmid2541223">{{cite journal | vauthors = Levy E, Lopez-Otin C, Ghiso J, Geltner D, Frangione B | title = Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases | journal = The Journal of Experimental Medicine | volume = 169 | issue = 5 | pages = 1771–8 | date = May 1989 | pmid = 2541223 | pmc = 2189307 | doi = 10.1084/jem.169.5.1771 }}</ref><ref name="pmid16612983">{{cite journal | vauthors = Levy E, Jaskolski M, Grubb A | title = The role of cystatin C in cerebral amyloid angiopathy and stroke: cell biology and animal models | journal = Brain Pathology | volume = 16 | issue = 1 | pages = 60–70 | date = January 2006 | pmid = 16612983 | doi = 10.1111/j.1750-3639.2006.tb00562.x }}</ref> The condition is inherited in a [[Dominance relationship|dominant fashion]].
+[[Mutation]]s in the cystatin 3 [[gene]] are responsible for the [[Iceland]]ic type of [[Hereditary cystatin C amyloid angiopathy|hereditary cerebral amyloid angiopathy]], a condition predisposing to [[intracerebral haemorrhage]], [[stroke]] and [[dementia]].<ref name="pmid2541223">{{cite journal | vauthors = Levy E, Lopez-Otin C, Ghiso J, Geltner D, Frangione B | title = Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases | journal = The Journal of Experimental Medicine | volume = 169 | issue = 5 | pages = 1771–8 | date = May 1989 | pmid = 2541223 | pmc = 2189307 | doi = 10.1084/jem.169.5.1771 }}</ref><ref name="pmid16612983">{{cite journal | vauthors = Levy E, Jaskolski M, Grubb A | title = The role of cystatin C in cerebral amyloid angiopathy and stroke: cell biology and animal models | journal = Brain Pathology | volume = 16 | issue = 1 | pages = 60–70 | date = January 2006 | pmid = 16612983 | doi = 10.1111/j.1750-3639.2006.tb00562.x | s2cid = 21279341 | pmc = 8095742 }}</ref> The condition is inherited in a [[Dominance relationship|dominant fashion]]. The monomeric cystatin C forms dimers and oligomers by domain swapping<ref>{{cite journal | vauthors = Janowski R, Kozak M, Janowska E, Grzonka Z, Grubb A, Abrahamson M, Jaskolski M | display-authors = 6 | title = Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping | journal = Nature Structural Biology | volume = 8 | issue = 4 | pages = 316–320 | date = April 2001 | pmid = 11276250 | doi = 10.1038/86188| s2cid = 28916747 | url = https://lup.lub.lu.se/record/131360 }}</ref> and the structures of both the dimers<ref>{{cite journal | vauthors = Janowski R, Kozak M, Abrahamson M, Grubb A, Jaskolski M | title = Glomerular protein sieving and implications for renal failure in Fanconi syndrome | journal = Proteins | volume = 61 | issue = 3 | pages = 570–578–92 | date = Nov 2005 | pmid = 16170782 | doi = 10.1002/prot.20633| s2cid = 633348 }}</ref> and oligomers<ref>{{cite journal | vauthors = Chrabaszczewska M, Sieradzan AK, Rodziewicz-Motowidło S, Grubb A, Dobson CM, Kunita JR, Kozak M | title = Structural characterization of covalently stabilized human cystatin C oligomers | journal = International Journal of Molecular Sciences| volume = 21 | issue = 5860 | date = Aug 2020 | page = 5860 | doi = 10.3390/ijms21165860| pmid = 32824145 | pmc = 7461555 | doi-access = free }}</ref> have been determined.
 Since cystatin 3 also binds [[amyloid β]] and reduces its aggregation and deposition, it is a potential target in [[Alzheimer's disease]].<ref name="pmid18026100">{{cite journal | vauthors = Mi W, Pawlik M, Sastre M, Jung SS, Radvinsky DS, Klein AM, Sommer J, Schmidt SD, Nixon RA, Mathews PM, Levy E | s2cid = 21332698 | display-authors = 6 | title = Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models | journal = Nature Genetics | volume = 39 | issue = 12 | pages = 1440–2 | date = December 2007 | pmid = 18026100 | doi = 10.1038/ng.2007.29 }}</ref><ref name="pmid18026102">{{cite journal | vauthors = Kaeser SA, Herzig MC, Coomaraswamy J, Kilger E, Selenica ML, Winkler DT, Staufenbiel M, Levy E, Grubb A, Jucker M | s2cid = 7001526 | display-authors = 6 | title = Cystatin C modulates cerebral beta-amyloidosis | journal = Nature Genetics | volume = 39 | issue = 12 | pages = 1437–9 | date = December 2007 | pmid = 18026102 | doi = 10.1038/ng.2007.23 }}</ref> Although not all studies have confirmed this, the overall evidence is in favor of a role for CST3 as a susceptibility gene for Alzheimer's disease.<ref name="pmid17192785">{{cite journal | vauthors = Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE | s2cid = 452851 | title = Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database | journal = Nature Genetics | volume = 39 | issue = 1 | pages = 17–23 | date = January 2007 | pmid = 17192785 | doi = 10.1038/ng1934 }}</ref> Cystatin C levels have been reported to be higher in subjects with Alzheimer's disease.<ref name="pmid17310123">{{cite journal | vauthors = Chuo LJ, Sheu WH, Pai MC, Kuo YM | s2cid = 29689590 | title = Genotype and plasma concentration of cystatin C in patients with late-onset Alzheimer disease | journal = Dementia and Geriatric Cognitive Disorders | volume = 23 | issue = 4 | pages = 251–7 | year = 2007 | pmid = 17310123 | doi = 10.1159/000100021 | url = https://www.karger.com/Article/PDF/000100021 }}</ref>
-The role of cystatin C in [[multiple sclerosis]] and other [[demyelinating disease]]s (characterized by a loss of the myelin nerve sheath) remains controversial.<ref name="pmid17006926">{{cite journal | vauthors = Del Boccio P, Pieragostino D, Lugaresi A, Di Ioia M, Pavone B, Travaglini D, D'Aguanno S, Bernardini S, Sacchetta P, Federici G, Di Ilio C, Gambi D, Urbani A | display-authors = 6 | title = Cleavage of cystatin C is not associated with multiple sclerosis | journal = Annals of Neurology | volume = 62 | issue = 2 | pages = 201–4; discussion 205 | date = August 2007 | pmid = 17006926 | doi = 10.1002/ana.20968 }}</ref>
+The role of cystatin C in [[multiple sclerosis]] and other [[demyelinating disease]]s (characterized by a loss of the myelin nerve sheath) remains controversial.<ref name="pmid17006926">{{cite journal | vauthors = Del Boccio P, Pieragostino D, Lugaresi A, Di Ioia M, Pavone B, Travaglini D, D'Aguanno S, Bernardini S, Sacchetta P, Federici G, Di Ilio C, Gambi D, Urbani A | display-authors = 6 | title = Cleavage of cystatin C is not associated with multiple sclerosis | journal = Annals of Neurology | volume = 62 | issue = 2 | pages = 201–4; discussion 205 | date = August 2007 | pmid = 17006926 | doi = 10.1002/ana.20968 | s2cid = 10687960 }}</ref>
 ===Other roles===
-Cystatin C levels are decreased in [[atherosclerosis|atherosclerotic]] (so-called 'hardening' of the arteries) and [[aneurysm]]al (saccular bulging) lesions of the [[aorta]].<ref name="pmid10545518">{{cite journal | vauthors = Shi GP, Sukhova GK, Grubb A, Ducharme A, Rhode LH, Lee RT, Ridker PM, Libby P, Chapman HA | display-authors = 6 | title = Cystatin C deficiency in human atherosclerosis and aortic aneurysms | journal = The Journal of Clinical Investigation | volume = 104 | issue = 9 | pages = 1191–7 | date = November 1999 | pmid = 10545518 | pmc = 409823 | doi = 10.1172/JCI7709 | url = https://dash.harvard.edu/bitstream/handle/1/13506934/Cystatin%20C%20deficiency%20in%20human%20atherosclerosis.pdf?sequence=1 }}</ref><ref name="pmid18155003">{{cite journal | vauthors = Abisi S, Burnand KG, Waltham M, Humphries J, Taylor PR, Smith A | title = Cysteine protease activity in the wall of abdominal aortic aneurysms | journal = Journal of Vascular Surgery | volume = 46 | issue = 6 | pages = 1260–6 | date = December 2007 | pmid = 18155003 | doi = 10.1016/j.jvs.2007.08.015 }}</ref><ref name="pmid17322367">{{cite journal | vauthors = Abdul-Hussien H, Soekhoe RG, Weber E, von der Thüsen JH, Kleemann R, Mulder A, van Bockel JH, Hanemaaijer R, Lindeman JH | display-authors = 6 | title = Collagen degradation in the abdominal aneurysm: a conspiracy of matrix metalloproteinase and cysteine collagenases | journal = The American Journal of Pathology | volume = 170 | issue = 3 | pages = 809–17 | date = March 2007 | pmid = 17322367 | pmc = 1864891 | doi = 10.2353/ajpath.2007.060522 | url = http://ajp.amjpathol.org/cgi/pmidlookup?view=long&pmid=17322367 | format = &ndash; <sup>[https://scholar.google.co.uk/scholar?hl=en&lr=&q=intitle%3ACollagen+degradation+in+the+abdominal+aneurysm%3A+a+conspiracy+of+matrix+metalloproteinase+and+cysteine+collagenases&as_publication=Am.+J.+Pathol.&as_ylo=2007&as_yhi=2007&btnG=Search Scholar search]</sup> }} {{dead link|date=April 2009}}</ref><ref name="pmid10481531">{{cite journal | vauthors = Gacko M, Chyczewski L, Chrostek L | title = Distribution, activity and concentration of cathepsin B and cystatin C in the wall of aortic aneurysm | journal = Polish Journal of Pathology | volume = 50 | issue = 2 | pages = 83–6 | year = 1999 | pmid = 10481531 | doi =  }}</ref>
+Cystatin C levels are decreased in [[atherosclerosis|atherosclerotic]] (so-called 'hardening' of the arteries) and [[aneurysm]]al (saccular bulging) lesions of the [[aorta]].<ref name="pmid10545518">{{cite journal | vauthors = Shi GP, Sukhova GK, Grubb A, Ducharme A, Rhode LH, Lee RT, Ridker PM, Libby P, Chapman HA | display-authors = 6 | title = Cystatin C deficiency in human atherosclerosis and aortic aneurysms | journal = The Journal of Clinical Investigation | volume = 104 | issue = 9 | pages = 1191–7 | date = November 1999 | pmid = 10545518 | pmc = 409823 | doi = 10.1172/JCI7709 | url = https://dash.harvard.edu/bitstream/handle/1/13506934/Cystatin%20C%20deficiency%20in%20human%20atherosclerosis.pdf?sequence=1 }}</ref><ref name="pmid18155003">{{cite journal | vauthors = Abisi S, Burnand KG, Waltham M, Humphries J, Taylor PR, Smith A | title = Cysteine protease activity in the wall of abdominal aortic aneurysms | journal = Journal of Vascular Surgery | volume = 46 | issue = 6 | pages = 1260–6 | date = December 2007 | pmid = 18155003 | doi = 10.1016/j.jvs.2007.08.015 | doi-access = free }}</ref><ref name="pmid17322367">{{cite journal |display-authors=6 |vauthors=Abdul-Hussien H, Soekhoe RG, Weber E, von der Thüsen JH, Kleemann R, Mulder A, van Bockel JH, Hanemaaijer R, Lindeman JH |date=March 2007 |title=Collagen degradation in the abdominal aneurysm: a conspiracy of matrix metalloproteinase and cysteine collagenases |url=http://ajp.amjpathol.org/cgi/pmidlookup?view=long&pmid=17322367 |journal=The American Journal of Pathology |volume=170 |issue=3 |pages=809–17 |doi=10.2353/ajpath.2007.060522 |pmc=1864891 |pmid=17322367}}</ref><ref name="pmid10481531">{{cite journal | vauthors = Gacko M, Chyczewski L, Chrostek L | title = Distribution, activity and concentration of cathepsin B and cystatin C in the wall of aortic aneurysm | journal = Polish Journal of Pathology | volume = 50 | issue = 2 | pages = 83–6 | year = 1999 | pmid = 10481531 }}</ref>
-Genetic and prognostic studies also suggest a role for cystatin C.<ref name="pmid14716800">{{cite journal | vauthors = Eriksson P, Jones KG, Brown LC, Greenhalgh RM, Hamsten A, Powell JT | title = Genetic approach to the role of cysteine proteases in the expansion of abdominal aortic aneurysms | journal = The British Journal of Surgery | volume = 91 | issue = 1 | pages = 86–9 | date = January 2004 | pmid = 14716800 | doi = 10.1002/bjs.4364 }}</ref><ref name="pmid11683743">{{cite journal | vauthors = Lindholt JS, Erlandsen EJ, Henneberg EW | title = Cystatin C deficiency is associated with the progression of small abdominal aortic aneurysms | journal = The British Journal of Surgery | volume = 88 | issue = 11 | pages = 1472–5 | date = November 2001 | pmid = 11683743 | doi = 10.1046/j.0007-1323.2001.01911.x }}</ref>
+Genetic and prognostic studies also suggest a role for cystatin C.<ref name="pmid14716800">{{cite journal | vauthors = Eriksson P, Jones KG, Brown LC, Greenhalgh RM, Hamsten A, Powell JT | title = Genetic approach to the role of cysteine proteases in the expansion of abdominal aortic aneurysms | journal = The British Journal of Surgery | volume = 91 | issue = 1 | pages = 86–9 | date = January 2004 | pmid = 14716800 | doi = 10.1002/bjs.4364 | s2cid = 45363107 | doi-access = free | pmc = 11439999 }}</ref><ref name="pmid11683743">{{cite journal | vauthors = Lindholt JS, Erlandsen EJ, Henneberg EW | title = Cystatin C deficiency is associated with the progression of small abdominal aortic aneurysms | journal = The British Journal of Surgery | volume = 88 | issue = 11 | pages = 1472–5 | date = November 2001 | pmid = 11683743 | doi = 10.1046/j.0007-1323.2001.01911.x | s2cid = 42364814 | doi-access = free }}</ref>
 Breakdown of parts of the vessel wall in these conditions is thought to result from an imbalance between proteinases ([[cysteine protease]]s and [[matrix metalloproteinase]]s, 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 [[age-related macular degeneration]].<ref name="pmid11815350">{{cite journal | vauthors = Zurdel J, Finckh U, Menzer G, Nitsch RM, Richard G | title = CST3 genotype associated with exudative age related macular degeneration | journal = The British Journal of Ophthalmology | volume = 86 | issue = 2 | pages = 214–9 | date = February 2002 | pmid = 11815350 | pmc = 1771004 | doi = 10.1136/bjo.86.2.214 }}</ref><ref name="pmid16893541">{{cite journal | vauthors = Im E, Kazlauskas A | title = The role of cathepsins in ocular physiology and pathology | journal = Experimental Eye Research | volume = 84 | issue = 3 | pages = 383–8 | date = March 2007 | pmid = 16893541 | doi = 10.1016/j.exer.2006.05.017 }}</ref> Cystatin C has also been investigated as a prognostic marker in several forms of cancer.<ref name="pmid15138478">{{cite journal | vauthors = Strojan P, Oblak I, Svetic B, Smid L, Kos J | title = Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis | journal = British Journal of Cancer | volume = 90 | issue = 10 | pages = 1961–8 | date = May 2004 | pmid = 15138478 | pmc = 2409457 | doi = 10.1038/sj.bjc.6601830 }}</ref><ref name="pmid10690531">{{cite journal | vauthors = Kos J, Krasovec M, Cimerman N, Nielsen HJ, Christensen IJ, Brünner N | title = Cysteine proteinase inhibitors stefin A, stefin B, and cystatin C in sera from patients with colorectal cancer: relation to prognosis | journal = Clinical Cancer Research | volume = 6 | issue = 2 | pages = 505–11 | date = February 2000 | pmid = 10690531 | doi =  | url = http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10690531 }}</ref> Its role in [[pre-eclampsia]] remains to be confirmed.<ref name="pmid14511964">{{cite journal | vauthors = Strevens H, Wide-Swensson D, Grubb A, Hansen A, Horn T, Ingemarsson I, Larsen S, Nyengaard JR, Torffvit O, Willner J, Olsen S | display-authors = 6 | title = Serum cystatin C reflects glomerular endotheliosis in normal, hypertensive and pre-eclamptic pregnancies | journal = BJOG | volume = 110 | issue = 9 | pages = 825–30 | date = September 2003 | pmid = 14511964 | doi = 10.1111/j.1471-0528.2003.02051.x }}</ref><ref name="pmid18197549">{{cite journal | vauthors = Franceschini N, Qiu C, Barrow DA, Williams MA | s2cid = 205592849 | title = Cystatin C and preeclampsia: a case control study | journal = Renal Failure | volume = 30 | issue = 1 | pages = 89–95 | year = 2008 | pmid = 18197549 | doi = 10.1080/08860220701742229 }}</ref><ref name="pmid17653875">{{cite journal | vauthors = Kristensen K, Wide-Swensson D, Schmidt C, Blirup-Jensen S, Lindström V, Strevens H, Grubb A | title = Cystatin C, beta-2-microglobulin and beta-trace protein in pre-eclampsia | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 86 | issue = 8 | pages = 921–6 | year = 2007 | pmid = 17653875 | doi = 10.1080/00016340701318133 }}</ref><ref name="pmid17227816">{{cite journal | vauthors = Kristensen K, Larsson I, Hansson SR | title = Increased cystatin C expression in the pre-eclamptic placenta | journal = Molecular Human Reproduction | volume = 13 | issue = 3 | pages = 189–95 | date = March 2007 | pmid = 17227816 | doi = 10.1093/molehr/gal111 | doi-access = free }}</ref>
+A few studies have looked at the role of cystatin C or the CST3 gene in [[age-related macular degeneration]].<ref name="pmid11815350">{{cite journal | vauthors = Zurdel J, Finckh U, Menzer G, Nitsch RM, Richard G | title = CST3 genotype associated with exudative age related macular degeneration | journal = The British Journal of Ophthalmology | volume = 86 | issue = 2 | pages = 214–9 | date = February 2002 | pmid = 11815350 | pmc = 1771004 | doi = 10.1136/bjo.86.2.214 }}</ref><ref name="pmid16893541">{{cite journal | vauthors = Im E, Kazlauskas A | title = The role of cathepsins in ocular physiology and pathology | journal = Experimental Eye Research | volume = 84 | issue = 3 | pages = 383–8 | date = March 2007 | pmid = 16893541 | doi = 10.1016/j.exer.2006.05.017 }}</ref> Cystatin C has also been investigated as a prognostic marker in several forms of cancer.<ref name="pmid15138478">{{cite journal | vauthors = Strojan P, Oblak I, Svetic B, Smid L, Kos J | title = Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis | journal = British Journal of Cancer | volume = 90 | issue = 10 | pages = 1961–8 | date = May 2004 | pmid = 15138478 | pmc = 2409457 | doi = 10.1038/sj.bjc.6601830 }}</ref><ref name="pmid10690531">{{cite journal | vauthors = Kos J, Krasovec M, Cimerman N, Nielsen HJ, Christensen IJ, Brünner N | title = Cysteine proteinase inhibitors stefin A, stefin B, and cystatin C in sera from patients with colorectal cancer: relation to prognosis | journal = Clinical Cancer Research | volume = 6 | issue = 2 | pages = 505–11 | date = February 2000 | pmid = 10690531 | url = http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10690531 }}</ref> Its role in [[pre-eclampsia]] remains to be confirmed.<ref name="pmid14511964">{{cite journal | vauthors = Strevens H, Wide-Swensson D, Grubb A, Hansen A, Horn T, Ingemarsson I, Larsen S, Nyengaard JR, Torffvit O, Willner J, Olsen S | display-authors = 6 | title = Serum cystatin C reflects glomerular endotheliosis in normal, hypertensive and pre-eclamptic pregnancies | journal = BJOG | volume = 110 | issue = 9 | pages = 825–30 | date = September 2003 | pmid = 14511964 | doi = 10.1111/j.1471-0528.2003.02051.x | s2cid = 26686328 | doi-access = free }}</ref><ref name="pmid18197549">{{cite journal | vauthors = Franceschini N, Qiu C, Barrow DA, Williams MA | s2cid = 205592849 | title = Cystatin C and preeclampsia: a case control study | journal = Renal Failure | volume = 30 | issue = 1 | pages = 89–95 | year = 2008 | pmid = 18197549 | doi = 10.1080/08860220701742229 }}</ref><ref name="pmid17653875">{{cite journal | vauthors = Kristensen K, Wide-Swensson D, Schmidt C, Blirup-Jensen S, Lindström V, Strevens H, Grubb A | title = Cystatin C, beta-2-microglobulin and beta-trace protein in pre-eclampsia | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 86 | issue = 8 | pages = 921–6 | year = 2007 | pmid = 17653875 | doi = 10.1080/00016340701318133 | s2cid = 45055267 | doi-access = free }}</ref><ref name="pmid17227816">{{cite journal | vauthors = Kristensen K, Larsson I, Hansson SR | title = Increased cystatin C expression in the pre-eclamptic placenta | journal = Molecular Human Reproduction | volume = 13 | issue = 3 | pages = 189–95 | date = March 2007 | pmid = 17227816 | doi = 10.1093/molehr/gal111 | doi-access = free }}</ref>
 ==Laboratory measurement==
-Cystatin C can be measured in a random sample of serum (the fluid in [[blood]] from which the [[red blood cell]]s and [[clotting factors]] have been removed) using [[immunoassay]]s such as [[nephelometry]] or particle-enhanced [[turbidimetry]].<ref name="pmid17624320"/> 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.<ref name="pmid14687406">{{cite journal | vauthors = Lamb EJ, O'Riordan SE, Webb MC, Newman DJ | title = Serum cystatin C may be a better marker of renal impairment than creatinine | journal = Journal of the American Geriatrics Society | volume = 51 | issue = 11 | pages = 1674; author reply 1674-5 | date = November 2003 | pmid = 14687406 | doi = 10.1046/j.1532-5415.2003.515244.x }}</ref><ref name="pmid17581641">{{cite journal | vauthors = Peake M, Whiting M | title = Measurement of serum creatinine--current status and future goals | journal = The Clinical Biochemist. Reviews | volume = 27 | issue = 4 | pages = 173–84 | date = November 2006 | pmid = 17581641 | pmc = 1784008 | doi =  }}</ref><ref name="pmid16332993">{{cite journal | vauthors = Myers GL, Miller WG, Coresh J, Fleming J, Greenberg N, Greene T, Hostetter T, Levey AS, Panteghini M, Welch M, Eckfeldt JH | display-authors = 6 | title = Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program | journal = Clinical Chemistry | volume = 52 | issue = 1 | pages = 5–18 | date = January 2006 | pmid = 16332993 | doi = 10.1373/clinchem.2005.0525144 | doi-access = free }}</ref>
+Cystatin C can be measured in a random sample of serum (the fluid in [[blood]] from which the [[red blood cell]]s and [[clotting factors]] have been removed) using [[immunoassay]]s such as [[nephelometry]] or particle-enhanced [[turbidimetry]].<ref name="pmid17624320"/> 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 [[Jaffe reaction]].<ref name="pmid14687406">{{cite journal | vauthors = Lamb EJ, O'Riordan SE, Webb MC, Newman DJ | title = Serum cystatin C may be a better marker of renal impairment than creatinine | journal = Journal of the American Geriatrics Society | volume = 51 | issue = 11 | pages = 1674; author reply 1674-5 | date = November 2003 | pmid = 14687406 | doi = 10.1046/j.1532-5415.2003.515244.x | s2cid = 34235014 | doi-access = free }}</ref><ref name="pmid17581641">{{cite journal | vauthors = Peake M, Whiting M | title = Measurement of serum creatinine--current status and future goals | journal = The Clinical Biochemist. Reviews | volume = 27 | issue = 4 | pages = 173–84 | date = November 2006 | pmid = 17581641 | pmc = 1784008 }}</ref><ref name="pmid16332993">{{cite journal | vauthors = Myers GL, Miller WG, Coresh J, Fleming J, Greenberg N, Greene T, Hostetter T, Levey AS, Panteghini M, Welch M, Eckfeldt JH | display-authors = 6 | title = Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program | journal = Clinical Chemistry | volume = 52 | issue = 1 | pages = 5–18 | date = January 2006 | pmid = 16332993 | doi = 10.1373/clinchem.2005.0525144 | doi-access = free }}</ref>
 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 [[percentile]]) was between 0.52 and 0.98&nbsp;mg/L. For women, the average reference interval is 0.52 to 0.90&nbsp;mg/L with a mean of 0.71&nbsp;mg/L. For men, the average reference interval is 0.56 to 0.98&nbsp;mg/L with a mean of 0.77&nbsp;mg/L.<ref name="pmid17624320">{{cite journal | vauthors = Croda-Todd MT, Soto-Montano XJ, Hernández-Cancino PA, Juárez-Aguilar E | title = Adult cystatin C reference intervals determined by nephelometric immunoassay | journal = Clinical Biochemistry | volume = 40 | issue = 13–14 | pages = 1084–7 | date = September 2007 | pmid = 17624320 | doi = 10.1016/j.clinbiochem.2007.05.011 }}</ref>
 The normal values decrease until the first year of life, remaining relatively stable before they increase again, especially beyond age 50.<ref name="NHNES"/><ref name="ADC">{{cite journal | vauthors = Finney H, Newman DJ, Thakkar H, Fell JM, Price CP | title = Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates, and older children | journal = Archives of Disease in Childhood | volume = 82 | issue = 1 | pages = 71–5 | date = January 2000 | pmid = 10630919 | pmc = 1718178 | doi = 10.1136/adc.82.1.71 }}</ref><ref name="pmid16730690">{{cite journal | vauthors = Ognibene A, Mannucci E, Caldini A, Terreni A, Brogi M, Bardini G, Sposato I, Mosconi V, Salvadori B, Rotella CM, Messeri G | display-authors = 6 | title = Cystatin C reference values and aging | journal = Clinical Biochemistry | volume = 39 | issue = 6 | pages = 658–61 | date = June 2006 | pmid = 16730690 | doi = 10.1016/j.clinbiochem.2006.03.017 }}</ref> Creatinine levels increase until puberty and differ according to gender from then on, making their interpretation problematic for pediatric patients.<ref name="ADC"/><ref name="Expertmeeting">{{cite journal | vauthors = Filler G, Bökenkamp A, Hofmann W, Le Bricon T, Martínez-Brú C, Grubb A | title = Cystatin C as a marker of GFR--history, indications, and future research | journal = Clinical Biochemistry | volume = 38 | issue = 1 | pages = 1–8 | date = January 2005 | pmid = 15607309 | doi = 10.1016/j.clinbiochem.2004.09.025 }}</ref>
-In a large study from the United States [[National Health and Nutrition Examination Survey]], the reference interval (as defined by the 1st and 99th [[percentile]]) was between 0.57 and 1.12&nbsp;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.<ref name="NHNES">{{cite journal | vauthors = Köttgen A, Selvin E, Stevens LA, Levey AS, Van Lente F, Coresh J | title = Serum cystatin C in the United States: the Third National Health and Nutrition Examination Survey (NHANES III) | journal = American Journal of Kidney Diseases | volume = 51 | issue = 3 | pages = 385–94 | date = March 2008 | pmid = 18295054 | doi = 10.1053/j.ajkd.2007.11.019 }}</ref> 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.<ref name="Stevens2008"/> For example, the cut-off values of cystatin C for [[chronic kidney disease]] for a 60-year-old white women would be 1.12&nbsp;mg/L and 1.27&nbsp;mg/L in a black man (a 13% increase). For serum creatinine values adjusted with the MDRD equation, these values would be 0.95&nbsp;mg/dL to 1.46&nbsp;mg/dL (a 54% increase).<ref name="pmid18295049">{{cite journal | vauthors = Shlipak MG | title = Cystatin C: research priorities targeted to clinical decision making | journal = American Journal of Kidney Diseases | volume = 51 | issue = 3 | pages = 358–61 | date = March 2008 | pmid = 18295049 | doi = 10.1053/j.ajkd.2008.01.002 }}</ref>
+In a large study from the United States [[National Health and Nutrition Examination Survey]], the reference interval (as defined by the 1st and 99th [[percentile]]) was between 0.57 and 1.12&nbsp;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.<ref name="NHNES">{{cite journal | vauthors = Köttgen A, Selvin E, Stevens LA, Levey AS, Van Lente F, Coresh J | title = Serum cystatin C in the United States: the Third National Health and Nutrition Examination Survey (NHANES III) | journal = American Journal of Kidney Diseases | volume = 51 | issue = 3 | pages = 385–94 | date = March 2008 | pmid = 18295054 | doi = 10.1053/j.ajkd.2007.11.019 }}</ref> 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.<ref name="Stevens2008">{{cite journal | vauthors = Stevens LA, Coresh J, Schmid CH, Feldman HI, Froissart M, Kusek J, Rossert J, Van Lente F, Bruce RD, Zhang YL, Greene T, Levey AS | display-authors = 6 | title = Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD | journal = American Journal of Kidney Diseases | volume = 51 | issue = 3 | pages = 395–406 | date = March 2008 | pmid = 18295055 | pmc = 2390827 | doi = 10.1053/j.ajkd.2007.11.018 }}</ref> For example, the cut-off values of cystatin C for  CKD for a 60-year-old white women would be 1.12&nbsp;mg/L and 1.27&nbsp;mg/L in a black man (a 13% increase). For serum creatinine values adjusted with the MDRD equation, these values would be 0.95&nbsp;mg/dL to 1.46&nbsp;mg/dL (a 54% increase).<ref name="pmid18295049">{{cite journal | vauthors = Shlipak MG | title = Cystatin C: research priorities targeted to clinical decision making | journal = American Journal of Kidney Diseases | volume = 51 | issue = 3 | pages = 358–61 | date = March 2008 | pmid = 18295049 | doi = 10.1053/j.ajkd.2008.01.002 }}</ref>
 Based on a threshold level of 1.09&nbsp;mg/L (the 99th percentile in a population of 20- to 39-year-olds without hypertension, diabetes, [[microalbuminuria]] or [[albuminuria|macroalbuminuria]] or higher than stage 3 chronic kidney disease), the [[prevalence]] of increased levels of cystatin C in the United States was 9.6% in subjects of normal weight, increasing in [[overweight]] and [[obese]] individuals.<ref name="pmid18374694">{{cite journal | vauthors = Muntner P, Winston J, Uribarri J, Mann D, Fox CS | title = Overweight, obesity, and elevated serum cystatin C levels in adults in the United States | journal = The American Journal of Medicine | volume = 121 | issue = 4 | pages = 341–8 | date = April 2008 | pmid = 18374694 | pmc = 3049932 | doi = 10.1016/j.amjmed.2008.01.003 }}</ref> In Americans aged 60 and 80 and older, serum cystatin is increased in 41% and more than 50%.<ref name="NHNES"/>
@@ Line 55: / Line 54: @@
 The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active [[Cysteine protease|cysteine protease inhibitor]]s, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins ([[stefin]]s), type 2 cystatins and the [[kininogen]]s. 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 [[gene locus|locus]] on the short arm of [[chromosome 20]] contains the majority of the type 2 cystatin genes and [[pseudogene]]s.
-The CST3 gene is located in the cystatin locus and comprises 3 [[exon]]s (coding regions, as opposed to [[intron]]s, non-coding regions within a gene), spanning 4.3 [[kilo-base pair]]s. 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 [[housekeeping gene]]). The highest levels are found in [[semen]], followed by [[breastmilk]], [[tears]] and [[saliva]]. The [[hydrophobic]] [[Leader sequence (mRNA)|leader sequence]] indicates that the protein is normally secreted. There are three [[Polymorphism (biology)|polymorphisms]] in the [[promoter (biology)|promoter]] region of the gene, resulting in two common variants.<ref>{{cite web | title = Entrez Gene: CST3 cystatin C (amyloid angiopathy and cerebral hemorrhage)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1471| access-date = }}</ref> Several [[single nucleotide polymorphism]]s have been associated with altered cystatin C levels.<ref name="pmid17903292">{{cite journal | vauthors = Hwang SJ, Yang Q, Meigs JB, Pearce EN, Fox CS | title = A genome-wide association for kidney function and endocrine-related traits in the NHLBI's Framingham Heart Study | journal = BMC Medical Genetics | volume = 8 Suppl 1 | pages = S10 | date = September 2007 | pmid = 17903292 | pmc = 1995611 | doi = 10.1186/1471-2350-8-S1-S10 | url = http://www.biomedcentral.com/1471-2350/8%20Suppl%201/S10 | url-status = dead | archive-url = https://archive.today/20080612011653/http://www.biomedcentral.com/1471-2350/8%20Suppl%201/S10 | archive-date = 2008-06-12 }}</ref>
+The CST3 gene is located in the cystatin locus and comprises 3 [[exon]]s (coding regions, as opposed to [[intron]]s, non-coding regions within a gene), spanning 4.3 [[kilo-base pair]]s. 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 [[housekeeping gene]]). The highest levels are found in [[semen]], followed by [[breastmilk]], [[tears]] and [[saliva]]. The [[hydrophobic]] [[Leader sequence (mRNA)|leader sequence]] indicates that the protein is normally secreted. There are three [[Polymorphism (biology)|polymorphisms]] in the [[promoter (biology)|promoter]] region of the gene, resulting in two common variants.<ref>{{cite web | title = Entrez Gene: CST3 cystatin C (amyloid angiopathy and cerebral hemorrhage)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1471}}</ref> Several [[single nucleotide polymorphism]]s have been associated with altered cystatin C levels.<ref name="pmid17903292">{{cite journal | vauthors = Hwang SJ, Yang Q, Meigs JB, Pearce EN, Fox CS | title = A genome-wide association for kidney function and endocrine-related traits in the NHLBI's Framingham Heart Study | journal = BMC Medical Genetics | volume = 8 | pages = S10 | date = September 2007 | issue = Suppl 1 | pmid = 17903292 | pmc = 1995611 | doi = 10.1186/1471-2350-8-S1-S10 | doi-access = free }}</ref>
 Cystatin C is a non-[[Glycosylation|glycosylated]], [[Base (chemistry)|basic]] protein ([[isoelectric point]] at [[pH]] 9.3). The [[Protein structure|crystal structure]] of cystatin C is characterized by a short [[alpha helix]] and a long alpha helix which lies across a large antiparallel, five-[[beta strand|stranded]] [[beta sheet]]. Like other type 2 cystatins, it has two [[disulfide bond]]s. Around 50% of the molecules carry a [[Hydroxyproline|hydroxylated proline]]. Cystatin C forms [[protein dimer|dimer]]s (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.<ref name="pmid11276250">{{cite journal | vauthors = Janowski R, Kozak M, Jankowska E, Grzonka Z, Grubb A, Abrahamson M, Jaskolski M | s2cid = 28916747 | title = Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping | journal = Nature Structural Biology | volume = 8 | issue = 4 | pages = 316–20 | date = April 2001 | pmid = 11276250 | doi = 10.1038/86188 | url = http://portal.research.lu.se/ws/files/4833049/624200.pdf }}</ref>
 ==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 [[cerebrospinal fluid]] and in the [[urine]] of people with [[kidney failure]].<ref name="pmid6283552">{{cite journal | vauthors = Grubb A, Löfberg H | title = Human gamma-trace, a basic microprotein: amino acid sequence and presence in the adenohypophysis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 9 | pages = 3024–7 | date = May 1982 | pmid = 6283552 | pmc = 346341 | doi = 10.1073/pnas.79.9.3024 | bibcode = 1982PNAS...79.3024G }}</ref> Grubb and Löfberg first reported its amino acid sequence.<ref name="pmid6283552"/> They noticed it was increased in patients with advanced [[kidney failure]].<ref name="pmid119302">{{cite journal | vauthors = Löfberg H, Grubb AO | title = Quantitation of gamma-trace in human biological fluids: indications for production in the central nervous system | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 39 | issue = 7 | pages = 619–26 | date = November 1979 | pmid = 119302 | doi = 10.3109/00365517909108866 }}</ref> It was first proposed as a measure of glomerular filtration rate by Grubb and coworkers in 1985.<ref name="pmid3911736">{{cite journal | vauthors = Grubb A, Simonsen O, Sturfelt G, Truedsson L, Thysell H | title = Serum concentration of cystatin C, factor D and beta 2-microglobulin as a measure of glomerular filtration rate | journal = Acta Medica Scandinavica | volume = 218 | issue = 5 | pages = 499–503 | year = 1985 | pmid = 3911736 | doi = 10.1111/j.0954-6820.1985.tb08880.x }}</ref><ref name="pmid3923607">{{cite journal | vauthors = Simonsen O, Grubb A, Thysell H | title = The blood serum concentration of cystatin C (gamma-trace) as a measure of the glomerular filtration rate | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 45 | issue = 2 | pages = 97–101 | date = April 1985 | pmid = 3923607 | doi = 10.3109/00365518509160980 }}</ref>
+Cystatin C was first described as 'gamma-trace' in 1961 as a trace protein together with other ones (such as beta-trace) in the [[cerebrospinal fluid]] and in the [[urine]] of people with [[kidney failure]].<ref name="pmid6283552">{{cite journal | vauthors = Grubb A, Löfberg H | title = Human gamma-trace, a basic microprotein: amino acid sequence and presence in the adenohypophysis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 9 | pages = 3024–7 | date = May 1982 | pmid = 6283552 | pmc = 346341 | doi = 10.1073/pnas.79.9.3024 | bibcode = 1982PNAS...79.3024G | doi-access = free }}</ref> Grubb and Löfberg first reported its amino acid sequence.<ref name="pmid6283552"/> They noticed it was increased in patients with advanced [[kidney failure]].<ref name="pmid119302">{{cite journal | vauthors = Löfberg H, Grubb AO | title = Quantitation of gamma-trace in human biological fluids: indications for production in the central nervous system | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 39 | issue = 7 | pages = 619–26 | date = November 1979 | pmid = 119302 | doi = 10.3109/00365517909108866 }}</ref> It was first proposed as a measure of glomerular filtration rate by Grubb and coworkers in 1985.<ref name="pmid3911736">{{cite journal | vauthors = Grubb A, Simonsen O, Sturfelt G, Truedsson L, Thysell H | title = Serum concentration of cystatin C, factor D and beta 2-microglobulin as a measure of glomerular filtration rate | journal = Acta Medica Scandinavica | volume = 218 | issue = 5 | pages = 499–503 | year = 1985 | pmid = 3911736 | doi = 10.1111/j.0954-6820.1985.tb08880.x }}</ref><ref name="pmid3923607">{{cite journal | vauthors = Simonsen O, Grubb A, Thysell H | title = The blood serum concentration of cystatin C (gamma-trace) as a measure of the glomerular filtration rate | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 45 | issue = 2 | pages = 97–101 | date = April 1985 | pmid = 3923607 | doi = 10.3109/00365518509160980 }}</ref>
-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.<ref name="pmid24004120">{{cite journal | vauthors = Shlipak MG, Matsushita K, Ärnlöv J, Inker LA, Katz R, Polkinghorne KR, Rothenbacher D, Sarnak MJ, Astor BC, Coresh J, Levey AS, Gansevoort RT | display-authors = 6 | title = Cystatin C versus creatinine in determining risk based on kidney function | journal = The New England Journal of Medicine | volume = 369 | issue = 10 | pages = 932–43 | date = September 2013 | pmid = 24004120 | pmc = 3993094 | doi = 10.1056/NEJMoa1214234 }}</ref>
+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.<ref name="pmid24004120">{{cite journal | vauthors = Shlipak MG, Matsushita K, Ärnlöv J, Inker LA, Katz R, Polkinghorne KR, Rothenbacher D, Sarnak MJ, Astor BC, Coresh J, Levey AS, Gansevoort RT | display-authors = 6 | title = Cystatin C versus creatinine in determining risk based on kidney function | journal = The New England Journal of Medicine | volume = 369 | issue = 10 | pages = 932–43 | date = September 2013 | pmid = 24004120 | pmc = 3993094 | doi = 10.1056/NEJMoa1214234 }}</ref>
 == References ==
@@ Line 68: / Line 67: @@
 == External links ==
-* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=I25.004 I25.004]
+* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=I25.004 I25.004] {{Webarchive|url=https://web.archive.org/web/20160120113947/http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=I25.004 |date=2016-01-20 }}
 * {{PDBe-KB2|P01034|Cystatin-C}}