Soluble urokinase plasminogen activator receptor (suPAR) (

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 Accession no. AAK31795) is a protein and the soluble form of 

uPAR The Urokinase receptor, also known as urokinase plasminogen activator surface receptor (uPAR) or CD87 (Cluster of Differentiation 87), is a protein encoded in humans by the PLAUR gene. It is a multidomain glycoprotein tethered to the cell membra ...

. uPAR is expressed mainly on immune cells, endothelial cells, and smooth muscle cells. uPAR is a membrane-bound receptor for uPA, also known as 

urokinase Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947. Urokinase was originally i ...

 and Vitronectin. The soluble version of uPAR, called suPAR, results from the cleavage and membrane-bound uPAR during inflammation or immune activation.Thunø, Maria; Macho, Betina; Eugen-Olsen, Jesper (2009). "SuPAR: The Molecular Crystal Ball". Disease Markers. 27 (3–4): 157–72 The suPAR concentration is positively correlated to the activation level of the 

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

. Therefore, suPAR is a marker of disease severity and aggressiveness and is associated with morbidity and mortality in several acute and chronic diseases. suPAR levels have been observed to increase with age. suPAR is present in 

plasma Plasma or plasm may refer to: Science * Plasma (physics), one of the four fundamental states of matter * Plasma (mineral), a green translucent silica mineral * Quark–gluon plasma, a state of matter in quantum chromodynamics Biology * Blood pla ...

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra. Cel ...

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...

,  serum, and 

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...

General population

In the general population, the suPAR level is higher in females than in males. The median suPAR level for men and women in blood donors is 2.22 ng/mL and 2.54 ng/mL, respectively. Haastrup E, Grau K, Eugen-Olsen J, Thorball C, Kessing LV, Ullum H. Soluble urokinase plasminogen activator receptor as a marker for use of antidepressants. PLoS One (2014) 9 In general, women have slightly higher suPAR than men. suPAR levels are higher in serum than in plasma for the same individual.

Clinical significance

suPAR is a 

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

reflecting the level of activity of the immune system in response to an inflammatory stimulus. suPAR levels positively correlate with pro-inflammatory biomarkers, including 

tumor necrosis factor-α Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

(TNFα)  and 

C-reactive protein C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 ...

(CRP) and other parameters, including leukocyte counts. suPAR is also associated with organ damage in various diseases. -5Elevated levels of suPAR are associated with increased risk of 

systemic inflammatory response syndrome Systemic inflammatory response syndrome (SIRS) is an inflammatory state affecting the whole body. It is the body's response to an infectious or noninfectious insult. Although the definition of SIRS refers to it as an "inflammatory" response, i ...

 (SIRS), 

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) is a histopathologic finding of scarring (sclerosis) of glomeruli and damage to renal podocytes.Rosenberg, Avi Z.; Kopp, Jeffrey B. (2017-03-07). "Focal Segmental Glomerulosclerosis". ''Clinical Journal o ...

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...

type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

infectious diseases An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

, and 

mortality Mortality is the state of being mortal, or susceptible to death; the opposite of immortality. Mortality may also refer to: * Fish mortality, a parameter used in fisheries population dynamics to account for the loss of fish in a fish stock throug ...

Acute medical patients

In the emergency departments, suPAR can aid in the triage and risk assessment of patients. This allows for many patients can be discharged rather than admitted. This also ensures that the most ill patients are prioritised first and put under careful observation without delay. A suPAR level below 4 ng/mL indicates a good prognosis in acute medical patients and supports discharge. In contrast, patients presenting with a suPAR level above 6 ng/mL have a high risk of a negative outcome.

COVID-19

In COVID-19, an early elevation of suPAR, e.g. in patients that present with symptoms of SARS-CoV-2 infection, is associated with an increased risk of severe COVID-19 development, which may lead to respiratory failure, acute kidney injury, and mortality. Clinical relevant cut-offs have been identified with a suPAR below 4 ng/mL indicating low risk of adverse outcomes and a suPAR above 6 ng/mL for high risk of negative outcomes such as severe respiratory failure.

Cardiovascular diseases

The suPAR level is elevated in patients with cardiovascular diseases compared to healthy individuals. suPAR is a predictor of cardiovascular morbidity and mortality in the general population.

Nephrology

In the kidneys, suPAR plays a role in regulating the permeability of the glomerular filtration barrier. An elevated suPAR level is associated with chronic renal diseases,Meijers B, Poesen R, Claes K et al. Soluble urokinase receptor is a biomarker of cardiovascular disease in chronic kidney disease. Kidney Int 2015 Jan;87(1):210-216. the future incidence of chronic renal diseases,Hayek S, Sever S, Ko Y et al. Soluble urokinase receptor and chronic kidney disease. N Engl J Med. 2015 Nov 12; 373(20):1916-25. and declining eGFR. A high level is significantly associated with mortality and incidence of cardiovascular diseases in these patients.

Molecular characteristics

suPAR has a secondary structure of 17 anti-parallel 

β-sheets The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...

 with three short 

α-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

. It consists of the three homologous domains D1, D2, and D3. Comparing cDNA sequences, D1 differs from D2 and D3 in its 

primary Primary or primaries may refer to: Arts, entertainment, and media Music Groups and labels * Primary (band), from Australia * Primary (musician), hip hop musician and record producer from South Korea * Primary Music, Israeli record label Works * ...

 and 

tertiary Tertiary ( ) is a widely used but obsolete term for the geologic period from 66 million to 2.6 million years ago. The period began with the demise of the non-avian dinosaurs in the Cretaceous–Paleogene extinction event, at the start ...

 structure, causing its distinct ligand binding properties. uPAR has cleavage sites for several proteases in the linker region (chymotrypsin, elastase, matrix metalloproteases, cathepsin G, plasmin, urokinase plasminogen activator (uPA, or urokinase), and in the GPI anchor (phospholipase C and D, cathepsin G, plasmin). The  GPI-anchor links uPAR to the cell membrane making it available for  uPA binding. When uPA is bound to the receptor, a cleavage between the GPI-anchor and D3 forms suPAR. Of the three suPAR forms: suPAR1-3, suPAR2-3, and suPAR1, suPAR2-3 is the chemotactic agent for promoting the immune system. The molecular weight of suPAR varies between 24–66 kDa due to variations in posttranslational glycosylations. Additional isoforms generated by alternative splicing have been described on the RNA level, but whether these are transcribed and their possible roles remain unclear.

Plasma and serum levels

suPAR is mainly measured in serum and plasma isolated from human venous blood.

Technology

The suPAR level can be measured using the suPARnostic® product line. suPARnostic® is a CE-IVD certified antibody-based product range applied for quantitative measurements of suPAR in the clinical setting. Three product formats are available: 1) TurbiLatex, validated for clinical chemistry systems currently including the Roche Diagnostics cobas c501/2 and c701/2 systems; the Siemens ADVIA XPT and Atellica systems, and the Abbott Architect c and Alinity systems. 2) Quick Triage, which is a platform that is applied at the Point-Of-Care. 3) ELISA.

References

{{DEFAULTSORT:Supar Human proteins Clusters of differentiation Biomarkers