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Soluble urokinase plasminogen activator receptor

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Soluble urokinase plasminogen activator receptor (suPAR) (NCBI Accession no. AAK31795) is a protein and the soluble form of uPAR. 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 and Vitronectin. The soluble version of uPAR, called suPAR, results from the cleavage and membrane-bound uPAR during inflammation or immune activation.[1] The suPAR concentration is positively correlated to the activation level of the immune system. Therefore, suPAR is a marker of disease severity and aggressiveness[1][2] and is associated with morbidity and mortality in several acute and chronic diseases.[3][4][5][6] suPAR levels have been observed to increase with age.[7] suPAR is present in plasma, urine, blood, serum, and cerebrospinal fluid.

General population

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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.[8] In general, women have slightly higher suPAR than men.[8][9] suPAR levels are higher in serum than in plasma for the same individual.[10][11]

Clinical significance

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suPAR is a biomarker 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 (TNFα)  and C-reactive protein (CRP) and other parameters, including leukocyte counts. suPAR is also associated with organ damage in various diseases.[2-5] Elevated levels of suPAR are associated with increased risk of systemic inflammatory response syndrome (SIRS), cancer, focal segmental glomerulosclerosis, cardiovascular disease, type 2 diabetes, infectious diseases, HIV, and mortality.[12][13]

Acute medical patients

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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

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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 death. 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.[14][15][16][17][18][19][20]

Cardiovascular diseases

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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.[21][22][23]

Nephrology

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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,[24] the future incidence of chronic renal diseases,[25] and declining eGFR.[25][26] A high level is significantly associated with mortality and incidence of cardiovascular diseases in these patients.[24]

Molecular characteristics

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suPAR has a secondary structure of 17 anti-parallel β-sheets with three short α-helices. It consists of the three homologous domains D1, D2, and D3. Comparing cDNA sequences, D1 differs from D2 and D3 in its primary and tertiary structure, causing its distinct ligand binding properties.[1][27]

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.[1]

The molecular weight of suPAR varies between 24–66 kDa due to variations in posttranslational glycosylations.[1] Additional isoforms generated by alternative splicing have been described on the RNA level, but whether these are transcribed and their possible roles remain unclear.[28]

Plasma and serum levels

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

Technology

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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.[29]

References

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  1. ^ a b c d e Thunø, Maria; Macho, Betina; Eugen-Olsen, Jesper (2009). "SuPAR: The Molecular Crystal Ball". Disease Markers. 27 (3–4): 157–72
  2. ^ Enocsson H, Wirestam L, Dahle C, Padyukov L, Jönsen A, Urowitz MB, Gladman DD, Romero-Diaz J, Bae SC, Fortin PR, Sanchez-Guerrero J, Clarke AE, Bernatsky S, Gordon C, Hanly JG, Wallace DJ, Isenberg DA, Rahman A, Merrill JT, Ginzler E, Alarcón GS, Chatham WW, Petri M, Khamashta M, Aranow C, Mackay M, Dooley MA, Manzi S, Ramsey-Goldman R, Nived O, Steinsson K, Zoma AA, Ruiz-Irastorza G, Lim SS, Kalunian KC, Inanc M, van Vollenhoven RF, Ramos-Casals M, Kamen DL, Jacobsen S, Peschken CA, Askanase A, Stoll T, Bruce IN, Wetterö J, Sjöwall C. Soluble urokinase plasminogen activator receptor (suPAR) levels predict damage accrual in patients with recent-onset systemic lupus erythematosus. J Autoimmun. 2020 Jan;106:102340. doi: 10.1016/j.jaut.2019.102340. Epub 2019 Oct 17. PMID 31629628.
  3. ^ Enocsson, Helena; Sjöwall, Christopher (April 2015). "Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?". Clinica Chimica Acta. 444: 234–241
  4. ^ Enocsson, Helena; Wetterö, Jonas; Skogh, Thomas; Sjöwall, Christopher (2013). "Soluble urokinase plasminogen activator receptor levels reflect organ damage in systemic lupus erythematosus". Translational Research. 162 (5): 287–296.
  5. ^ Sjöwall, C; Martinsson, K; Cardell, K; Ekstedt, M; Kechagias, S (2014). "Soluble urokinase plasminogen activator receptor levels are associated with severity of fibrosis in non-alcoholic fatty liver disease". Translational Research. 165 (6): 658–66.
  6. ^ Hahm, E; et al. (December 2016). "Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease". Nature Medicine. 23 (1): 100–106. 
  7. ^ Eugen-Olsen, J. et al. "Circulating Soluble Urokinase Plasminogen Activator Receptor Predicts Cancer, Cardiovascular Disease, Diabetes and Mortality in the General Population."Journal of Internal Medicine (2010).
  8. ^ a b 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
  9. ^ Chew-Harris J, Appleby S, Richards AM, Troughton RW, Pemberton CJ. Analytical, biochemical and clearance considerations of soluble urokinase plasminogen activator receptor (suPAR) in healthy individuals. Clin Biochem (2019) 69:36–44.
  10. ^ Wlazel R, Szwabe K, Guligowska A, Kostka T. Soluble urokinase plasminogen activator receptor level in individuals of advanced age. Sci Rep. 2020; 10: 15462
  11. ^ Stephens RW, Pedersen AN, Nielsen HJ, Hamers MJAG, Høyer-Hansen G, Rønne E, Dybkjær E, Danø K, Brünner N. ELISA determination of soluble urokinase receptor in blood from healthy donors and cancer patients. Clin Chem (1997) 43:1868–1876.
  12. ^ Eugen-Olsen, J. et al. "Circulating Soluble Urokinase Plasminogen Activator Receptor Predicts Cancer, Cardiovascular Disease, Diabetes and Mortality in the General Population."Journal of Internal Medicine (2010)
  13. ^ ViroGates. "What is suPAR".
  14. ^ Enocsson H, Idoff C, Gustafsson A, Govender M, Hopkins F, Larsson M, Nilsdotter-Augustinsson Å, Sjöwall J. Soluble Urokinase Plasminogen Activator Receptor (suPAR) Independently Predicts Severity and Length of Hospitalisation in Patients With COVID-19. Front Med (Lausanne). 2021 Dec 2;8:791716. doi: 10.3389/fmed.2021.791716. PMID 34926532; PMCID: PMC8674575.
  15. ^ Rovina, Nikoletta; Akinosoglou, Karolina; Eugen-Olsen, Jesper; Hayek, Salim; Reiser, Jochen; Giamarellos-Bourboulis, Evangelos J. (2020-04-30). "Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in patients with COVID-19 pneumonia". Critical Care. 24 (1): 187
  16. ^ Rovina N, Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in patients with COVID-19 pneumonia. Crit Care. 2020 Apr 30;24(1):187. doi: 10.1186/s13054-020-02897-4.  
  17. ^ Arnold DT et al. Predicting outcomes of COVID-19 from admission biomarkers: a prospective UK cohort study. Emerg Med J. 2021 May 21;emermed-2020-210380. doi: 10.1136/emermed-2020-210380.  
  18. ^ Oulhaj A et al. Admission levels of Soluble Urokinase Plasminogen Activator Receptor (suPAR) are Associated with the Development of Severe Complications in Hospitalised COVID-19 Patients: A Prospective Cohort Study. Int J Infect Dis. 2021 Apr 20;107:188-194. doi: 10.1016/j.ijid.2021.04.026.  
  19. ^ Azam et al. Soluble Urokinase Receptor (SuPAR) in COVID-19-Related AKI J Am Soc Nephrol. 2020 Nov;31(11):2725-2735.
  20. ^ Altintas, I., et al. suPAR Cut-Offs for Risk Stratification in Patients With Symptoms of COVID-19. Biomark Insights 2021 Aug 15;16
  21. ^ Botha S, Fourie CM, Schutte R, Eugen-Olsen J, Pretorius R, Schutte AE. Soluble urokinase plasminogen activator receptor as a prognostic marker of all-cause and cardiovascular mortality in a black population. Int J Cardiol. 2015;184:631-636.
  22. ^ Eugen-Olsen J, Andersen O, Linneberg A, et al. Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med. 2010;268(3):296-308.
  23. ^ Lyngbaek S, Marott JL, Sehestedt T, et al. Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score. Int J Cardiol. 2013;167(6):2904-2911.
  24. ^ a b 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.  
  25. ^ a b 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.
  26. ^ Musetti C, Quaglia M, Cena T et al. Circulating suPAR levels are affected by glomerular filtration rate and proteinuria in primary and secondary glomerulonephritis. J Nephrol 2015 Jun;28(3):299-305.  
  27. ^ M. Huang, A. P. Mazar, G. Parry, A. A.-R. "Higazi, A. Kuo and D. B. Cines. Crystallisation of soluble urokinase receptor (suPAR) in complex with urokinase amino-terminal fragment (1-143)". Acta Crystallographica (2005): D61 (6), 697-700.
  28. ^ Wei C, Li J, Adair BD, Zhu K, Cai J, Merchant M, Samelko B, Liao Z, Koh KH, Tardi NJ, et al. uPAR isoform 2 forms a dimer and induces severe kidney disease in mice. J Clin Invest (2019) 129:1946–1959
  29. ^ ViroGates. "suPARnostic® Products".
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