suPAR-Background

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The biomarker suPAR (soluble urokinase plasminogen activator receptor) is the soluble form of the cell membrane-bound protein uPAR, which is expressed mainly on immune cells, endothelial cells, and smooth muscle cells. uPAR is released during inflammation or immune activation, and therefore the suPAR level reflects the extent of immune activation in the individual1. All human beings have a baseline level of suPAR that is individually determined and increases with age.

Studies have shown that the suPAR level is associated with morbidity and mortality in a number of acute and chronic diseases and in the general population2-15. The suPAR level is elevated across diseases, and not solely associated with one specific disease. Therefore, suPAR is applicable as a prognostic marker and not as a diagnostic marker. This characteristic may be utilized for risk stratification in unselected patients.

Originally, uPAR (urokinase plasminogen activator receptor) was proven a receptor for urokinase (uPA) which splits plasminogen into active plasmin. Moreover, uPAR interacts with other proteins and plays a role in several important cell processes like migration, adhesion, angiogenesis, proliferation, and chemotaxis1.

The suPAR protein was discovered in 1991, when it was found to be a marker of cancer progression1. In recent years, several studies have shown that suPAR is associated with a number of chronic diseases2-12 (including cardiovascular, hepatic, renal, and pulmonary diseases), and that the level is a predictor of a negative outcome of various infectious diseases17-21 (tuberculosis, HIV, malaria, sepsis, meningitis, pneumonia) and in critically ill patients15.

Across diseases, the suPAR level discriminates non-survivors from survivors. suPAR reflects the level of chronic inflammation, and therefore it has been studied as a potential marker of development of diseases, and studies have shown that an elevated level predicts development of chronic diseases and cancer in the general population2,15.

The suPAR blood level is stable with no diurnal variation and no changes following fasting. suPAR can be measured in blood, plasma, urine, cerebrospinal fluid, ascites fluid and pleural fluid1. The level increases and decreases with progression and improvement of a disease, respectively, but more slowly compared to e.g. C-reactive protein (CRP).

The normal suPAR plasma level is 2-3 ng/mL in healthy individuals, about 3-4 ng/mL in unselected patients in emergency departments, and about 9-10 ng/mL in critically ill patients.

At Copenhagen University Hospital, Hvidovre in Denmark, suPAR measurement has been implemented as a clinical routine procedure. For further information, please see appendices and subsequent sections

  1. Thunø M, Macho B, Eugen-Olsen J. suPAR: The molecular crystal ball. Dis Markers. 2009;27(3):157-72.
  2. Eugen-Olsen, J. et al. Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J. Intern. Med. 2010;268, 296–308.
  3. Borne Y, Persson M, Melander O, et al. Increased plasma level of soluble urokinase plasminogen activator receptor is associated with incidence of heart failure but not atrial fibrillation. European journal of heart failure 2014;16:377-83.
  4. Eapen DJ, Manocha P, Ghasemzedah N, et al. Soluble urokinase plasminogen activator receptor level is an independent predictor of the presence and severity of coronary artery disease and of future adverse events. Journal of the American Heart Association 2014;3:e001118.
  5. Gumus A, Altintas N, Cinarka H, et al. Soluble urokinase-type plasminogen activator receptor is a novel biomarker predicting acute exacerbation in COPD. International journal of chronic obstructive pulmonary disease 2015;10:357-65.
  6. Lyngbaek S, Andersson C, Marott JL, et al. Soluble urokinase plasminogen activator receptor for risk prediction in patients admitted with acute chest pain. Clinical chemistry 2013;59:1621-9.
  7. Lyngbaek S, Marott JL, Moller DV, et al. Usefulness of soluble urokinase plasminogen activator receptor to predict repeat myocardial infarction and mortality in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous intervention. The American journal of cardiology 2012;110:1756-63.
  8. Molkanen T, Ruotsalainen E, Thorball CW, et al. Elevated soluble urokinase plasminogen activator receptor (suPAR) predicts mortality in Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis. 2011;30:1417-24.
  9. Persson M, Ostling G, Smith G, et al. Soluble urokinase plasminogen activator receptor: a risk factor for carotid plaque, stroke, and coronary artery disease. Stroke; a journal of cerebral circulation 2014;45:18-23.
  10. Raggam RB, Wagner J, Pruller F, et al. Soluble urokinase plasminogen activator receptor predicts mortality in patients with systemic inflammatory response syndrome. Journal of internal medicine 2014;276:651-8.
  11. 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.
  12. Reichsoellner M, Raggam RB, Wagner J, Krause R, Hoenigl M. Clinical evaluation of multiple inflammation biomarkers for diagnosis and prognosis for patients with systemic inflammatory response syndrome. Journal of clinical microbiology 2014;52:4063-6.
  13. Suberviola B, Castellanos-Ortega A, Ruiz Ruiz A, Lopez-Hoyos M, Santibanez M. Hospital mortality prognostication in sepsis using the new biomarkers suPAR and proADM in a single determination on ICU admission. Intensive care medicine 2013;39:1945-52.
  14. Zimmermann HW, Koch A, Seidler S, Trautwein C, Tacke F. Circulating soluble urokinase plasminogen activator is elevated in patients with chronic liver disease, discriminates stage and aetiology of cirrhosis and predicts prognosis. Liver international : official journal of the International Association for the Study of the Liver 2012;32:500-9.
  15. Donadello K, Scolletta S, Taccone FS, et al. Soluble urokinase-type plasminogen activator receptor as a prognostic biomarker in critically ill patients. Journal of critical care 2014;29:144-9.
  16. Lyngbaek S, Marott JL, Sehestedt T, et al. Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score. International journal of cardiology 2013;167:2904-11.
  17. Sidenius N, Sier CF, Ullum H et al. Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection. Blood 2000;96(13):4091-4095.
  18. Eugen-Olsen J, Gustafson P, Sidenius N et al. The serum level of soluble urokinase receptor is elevated in tuberculosis patients and predicts mortality during treatment: a community study from Guinea-Bissau. Int J Tuberc Lung Dis 2002;6(8):686-692.
  19. Perch M, Kofoed P, Fischer TK et al. Serum levels of soluble urokinase plasminogen activator receptor is associated with parasitemia in children with acute Plasmodium falciparum malaria infection. Parasite Immunol 2004;26(5):207-211.
  20. Tzanakaki G, Paparoupa M, Kyprianou M, Barbouni A, Eugen-Olsen J, Kourea-Kremastinou J. Elevated soluble urokinase receptor values in CSF, age and bacterial meningitis infection are independent and additive risk factors of fatal outcome. Eur J Clin Microbiol Infect Dis 2012;31(6):1157-1162.
  21.  Wrotek A, Jackowska T. The role of the soluble urokinase plasminogen activator (suPAR) in children with pneumonia. Respir Physiol Neurobiol 2015;209:120-3. doi: 10.1016/j.resp.2014.12.018. Epub; 2015 Jan 17.:120-123.