suPAR (soluble uPAR) is a protein in the blood that reflects immune activation. All human beings have a baseline level of suPAR that is individually determined and increases with age.
High suPAR levels are associated with increased inflammation, disease progression, and risk of mortality in acute and chronic diseases, and in the general population3-16.
Measuring suPAR levels can thus serve as a marker to determine who can be classified into low-risk category and their chances for survival upon hospital admission. suPAR can also be used for monitoring for prevention of disease progression and earlier intervention time point.
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.
The suPAR blood level is stable with no diurnal variation and no changes following fasting. It 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.
suPAR level < 4 ng/ml
Supports patient discharge
suPAR level > 6 ng/ml
Supports patient hospitalisation
suPAR in Triage
The normal suPAR plasma level is below 3 ng/mL in healthy individuals, about 3-6 ng/mL in unselected patients in emergency departments, and above 6 ng/mL in critically ill patients.
A low suPAR level indicates a good prognosis and supports the decision to discharge the patient.
A high suPAR level indicates presence, progression and severity of disease, and supports further clinical attention.
suPARnostic® Patient Guideline: suPARnostic® improves patient care and reduces healthcare costs by classifying 34% more patients into low-risk category. 2
The suPAR level can be used for triage in the hospital’s Emergency Department and can be measured using the suPARnostic® products, the only CE-IVD certified product range applied for clinical determination of suPAR.
By using suPARnostic® in the triage process, performance of the ED is significantly improved. suPARnostic®
can identify 22% more patients that can be sent home without hospitalization, and help to avoid unnecessary
treatments and readmissions.2
Figure 1. Schematic representation of uPA receptor. The GPI-anchor links uPAR to the cell membrane making it available for uPA to bind to the receptor (1 A). When the receptor is cleaved between the GPI-anchor and D3, it becomes soluble (suPAR) (1 B). suPAR is a stable protein that can be measured in various body fluids. uPAR: uPA receptor, suPAR: soluble uPAR, 1: Domain 1, D2: Domain 2, D3: Domain
The suPAR protein
suPAR is the soluble form of the cell membrane-bound protein uPAR, a three domain receptor23 mainly expressed on immune cells, including neutrophils, activated T-cells, and macrophages, 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 individual.
The membrane-bound uPAR is illustrated in figure 1 A. uPAR is linked to the cell membrane by a glycosyl phosphatidylinositol (GPI)-anchor and binding of uPA to uPAR, facilitates cleavage of the anchor and hence shedding of the receptor (Fig 1.)23.
Once this anchor is cleaved the protein is released from the membrane and becomes soluble as illustrated in figure 1 B.
The History of suPAR
Originally, uPAR was proven a receptor for 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 diseases3-13 (including cardiovascular, hepatic, renal, and pulmonary diseases), and that the level is a predictor of a negative outcome of various infectious diseases18-22 (tuberculosis, HIV, malaria, sepsis, meningitis, pneumonia) and in critically ill patients16
suPAR also reflects the level of chronic inflammation, and has therefore been studied as a potential marker of development of diseases. Studies have shown that an elevated level predicts development of chronic diseases and cancer in the general population3,16
“It has become clear that suPAR is a very strong prognostic marker, exceeding the prognostic value of all other routinely measured biomarkers in our hospital.”
Prof. Ove Andersen,
MD, PhD, DmSc, Copenhagen University Hospital Hvidovre, Denmark
suPAR News Vol. 3, June 2020
suPARnostic® Patient Case Stories
Healthy male, age 50, experienced weight loss, non-well-being and had repeated standard blood tests done. All blood parameters were normal, his suPAR value was rising though and hit the critical level after approx. 6 months. Although still labelled “healthy” by the medical system, he shortly after was admitted to ICU, and liver failure was imminent soon after. The patient did not survive and was post-mortem diagnosed with Q-fever, a tropical disease.
More elaborate tests only one month earlier would most likely have saved his life and revealed that he was suffering from a critical condition.
suPARnostic® would have flagged that patient correctly early enough to save his life.
Healthy male, age 25 years, experienced feeling of sickness and symptoms like paleness and fatigue. Repeated doctor visits resulted in no diagnosis, all blood values were normal and no further tests were authorized.
The slowly rising suPAR value predicted that the person was developing a potential critical condition, and at suPAR value 4,1 the person was admitted to an Emergency Room. A series of more elaborate tests diagnosed the person with latent tuberculosis and mononucleosis.
As a result of the early recognition, the person did not require hospitalization or drug treatment. Later recognition might have involved sick days, medical treatment and hospitalization days.
suPARnostic® was an early and correct warning sign.
Healthy male, age 45, experienced the same symptoms as the patient in case 2, including weight loss. Blood values were normal and the person’s suPAR level was slightly elevated, but was not rising into the critical area.
Adjustment of lifestyle (more sleep, better food, more sports) lowered the suPAR level a few months later into the “normal” level.
suPARnostic® recognized correctly that this person was not a critical case requiring immediate hospital attention.
1: Thunø M, Macho B, Eugen-Olsen J. suPAR: The molecular crystal ball. Dis Markers. 2009;27(3):157-72.
2: Schultz et al. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, 2019, 27:43
3: 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.
4: Borne Y, Persson M, Melander O,et al. Increased plasma level of soluble urokinase plasminogen activator receptor is associated with incidence of heart failure butnotatrial fibrillation. European journal of heart failure 2014;16:377-83.
5: Eapen DJ, Manocha P, Ghasemzedah N,et al. Soluble urokinase plasminogen activator receptor level isan independent predictor of the presence and severity ofcoronary artery disease andof future adverse events. Journal of the American Heart Association 2014;3:e001118.
6: 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.
7: 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.
8: 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 ofcardiology 2012;110:1756-63.
9: 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.
10: 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.
11: 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.
12: 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.
13: Reichsoellner M, Raggam RB, Wagner J, Krause R, Hoenigl M. Clinical evaluation ofmultiple inflammation biomarkers for diagnosis and prognosis for patients with systemic inflammatory response syndrome. Journal of clinical microbiology 2014;52:4063-6.
14: 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.
15: 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.
16: 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.
17: 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.
18: 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.
19: 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.
20: 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.
21: 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.
22: 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.
23: Huai Q, et al. Structure of human urokinase plasminogen activator in complex with its receptor, Science. 2006 Feb 3;311(5761):656-9.