Tue Mar 26 2024

1000 papers on suPAR on Pubmed

Since uPAR and suPAR was discovered by Danish scientists in the 1990ties, the insight into the functions and clinical significance has exploded. Today, suPAR is understood as the biomarker of chronic inflammation, and has contributed to the understanding of the role of chronic inflammation in disease development, disease progression and risk of premature mortality.
Today, suPAR has a variety of uses, from health screening to decision of treatment in infectious diseases. In health screening, it is known that individuals with elevated screening age faster and have increased risk of developing diseases such as cardiovascular disease, cancer and diabetes.

Below is a list of the most significant studies split into three research area. 1: Acute care triage, 2: suPAR in guiding treatment, and 3: in general health.

Acute care triage

The first hospital to implement suPAR as part of the routine panel of biomarkers measured in the Emergency Department was Copenhagen University Hospital Hvidovre in Denmark. Perhaps not surprising, as this is where ViroGates CSO Jesper Eugen-Olsen was working, and research on suPAR carried out. At the time of implementing suPAR, the only available technology to measure suPAR was ELISA. As suPAR measurement on ELISA is done batchwise and assay time is two hours, the results often came to late to have impact on clinical decisions. Nevertheless, the studies gave insight into the very strong prognostic ability of suPAR, and the title of the first paper published on 4343 acute medical patients captures the findings:

Rasmussen LJ, Ladelund S, Haupt TH, Ellekilde G, Poulsen JH, Iversen K, Eugen-Olsen J, Andersen O. Soluble urokinase plasminogen activator receptor (suPAR) in acute care: a strong marker of disease presence and severity, readmission and mortality. A retrospective cohort study. Emerg Med J. 2016 Nov;33(11):769-775. Read the study here.

But we already have clinical signs for triage (e.g. National Early Warning Score, NEWS or EWS). Does suPAR add to this. The answer is yes, suPAR is a very strong and independent marker of outcome, as shown in this study with more than 17.000 acute medical patients:

Rasmussen LJH, Ladelund S, Haupt TH, Ellekilde GE, Eugen-Olsen J, Andersen O. Combining National Early Warning Score With Soluble Urokinase Plasminogen Activator Receptor (suPAR) Improves Risk Prediction in Acute Medical Patients: A Registry-Based Cohort Study. Crit Care Med. 2018 Dec;46(12):1961-1968. Read the study here.

So, suPAR is very strong in prediction of morbidity and mortality in acute medical patients and very few patients with low suPAR dies. These few patients, why do the die? This study including more than 26.000 patients showed that the few that die with low suPAR likely die due to side effects of polypharmacy:

Bengaard AK, Iversen E, Kallemose T, Juul-Larsen HG, Rasmussen LJH, Dalhoff KP, Andersen O, Eugen-Olsen J, Houlind MB. Using soluble urokinase plasminogen activator receptor to stratify patients for medication review in the emergency department. Br J Clin Pharmacol. 2022 Feb;88(4):1679-1690. Read the study here.

Clinical guidelines for using suPAR was discussed at a round table meeting, and the consensus is that a suPAR blow 4 ng/ml supports discharge, and a suPAR above 6 ng/ml supports clinical attention and admission. A round table discussion on this subject can be read in this publication:

Velissaris D, Dimopoulos G, Parissis J, Alexiou Z, Antonakos N, Babalis D, Gerakari S, Kaldis V, Koutoukas P, Lada M, Leventogiannis K, Pantazopoulos I, Papadopoulos A, Polyzogopoulou E, Gogos C, Armaganidis A, Giamarellos-Bourboulis EJ. Prognostic Role of Soluble Urokinase Plasminogen Activator Receptor at the Emergency Department: A Position Paper by the Hellenic Sepsis Study Group. Infect Dis Ther. 2020 Sep;9(3):407-416. Read the study here.

Finally, a meta-analysis on suPAR in triage has recently been published:

Rehan ST, Hussain HU, Ali E, Kumar KA, Tabassum S, Hasanain M, Shaikh A, Ali G, Yousaf Z, Asghar MS. Role of soluble urokinase type plasminogen activator receptor (suPAR) in predicting mortality, readmission, length of stay and discharge in emergency patients: A systematic review and meta analysis. Medicine (Baltimore). 2023 Nov 10;102(45):e35718. Read the study here.

suPAR in guiding treatment

During COVID-19, a large international collaboration showed that suPAR was the strongest prognostic biomarker for prediction progression to respiratory failure requiring mechanical ventilation or mortality I COVID-19:

Vasbinder A, Padalia K, Pizzo I, Machado K, Catalan T, Presswalla F, Anderson E, Ismail A, Hutten C, Huang Y, Blakely P, Azam TU, Berlin H, Feroze R, Launius C, Meloche C, Michaud E, O’Hayer P, Pan M, Shadid HR, Rasmussen LJH, Roberts DA, Zhao L, Banerjee M, Murthy V, Loosen SH, Chalkias A, Tacke F, Reiser J, Giamarellos-Bourboulis EJ, Eugen-Olsen J, Pop-Busui R, Hayek SS; ISIC investigators. SuPAR, biomarkers of inflammation, and severe outcomes in patients hospitalized for COVID-19: The International Study of Inflammation in COVID-19. J Med Virol. 2024 Jan;96(1):e29389. Read the study here.

During COVID-19, it was attempted to treat patients with the IL-1 receptor antagonist Anakinra, but without success. Likely because the innate immune system is important in combatting infections. But what if you are suffering from elevated suPAR, a state of immune activation and chronic inflammation leading you unable to cope with a disease challenge? This was tested in the SAVE MORE randomized controlled trial. 37 hospitals participated, and only patients with suPAR above 6 ng/ml were included. Now Anakinra was a success:

Kyriazopoulou E, Poulakou G, Milionis H, Metallidis S, Adamis G, Tsiakos K, Fragkou A, Rapti A, Damoulari C, Fantoni M, Kalomenidis I, Chrysos G, Angheben A, Kainis I, Alexiou Z, Castelli F, Serino FS, Tsilika M, Bakakos P, Nicastri E, Tzavara V, Kostis E, Dagna L, Koufargyris P, Dimakou K, Savvanis S, Tzatzagou G, Chini M, Cavalli G, Bassetti M, Katrini K, Kotsis V, Tsoukalas G, Selmi C, Bliziotis I, Samarkos M, Doumas M, Ktena S, Masgala A, Papanikolaou I, Kosmidou M, Myrodia DM, Argyraki A, Cardellino CS, Koliakou K, Katsigianni EI, Rapti V, Giannitsioti E, Cingolani A, Micha S, Akinosoglou K, Liatsis-Douvitsas O, Symbardi S, Gatselis N, Mouktaroudi M, Ippolito G, Florou E, Kotsaki A, Netea MG, Eugen-Olsen J, Kyprianou M, Panagopoulos P, Dalekos GN, Giamarellos-Bourboulis EJ. Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. Nat Med. 2021 Oct;27(10):1752-1760. Read the study here.

Same principle, now in sepsis. Some patients with qSOFA 1 may require early treatment with antibiotics, others may not require treatment with antibiotics. But how can we find those patients that may benefit from early treatment? By using suPAR. When suPAR is above 12 ng/ml, it is typically a bacterial infection and will result in mortality. Thus, these patients require immediate treatment to stand a better chance of survival. The SUPERIOR trial was a randomized controlled trial including patients with suspicion of infection, a qSOFA of 1 and a suPAR above 12 ng/ml, and randomized to broad spectra antibiotics or placebo. The primary endpoint war prevention of progression as recorded by SOFA score after 24 hours. The trial was successful:

Adami ME, Kotsaki A, Antonakos N, Giannitsioti E, Chalvatzis S, Saridaki M, Avgoustou C, Akinosoglou K, Dakou K, Damoraki G, Katrini K, Koufargyris P, Lekakis V, Panagaki A, Safarika A, Eugen-Olsen J, Giamarellos-Bourboulis EJ. qSOFA combined with suPAR for early risk detection and guidance of antibiotic treatment in the emergency department: a randomized controlled trial. Crit Care. 2024 Feb 6;28(1):42. doi: 10.1186/s13054-024-04825-2. Read the study here.

General health/longevity

First paper was published in 2010 showing suPAR predicts disease development and premature mortality in a general population:

Eugen-Olsen J, Andersen O, Linneberg A, Ladelund S, Hansen TW, Langkilde A, Petersen J, Pielak T, Møller LN, Jeppesen J, Lyngbaek S, Fenger M, Olsen MH, Hildebrandt PR, Borch-Johnsen K, Jørgensen T, Haugaard SB. Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med. 2010 Sep;268(3):296-308. Read the full study here.

The prognostic value of suPAR in predicting cardiovascular disease in the general population was validated in a Swedish study of 5378 individuals aged 45-69 years old:

Persson M, Östling G, Smith G, Hamrefors V, Melander O, Hedblad B, Engström G. Soluble urokinase plasminogen activator receptor: a risk factor for carotid plaque, stroke, and coronary artery disease. Stroke. 2014 Jan;45(1):18-23. Read the full study here.

What is a normal healthy suPAR level? To determine this, suPAR was measured on 9305 blood donors aged 18-65 years old:

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 Oct 20;9(10):e110555. Read the full study here.

If you change towards a healthier lifestyle, e.g., stop smoking, the suPAR level will drop significantly:

Eugen-Olsen J, Ladelund S, Sørensen LT. Plasma suPAR is lowered by smoking cessation: a randomized controlled study. Eur J Clin Invest. 2016 Apr;46(4):305-11. Read the full study.

And if you change lifestyle and lower your suPAR, you also lower your risk of disease and premature mortality. So, suPAR is an early warning, not a death sentence:

Haupt TH, Rasmussen LJH, Kallemose T, Ladelund S, Andersen O, Pisinger C, Eugen-Olsen J. Healthy lifestyles reduce suPAR and mortality in a Danish general population study. Immun Ageing. 2019 Jan 22;16:1. Read the full study.

Healthy food intake is good for the suPAR level

Törnkvist PBS, Haupt TH, Rasmussen LJH, Ladelund S, Toft U, Pisinger C, Eugen-Olsen J. Soluble urokinase plasminogen activator receptor is linearly associated with dietary quality and predicts mortality. Br J Nutr. 2019 Mar;121(6):699-708. Read the full study.

All the bad things in life accumulate into chronic inflammation/suPAR and increases our risk of disease and premature mortality. An example is the paper from Moffitt/Caspi group showing that major life stressors such as divorce, bankruptcy, loss of close relative, job loss etc. accumulate in chronic inflammation/suPAR:

Bourassa KJ, Rasmussen LJH, Danese A, Eugen-Olsen J, Harrington H, Houts R, Poulton R, Ramrakha S, Sugden K, Williams B, Moffitt TE, Caspi A. Linking stressful life events and chronic inflammation using suPAR (soluble urokinase plasminogen activator receptor). Brain Behav Immun. 2021 Oct;97:79-88. Read the full study.

Another example of this; We know that loneliness is associated with increased risk of mortality. And loneliness is also reflected in elevated suPAR:

Matthews T, Rasmussen LJH, Ambler A, Danese A, Eugen-Olsen J, Fancourt D, Fisher HL, Iversen KK, Schultz M, Sugden K, Williams B, Caspi A, Moffitt TE. Social isolation, loneliness, and inflammation: A multi-cohort investigation in early and mid-adulthood. Brain Behav Immun. 2023 Nov 21;115:727-736. Read the full study.

The higher the suPAR, the faster you age and older you look – even the brain ages faster in individuals with elevated suPAR. Or as we can say in longevity, the lower the suPAR, the slower you age and the younger you look:

Rasmussen LJH, Caspi A, Ambler A, Danese A, Elliott M, Eugen-Olsen J, Hariri AR, Harrington H, Houts R, Poulton R, Ramrakha S, Sugden K, Williams B, Moffitt TE. Association Between Elevated suPAR, a New Biomarker of Inflammation, and Accelerated Aging. J Gerontol A Biol Sci Med Sci. 2021 Jan 18;76(2):318-327. Read the full study.

suPAR is not only predicting disease development, but suPAR itself is causing atherosclerotic disease:

Hindy G, Tyrrell DJ, Vasbinder A, Wei C, Presswalla F, Wang H, Blakely P, Ozel AB, Graham S, Holton GH, Dowsett J, Fahed AC, Amadi KM, Erne GK, Tekmulla A, Ismail A, Launius C, Sotoodehnia N, Pankow JS, Thørner LW, Erikstrup C, Pedersen OB, Banasik K, Brunak S, Ullum H, Eugen-Olsen J, Ostrowski SR; DBDS Consortium; Haas ME, Nielsen JB, Lotta LA; Regeneron Genetics Center; Engström G, Melander O, Orho-Melander M, Zhao L, Murthy VL, Pinsky DJ, Willer CJ, Heckbert SR, Reiser J, Goldstein DR, Desch KC, Hayek SS. Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis. J Clin Invest. 2022 Dec 15;132(24):e158788. Read the full study.

Other major papers on suPAR

In this Nature publication, the authors identify uPAR (cell bound suPAR) as highly expressed on senescent cells as a part of the SASP, the molecules released from senescent cells that is one source to chronic inflammation:

Amor C, Feucht J, Leibold J, Ho YJ, Zhu C, Alonso-Curbelo D, Mansilla-Soto J, Boyer JA, Li X, Giavridis T, Kulick A, Houlihan S, Piroschki E, Friedman SL, Ponomarev V, Piersigilli A, Sadelain M, Lowe SW. Senolytic CAR T cells reverse senescence-associated pathologies. Nature. 2020 Jul;583(7814):127-132. Read the full study.

Amor C, Fernández-Maestre I, Chowdhury S, Ho YJ, Nadella S, Graham C, Carrasco SE, Nnuji-John E, Feucht J, Hinterleitner C, Barthet VJA, Boyer JA, Mezzadra R, Wereski MG, Tuveson DA, Levine RL, Jones LW, Sadelain M, Lowe SW. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nat Aging. 2024 Jan 24. Read the full study.

suPAR is also causal in the development of acute and chronic kidney disease. High suPAR drives loss of kidney function:

Hayek SS, Sever S, Ko YA, Trachtman H, Awad M, Wadhwani S, Altintas MM, Wei C, Hotton AL, French AL, Sperling LS, Lerakis S, Quyyumi AA, Reiser J. Soluble Urokinase Receptor and Chronic Kidney Disease. N Engl J Med. 2015 Nov 12;373(20):1916-25. Read the full study.

Hayek SS, Leaf DE, Samman Tahhan A, Raad M, Sharma S, Waikar SS, Sever S, Camacho A, Wang X, Dande RR, Ibrahim NE, Baron RM, Altintas MM, Wei C, Sheikh-Hamad D, Pan JS, Holliday MW Jr, Januzzi JL, Weisbord SD, Quyyumi AA, Reiser J. Soluble Urokinase Receptor and Acute Kidney Injury. N Engl J Med. 2020 Jan 30;382(5):416-426. Read the full study.

These two NEJM papers laid the foundation of https://www.waldenbiosciences.com/, who just completed face 1 trials on anti-suPAR treatment.


published suPAR studies in leading medical journals

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