Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review

Yara Backes, Koenraad F van der Sluijs, David P Mackie, Frank Tacke, Alexander Koch, Jyrki J Tenhunen, Marcus J Schultz, Yara Backes, Koenraad F van der Sluijs, David P Mackie, Frank Tacke, Alexander Koch, Jyrki J Tenhunen, Marcus J Schultz

Abstract

Purpose: Systemic levels of soluble urokinase-type plasminogen activator receptor (suPAR) positively correlate with the activation level of the immune system. We reviewed the usefulness of systemic levels of suPAR in the care of critically ill patients with sepsis, SIRS, and bacteremia, focusing on its diagnostic and prognostic value.

Methods: A PubMed search on suPAR was conducted, including manual cross-referencing. The list of papers was narrowed to original studies of critically ill patients. Ten papers on original studies of critically ill patients were identified that report on suPAR in sepsis, SIRS, or bacteremia.

Results: Systematic levels of suPAR have little diagnostic value in critically ill patients with sepsis, SIRS, or bacteremia. Systemic levels of suPAR, however, have superior prognostic power over other commonly used biological markers in these patients. Mortality prediction by other biological markers or severity-of-disease classification system scores improves when combining them with suPAR. Systemic levels of suPAR correlate positively with markers of organ dysfunction and severity-of-disease classification system scores. Finally, systemic levels of suPAR remain elevated for prolonged periods after admission and only tend to decline after several weeks. Notably, the type of assay used to measure suPAR as well as the age of the patients and underlying disease affect systemic levels of suPAR.

Conclusions: The diagnostic value of suPAR is low in patients with sepsis. Systemic levels of suPAR have prognostic value, and may add to prognostication of patients with sepsis or SIRS complementing severity-of-disease classification systems and other biological markers.

Figures

Fig. 1
Fig. 1
Systemic levels of suPAR in healthy controls and critically ill patients with SIRS or sepsis, and patients with bacteremia. Systemic levels of suPAR are significantly higher in patients with sepsis, as compared to patient without sepsis or patients with SIRS. Data represent medians with their interquartile range. Extremes were excluded from the figure. Stars indicate the level of statistical difference. Reproduced with permission from [25] and [26]
Fig. 2
Fig. 2
Diagnostic power of suPAR. ROC curve analysis showing the diagnostic power of systemic levels of suPAR in predicting sepsis on admission. AUC, area under the curve. The p value indicates the level of statistical significance. Adapted with permission from [25]
Fig. 3
Fig. 3
Prognostic power of suPAR in ICU patients. Box plot graphics and ROC curve analyses showing the prognostic power of suPAR for mortality on admission, and day 3 and 7 after admission in ICU patients. AUC, area under the curve. The P–value indicates the level of statistical significance. Adapted with permission from [25]
Fig. 4
Fig. 4
Prognostic power of suPAR in patients with sepsis. Box plot graphics and ROC curve analyses showing the prognostic power of suPAR for mortality on admission in patients with sepsis. AUC area under the curve. The p value indicates the level of statistical significance. Adapted with permission from [25]

References

    1. Stephens RW, Pedersen AN, Nielsen HJ, Hamers MJ, Høyer-Hansen G, Rønne E, Dybkjaer 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.
    1. Sier CF, Stephens R, Bizik J, Mariani A, Bassan M, Pedersen N, Frigerio L, Ferrari A, Danø K, Brünner N, Blasi F. The level of urokinase-type plasminogen activator receptor is increased in serum of ovarian cancer patients. Cancer Res. 1998;58:1843–1849.
    1. Ostrowski SR, Katzenstein TL, Piironen T, Gerstoft J, Pedersen BK, Ullum H. Soluble urokinase receptor levels in plasma during 5 years of highly active antiretroviral therapy in HIV-1-infected patients. J Acquir Immune Defic Syndr. 2004;35:337–342. doi: 10.1097/00126334-200404010-00002.
    1. Perch M, Kofoed P, Fischer TK, Có F, Rombo L, Aaby P, Eugen-Olsen J. Serum levels of soluble urokinase plasminogen activator receptor is associated with parasitemia in children with acute Plasmodium falciparum malaria infection. Parasite Immunol. 2004;26:207–211. doi: 10.1111/j.0141-9838.2004.00695.x.
    1. Ostrowski SR, Ullum H, Goka BQ, Høyer-Hansen G, Obeng-Adjei G, Pedersen BK, Akanmori BD, Kurtzhals JA. Plasma concentrations of soluble urokinase-type plasminogen activator receptor are increased in patients with malaria and are associated with a poor clinical or a fatal outcome. J Infect Dis. 2005;191:1331–1341. doi: 10.1086/428854.
    1. Eugen-Olsen J, Gustafson P, Sidenius N, Fischer TK, Parner J, Aaby P, Gomes VF, Lisse I. 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;6:686–692.
    1. Ostrowski SR, Ravn P, Hoyer-Hansen G, Ullum H, Andersen AB. Elevated levels of soluble urokinase receptor in serum from mycobacteria infected patients: still looking for a marker of treatment efficacy. Scand J Infect Dis. 2006;38:1028–1032. doi: 10.1080/00365540600868305.
    1. Garcia-Monco JC, Coleman JL, Benach JL. Soluble urokinase receptor (uPAR, CD 87) is present in serum and cerebrospinal fluid in patients with neurologic diseases. J Neuroimmunol. 2002;129:216–223. doi: 10.1016/S0165-5728(02)00186-8.
    1. Slot O, Brunner N, Locht H, Oxholm P, Stephens RW. Soluble urokinase plasminogen activator receptor in plasma of patients with inflammatory rheumatic disorders: increased concentrations in rheumatoid arthritis. Ann Rheum Dis. 1999;58:488–492. doi: 10.1136/ard.58.8.488.
    1. Pliyev BK, Menshikov MY. Release of the soluble urokinase-type plasminogen activator receptor (suPAR) by activated neutrophils in rheumatoid arthritis. Inflammation. 2010;33:1–9. doi: 10.1007/s10753-009-9152-0.
    1. Andersen ES, Ruhwald M, Moessner B, Christensen PB, Andersen O, Eugen-Olsen J, Weis N. Twelve potential fibrosis markers to differentiate mild liver fibrosis from cirrhosis in patients infected with chronic hepatitis C genotype 1. Eur J Clin Microbiol Infect Dis. 2011;30:761–766. doi: 10.1007/s10096-010-1149-y.
    1. Lonnkvist MH, Theodorsson E, Holst M, Ljung T, Hellström PM. Blood chemistry markers for evaluation of inflammatory activity in Crohn’s disease during infliximab therapy. Scand J Gastroenterol. 2011;46:420–427. doi: 10.3109/00365521.2010.539253.
    1. Stephens RW, Nielsen HJ, Christensen IJ, Thorlacius-Ussing O, Sørensen S, Danø K, Brünner N. Plasma urokinase receptor levels in patients with colorectal cancer: relationship to prognosis. J Natl Cancer Inst. 1999;91:869–874. doi: 10.1093/jnci/91.10.869.
    1. Brunner N, Nielsen HJ, Hamers M, Christensen IJ, Thorlacius-Ussing O, Stephens RW. The urokinase plasminogen activator receptor in blood from healthy individuals and patients with cancer. APMIS. 1999;107:160–167. doi: 10.1111/j.1699-0463.1999.tb01539.x.
    1. Sidenius N, Sier CF, Ullum H, Pedersen BK, Lepri AC, Blasi F, Eugen-Olsen J. Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection. Blood. 2000;96:4091–4095.
    1. Ostrowski SR, Piironen T, Hoyer-Hansen G, Gerstoft J, Pedersen BK, Ullum H. High plasma levels of intact and cleaved soluble urokinase receptor reflect immune activation and are independent predictors of mortality in HIV-1-infected patients. J Acquir Immune Defic Syndr. 2005;39:23–31. doi: 10.1097/01.qai.0000157950.02076.a6.
    1. Mizukami IF, Faulkner NE, Gyetko MR, Sitrin RG, Todd RF., 3rd Enzyme-linked immuno-absorbent assay detection of a soluble form of urokinase plasminogen activator receptor in vivo. Blood. 1995;86:203–211.
    1. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, Lijmer JG, Moher D, Rennie D, de Vet HC, Standards for Reporting of Diagnostic Accuracy Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Standards for Reporting of Diagnostic Accuracy. Clin Chem. 2003;49:1–6. doi: 10.1373/49.1.1.
    1. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, Moher D, Rennie D, de Vet HC, Lijmer JG. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Clin Chem. 2003;49:7–18. doi: 10.1373/49.1.7.
    1. Molkanen T, Ruotsalainen E, Thorball CW, Järvinen A. Elevated soluble urokinase plasminogen activator receptor (suPAR) predicts mortality in Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis. 2011;30:1417–1424. doi: 10.1007/s10096-011-1236-8.
    1. Moller HJ, Moestrup SK, Weis N, Wejse C, Nielsen H, Pedersen SS, Attermann J, Nexø E, Kronborg G. Macrophage serum markers in pneumococcal bacteremia: prediction of survival by soluble CD163. Crit Care Med. 2006;34:2561–2566. doi: 10.1097/01.CCM.0000239120.32490.AB.
    1. Kofoed K, Andersen O, Kronborg G, Tvede M, Petersen J, Eugen-Olsen J, Larsen K. Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage migration inhibitory factor, soluble urokinase-type plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diagnose infections: a prospective study. Crit Care. 2007;11:R38. doi: 10.1186/cc5723.
    1. Kofoed K, Eugen-Olsen J, Petersen J, Larsen K, Andersen O. Predicting mortality in patients with systemic inflammatory response syndrome: an evaluation of two prognostic models, two soluble receptors, and a macrophage migration inhibitory factor. Eur J Clin Microbiol Infect Dis. 2008;27:375–383. doi: 10.1007/s10096-007-0447-5.
    1. Kofoed K, Schneider UV, Scheel T, Andersen O, Eugen-Olsen J. Development and validation of a multiplex add-on assay for sepsis biomarkers using xMAP technology. Clin Chem. 2006;52:1284–1293. doi: 10.1373/clinchem.2006.067595.
    1. Koch A, Voigt S, Kruschinski C, Sanson E, Dückers H, Horn A, Yagmur E, Zimmermann H, Trautwein C, Tacke F. Circulating soluble urokinase plasminogen activator receptor is stably elevated during the first week of treatment in the intensive care unit and predicts mortality in critically ill patients. Crit Care. 2011;15:R63. doi: 10.1186/cc10037.
    1. Wittenhagen P, Kronborg G, Weis N, Nielsen H, Obel N, Pedersen SS, Eugen-Olsen J. The plasma level of soluble urokinase receptor is elevated in patients with Streptococcus pneumoniae bacteraemia and predicts mortality. Clin Microbiol Infect. 2004;10:409–415. doi: 10.1111/j.1469-0691.2004.00850.x.
    1. Huttunen R, Syrjanen J, Vuento R, Hurme M, Huhtala H, Laine J, Pessi T, Aittoniemi J. Plasma level of soluble urokinase-type plasminogen activator receptor as a predictor of disease severity and case fatality in patients with bacteraemia: a prospective cohort study. J Intern Med. 2011;270:32–40. doi: 10.1111/j.1365-2796.2011.02363.x.
    1. Florquin S, van den Berg JG, Olszyna DP, Claessen N, Opal SM, Weening JJ, van der Poll T. Release of urokinase plasminogen activator receptor during urosepsis and endotoxemia. Kidney Int. 2001;59:2054–2061.
    1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ, ACCP/SCCM Consensus Conference Committee Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine 1992. Chest. 2009;136(5 suppl):e28. doi: 10.1378/chest.09-2267.
    1. Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care. 2010;14:R15. doi: 10.1186/cc8872.
    1. Christ-Crain M, Muller B. Biomarkers in respiratory tract infections: diagnostic guides to antibiotic prescription, prognostic markers and mediators. Eur Respir J. 2007;30:556–573. doi: 10.1183/09031936.00166106.
    1. Kibe S, Adams K, Barlow G. Diagnostic and prognostic biomarkers of sepsis in critical care. J Antimicrob Chemother. 2011;66(Suppl 2):ii33–ii40. doi: 10.1093/jac/dkq523.
    1. Standage SW, Wong HR. Biomarkers for pediatric sepsis and septic shock. Expert Rev Anti Infect Ther. 2011;9:71–79. doi: 10.1586/eri.10.154.
    1. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med. 2008;36:941–952. doi: 10.1097/CCM.0B013E318165BABB.
    1. Schuetz P, Christ-Crain M, Muller B. Procalcitonin and other biomarkers to improve assessment and antibiotic stewardship in infections—hope for hype? Swiss Med Wkly. 2009;139:318–326.
    1. Sier CF, Sidenius N, Mariani A, Aletti G, Agape V, Ferrari A, Casetta G, Stephens RW, Brünner N, Blasi F. Presence of urokinase-type plasminogen activator receptor in urine of cancer patients and its possible clinical relevance. Lab Invest. 1999;79:717–722.
    1. Thuno M, Macho B, Eugen-Olsen J. suPAR: the molecular crystal ball. Dis Markers. 2009;27:157–172.
    1. Ossowski L, Aguirre-Ghiso JA. Urokinase receptor and integrin partnership: coordination of signaling for cell adhesion, migration and growth. Curr Opin Cell Biol. 2000;12:613–620. doi: 10.1016/S0955-0674(00)00140-X.
    1. Resnati M, Guttinger M, Valcamonica S, Sidenius N, Blasi F, Fazioli F. Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect. EMBO J. 1996;15:1572–1582.
    1. Mondino A, Blasi F. uPA and uPAR in fibrinolysis, immunity and pathology. Trends Immunol. 2004;25:450–455. doi: 10.1016/j.it.2004.06.004.
    1. Rijneveld AW, Levi M, Florquin S, Speelman P, Carmeliet P, van Der Poll T. Urokinase receptor is necessary for adequate host defense against pneumococcal pneumonia. J Immunol. 2002;168:3507–3511.
    1. Selleri C, Montuori N, Ricci P, Visconte V, Carriero MV, Sidenius N, Serio B, Blasi F, Rotoli B, Rossi G, Ragno P. Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization. Blood. 2005;105:2198–2205. doi: 10.1182/blood-2004-06-2424.
    1. Park YJ, Liu G, Tsuruta Y, Lorne E, Abraham E. Participation of the urokinase receptor in neutrophil efferocytosis. Blood. 2009;114:860–870. doi: 10.1182/blood-2008-12-193524.
    1. Wiersinga WJ, Kager LM, Hovius JW, van der Windt GJ, de Vos AF, Meijers JC, Roelofs JJ, Dondorp A, Levi M, Day NP, Peacock SJ, van der Poll T. Urokinase receptor is necessary for bacterial defense against pneumonia-derived septic melioidosis by facilitating phagocytosis. J Immunol. 2010;184:3079–3086. doi: 10.4049/jimmunol.0901008.
    1. McMaken S, Exline MC, Mehta P, Piper M, Wang Y, Fischer SN, Newland CA, Schrader CA, Balser SR, Sarkar A, Baran CP, Marsh CB, Cook CH, Phillips GS, Ali NA. Thrombospondin-1 contributes to mortality in murine sepsis through effects on innate immunity. PLoS ONE. 2011;6:e19654. doi: 10.1371/journal.pone.0019654.
    1. Quach S, Hennessy DA, Faris P, Fong A, Quan H, Doig C. A comparison between the APACHE II and Charlson index score for predicting hospital mortality in critically ill patients. BMC Health Serv Res. 2009;9:129. doi: 10.1186/1472-6963-9-129.
    1. Le Gall JR, Lemeshow S, Saulnier F. A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. JAMA. 1993;270:2957–2963. doi: 10.1001/jama.1993.03510240069035.
    1. Mirsaeidi M, Peyrani P, Ramirez JA, Improving Medicine through Pathway Assessment of Critical Therapy of Hospital-Acquired Pneumonia (IMPACT-HAP) Investigators Predicting mortality in patients with ventilator-associated pneumonia: the APACHE II score versus the new IBMP-10 score. Clin Infect Dis. 2009;49:72–77. doi: 10.1086/599349.
    1. Riisbro R, Christensen IJ, Hogdall C, Brünner N, Høgdall E. Soluble urokinase plasminogen activator receptor measurements: influence of sample handling. Int J Biol Markers. 2001;16:233–239.
    1. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34:1589–1596. doi: 10.1097/01.CCM.0000217961.75225.E9.
    1. Moran JL, Bristow P, Solomon PJ, George C, Hart GK, Australian and New Zealand Intensive Care Society Database Management Committee (ADMC) Mortality and length-of-stay outcomes, 1993–2003, in the binational Australian and New Zealand intensive care adult patient database. Crit Care Med. 2008;36:46–61. doi: 10.1097/01.CCM.0000295313.08084.58.
    1. Kaufmann PA, Smolle KH, Krejs GJ. Short- and long-term survival of nonsurgical intensive care patients and its relation to diagnosis, severity of disease, age and comorbidities. Curr Aging Sci. 2009;2:240–248. doi: 10.2174/1874609810902030240.

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