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
© Koch et al.; licensee BioMed Central Ltd. 2011
Received: 2 July 2010
Accepted: 16 February 2011
Published: 16 February 2011
suPAR is the soluble form of the urokinase plasminogen activator receptor (uPAR), which is expressed in various immunologically active cells. High suPAR serum concentrations are suggested to reflect the activation of the immune system in circumstances of inflammation and infection, and have been associated with increased mortality in different populations of non-intensive care patients. In this study we sequentially analyzed suPAR serum concentrations within the first week of intensive care in a large cohort of well characterized intensive care unit (ICU) patients, in order to investigate potential regulatory mechanisms and evaluate the prognostic significance in critically ill patients.
A total of 273 patients (197 with sepsis, 76 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU), on Day 3 and Day 7, and compared to 43 healthy controls. Clinical data, various laboratory parameters as well as investigational inflammatory cytokine profiles were assessed. Patients were followed for approximately one year.
Upon admission to the ICU suPAR serum concentrations were elevated in critically ill patients as compared with healthy controls. In sepsis patients suPAR levels were higher than in non-sepsis patients (with or without systemic inflammatory response syndrome (SIRS)). During the first week after admission to the ICU serum suPAR concentrations remained stably elevated. suPAR serum concentrations measured upon admission were closely and independently correlated to various laboratory parameters, specifically biomarkers of inflammation (tumor necrosis factor (TNF), C-reactive protein (CRP)), hepatic and renal dysfunction. High suPAR levels at admission and at Day 3 were a strong independent predictor for both ICU and long-term mortality in critically ill patients.
In sepsis and non-sepsis patients suPAR serum concentrations are increased upon admission to the ICU, likely reflecting the activation state of the immune system, and remain stably elevated in the initial course of treatment. Low suPAR levels are a positive predictor of ICU- and overall survival in critically ill patients, including sepsis and non-sepsis patients. Aside from its value as a promising new prognostic biomarker, both experimental and clinical studies are required in order to understand the specific effects and regulatory mechanisms of suPAR in SIRS and sepsis, and may reveal new therapeutic options.
The urokinase plasminogen activator receptor (uPAR) is expressed on different cell types including neutrophils, lymphocytes, monocytes, macrophages, certain cancer cells and vascular endothelial cells. uPAR and its ligand urokinase plasminogen activator (uPA) are participants in numerous immunologic functions including migration, adhesion, angiogenesis, fibrinolysis and cell proliferation and have been found to promote tissue invasion in malignant diseases by converting plasminogen into plasmin, resulting in degradation of extracellular matrix [1–4]. Migration of inflammatory cells from the blood stream into tissues is also an essential component of inflammation and immune response against infection, in which the uPAR/uPA system is directly involved .
Through inflammatory stimulation uPAR is cleaved from the cell surface by proteases to the soluble form of the receptor, suPAR, which has been detected in blood, urine and cerebro-spinal fluid [6–9]. Increased activation of the immune system caused by different types of infections or various solid tumours, results in increased suPAR concentrations in body fluids. Thereby serum suPAR levels are believed to mirror the degree of immunoactivation. Moreover, high suPAR serum concentrations have been found to predict mortality in patients with active tuberculosis and in healthy subjects . In a recent study, high suPAR serum concentrations have been shown to indicate a poor outcome in patients with systemic inflammatory response syndrome (SIRS) admitted to an emergency department and to a department of infectious diseases without an intensive-care environment . Yet, these findings have been regarded as possibly applicable only to patients with community-acquired infections, which did not require intensive-treatment, and the validity for critically ill patients was questioned.
The present study was conducted with a large cohort of well characterized critically ill patients in a medical ICU to provide information on suPAR serum concentrations in different circumstances of critical disease, to identify potential regulatory mechanisms of suPAR by correlations with a wide number of markers of inflammation, organ dysfunction and metabolism and to elucidate the prognostic impact of suPAR in critically ill patients.
Materials and methods
Study design and patient characteristics
Baseline patient characteristics and suPAR serum concentrations
Age median (range) (years)
64 (18 to 90)
65 (20 to 90)
60 (18 to 85)
APACHE-II score median (range)
17 (0 to 40)
18 (0 to 40)
15 (0 to 31)
SOFA score median (range)
11 (0 to 17)
11 (2 to 17)
7 (0 to 16)
SAPS2 score median (range)
44 (0 to 80)
44.5 (0 to 79)
41.5 (13 to 80)
ICU days median (range)
9 (0 to 137)
12 ** (0 to 137)
6 ** (1 to 45)
Hospital days median (range)
27 (2 to 151)
30 ** (2 to 151)
14 ** (2 to 85)
Death during ICU n (%)
Death during follow-up n (%)
Mechanical ventilation n (%)
Ventilation time median (range) (h)
126 (0 to 2,966)
180 * (0 to 2,966)
48.5 * (0 to 986)
pre-existing diabetes n (%)
BMI median (range) (m2/kg)
25.8 (14.0 to 66.7)
25.9 (14.0 to 66.7)
25.8 (15.9 to 53.3)
suPAR Day 1 median (range) (ng/mL)
9.80 (0 to 20)
11.05 ** (1.87 to 20)
7.62 ** (0 to 20)
suPAR Day 3 median (range) (ng/mL)
10.83 (2.33 to 20)
12.11 * (2.59 to 20)
8.47 * (2.33 to 20)
suPAR Day 7 median (range) (ng/mL)
11.90 (3.67 to 20)
12.27 (3.94 to 20)
9.73 (3.67 to 20)
Patient data, clinical information and blood samples were collected prospectively. The clinical course of patients was observed in a follow-up period by directly contacting the patients, the patients' relatives or their primary care physician. Patients who met the criteria proposed by the American College of Chest Physicians and the Society of Critical Care Medicine Consensus Conference Committee for severe sepsis and septic shock were categorized as sepsis patients, the others as non-sepsis patients .
As a control population we analyzed 43 healthy blood donors (28 male, 15 female; median age 53, range 24 to 68 years) with normal values for blood counts, C-reactive protein and liver enzymes.
Characteristics of sepsis and non-sepsis patients
Disease etiology of the study population
n = 197
n = 76
Etiology of sepsis critical illness
Site of infection
Etiology of non-sepsis critical illness
decompensated liver cirrhosis
Blood samples were collected upon admission to the ICU (prior to therapeutic interventions) as well as in the morning of Day 3 and Day 7 after admission. After centrifugation at 2,000 g at 4°C for 10 minutes, serum and plasma aliquots of 1 mL were frozen immediately at -80°C. suPAR serum concentrations were analysed using a commercial enzyme immunoassay (ViroGates, Birkeroed, Denmark). Interleukin-6, Interleukin-10, tumour necrosis factor alpha (TNF-α) (all Siemens Healthcare, Erlangen, Germany), and procalcitonin (Kryptor, B.R.A.H.M.S. Diagnostica, Henningsdorf, Germany) were measured by commercial chemiluminescence assays, following the manufacturers' instructions.
Data are given as median and range due to the skewed distribution of most of the parameters. Differences between two groups were assessed by Mann-Whitney-U-test and multiple comparisons between more than two groups have been conducted by Kruskal-Wallis-ANOVA and Mann-Whitney-U-test for post hoc analysis. Box plot graphics illustrate comparisons between subgroups and they display a statistical summary of the median, quartiles, range and extreme values. The whiskers extend from the minimum to the maximum value excluding outside and far out values which are displayed as separate points. An outside value (indicated by an open circle) was defined as a value that is smaller than the lower quartile minus 1.5-times the interquartile range, or larger than the upper quartile plus 1.5-times the interquartile range. A far out value was defined as a value that is smaller than the lower quartile minus three times the interquartile range, or larger than the upper quartile plus three times the interquartile range . All values, including "outliers", have been included for statistical analyses. Correlations between variables have been analysed using the Spearman correlation tests, where values of P < 0.05 were considered statistically significant. All single parameters that correlated significantly with suPAR levels at admission were included in a multivariate linear regression analysis with suPAR as the dependent variable to identify independent (meaningful) predictors of elevated suPAR. The prognostic value of the variables was tested by univariate and multivariate analysis in the Cox regression model. Kaplan Meier curves were plotted to display the impact on survival . Receiver operating characteristic (ROC) curve analysis and the derived area under the curve (AUC) statistic provide a global and standardized appreciation of the accuracy of a marker or a composite score for predicting an event. ROC curves were generated by plotting sensitivity against 1-specificity . All statistical analyses were performed with SPSS version 12.0 (SPSS, Chicago, IL, USA).
suPAR serum concentrations upon admission to the ICU are elevated in critically ill patients as compared with healthy controls and are higher in sepsis than in non-sepsis patients
Among the total cohort of ICU patients, we could demonstrate a stepwise increase in suPAR levels from critically ill patients, who did not fulfill SIRS criteria, to patients with SIRS and patients with sepsis (Figure 1b). However, differences among non-sepsis patients (SIRS vs non-SIRS) did not reach statistical significance. In order to investigate the impact of the underlying etiology more precisely, we extended our subgroup analyses. Therefore, the cohort of sepsis patients was subdivided into a pulmonary and a non-pulmonary site of infection and the non-sepsis patients were categorized into liver cirrhosis and others (mostly cardiovascular disorders). By these means we could reveal the highest suPAR serum levels in patients with decompensated liver cirrhosis as compared with other causes of critical illness (Figure 1c, Table 2).
suPAR serum concentrations remain stably elevated during the clinical course within the first week after ICU admission
suPAR serum concentrations at admission to the ICU are closely correlated to biomarkers of inflammation, organ function and clinical scores
Correlations with suPAR serum concentrations at admission day
Markers of inflammation
Markers of organ function
Cystatin C GFR
ICU treatment measures
For the total cohort of critically ill patients a strong association of suPAR serum concentrations at admission to the ICU and established clinical scores like APACHE II (r = 0.345, P < 0.001), SOFA (r = 0.337, P = 0.004) and SAPS2 (r = 0.271, P = 0.004) could be shown, suggesting that suPAR levels are closely linked to disease severity in critical illness. This result was corroborated by (relatively weaker) correlations between suPAR and ICU treatment measures such as ventilation settings and vasopressor doses (Table 3). However, these correlations cannot be considered significant, if post-hoc adjustments (Bonferroni) are applied, as the level of significance would then be P < 0.002 (instead of P < 0.05).
suPAR is a strong predictive marker for ICU- and overall survival in critically ill patients
We used Cox regression analyses and Kaplan-Meier curves to assess the impact of suPAR serum concentrations on ICU- and overall survival among all critically ill patients and the subgroups of sepsis and non-sepsis patients over a long-term follow-up period (median observation time 348 days, range 29 to 884).
suPAR serum concentrations and association with survival
n = 180
n = 135
n = 87
suPAR median (range)(ng/mL)
9.47 (0 to 20)
10.07 (2.3 to 20)
10.93 (3.6 to 20)
n = 61
n = 51
n = 34
suPAR median (range) (ng/mL)
11.73 (3.4 to 20)
14.01 (3.2 to 20)
14.46 (5.6 to 20)
n = 116
n = 95
n = 58
suPAR median (range) (ng/mL)
7.98 (2.31 to 20)
9.84 (2.33 to 20)
10.66 (3.67 to 20)
n = 115
n = 85
n = 60
suPAR median (range) (ng/mL)
11.25 (0 to 20)
12.10 (3.10 to 20)
12.75 (5.38 to 20)
Multivariate Cox regression analysis for suPAR levels at admission to predict ICU mortality
Unadjusted HR (95% CI)
Adjusted HR (95% CI)
0.940 (0.907 to 0.973)
0.926 (0.885 to 0.969)
1.723 (1.302 to 2.28)
1.067 (1.022 to 1.113)
1.089 (1.027 to 1.154)
To test whether a rise in suPAR serum concentrations from Day 1 to Day 3 is associated with an unfavourable prognosis, we compared the individual difference in suPAR levels between Day 3 and Day 1 of ICU-treatment. Survivors and non-survivors did not display different deltas of suPAR serum concentrations between Day 3 and Day 1 (data not shown).
suPAR has superior prognostic value as compared with single parameters of inflammation and organ dysfunction in critically ill patients
In the present study we demonstrate the prognostic impact of suPAR in a large, well characterized cohort of critically ill patients in a medical ICU. We measured suPAR serum concentrations upon admission, prior to intensive care treatment, and during the first week of clinical course. Compared to healthy volunteers critical care patients showed elevated suPAR serum concentrations. Levels were higher in sepsis than in non-sepsis patients. Further subgroup analyses found highest concentrations of suPAR in patients with decompensated liver cirrhosis. In contrast to previous findings in healthy subjects , we could not reveal a significant correlation of suPAR either with age or with sex in our cohort of critically ill patients as well as in our control group.
The differences in suPAR levels between sepsis and non-sepsis patients prompted us to test the diagnostic power of suPAR to diagnose sepsis. In a prior study on patients with SIRS and suspicion of having community-acquired infections in a non-intensive care setting suPAR was found to have a low accuracy in diagnosing bacterial infection in SIRS patients . The authors also noted, that the diagnostic accuracies of sepsis markers are highly dependent on the setting in which they are tested and that their results could only be applicable to patients not requiring ICU treatment. To investigate the diagnostic precision of suPAR and classic clinical inflammatory parameter in an intensive care environment we performed ROC analyses. The obtained AUC of suPAR for predicting sepsis in critically ill patients at admission to the ICU was low compared with CRP and PCT.
In contrast to many pro-inflammatory cytokines, suPAR as a potential biomarker exhibits favourable properties due its high stability in serum samples and limited circadian changes in plasma concentrations [6, 18, 19]. In clinical trials it could be demonstrated that effective treatment of infectious diseases and cancer resulted in a proportional decrease in suPAR serum concentrations, leading to normalization of suPAR levels after full recovery [10, 20, 21]. Though, it has been unclear whether the decrease of suPAR levels was due to anti-inflammatory treatment and the decline in suPAR serum concentrations had specific impact on prognosis. To verify these observations in critically ill patients, we measured suPAR levels upon admission and during the clinical course within the first week. Serum suPAR concentrations did not significantly differ within the first week, either for the total cohort of critically ill patients or the subgroups of sepsis/non sepsis patients and survivors/non-survivors. The continuous elevation of suPAR underscores the easy applicability in clinical practise during the first week in ICU patients. However, our analysis did not include follow-up measurements of suPAR after full recovery and discharge from the hospital.
suPAR seems to exert a variety of functions in diverse physiological pathways, including the plasminogen activating pathway, inflammation, modulation of cell adhesion, migration and proliferation [10, 22–24]. However, It is important to note that suPAR consists of three domains (D1, D2, D3), and proteolytic cleavage between the domains generates different soluble forms of suPAR. The commercial suPARnostic assay (used in this study) measures both full length and D2D3 forms of the highly glucosylated suPAR molecule. It is diffcult to measure suPAR exactly because of the differential glucosylation (suPAR appears as a smear on Western blots) and the mixture of D1D2D3 and D2D3. In a previous study on different forms of suPAR and prognosis in HIV infected patients, the combined clinical value of suPAR D1D2D3 and suPAR D2D3 ('bulk suPAR') was compared to the individual suPAR forms, and the combined measurement (suPAR, expressed in ng/ml) had the strongest prognostic value . Thus, our study allows us to compare the obtained suPAR values to previous studies and to assess the diagnostic/prognostic value of total suPAR levels from a clinical point, but we cannot distinguish between different suPAR cleavage products. We can, therefore, not elucidate the exact pathogenic involvement of the different suPAR forms during critical illness or sepsis.
Importantly, the association of suPAR with inflammation (elevated levels in sepsis patients, independent association with inflammatory cytokines in multivariate linear regression analysis) does not necessarily mean that suPAR exerts proinflammatory actions. A recent study demonstrated that uPA-uPAR interactions are required to control and reduce fibrin-mediated inflammation (in the liver especially) . This suggests that high suPAR levels may not be harmful per se, but may serve to rescue and dampen inflammation induced by fibrinogen.
Supporting previous findings in healthy subjects and patients with prostate cancer , suPAR serum concentrations were found to be inversely correlated to renal function, indicating renal excretion in critical disease. Subgroup analyses revealed significantly higher levels of suPAR in ICU patients with decompensated liver cirrhosis. Furthermore, suPAR was inversely correlated to pseudocholinesterase, reflecting hepatic synthesis capacity, and is directly associated with parameters indicating cholestasis. Most likely, this could be due to a biliary secretion of suPAR. Interestingly, these two principal associations of elevated suPAR with inflammation and organ function were also identified by a multivariate linear regression analysis revealing that organ function (kidney/urea, liver/pseudocholinesterase) and inflammation (TNFa, CRP) were independent predictors of elevated suPAR.
As serum suPAR has been related to different conditions of immune activation and has been proven as a reliable marker for the level of inflammation, it has been consequentially evaluated as prognostic marker. Moreover, uPAR is highly expressed by the endothelium and various triggers, which are present in sepsis, stimulate release of endothelial uPAR and, hence, increase suPAR levels . It is, therefore, possible that high suPAR concentrations primarily reflect endothelial dysfunction that is a key driver in sepsis morbidity and mortality . In previous studies increased suPAR serum concentrations have been associated with an unfavourable prognosis in individuals with disease due to viral [24, 28], bacterial [10, 29] or parasitic infections as well as cancer  and rheumatic arthritis . Lately, elevated suPAR serum concentrations have been associated with a shortened life expectancy in a general population due to increased risk of developing cancer, cardiovascular disease and diabetes mellitus type 2, proposing suPAR as an early warning biomarker for screening purposes . Most recently, a clinical study matched the prognostic value of easily obtainable urine suPAR with that of plasma suPAR, demonstrating inferior prognostic significance of urine suPAR as compared with plasma suPAR .
For the first time we now demonstrated the prognostic impact of suPAR serum concentrations at admittance and during the initial clinical course in a large cohort of critically ill patients in a medical ICU. In fact, critically ill patients with low endogenous suPAR levels upon admission, on Day 3 and on Day 7 had a significantly better outcome (short-term at ICU and long-term during follow-up). Interestingly, in a study investigating HIV-positive patients with low CD4 count (<200 cells/μl), high suPAR levels were significantly associated with increased mortality . The authors suggested the initiation of antiviral therapy in patients with low CD4 count and suPAR serum concentration at a maximum of 6 ng/mL, a cut-off for a high risk situation, which is similar to the cut-off values identified by our study.
Comparing suPAR with single, routinely used clinical biomarkers of organ dysfunction and inflammation, suPAR displayed better predictive accuracy for both ICU and overall survival in critically ill patients. Regarding established clinical scoring systems, the SAPS2 score revealed the best predictive accuracy for survival as compared with suPAR and APACHE II score. Given the high prognostic value of suPAR revealed by our study, future studies should address the implementation of suPAR measurements to improve the power of established scoring systems in large cohorts of critically ill patients.
Based on our findings that serum suPAR is a strong and robust marker of mortality risk, one could speculate that suPAR eventually may help to triage patients at the Emergency Room for relocation to the ICU or to guide therapeutic decisions within the first week of ICU treatment, especially in "high suPAR" patients with a high likelihood of death. Future studies are needed to test this hypothesis and also to assess whether the response to efficient therapy will correlate with a decrease in suPAR and whether this in turn is associated with a better chance of survival.
Our study identifies suPAR as a stable and robust marker in critical ill patients to assess disease severity and mortality risk. Low individual suPAR levels are highly predictive for ICU- and overall survival. In line with prognostic properties, suPAR is closely correlated to inflammation, and renal and hepatic dysfunction, which are central pathophysiological and therapeutic targets in critical disease. At present, it is unclear whether serum suPAR is truly causatively involved in mechanisms of critical disease resulting in high mortality or whether it reflects general inflammation in critical illness. Further studies are required for a satisfying understanding of the biochemical properties and regulatory mechanisms of suPAR in critical disease in order to evaluate whether suPAR could also be a potential novel therapeutic target in critically ill patients.
Soluble urokinase plasminogen activator receptor (suPAR) is derived from various immunologically active cells and suggested to reflect general inflammation and the extent of resulting immune-activation.
In critically ill patients suPAR serum concentrations are significantly increased compared to healthy controls, especially in patients with sepsis, and remain stably elevated within the first week of critical disease.
suPAR is closely correlated to inflammatory markers indicating substantial involvement in systemic inflammatory response in critical disease.
suPAR correlates to renal and liver function indicating possible routes of clearance.
suPAR is a strong predictor for ICU and overall survival in critically ill patients.
- APACHE II:
Acute Physiology and Chronic Health Evaluation II
area under the curve
body mass index
enzyme-linked immunosorbent assay
glomerular filtration rate
intensive care unit
insulin-like growth factor 1
international normalized ratio
- P P :
receiver operating characteristic
Simplified Acute Physiology Score
systemic inflammatory response syndrome
Sequential Organ Failure Assessment
soluble urokinase plasminogen activator receptor
tumor necrosis factor α
urokinase plasminogen activator
urokinase plasminogen activator receptor
This work was supported by the German Research Foundation (DFG Ta434/2-1 & SFB/TRR57). The suPARnostic™ kits were gifts from ViroGates (Birkeroed, Denmark). We thank Jesper Eugen-Olsen (Copenhagen University Hospital) and Henrik Tommerup (ViroGates, Birkeroed, Denmark) for helpful discussions.
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