Circulating Soluble Urokinase Plasminogen Activator Receptor Is
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Koch et al. Critical Care 2011, 15:R63 http://ccforum.com/content/15/1/R63 RESEARCH Open Access 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 Alexander Koch1, Sebastian Voigt1, Carsten Kruschinski2, Edouard Sanson1, Hanna Dückers1, Andreas Horn1, Eray Yagmur3, Henning Zimmermann1, Christian Trautwein1 and Frank Tacke1* Abstract Introduction: 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. Methods: 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. Results: 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. Conclusions: 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. * Correspondence: [email protected] 1Department of Medicine III, RWTH-University Hospital Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany Full list of author information is available at the end of the article © 2011 Koch et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Koch et al. Critical Care 2011, 15:R63 Page 2 of 14 http://ccforum.com/content/15/1/R63 Introduction female with a median age of 64 years; range 18 to The urokinase plasminogen activator receptor (uPAR) is 90 years) in our study who were admitted to the General expressed on different cell types including neutrophils, Internal Medicine ICU at the RWTH-University Hospital lymphocytes, monocytes, macrophages, certain cancer Aachen, Germany (Table 1). Written informed consent cells and vascular endothelial cells. uPAR and its ligand was obtained from the patient, his or her spouse or the urokinase plasminogen activator (uPA) are participants appointed legal guardian. Not included in this study were in numerous immunologic functions including migra- patients who were expected to have a short-term (< 72 h) tion, adhesion, angiogenesis, fibrinolysis and cell prolif- intensive care treatment due to post-interventional eration and have been found to promote tissue invasion observation or acute intoxication [12]. The medium in malignant diseases by converting plasminogen into length of stay at the ICU was 9 days (range 1 to 137 days) plasmin, resulting in degradation of extracellular matrix and medium length of stay in the hospital was 27 days [1-4]. Migration of inflammatory cells from the blood (range 2 to 151 days). stream into tissues is also an essential component of Patient data, clinical information and blood samples inflammation and immune response against infection, in were collected prospectively. The clinical course of which the uPAR/uPA system is directly involved [5]. patients was observed in a follow-up period by directly Through inflammatory stimulation uPAR is cleaved contacting the patients, the patients’ relatives or their from the cell surface by proteases to the soluble form of primary care physician. Patients who met the criteria the receptor, suPAR, which has been detected in blood, proposed by the American College of Chest Physicians urine and cerebro-spinal fluid [6-9]. Increased activation and the Society of Critical Care Medicine Consensus of the immune system caused by different types of infec- Conference Committee for severe sepsis and septic tions or various solid tumours, results in increased shock were categorized as sepsis patients, the others as suPAR concentrations in body fluids. Thereby serum non-sepsis patients [13]. suPAR levels are believed to mirror the degree of immu- As a control population we analyzed 43 healthy blood noactivation. Moreover, high suPAR serum concentra- donors (28 male, 15 female; median age 53, range 24 to tions have been found to predict mortality in patients 68 years) with normal values for blood counts, C-reactive with active tuberculosis and in healthy subjects [10]. In protein and liver enzymes. a recent study, high suPAR serum concentrations have been shown to indicate a poor outcome in patients with Characteristics of sepsis and non-sepsis patients systemic inflammatory response syndrome (SIRS) Among the 273 critically ill patients enrolled in this admitted to an emergency department and to a depart- study, 197 patients conformed to the criteria of bacterial ment of infectious diseases without an intensive-care sepsis (Table 1). Pneumonia was identified in the major- environment [11]. Yet, these findings have been ity of sepsis patients as the origin of infection (Table 2). regarded as possibly applicable only to patients with Non-sepsis patients were admitted to the ICU mainly community-acquired infections, which did not require due to cardiopulmonary diseases (myocardial infarction, intensive-treatment, and the validity for critically ill pulmonary embolism, and cardiac pulmonary edema), patients was questioned. decompensated liver cirrhosis or other critical condi- Thepresentstudywasconductedwithalargecohort tions and did not differ in age or sex from sepsis of well characterized critically ill patients in a medical patients. Sepsis patients were more often in need of ICU to provide information on suPAR serum concentra- mechanical ventilation in longer terms as compared to tions in different circumstances of critical disease, to the non-sepsis patients’ cohort (Table 1). In sepsis identify potential regulatory mechanisms of suPAR by patients significantly higher levels of routinely used bio- correlations with a wide number of markers of inflam- markers of inflammation (that is, C-reactive protein, mation, organ dysfunction and metabolism and to eluci- procalcitonin, white blood cell count) were found (Table 1, date the prognostic impact of suPAR in critically ill and data not shown). Both groups did not differ in Acute patients. Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA) and Simpli- Materials and methods fied Acute Physiology Score (SAPS)2 score, vasopressor Study design and patient characteristics demand, or laboratory parameters indicating liver or renal The study protocol was approved by the local ethics dysfunction (data not shown). committee and conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki suPAR measurements (ethics committee of the University Hospital Aachen, Blood samples were collected upon admission to the ICU RWTH-University, Aachen, Germany, reference number (prior to therapeutic interventions) as well as in the morn- EK 150/06). We enrolled 273 patients (172 male, 101 ing of Day 3 and Day 7 after admission. After centrifugation Koch et al. Critical Care 2011, 15:R63 Page 3 of 14 http://ccforum.com/content/15/1/R63 Table 1 Baseline patient characteristics and suPAR serum concentrations Parameter All patients Sepsis Non-sepsis Number 273 197 76 Sex (male/female) 172/101 128/69 44/32 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)