Why high suPAR is not super - diagnostic, prognostic and potential pathogenic properties of a novel biomarker in the ICU

The soluble urokinase plasminogen activator receptor (suPAR) has been suggested as a biomarker that reflects immune cell activation. In critically ill patients, several independent investigations have reported elevated suPAR in conditions of systemic inflammatory response syndrome (SIRS), bacteriemia, sepsis, and septic shock, in which high circulating suPAR levels indicated an unfavorable prognosis. In a prospective cohort study in this issue of Critical Care, suPAR levels were detected in bronchoalveolar lavage (BAL) and identified inhalation injury. High systemic levels indicated an adverse prognosis. This study expands our knowledge of the diagnostic power of suPAR, confirms its prognostic value, and raises the demand for future studies investigating the pathogenic involvement of suPAR.

Infl ammation is a key pathogenic factor in various conditions of critical illness, even in the absence of an infection. However, most of the biomarkers currently established in clinical practice are not sensitive enough to detect non-infectious states of infl ammation early and reliably [1]. Th e urokinase plasminogen activator recep tor (uPAR) is expressed on most leukocytes and is cleaved from the cell surface through infl ammatory stimulation ( Figure 1) [2]. Th e soluble uPAR, termed suPAR, has been suggested to mirror the degree of immunoactivation ( Figure 1) and can be measured from blood, urine, saliva, or cerebrospinal fl uid [3][4][5]. In this issue of Critical Care, Backes and colleagues [1] report, for the fi rst time, that suPAR is also detectable in lung lavage fl uid. In a prospective longitudinal cohort study of 26 patients (11 with and 15 without burn injury), the authors found that pulmonary suPAR levels were useful for the diagnosis of inhalation injury and that high systemic levels indicated an adverse prognosis in terms of duration of mechanical ventilation and length of intensive care unit (ICU) stay.
On the one hand, this study supports recent fi ndings from several groups that circulating suPAR levels are valid biomarkers in determining the prognosis of critically ill patients in the ICU [6][7][8][9] and extends prior results to this specialized subset of ICU patients with burn injuries (Figure 1). On the other hand, this study suggests that the measurement of suPAR from bronchoalveolar lavage can serve as a specifi c tool for the diagnosis of inhalation trauma. Th e fi ndings thereby challenge the current view that suPAR is a useful prognostic biomarker rather than a specifi c diagnostic biomarker [3]. Th is 'dogma' had been based on various studies investigating circulating suPAR levels in diff erent disease etiologies, including sepsis, cardiovascular disorders, and cancer [6,10,11]. However, we could already demonstrate a diagnostic value of serum suPAR levels for identifying alcoholic etiology among patients with chronic liver diseases [12]. Th e paper by Backes and colleagues [1] indicates that suPAR measurements obtained from distinct body fl uids, namely broncho alveolar lavage, may be diagnostically important in the ICU setting. Nevertheless, before they can be applied to clinical routine, these results need to be validated in a larger cohort, which must include other pulmonary disorders such as pneumonia, non-infectious acute lung injury, and acute respiratory distress syndrome.
Another future direction of research should address the potential pathogenic role of elevated suPAR levels in diff erent compartments because suPAR not only may be a valid biomarker but also may promote disease pro gression. Recently, suPAR has been mechanistically linked to the pathogenesis of focal segmental glomerulo sclerosis.

Abstract
The soluble urokinase plasminogen activator receptor (suPAR) has been suggested as a biomarker that refl ects immune cell activation. In critically ill patients, several independent investigations have reported elevated suPAR in conditions of systemic infl ammatory response syndrome (SIRS), bacteriemia, sepsis, and septic shock, in which high circulating suPAR levels indicated an unfavorable prognosis. In a prospective cohort study in this issue of Critical Care, suPAR levels were detected in bronchoalveolar lavage (BAL) and identifi ed inhalation injury. High systemic levels indicated an adverse prognosis. This study expands our knowledge of the diagnostic power of suPAR, confi rms its prognostic value, and raises the demand for future studies investigating the pathogenic involvement of suPAR.
Circulating suPAR enters the glomerulus and binds β3 integrin, which normally anchors podocytes to the glomerular basement membrane [13]. Elevated plasma levels of suPAR lead to increased β3 integrin activation and consequently cause podocyte dysfunction and proteinuria. Th is cascade has been identifi ed as a major promoting Upon infl ammation, the receptor is cleaved from the cell surface at the GPI anchor and is released into various body fl uids (upper right corner). Circulating suPAR levels in serum are closely linked to infl ammation in patients with type 2 diabetes, cardiovascular (CV) disorders, or cancer. The highest suPAR serum concentrations are found in critically ill patients with systemic infl ammatory response syndrome (SIRS) or sepsis, and elevated suPAR values indicate an unfavorable prognosis (lower left corner). This was confi rmed by Backes and colleagues [1] in a prospective observational cohort study of 26 intensive care unit patients (11 with and 15 without burn injury). As also demonstrated by the study, suPAR can be detected in bronchoalveolar lavage (BAL) and is indicative of inhalation injury (lower right corner  [13]. Th us, it appears possible that elevated pulmonary suPAR in burn injury exerts directly chemotactic or other pro-infl ammatory functions, thereby perpetuating infl ammation and tissue damage. Future clinical studies and experimental animal models may therefore consider suPAR not only as an epi phenomenon but also as a potential therapeutic target in infl ammatory disorders.