This systematic review shows that although systemic levels of suPAR are elevated with SIRS, bacteremia, and sepsis, its diagnostic value is low, as suPAR is a non-specific marker of inflammation. Systemic levels of suPAR, however, do have prognostic value, with higher levels being associated with increased mortality. Systemic levels of suPAR correlate positively with severity-of-disease classification scores. Systemic levels of suPAR also correlate positively with several markers of organ dysfunction. After initiation of therapy, levels of suPAR decline only on long-term follow-up.
Ideally, biological markers of sepsis should differentiate among bacterial, viral and fungal infection, and between systemic sepsis and local infection. Over 150 biological markers have been clinically evaluated for use in sepsis [30
]. Relatively few biological markers, however, have been used for diagnosing (the type of) sepsis, and none has sufficient sensitivity or specificity to be used routinely in daily practice [30
]. C-reactive protein and procalcitonin are the most widely used values, despite their limited ability to distinguish sepsis from other inflammatory conditions [30
]. Our review showed suPAR to have low diagnostic value in patients with SIRS, bacteremia, or sepsis, even lower than CRP, PCT, and sTREM-1.
The majority of the biological markers investigated in septic patients have been assessed according to their prognostic value [30
]. Traditional markers such as fever, white blood cell count, and CRP levels are not reliable for assessing disease severity and mortality risk [30
]. Procalcitonin seems to be an improvement on these markers, but is not ideal [32
]. Although PCT has repeatedly been shown to have prognostic value in critically ill patients, the value of a single level on admission is limited [35
]. The compiled data in this paper suggest that suPAR has superior prognostic value compared to commonly used biological markers, including PCT. Moreover, in contrast to most other markers, circadian changes in plasma levels of suPAR are minimal [28
]. Measurement is therefore largely independent of the sampling schedule, improving the potential of suPAR as a marker in clinical routine.
It has been suggested that suPAR is involved in the plasminogen-activating pathway, inflammation, and the modulation of cell adhesion, migration, and proliferation [37
]. Soluble urokinase-type plasminogen activator receptor derives from proteolytic cleavage and release from cell membrane-bound urokinase plasminogen activator receptor (uPAR). Both membrane-bound and soluble uPARs have been shown to bind to integrins [38
], and have been proposed to be involved in cell adhesion and proliferation. The soluble form of uPAR has been reported to have direct chemotactic properties, which may facilitate recruitment of inflammatory cells such as neutrophils and monocytes [40
], and the mobilization of hematopoietic stem cells [42
]. In addition to its role in adhesion and migration, suPAR has recently been shown to inhibit neutrophil efferocytosis [43
], while the membrane-bound form of uPAR has been shown to facilitate phagocytosis of bacteria [44
]. Impaired engulfment of apoptotic neutrophils or bacteria has been associated with poor outcome in preclinical models of sepsis [44
]. Cleavage of uPAR may therefore reflect a functional impairment of the host defense rather than a surrogate marker of inflammation, which might explain the higher prognostic value of suPAR compared to other biological markers.
Although suPAR alone did not perform as well as the SAPS II score, this does not necessarily preclude its use in prognostication. APACHE II score, SAPS II, SOFA score, and other scoring systems estimating the risk of mortality have become increasingly popular in the field of research with critically ill patients over the last decades. However, in clinical practice these scoring systems have important limitations. Data collection requires multiple laboratory measurements and the computation of multiple variables, and is labor intensive and expensive [46
]. Therefore, the application of these scoring systems may be limited, particularly when health care is subject to financial constraint. Soluble urokinase-type plasminogen activator receptor may have other important advantages. Only one blood sample instead of multiple clinical and laboratory measurements are needed. Measurement of suPAR can be performed using a simple ELISA. In addition, suPAR is stable in plasma samples subjected to repeated freeze-thaw procedures [49
], increasing its practicality as a practical biological marker. Thus, based on the findings that systemic levels of suPAR are a strong and robust marker of mortality risk, one could speculate that suPAR will eventually serves as a quick, technically simple and inexpensive alternative to the current sophisticated severity-of-disease classification systems. Future studies are needed to address this hypothesis.
The usefulness of suPAR in mortality prediction of individual patients is uncertain. One can hypothesize that specific therapeutic strategies should be restricted to patients with a certain level of suPAR as an alternative to APACHE II or SAPS II scores. Risk stratification and prediction of outcome can be used for safe decision making on the need for hospitalization or ICU admission and identifying patients at low risk suitable for outpatient management. Thus, suPAR may eventually help to triage patients. Also, predicted mortalities can be averaged for groups of patients in order to specify the group’s morbidity. However, conclusions should be drawn with some caution. First, patient numbers in studies of suPAR are still very low. More and larger studies are needed to better define the prognostic power of suPAR in critically ill patients.
Notably, systemic levels of suPAR remain elevated long after clinical recovery and only decline after several weeks. Therefore, the use of suPAR as a biological marker for guiding therapy is probably limited. However studies addressing this issue are lacking.
Importantly, the type of assay used to measure suPAR, as well as age and presence or absence of underlying diseases all influence suPAR levels. The difference in prognostic performance between different assays can be explained by the fact that the Luminex assay uses a polyclonal detection antibody, whereas the suPARnostic™ assay uses monoclonal antibodies selected because of their superior clinical value in HIV disease progression [23
]. On the other hand, the Luminex assay has its advantage in measuring multiple analytes at the same time [24
]. With the prognostic value of suPAR increasing in combination with other markers, this might compensate for the slightly impaired performance.
The finding that age as well as underlying disease influences the systemic level of suPAR is of limited relevance as both age and underlying diseases are known to increase mortality risk in critically ill patients [50
]. Systemic levels of suPAR remained independently prognostic for mortality after adjusting for age and/or underlying diseases [20
]. As with other markers such as CRP and PCT, experience will eventually dictate the value of suPAR levels in diverse clinical situations.
Of interest, suPAR is not only present in human plasma or serum, but can also be found in other body fluids, including urine, cerebrospinal fluid [37
], and pleural, pericardial, and peritoneal fluids [17
]. The number of studies investigating the value of suPAR in body fluids other than plasma or serum, however, is very limited. It would be interesting to evaluate the value of local levels of suPAR in other body fluids, i.e., in bronchoalveolar lavage fluid of patients with frequent pulmonary complications, such as acute lung injury or ventilator-associated pneumonia.
Finally, this review has limitations. An important limitation is that not all studies used the ACCP/SCCM criteria for the diagnosis of bacteremia, SIRS, and sepsis. Differences in used definitions may hamper interpretation of the data. However, since the aim of this review is to describe the value of suPAR in patients with systemic infection or inflammation and not to compare patients with SIRS with patients with bacteremia or sepsis, overlap between these groups may not hamper interpretation of the results.
The most common limitation of any systematic review is publication bias. Unpublished materials were not found and thus not used. Another limitation is the small number of studies that could be included. Soluble urokinase-type plasminogen activator receptor is a relatively new marker, and the number of publications in critically ill patients is still low. Also, studies on the prognostic value of suPAR were very restricted as they focused only on mortality. No conclusions can be drawn on the prognostic value of suPAR on other clinical outcomes, such as length of ICU and hospital stay, and duration of mechanical ventilation.