suPAR - a future risk marker

Soluble urokinase plasminogen activator receptor (suPAR) is a protein that is present in blood in all individuals. An elevated suPAR level has been associated with a negative outcome in various cohort studies. In the current issue of Journal of Internal Medicine, Huttunen and colleagues investigate suPAR as a predictor of disease severity and mortality in patients with bacteraemia. Plasma samples were obtained from 132 patients following a bacteria-positive blood culture: 1–4 days after hospitalization, after 13–18 days and after patient recovery. During 30 days of follow-up, 18 patients died. The cut-off level with the highest sensitivity and specificity with regard to the ability of suPAR to predict mortality was found to be 11 ng mL−1. Fifteen (36%) of the 42 patients with suPAR levels above 11 ng mL−1 died within 1 month of follow-up, compared to only 3/90 patients (3%) with suPAR levels below 11 ng mL−1. Logistic regression analysis demonstrated that this translates into an odds ratio of 16.1 (95% confidence interval: 4.3–59.9), and the odds ratio remained significant after adjustment for potential confounders. It is interesting that a simple suPAR measurement had a similar or better ability to predict mortality compared to the sequential organ failure assessment (SOFA) score, a sepsis mortality risk algorithm including multiple laboratory and clinical measures. Huttunen and co-workers suggest that suPAR measurement may be valuable in the management of patients with sepsis as 'early identification of patients with severe sepsis is a major goal in order to improve patient outcomes' and 'suPAR may offer a novel opportunity to the early stratification of patients'. Future studies may address whether suPAR has most value as a marker of low risk of life-threatening disease (Fig. 1, green area) or whether it is more useful for identification and disease monitoring of high-risk patients (Fig. 1, red area). Spectrum of suPAR level in disease. The numbers on the left side refer to suPAR concentration in ng mL−1; data obtained using the suPARnostic® assay. The study by Huttunen et al. confirms and extends previous studies on the prognostic value of suPAR in critically ill patients. In agreement with the results of Huttunen et al., Wittenhagen and colleagues found suPAR levels and predictive of mortality in patients with Streptococcus pneumoniae bacteraemia with an odds ratio of 13 in those with suPAR levels above 10 ng mL−1 compared to those with levels below 5 ng mL−1 (multivariate logistic regression) [1]. Thus, suPAR levels in the double digits are associated with a high risk of short-term mortality (Fig. 1, red area). It should be emphasized, however, that suPAR is not a specific marker for bacteraemia or sepsis. The same association between high suPAR levels and high mortality is observed in patients with HIV [2], tuberculosis [3], malaria [4], Crimean-Congo haemorrhagic fever [5] and even in ill patients with no obvious infectious disease diagnosis [6]. Thus, suPAR is a non-specific biomarker with no diagnostic value. This was clearly illustrated by Kofoed and co-workers in a study of 156 patients with systemic inflammatory response syndrome at Copenhagen University Hospital, Hvidovre [7]. Of these 156 patients, 96 had bacterial infection, and the area under the curve (AUC) values for procalcitonin (PCT) and C-reactive protein (CRP) for diagnosis of bacterial sepsis were 0.72 and 0.81, respectively; the AUC for suPAR was 0.50. Hence, PCT and CRP have diagnostic value and suPAR does not. However, when predicting 30-day mortality, PCT and CRP had no prognostic value whilst the AUC for suPAR was 0.80 [8]. PCT and CRP are both strongly induced by lipopolysaccharides (LPS), which probably explains their usefulness in diagnosing bacterial infection. suPAR is not strongly induced by bacterial proteins such as LPS. Injection of LPS into healthy volunteers resulted in less than a twofold increase in plasma suPAR level [9]. PCT and CRP may have prognostic value in specific patient populations. The prognostic value of suPAR and PCT head to head in bacterial sepsis still needs to be investigated. However, as general markers of risk of disease progression and mortality, PCT and CRP have limited value, because of their diagnostic value in bacterial infection. It is often stated that suPAR is of limited value as it is not specific. However, this lack of specificity is exactly why suPAR may be useful. If results continue to show that suPAR is a non-specific marker of risk of negative outcome, identification of individuals with high suPAR levels should lead to further clinical and diagnostic examination whereas low levels may aid in early discharge decisions. In 1990, two research teams headed by Prof. Keld Danø and Prof. Francesco Blasi cloned the urokinase plasminogen activator receptor (uPAR) [10] and in 1991 its soluble form (suPAR) was identified [11]. Since then, intensive research has been carried out to investigate the biochemistry and the role of uPAR in carcinogenesis [12], the cellular and molecular biology of uPAR [13] and the role of suPAR as a risk marker in infectious diseases [14]. After 20 years of research, it is clear that uPAR/suPAR participates in a range of immunological effector functions including cell adhesion, migration, chemotaxis, proteolysis, immune activation, tissue remodelling, invasion and signal transduction, and all of these functions may add to the systemic suPAR concentration. When a pathogen invades the blood stream, these effector functions are activated and the suPAR level may reflect the severity of the infection. In recent years, the term 'low-grade inflammation' (LGI) has been widely used to describe an underlying mechanism leading to disease in otherwise healthy individuals. LGI has not yet been defined but is characterized by increased levels of pro-inflammatory cytokines and immune activation markers and a raised white blood cell count. The current gold standard measurement of LGI is CRP using a highly sensitive assay. Slightly increased levels of CRP (normally above 3 mg mL−1 compared to below 1 mg mL−1) are associated with increased risk of cardiovascular disease, diabetes and certain types of cancer in the general population [15]. The observation that suPAR carries prognostic value across a range of infectious diseases, including viral, bacterial and parasitic diseases, facilitated the idea that suPAR might be a marker of inflammation. As even a slightly elevated level of inflammation is thought to be a driver of disease, suPAR level could be a marker of LGI. We recently tested the hypothesis that suPAR is a risk marker in the general population [16] and found that suPAR level was predictive of all end-points investigated, i.e. type 2 diabetes, cardiovascular disease, cancer and overall mortality. Multivariate adjustment for lifestyle and other relevant factors such as CRP level had little influence on the predictive value of suPAR. The independent predictive value of suPAR has been observed in several studies; suPAR measurement adds value for predicting the end-point after relevant adjustment, for example for CD4 cell count in HIV-infected patients [17] or SOFA score in patients with sepsis [18]. This raises the question of whether suPAR measurement can be used in lifestyle management. We have recently reported that in the general population, smokers have higher suPAR levels than nonsmokers and ex-smokers [17], and that smokers with the highest suPAR levels are most likely to develop lung cancer [19]. An algorithm combining lifestyle factors and markers of inflammation may, in future, be used in health screening to classify individuals with LGI (e.g. within grades 1–4), with the aim of identifying, treating or changing lifestyle in high-risk individuals before disease becomes clinically manifest. Both suPAR and CRP may be candidates for inclusion in such an algorithm, as they seem to reflect different aspects of inflammation. CRP, produced by the liver, appears to be a good marker of both bacterial infection and of metabolic inflammation with its close ties to body mass index and lipids, whereas suPAR appears to be a stabile marker of immune activation and cellular inflammation. The author has three issued patents on suPAR and is a co-founder, board member and shareholder of ViroGates A/S, Denmark, the company that developed the suPARnostic® assay based on clinical value for monitoring HIV disease progression.