Elevated soluble urokinase plasminogen activator receptor (suPAR) in COVID-19 patients

To the Editor,

Soluble urokinase-type plasminogen activator receptor (suPAR) is a soluble receptor derived from enzymatic cleavage of the membrane uPAR receptor at the surface of blood mononuclear and endothelial cells in response to a vast array of inflammatory and immunomodulatory stimuli, including viral infections [1]. Beside its consolidated role as a bioactive factor associated with various forms of endothelial dysfunction and sepsis [1], plasma levels of suPAR can predict the risk of developing both acute and chronic renal injury and failure [2, 3]. Recent evidence also suggests that this biomarker may have a role in a variety of thrombotic diseases. In a large population-based cohort study conducted by Engström et al. [4], including over 5,000 participants of the Malmö Diet and Cancer (MDC) study, high levels of suPAR were found to independently predict the risk of developing venous thromboembolism (hazard ratio, 1.7; 95% confidence interval [95% CI], 1.1–2.5 in the fully-adjusted model). In another study, not only were suPAR values found to be higher in patients with paroxysmal nocturnal hemoglobinuria (PNH) compared to healthy controls, but levels were also associated with the risk of developing thrombotic events, and thrombosis-free survival was shorter in patients with suPAR values ≥2 ng/mL [5]. Since renal injury [6], and various forms of venous thrombosis [7, 8], are commonplace in patients with severe coronavirus disease 2019 (COVID-19), we aimed to review scientific studies which explored the concentration of suPAR in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with or without critical illness.

We carried out an electronic search in PubMed, Scopus and Web of Science, with the keywords “soluble urokinase plasminogen activator receptor” OR “suPAR” AND “coronavirus disease 2019” OR “COVID-19” OR “SARS-CoV-2” within all fields, and without language or date limits (i.e., up to May 10, 2021 and updated June 5, 2021). Two authors (G.L. and B.M.H.) reviewed title, abstract and full text (when available) of all documents that could be identified according to the predefined search criteria, choosing those which reported suPAR values in COVID-19 patients with or without critical disease and with cumulative sample size ≥50. The reference list all initially identified articles was also scrutinized for detecting additional eligible studies. Mean and standard deviation (SD) of suPAR values were then included in a pooled analysis, with estimation of weighted mean difference (WMD) and 95% CI in patients with or without critical COVID-19 illness. When the mean value and/or the standard deviation (SD) were unavailable, these were approximated from the sample size, the median and the interquartile range (IQR), as for Hozo et al. [9], and/or from the graphical representation. A random effects model was also estimated for adjusting for the possible heterogeneity emerged among the different studies. Study heterogeneity was assessed with χ ² test and I² statistic. The statistical analysis was performed using MetaXL, software Version 5.3 (EpiGear International Pty Ltd., Sunrise Beach, Australia), and the meta-analysis was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Supplementary File 1). The study was conducted in agreement with the declaration of Helsinki and within the terms of local legislation.

After elimination of duplicates among the three scientific repositories, a total number of 57 documents could be initially identified with our electronic search, 52 of which were excluded because they were review articles (n=27), did not specifically deal with COVID-19 illness (n=12), were commentaries or other editorial material (n=7), or did not show suPAR value differentiated between patients with or without severe COVID-19 illness (n=6). One study ought to be excluded since suPAR concentration was compared between COVID-19 patients with moderate or severe illness, but not between those with or without severe disease. No disagreement emerged between the two reviewers. Therefore, five studies could be included in our final pooled analysis, totalling 1,077 COVID-19 patients, 197 (18.3%) with various forms of critical illness [10], [11], [12], [13], [14]. The main characteristics of these studies as summarized in Table 1. Notably, the clinical endpoints reflecting severe/critical COVID-19 illness were different, represented by acute kidney failure (n=1), acute respiratory distress syndrome or intensive care unit (ICU) admission or death from any cause (n=2), and severe respiratory failure (n=1), whilst no specific definition of critical disease was available in the remaining study.

The pooled analysis of these five studies is shown in Figure 1, which demonstrates a positive difference of suPAR values in each study in patients with critical COVID-19 compared to those without. The WMD of suPAR values in patients with critical illness vs. those without was 2.44 (95% CI, 2.17–2.72) ng/mL (heterogeneity, I ²=64%) (Figure 1), and 2.40 (95% CI, 1.72–3.08) ng/mL using the random effects model, respectively. Overall, suPAR values were found to be increased by 55% (95% CI, 35–75%) in COVID-19 patients with various forms of critical illness compared to those without. In the study of Kerget et al. [15], excluded from our analysis since suPAR concentration was compared between patients with severe or moderate COVID-19 illness and controls, COVID-19 cases displayed 4.2–6.5 folds higher values than asymptomatic healthcare workers.

Figure 1:

Weighted mean difference (WMD) and 95% confidence interval (95% CI) of soluble urokinase plasminogen activator receptor (suPAR) levels in patients with or without severe coronavirus disease 2019 (COVID-19) illness.

Taken together, the results of our analysis suggest that the measurement of suPAR in COVID-19 patients may represent a valuable tool for improving risk stratification accuracy, helping to predict the risk of developing severe consequences of SARS-CoV-2 infection, especially acute kidney injury (AKI), along with micro- and macro-thrombosis. Some plausible mechanisms may support this conclusion. First, increased suPAR concentration has been associated with enhanced extra-mitochondrial enzymatic oxidation and oxidative stress in renal cells [2, 3], which may act in synergy with the direct kidney cell injury caused by SARS-CoV-2 and indirect injury triggered by microthrombi in the renal vasculature, thus augmenting the risk of developing AKI [16]. It has also been suggested that enhanced suPAR release in the bloodstream may contribute to reduce plasmin generation by competitive inhibition of urokinase-type plasminogen activator (uPA) at cell surface [17]. This would ultimately promote the development of a hypofibrinolytic condition, a characteristic component of the hypercoagulable state that is common in patients with severe COVID-19 [7, 8], and would finally converge to synergically exacerbate the severity of thrombosis.