Serum soluble urokinase-type plasminogen activator receptor as a biological marker of bacterial infection in adults: a systematic review and meta-analysis

Ni, Wentao; Han, Yuliang; Zhao, Junlong; Cui, Jiayue; Wang, Kai; Wang, Rui; Liu, You-ning

doi:10.1038/srep39481

Cited by 50 publications

(49 citation statements)

References 40 publications

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“…In critical illness and sepsis, serum levels of suPAR indicate an adverse prognosis, as consistently demonstrated in several cohort studies as well as a meta-analysis [4,5,[16][17][18]. However, suPAR has in the ICU setting a rather low accuracy in diagnosing sepsis [16,18,19].…”

Section: Introductionmentioning

confidence: 87%

“…Despite the different etiologies and modes of injury, systemic inflammation, infections, and organ failure represent common determinants of outcome in ICU patients [1][2][3]. Circulating levels of the soluble plasminogen activation receptor (suPAR) are linked to inflammation, immune cell activation, and sepsis [4,5], supporting the concept that suPAR could be a universally applicable prognostic biomarker in the setting of emergency and intensive care medicine [6,7]. However, suPAR levels are also elevated in various clinical conditions including chronic kidney disease [8], liver cirrhosis [9], cardiac arrest [10], and HIV infection [11].…”

Section: Introductionmentioning

confidence: 99%

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Neutrophils are a main source of circulating suPAR predicting outcome in critical illness

et al. 2019

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Background: Circulating levels of soluble urokinase plasminogen activation receptor (suPAR) have been proposed as a prognostic biomarker in patients with critical illness and sepsis. However, the origin of suPAR in sepsis has remained obscure. We investigated the potential cellular sources of suPAR by analyzing membrane-bound urokinase plasminogen activator receptor (uPAR, CD87) and evaluated its clinical relevance in critically ill patients. Methods: We studied 87 critically ill patients (44 with sepsis, 43 without sepsis) from the medical intensive care unit (ICU) in comparison to 48 standard care patients with infections and 27 healthy controls in a prospective single-center noninterventional cohort study. Cellular uPAR expression of different immune cell subsets (by flow cytometry from peripheral blood) and corresponding serum suPAR concentrations were determined upon ICU admission and at day 3. Furthermore, we analyzed the effects of serum from sepsis patients on the activation and uPAR cleavage of primary human neutrophils and macrophages in vitro. Results: In healthy controls, uPAR (CD87) expression was detected on nearly all blood neutrophils and monocytes, but only scarcely on lymphocytes. While uPAR expression on monocytes was maintained in ICU patients, only 58% of neutrophils from critically ill patients expressed uPAR, which was significantly lower than in healthy controls or standard care patients. Concomitantly, serum suPAR levels were significantly increased in ICU patients. We noted a clear inverse correlation between low neutrophilic uPAR and high serum suPAR in standard care and ICU patients, indicating that shedding of uPAR from activated neutrophils represents a main source of suPAR in systemic inflammation. Both low uPAR and high suPAR were closely associated with mortality in critically ill patients. Furthermore, serum from sepsis patients induced uPAR protein expression and subsequent receptor shedding on isolated primary neutrophils, but not on macrophages, in vitro. Conclusions: The inverse correlation between low uPAR surface expression on neutrophils and high serum suPAR in critically ill patients supports that neutrophils are a main source of shed suPAR proteins in systemic inflammation. Furthermore, high suPAR levels and low neutrophilic uPAR expression predict mortality in ICU patients.

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Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Neutrophils are a main source of circulating suPAR predicting outcome in critical illness

et al. 2019

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“…A recent meta-analysis study showed that high suPAR levels were associated with mortality in septic patients. 51 …”

Section: Discussionmentioning

confidence: 99%

Aptamer-Based Proteomics Identifies Mortality-Associated Serum Biomarkers in Dialysis-Dependent AKI Patients

Sun

Daniels

et al. 2018

Kidney International Reports

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IntroductionCurrently, no effective therapies exist to reduce the high mortality associated with dialysis-dependent acute kidney injury (AKI-D). Serum biomarkers may be useful in understanding the pathophysiological processes involved with AKI and the severity of injury, and point to novel therapeutic targets.MethodsStudy day 1 serum samples from 100 patients and day 8 samples from 107 patients enrolled in the Veteran’s Affairs/National Institutes of Health Acute Renal Failure Trial Network study were analyzed by the slow off-rate modified aptamers scan proteomic platform to profile 1305 proteins in each sample. Patients in each cohort were classified into tertiles based on baseline biomarker measurements. Cox regression analyses were performed to examine the relationships between serum levels of each biomarker and mortality.ResultsChanges in the serum levels of 54 proteins, 33 of which increased and 21 of which decreased, were detected when comparing samples of patients who died in the first 8 days versus patients who survived >8 days. Among the 33 proteins that increased, higher serum levels of fibroblast growth factor-23 (FGF23), tissue plasminogen activator (tPA), neutrophil collagenase (matrix metalloproteinase-8), and soluble urokinase plasminogen activator receptor, when stratified by tertiles, were associated with higher mortality. The association with mortality persisted for each of these proteins after adjusting for other potential risk factors, including age, sex, cardiovascular sequential organ failure assessment score, congestive heart failure, and presence of diabetes. Upper tertile levels of FGF23, tPA, and interleukin-6 on day 8 were associated with increased mortality; however, FGF23 barely lost significance after multivariable adjustment.ConclusionsOur results underscore an emerging proteomics tool capable of identifying low-abundance serum proteins important not only in the pathogenesis of AKI-D, but which is also helpful in discriminating AKI-D patients with high mortality.

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“…Interest in suPAR rests mainly on the strong relationship between circulating levels of this compound and all-cause and CV mortality and other adverse clinical outcomes in patients with severe multiorgan diseases admitted into intensive care units, 9 , 10 in the general population, 11 as well as in patients with CV disease, 12 , 13 cancer, 11 sepsis, 28 and HIV. 29 In the present study, suPAR associated with all-cause, CV, and non-CV mortality in a dose-dependent fashion, and these associations held true both in diabetic and in nondiabetic patients.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the production of suPAR from immature myeloid cells has been shown to be a constant source in focal and segmental glomerulosclerosis. 31 On binding its receptor, uPAR triggers the production plasmin as well as cell adhesion, migration, and proliferation, which are wide-ranging phenomena that participate in atherosclerosis, 32 infectious diseases, 28 and cancer. 11 , 33 …”

Section: Discussionmentioning

confidence: 99%

Soluble Urokinase Plasminogen Activator Receptor (suPAR) and All-Cause and Cardiovascular Mortality in Diverse Hemodialysis Patients

Torino

Pizzini

Cutrupi

et al. 2018

Kidney International Reports

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IntroductionThe soluble receptor of urokinase plasminogen activator (suPAR) is an innate immunity/inflammation biomarker predicting cardiovascular (CV) and non-CV events in various conditions, including type 2 diabetic patients on dialysis. However, the relationship between suPAR and clinical outcomes in the hemodialysis population at large has not been tested.MethodsWe measured plasma suPAR levels (R&D enzyme-linked immunosorbent assay [ELISA]) in 1038 hemodialysis patients with a follow-up of 2.9 years (interquartile range = 1.7−4.2) who were enrolled in the PROGREDIRE study, a cohort study involving 35 dialysis units in 2 regions in Southern Italy.ResultssuPAR was strongly (P < 0.001) and independently related to female gender (β = −0.160), age (β = 0.216), dialysis vintage (β = 0.264), CV comorbidities (β = 0.105), alkaline phosphatase (β = 0.136), albumin (β = −0.147), and body mass index (BMI; β = 0.174) (all P < 0.006). In fully adjusted analyses, suPAR tertiles predicted the risk of all-cause mortality (third tertile vs. first tertile hazard ratio (HR) = 1.91, 95% confidence interval (CI) = 1.47 – 2.48, P < 0.001), CV mortality (HR = 1.47, 95% CI = 1.03–2.09, P = 0.03), and non-CV mortality (HR = 1.94, 95% CI = 1.28–2.93, P = 0.002); these relationships were not modified by diabetes or other risk factors. suPAR added only modest prognostic risk discrimination and reclassification power for these outcomes to parsimonious models based on simple clinical variables.ConclusionIn conclusion, suPAR robustly predicted all-cause and both CV and non-CV mortality in a large unselected hemodialysis population. Intervention studies are needed to definitively test the hypothesis that suPAR is causally implicated in clinical outcomes in this population.

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Serum soluble urokinase-type plasminogen activator receptor as a biological marker of bacterial infection in adults: a systematic review and meta-analysis

Cited by 50 publications

References 40 publications

Neutrophils are a main source of circulating suPAR predicting outcome in critical illness

Neutrophils are a main source of circulating suPAR predicting outcome in critical illness

Aptamer-Based Proteomics Identifies Mortality-Associated Serum Biomarkers in Dialysis-Dependent AKI Patients

Soluble Urokinase Plasminogen Activator Receptor (suPAR) and All-Cause and Cardiovascular Mortality in Diverse Hemodialysis Patients

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