Serum Levels Of suPAR Research Articles

Association between serum levels of GDF-15, suPAR, PIVKA-II, sdLDL and clinical outcomes in hospitalized COVID-19 patients.

To quantify the circulating levels of novel serum biomarkers including GDF-15, PIVKA-II, sdLDL, suPAR, and of CRP in hospitalized COVID-19 patients compared with healthy subjects, and to evaluate their association(s) with outcomes in COVID-19. We considered patients with confirmed COVID-19, hospitalized in an Internal Medicine ward. The clinical characteristics were collected, including the number and type of comorbidities. Serum levels of GDF-15, PIVKA-II, suPAR, sdLDL, as well as CRPwere measured. As outcomes, we considered Intensive Care Unit (ICU) transfer or death, as well as the length of stay (days) and in-hospital complications. Data were statistically analyzed, as appropriate, and a p value < 0.05 was considered significant. Ninety-three patients and 20 healthy controls were enrolled. COVID-19 patients vs. controls showed higher median levels of GDF-15 (p < 0.0001), PIVKA-II (p < 0.0001) and sdLDL (p = 0.0002), whereas no difference was observed for suPAR. In COVID-19 patients, the most frequent comorbidities were arterial hypertension (62.4%) and cardiovascular disease (30.1%). GDF-15 levels positively correlated with age (r = 0.433, p < 0.0001), and this correlation was confirmed for suPAR (r = 0.308, p = 0.003) and CRP (Rho = 0.40 p < 0.0001), but not for PIVKA-II and sdLDL. Higher GDF-15 levels were associated with a higher number of comorbidities (p = 0.021). The median length of stay was 22 (15; 30) days. During hospitalization, 15 patients (16%) were ICU transferred, and 6 (6.45%) died. GDF-15 serum levels correlated with the length of stay (rho = 0.27 p = 0.010), and were associated with ICU transfer or death (p = 0.003), as well as PIVKA-II (p = 0.038) and CRP (p < 0.001). Moreover, higher GDF-15 and PIVKA-II serum levels were associated with infectious complications (p = 0.008 and p = 0.017, respectively). In this cohort of hospitalized COVID-19 patients, novel inflammatory biomarkers, including GDF-15, suPAR and PIVKA II were associated with some patient's clinical characteristics, complications, and poor outcomes.

Circulating miR-10b, soluble urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 as predictors of non-small cell lung cancer progression and treatment response.

Despite advances in lung cancer treatment, most lung cancers are diagnosed at an advanced stage. Expression of microRNA10b (miR-10b) and fibrinolytic activity, as reflected by soluble urokinase-type plasminogen activator receptor (suPAR) and plasminogen activator inhibitor 1 (PAI-1), are promising biomarker candidates. To assess the expression of miR-10b, and serum levels of suPAR and PAI-1 in advanced stage non-small cell lung cancer (NSCLC) patients, and their correlation with progression, treatment response and prognosis. The present prospective cohort and survival study was conducted at Dharmais National Cancer Hospital and included advanced stage NSCLC patients diagnosed between March 2015 and September 2016. Expression of miR-10b was quantified using qRT-PCR. Levels of suPAR and PAI-1 were assayed using ELISA. Treatment response was evaluated using the RECIST 1.1 criteria. Patients were followed up until death or at least 1 year after treatment. Among the 40 patients enrolled, 25 completed at least four cycles of chemotherapy and 15 patients died during treatment. Absolute miR-10b expression ⩾ 592,145 copies/μL or miR-10b fold change ⩾ 0.066 were protective for progressive disease and poor treatment response, whereas suPAR levels ⩾ 4,237 pg/mL was a risk factor for progressive disease and poor response. PAI-1 levels > 4.6ng/mL was a protective factor for poor response. Multivariate analysis revealed suPAR as an independent risk factor for progression (ORa⁢d⁢j, 13.265; 95% confidence intervals (CI), 2.26577.701; P= 0.006) and poor response (ORa⁢d⁢j, 15.609; 95% CI, 2.221-109.704; P= 0.006), whereas PAI-1 was an independent protective factor of poor response (ORa⁢d⁢j, 0.127; 95% CI, 0.019-0.843; P= 0.033). Since miR-10b cannot be used as an independent risk factor for NSCLC progression and treatment response, we developed a model to predict progression using suPAR levels and treatment response using suPAR and PAI-1 levels. Further studies are needed to validate this model.

Comparison of C-reactive protein with distinct hyperinflammatory biomarkers in association with COVID-19 severity, mortality and SARS-CoV-2 variants.

C-reactive protein (CRP) has been one of the most investigated inflammatory-biomarkers during the ongoing COVID-19 pandemics caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The severe outcome among patients with SARS-CoV-2 infection is closely related to the cytokine storm and the hyperinflammation responsible for the acute respiratory distress syndrome and multiple organ failure. It still remains a challenge to determine which of the hyperinflammatory biomarkers and cytokines are the best predictors for disease severity and mortality in COVID-19 patients. Therefore, we evaluated and compared the outcome prediction efficiencies between CRP, the recently reported inflammatory modulators (suPAR, sTREM-1, HGF), and the classical biomarkers (MCP-1, IL-1β, IL-6, NLR, PLR, ESR, ferritin, fibrinogen, and LDH) in patients confirmed with SARS-CoV-2 infection at hospital admission. Notably, patients with severe disease had higher serum levels of CRP, suPAR, sTREM-1, HGF and classical biomarkers compared to the mild and moderate cases. Our data also identified CRP, among all investigated analytes, to best discriminate between severe and non-severe forms of disease, while LDH, sTREM-1 and HGF proved to be excellent mortality predictors in COVID-19 patients. Importantly, suPAR emerged as a key molecule in characterizing the Delta variant infections.

Studying the estimation levels of inflammatory markers and NF-κB in MDR and DS-TB patients

Tuberculosis (TB) is one of the most infectious and deadly diseases, especially after the emergence of drug-resistant bacteria. Therefore, in this study, we developed a method to evaluate the ability of using CXCL10, CXCL9, MMP9, suPAR and the expression gene (NF-κB) and their rolesin the diagnosis and treatment of the disease in patients. Also, we used ELISA and qPCR techniques to compare the serum levels of CXCL10, CXCL9, MMP9, suPAR and NF-κB gene in drug resistant and drug sensitive TB. The serum levels of CXCL10, CXCL9, MMP9, suPAR and the expression of NF-κB gene was compared among drug resistant and drug sensitive TB using ELISA and qPCR Techniques, respectively. Our results showed an increasing in the serum levels of CXCL10, CXCL9 and suPAR, in the drug resistant of TB patients but not in the drug sensitive group, however, all of them did not reach the significant level, it was found that expression of NF-κB in drug sensitive group was higher (3.22-fold) than that in the drug resistant-TB patients (2.70-fold).

Circulating Soluble Urokinase Plasminogen Activator Receptor as a Predictive Indicator for COVID-19-Associated Acute Kidney Injury and Mortality: Clinical and Bioinformatics Analysis.

Urokinase receptors regulate the interplay between inflammation, immunity, and blood clotting. The soluble urokinase plasminogen activator system is an immunologic regulator affecting endothelial function and its related receptor; the soluble urokinase plasminogen activator receptor (suPAR) has been reported to impact kidney injury. This work aims to measure serum levels of suPAR in COVID-19 patients and correlate the measurements with variable clinicolaboratory parameters and patient outcomes. In this prospective cohort study, 150 COVID-19 patients and 50 controls were included. The circulating suPAR levels were quantified by Enzyme-linked immunosorbent assay (ELISA). Routine COVID-19 laboratory assessments, including CBC, CRP, LDH, serum creatinine, and estimated glomerular filtration rates, were performed. The need for oxygen therapy, CO-RAD score, and survival rates was assessed. Bioinformatic analysis and molecular docking were run to explore the urokinase receptor structure/function and to characterize molecules as potential anti-suPAR therapeutic targets, respectively. We found higher circulating suPAR levels in COVID-19 patients vs. controls (p < 0.001). Circulating suPAR levels positively correlated with COVID-19 severity, the need for O2 therapy, the total leukocytes count, and the neutrophils to lymphocyte ratio, while they were negatively correlated with the O2 saturation level, albumin, blood calcium, lymphocytic count, and GFR. In addition, the suPAR levels were associated with poor prognostic outcomes such as a high incidence of acute kidney injury (AKI) and mortality rate. Kaplan-Meier curves showed a lower survival rate with higher suPAR levels. The logistic regression analysis confirmed the significant association of suPAR levels with the occurrence of AKI related to COVID-19 and with increased mortality probability within three months of COVID-19 follow-up. Some compounds that can act similarly to uPAR were discovered and tested by molecular docking to identify the possible ligand-protein interactions. In conclusion, higher circulating suPAR levels were associated with COVID-19 severity and could be considered a putative predictor of AKI development and mortality.

Comparative Study on Soluble Urokinase-Type Plasminogen Activator Receptor (Supar) and C-Reactive Protein (Crp) Levels in Stable Chronic Obstructive Pulmonary Disease.

Background and objective: Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and irreversible airflow limitation. In COPD, the initial low-grade pulmonary inflammation slowly progress to systemic inflammation which is usually confirmed by non-specific inflammatory biomarker like C-reactive protein (CRP). However, the disease progress can be diagnosed at the early stage of pulmonary inflammation by using a novel biomarker, like Soluble urokinase-type plasminogen activator receptor (suPAR) released from the respiratory epithelium in COPD. The objective of this study was to compare the serum levels of suPAR and CRP in stable COPD and to assess the progress of low-grade pulmonary inflammation in COPD. Methods: Stable COPD [SCOPD] study participants (male-35; female-15) and healthy controls (male-38; female-12) were recruited for the study after obtaining informed consent. Based on post-bronchodilator FEV1% predicted values as specified by GOLD criteria, SCOPD study participants were graded into grades I-IV. Serum suPAR and CRP assays were done for all the study participants. Results: The level of suPAR among SCOPD grades I-IV (4.03±0.40 ng/ml; 5.16 ±0.26 ng/ml; 5.82±0.17ng/ml; 6.39±0.07ng/ml respectively) were high compared to healthy control (1.84±0.90ng/ml) and was statistically significant. The level of CRP among SCOPD grade I-IV (3.30±0.13 ng/ml; 3.60 ±0.09 ng/ml; 3.91±0.12ng/ml; 4.41±0.10 ng/ml respectively) were high compared to healthy control (1.63±0.77ng/ml) and was statistically significant.. Conclusion: Our study indicated that serum suPAR and CRP may play an important role in the inflammatory process of COPD particularly in grades III and IV SCOPD. Hence, serum suPAR and CRP measurements may be useful for the evaluation and prognosis of stable COPD.

Personalised Approach to Diagnosing and Managing Ischemic Stroke with a Plasma-Soluble Urokinase-Type Plasminogen Activator Receptor.

Background: The increasing incidence of ischemic stroke has led to the search for a novel biomarker to predict the course of disease and the risk of mortality. Recently, the role of the soluble urokinase plasminogen activator receptor (suPAR) as a biomarker and indicator of immune system activation has been widely examined. Therefore, the aim of the current study was to assess the dynamics of changes in serum levels of suPAR in ischemic stroke and to evaluate the prognostic value of suPAR in determining mortality risk. Methods: Eighty patients from the Department of Neurology, diagnosed with ischemic stroke, were enrolled in the study. Residual blood was obtained from all the patients on the first, third and seventh days after their ischemic stroke and the concentrations of suPAR and C-reactive protein (CRP), as well as the number of leukocytes and National Institute of Health’s Stroke Scale (NIHSS) scores, were evaluated. Results: On the first day of ischemic stroke, the average suPAR concentration was 6.55 ng/mL; on the third day, it was 8.29 ng/mL; on the seventh day, it was 9.16 ng/mL. The average CRP concentration on the first day of ischemic stroke was 4.96 mg/L; on the third day, it was 11.76 mg/L; on the seventh day, it was 17.17 mg/L. The number of leukocytes on the first day of ischemic stroke was 7.32 × 103/mm3; on the third day, it was 9.27 × 103/mm3; on the seventh day, it was 10.41 × 103/mm3. Neurological condition, which was assessed via the NIHSS, on the first day of ischemic stroke, was scored at 10.71 points; on the third day, it was scored at 12.34 points; on the seventh day, it was scored at 13.75 points. An increase in the values of all the evaluated parameters on the first, third and seventh days of hospitalisation was observed. The patients with hypertension, ischemic heart disease and type 2 diabetes showed higher suPAR and CRP concentrations at the baseline as well as on subsequent days of hospitalisation. The greatest sensitivity and specificity were characterised by suPAR-3, where a value above 10.5 ng/mL resulted in a significant increase in mortality risk. Moreover, an NIHSS-1 score above 12 points and a CRP-3 concentration above 15.6 mg/L significantly increased the risk of death in the course of the disease. Conclusions: The plasma suPAR concentration after ischemic stroke is strongly related to the patient’s clinical status, with a higher concentration on the first and third days of stroke resulting in a poorer prognosis at a later stage of treatment. Therefore, assessing the concentration of this parameter has important prognostic value.

Analysis of Selected Cardiovascular Biomarkers in Takotsubo Cardiomyopathy and the Most Frequent Cardiomyopathies.

Introduction: Among the causes of de novo diagnosed cardiomyopathy, Takotsubo cardiomyopathy (TTC) plays a minor role, with an occurrence of 50,000–100,000 cases per annum in the United States. In clinical practice, a differentiation of a TTC toward an ischemic cardiomyopathy (ICMP) or a dilatative cardiomyopathy (DCMP) appears to be challenging, especially in a subacute setting or in atypical types of TTC.Methods: To investigate this issue, we analyzed serum levels of sST2, GDF-15, suPAR, HFABP, and clinical parameters including echocardiography in 51 patients with TTC, 52 patients with ischemic cardiomyopathy (ICMP) and 65 patients with dilated cardiomyopathy (DCMP).Results: sST-2 seemed to be the most promising biomarker for prediction of a TTC in differential diagnosis to an ICMP (AUC: 0.879, p = < 0.001, Cut off values: 12,140.5 pg/ml) or to a DCMP (AUC: 0.881, p = < 0.001, cut off value: 14521.9 pg/ml). GDF-15 evidenced a slightly lower AUC for prediction of a TTC in differential diagnosis to an ICMP (AUC: 0.626, p = 0.028) and to a DCMP (AUC: 0.653, p = 0.007). A differential diagnostic value was found for H-FABP in the prediction of a DCMP compared to TTC patients (AUC: 0.686, p = < 0.001). In propensity score matching for left ventricular ejection fraction, sex, and cardiovascular risk factors, differences in the plasma levels of sST2 and H-FABP in the matched cohort of TTC vs. DCMP remained statistically significant. In the matched cohort of TTC vs. ICMP, differences in sST2 also remained statistically significantConclusion: As medical therapy, long term prognosis, interval of follow-ups, rehabilitation program and recommendations differ completely between TTC and ICMP/DCMP, biomarkers for differential diagnosis, or rather for confirmation of diagnosis, are warranted in cases of cardiomyopathies with unsure origin. sST-2, GDF-15 and H-FABP might facilitate the classification.

The differential diagnostic value of selected cardiovascular biomarkers in Takotsubo syndrome

IntroductionTakotsubo syndrome (TTS) is clinically indistinguishable from an acute coronary syndrome (ACS). In the absence of valid markers for differential diagnosis, coronary angiography has been indispensable.MethodsIn our study, we evaluated the serum levels of sST-2, GDF-15, suPAR and H-FABP in 92 patients with the suspicion of TTS (51 TTS and 41 ACS patients) and 40 gender matched controls (no coronary artery disease or signs of heart failure) at baseline.ResultsH-FABP was significantly higher in ACS patients compared to TTS patients. Even in in propensity score matching for left ventricular ejection fraction, sex and cardiovascular risk factors, differences in the plasma levels of H-FABP in the matched cohort of TTS vs ACS remained statistically significant. Whereas, sST-2 was significantly elevated in TTS patients. H-FABP was superior for prediction of an ACS with even higher accuracy than hs troponin in differential diagnosis (AUC 0.797, p ≤ 0.0001); the optimal cut off for discrimination towards a TTS was calculated as 2.93 ng/ml (sensitivity 70.0%, specificity 82.4%, PPV 75.7%, NPV 77.4%). sST-2 seemed most appropriate for identification of a TTS (AUC 0.653, p = 0.012). The optimal cut off for differential diagnosis was 11018.06 pg/ml (sensitivity 82.0%, specificity 51.2%, PPV 69.4%, NPV 71.9 %).ConclusionH-FABP and sST-2 are the most promising markers with better accuracy than preexisting biomarkers in differential diagnosis in our study and therefore, could be crucial for the guidance of treatment in patients with high bleeding risk, advanced renal failure or multimorbidity.Graphical abstract

Evaluation of sTREM1 and suPAR Biomarkers as Diagnostic and Prognostic Predictors in Sepsis Patients.

BackgroundThe purpose of this study was to explore the diagnostic role of sTREM1 in the diagnosis of sepsis and in differentiating between sepsis and systemic inflammatory response syndrome (SIRS). We also aimed to assess the prognostic value of suPAR in comparison to sequential organ-failure assessment (SOFA), acute physiology and chronic health evaluation (APACHE) II scores, and 28-day mortality.MethodsThis was a cross-sectional study conducted in the Medical Microbiology and Immunology Department and Central Research Laboratory, Faculty of Medicine, Sohag University from June 2019 to January 2021. The study population was classified into two groups: SIRS (no evidence of infection) and sepsis (with SIRS and evidence of infection). Patients were rated on the SOFA and APACHE II scoring systems at admission and after 7 days. Serum levels of sTREM1 and suPAR were measured by ELISA at the same time points.ResultsCRP and sTREM1 values were significantly higher in the sepsis group than the SIRS group on both days (P<0.0001). The area under the curve (AUC) for CRP was 0.87 on the first day and 0.97 on the seventh, while the AUC for sTREM1 was 1.00 and 0.93 on the first and seventh days, respectively. The sensitivity of sTREM1 was 100% and specificity 84% at a cutoff of 49 pg/mL. There was a significantly positive correlation between CRP and sTREM1 values (P<0.0001). On the seventh day, nonsurvivors had significantly higher serum levels of suPAR (median 4.9 ng/mL) than survivors (median 2.9 ng/mL; P<0.0001). Nonsurvivors also had significantly higher SOFA and APACHE II scores than survivors (P<0.0001 and P<0.0001, respectively).ConclusionsTREM1 can be used as a good indicator for diagnosing sepsis in intensive care–unit patients. suPAR can also be used as a predictor of bad prognosis and poor survival at 7 days following admission.

Salvianolic acid A attenuates steroid resistant nephrotic syndrome through suPAR/uPAR-αvβ3 signaling Inhibition

Ethnopharmacological relevanceSalvianolic acid A (SAA) is extracted from traditional Chinese medicine Salvia miltiorrhiza and is the main water-soluble and the biologically active ingredient. SAA possesses a variety of pharmacological activities and has an excellent protective effect on kidney disease, especially steroid resistant nephrotic syndrome (SRNS), and has advantages in improving the efficacy of glucocorticoids, but its mechanism needs to be further explored. PurposeThe study was designed to explore the effect of suPAR and uPAR in SRNS patients and evaluate the potential effect of SAA in improving podocyte steroid resistance and explore its mechanism. Methods and materialsThe ELISA kits were used to detect the levels of suPAR in the blood and urine of subjects. The levels of uPAR, GRα, and GRβ expression in renal tissues of SRNS patients was detected by immunohistochemistry and analyzed using the Pearson method. In vitro studies, steroid resistance model was induced by the TNF-α and IFN-γ. The protein and mRNA expression of Nephrin, GR, GRα and GRβ were analyzed using western blot and qRT-PCR. The activity of GR-DNA binding was detected by using TransAM™ GR kits. Adriamycin further induced steroid resistance podocyte. Flow cytometry was used to detect the effect of SAA on podocyte apoptosis. ELISA assay was used to detect the suPAR expression in the podocyte supernatant. Western blot and qRT-PCR were used to detect the protein and mRNA expression of uPAR and Nephrin in podocytes. ResultsThe serum and urine levels of suPAR were conspicuously higher in SRNS patients than healthy volunteers and SSNS patients, and the expression of uPAR in renal tissue of SRNS patients is negatively correlated with GRα, but positively correlated with GRβ. The combination of TNF-α and IFN-γ could conspicuously increase the GRβ expression and reduce GRα/GRβ, and induce steroid resistance in podocytes. Moreover, we found that SAA could reduce the apoptosis of podocytes and suppress the expression of suPAR/uPAR, and increase the expression of Nephrin. ConclusionThe level of suPAR and uPAR expression may have important value in predicting glucocorticoids resistance in patients with idiopathic nephrotic syndrome (INS). The combination of TNF-α and IFN-γ induce podocytes can establish steroid resistance model in vitro. SAA could improve glucocorticoids resistance of podocyte which can be attributed in part to regulate the suPAR/uPAR-αvβ3 signaling pathway.

Serum Levels of Soluble Urokinase Plasminogen Activator Receptor Predict Tumor Response and Outcome to Immune Checkpoint Inhibitor Therapy.

BackgroundImmune checkpoint inhibitors (ICIs) have led to a paradigm shift in cancer therapy, improving outcomes in the treatment of various malignancies. However, not all patients benefit to the same extend from ICI. Reliable tools to predict treatment response and outcome are missing. Soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation, whose levels are prognostic in various cancers. We evaluated circulating suPAR levels as a novel predictive and prognostic biomarker in patients receiving ICI therapy for solid tumors.MethodsA total of n = 87 patients receiving ICI therapy for different solid malignancies as well as 32 healthy controls were included into this study. Serum levels of suPAR were measured by ELISA prior to and sequentially at two time points during ICI therapy.ResultsBaseline suPAR serum levels were significantly higher in solid tumor patients compared to healthy controls. Importantly, patients with low suPAR levels both before or during ICI treatment were more likely to have a favorable response to treatment at three and six months, respectively. This finding was confirmed by multivariate binary logistic regression analysis including several clinicopathological parameters. Moreover, circulating suPAR levels before and during therapy were an independent prognostic factor for overall survival (OS). As such, patients with initial suPAR levels above our ideal prognostic cut-off value (4.86 ng/ml) had a median OS of only 160 days compared to 705 days for patients with suPAR levels below this cut-off value. Finally, low baseline suPAR levels identified a subgroup of patients who experienced ICI-related side effects which in turn were associated with favorable treatment response and outcome.ConclusionOur data suggest that measurements of suPAR serum levels are a previously unknown, easily accessible tool to predict individual treatment response and outcome to ICI therapy. Circulating suPAR might therefore be implemented into stratification algorithms to identify the ideal candidates for ICI treatment.

Serum biomarkers in patients with stable and exacerbated COPD-bronchiectasis overlap syndrome.

Bronchiectasis (B), commonly seen in patients with chronic obstructive pulmonary disease (COPD), is associated with exacerbations and predicts mortality. To differentiate patient groups with COPD-(B+) or COPD-(B-) and their exacerbations by using inflammatory markers. Consecutive COPD patients were divided into two groups according to findings on high resolution thorax CT (HRCT) images using Smith and modified Reiff scores. Patients were prospectively followed for possible future exacerbations. Serum fibrinogen, C-reactive protein (CRP), soluble urokinase-type plasminogen activator receptor (suPAR) and Plasminogen activator inhibitor-1 (PAI-1) levels were studied during exacerbation and stable periods. Eighty-seven patients were included and (85M, 2 F), mean aged was 68.1±9 (46-87). HRCT confirmed bronchiectasis in 38 (43.7%) patients, most commonly in tubular form (89.4%) and in lower lobes. COPD-B(+) group had lower body mass index (P=0.036), more advanced stage of disease (P=0.004) and more frequent exacerbation (P=0.01). The HRCT scores were correlated with exacerbation rate (r=0.356, P<0.05). Fibrinogen and CRP values were higher in exacerbation (P= 0.01, P= 0.013, respectively) especially in COPD-B(+) patients. suPAR and PAI-1 levels were also higher in COPD-B(+) patients although it was not statistically significant. Bronchiectasis is common and causes frequent exacerbations in COPD. Identifying of COPD-B(+) phenotype by HRCT scoring systems has considerable importance for both therapeutic options and clinical outcome of the disease. In addition to fibrinogen and CRP, high serum levels of suPAR and PAI-1 suggest us their significant roles in increased systemic inflammation associated with coexisting of COPD and bronchiectasis.

Associations of Serological Biomarkers of sICAM-1, IL-1β, MIF, and su-PAR with 3-Month Mortality in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

Objective To investigate prognostic values of serum biomarkers of soluble intercellular adhesion molecule 1 (sICAM-1), macrophage migration inhibitor factor (MIF), interleukin 1β (IL-1β), and soluble urokinase plasminogen activator receptor (su-PAR) in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). Methods From August 2017 to November 2019, 122 consecutive IPF patients treated in our center were classified as stable IPF and AE-IPF based on the newly published international guidelines. Serum levels of four biomarkers at admission were measured by the enzyme-linked immunosorbent assay (ELISA). The primary endpoint was 3-month mortality. The log-rank test and logistic regression analysis were used to evaluate the effects of these biomarkers for survival in patients with AE-IPF. Cox proportional hazards analysis was performed to evaluate the prognostic values of serological biomarkers and clinical data. Results Eighty-one patients were diagnosed with stable IPF, and 41 AE-IPF patients were enrolled in the study. Serum levels of sICAM-1 (p < 0.001), IL-1β (p < 0.001), MIF (p < 0.001), and su-PAR (p < 0.001) in patients with IPF were significantly increased compared to those in healthy controls. All the four biomarkers were elevated in patients with AE-IPF compared to those with stable IPF. The 3-month mortality in AE-IPF was 56.1% (23/41). Increased levels of MIF (p = 0.01) and IL-1β (>5 pg/mL, p = 0.033) were independent risk factors for 3-month mortality in patients with AE-IPF. Conclusions We showed the higher serum levels of IL-1β, and MIF had prognostic values for 3-month mortality in AE-IPF. This study provided a clue to promote our understanding in the pathogenesis of the disease.

Serum Calprotectin, a Marker of Neutrophil Activation, and Other Mediators of Inflammation in Response to Various Types of Extreme Physical Exertion in Healthy Volunteers.

PurposeWhile extreme physical exertion is known to induce changes in the status of inflammation comparisons of the responses for various mediators of inflammation after acute bouts of high-intensity exercise have been limited.Subjects and MethodsWe examined the responses in serum levels of novel inflammatory proteins, calprotectin, suPAR, CD163, and pro- and anti-inflammatory cytokines in 12 physically active volunteers (10 men, 2 women, mean age 37±14 years) before and after completing various types of extreme physical exertion (marathon run, half-marathon run or 24-h cross-country skiing). For comparisons, the levels of the biomarkers were also measured at rest in 30 healthy controls (25 men, 5 women, mean age 42 ± 12 years) with low or sedentary activity.ResultsExtreme physical exertion induced significant increases in serum calprotectin (p < 0.0005), suPAR (p < 0.01), CD163 (p < 0.05), IL-6 (p < 0.0005), IL-8 (p < 0.01) and IL-10 (p < 0.0005) (pre- vs 3h-post-exercise). These responses were found to normalize within 48 hours. While the increases in blood leukocytes were of similar magnitude following the different types of exercise, markedly more pronounced responses occurred in serum TNF-α (p < 0.01), IL-8 (p < 0.01) and CD163 (p < 0.05) in those with more intense activity. In 3-h post-exercise samples significant correlations were observed between serum calprotectin and IL-6 (rs = 0.720, p < 0.01), IL-10 (rs = 0.615, p < 0.05), TNF-α (rs = 0.594, p < 0.05), suPAR (rs = 0.587, p < 0.05) and blood leukocytes (rs = 0.762, p < 0.01).ConclusionThe present results suggest distinct exercise-intensity dependent changes in mediators of inflammation (including calprotectin, suPAR and CD163) following extreme physical exertion. Our findings indicate that there is a major reversible impact of high-intensity physical exertion on the status of inflammation.

Circulating levels of soluble urokinase plasminogen activator receptor (suPAR) to predict outcome after resection of biliary tract cancer.

572 Background: Surgical resection is the only curatively intended therapy for patients with biliary tract cancer (BTC), but 5-year survival rates after tumor resection have remained below 30%, corroborating the need for better preoperative stratification tools to identify the ideal surgical candidates. The soluble urokinase plasminogen activator receptor (suPAR) represents a mediator of inflammation and has recently been associated with cancer. In this study, we evaluated a potential role of suPAR as a novel biomarker in patients undergoing resection of BTC. Methods: Tumor expression of uPAR, the membrane bound source of suPAR, was analyzed by IHC in 108 BTC samples. Serum levels of suPAR were analyzed by ELISA in a training and validation cohort comprising a total of 117 BTC patients and 76 healthy controls. Results: A high tumoral uPAR expression was associated with an adverse outcome after BTC resection. In line, circulating levels of suPAR were significantly elevated in BTC patients compared to healthy controls and patients with primary sclerosing cholangitis (PSC). Using a small training set, we established an optimal prognostic suPAR cut-off value of 3.72ng/ml for BTC patients. Importantly, preoperative suPAR serum levels above this cut-off value were associated with significantly impaired overall survival in both the training and validation cohort. Multivariate Cox-regression analysis including clinicopathological parameters such as the tumor stage, markers of systemic inflammation or organ dysfunction and established tumor markers revealed suPAR as an independent prognostic marker following BTC resection. Finally, high preoperative suPAR levels were indicative for acute kidney injury after tumor resection. Conclusions: Circulating suPAR represents a previously unrecognized biomarker in patients with resectable BTC, which might be useful to preoperatively identify the ideal candidates for tumor resection.

Circulating levels of soluble urokinase plasminogen activator receptor predict outcome after resection of biliary tract cancer.

Background & AimsSurgical resection is the only potentially curative therapy for patients with biliary tract cancer (BTC), but 5-year survival rates after tumor resection have remained below 30%, corroborating the need for better stratification tools to identify the ideal surgical candidates. The soluble urokinase plasminogen activator receptor (suPAR) represents a mediator of inflammation and has been associated with distinct types of cancer. In this study, we evaluated a potential role of suPAR as a novel biomarker in patients undergoing BTC resection.MethodsTumor expression of uPAR was analyzed by immunohistochemistry in 108 BTC samples. Serum levels of suPAR were analyzed by ELISA in a training and validation cohort comprising a total of 117 patients with BTC and 76 healthy controls.ResultsHigh tumoral uPAR expression was associated with an adverse outcome after BTC resection. Accordingly, circulating levels of suPAR were significantly elevated in patients with BTC compared to healthy controls, as well as in patients with primary sclerosing cholangitis. Using a small training set, we established an optimal prognostic suPAR cut-off value of 3.72 ng/ml for patients with BTC. Importantly, preoperative suPAR serum levels above this cut-off value were associated with significantly impaired overall survival in both the training and validation cohort. Multivariate Cox-regression analysis including various clinicopathological parameters such as tumor stage, markers of inflammation and organ dysfunction, as well as tumor markers, revealed circulating suPAR levels as an independent prognostic marker following BTC resection. Finally, high preoperative suPAR levels were indicative of acute kidney injury after tumor resection.ConclusionCirculating suPAR represents a previously unrecognized biomarker in patients with resectable BTC, which might help to preoperatively identify the ideal candidates for liver surgery.Lay summarySurgical resection represents the only curative treatment option for patients with biliary tract cancer, but not all patients benefit to the same extent in terms of overall survival. Here, we provide evidence that serum levels of an inflammatory mediator (suPAR) are indicative of a patient's postoperative outcome and might thus help to identify the ideal surgical candidates.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Is a Renal Biomarker with Potential Clinical Applications in Monoclonal Gammopathy of Renal Significance (MGRS)

Monoclonal Gammopathy of Renal significance encompasses a spectrum of different renal pathologies that have a causal relationship with an underlying monoclonal protein produced by a, relatively indolent, plasma or other B-cell clone. These patients require anti-clonal treatment in order to salvage kidney function, however, there are few prognostic biomarkers that can help identify patients at higher risk for progression of renal disease. Increased plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and an elevated level of suPAR was independently associated with incident chronic kidney disease and an accelerated decline in the eGFR, in a large study (Hayek S et al, N Engl J Med 2015; 373:1916-1925). Increased Growth Differentiation Factor-15 (GDF-15) has been associated with the deterioration of renal function and progression to ESRD in diabetic patients but also in patients with AL amyloidosis. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is one of the earliest and most robust markers of acute kidney injury while serum Cystatin C (CysC) reflects renal function more accurately than creatinine and correlates with both tumor burden and renal function in MM. We measured serum levels of suPAR, NGAL, GDF-15 and CysC in the same frozen serum sample that was collected before any therapy was given. Measurements of the analytes were performed by means of immunoenzymatic techniques: suPAR (ViroGates A/S, Birkerod, Denmark), NGAL and GDF-15 (R&amp;D Systems, Minneapolis, MN, USA), while CysC was measured with an immunoturbidimetric assay using the Roche Cobas 6000 Clinical Chemistry System. The study included 23 patients with MGRS (MIDD: 18, C3GN: 3, PGNMID: 2), 57% were men, median age was 66 years (range 47-85). Median baseline eGFR (by CKD-EPI) was 30.5 ml/min/1.73 m2 (range 3-102) and at the time of initiation of therapy one (4%) required dialysis. Median baseline proteinuria was 1.7 gr/d (range 0.6-10.2). Median dFLC was 57 mg/L (range 2-2,239) and median BM infiltration was 10% (range 0-50%). At initial presentation 92% had hypertension, requiring a median of 2 different drug classes (range 1-5). Median baseline levels of suPAR were 8.02 ng/ml (range 2.2-21), of CysC were 2.33 mg/L (0.94-7.03), of NGAL were 150.6 ng/ml (range 51.7-573) and of GDF-15 were 2,144 pg/ml (range 548-6,956). A correlation of suPAR levels was found with proteinuria (r=0.691, p=0.001), serum albumin levels (r=-0.706, p&lt;0.001) and age (p=0.012) but not with baseline eGFR (p=0.49). GDF-15 correlated with eGFR (r=-0.662, p=0.001) but also with proteinuria (r=-0.535, p=0.018), while NGAL (r=-0.714, p&lt;0.001), CysC (r=-0.727, p&lt;0.001) correlated strongly with eGFR but not with proteinuria or serum albumin (p&gt;0.2 for all). All these biomarkers showed significant correlations with each other (p&lt;0.007 for all in between correlations). All patients received bortezomib-based therapy (with cyclophosphamide and dexamethasone); median follow up is 9 months and at 3 month landmark, 55% of evaluable patients had achieved a hematologic response while at 6 months 60% had a hematologic response. At the same time points a renal response (&gt;50% reduction of proteinuria and &lt;25% decline in eGFR) was 44% and 53% respectively. There was no significant correlation of baseline levels of suPAR, NGAL, GDF-15 or CysC with renal response; however, we found a trend towards an association of lower baseline suPAR with a higher probability of &gt;50% reduction of proteinuria (p=0.096), which after adjustment for baseline proteinuria and eGFR became clearer (p=0.054). We conclude that suPAR, NGAL, GDF-15 and CysC are markers with significant associations with renal function in patients with MGRS, but, from a clinical standpoint suPAR is probably the most promising marker with potential prognostic significance for renal outcomes. Additional follow up of the cohort and inclusion of additional patients will allow us to further evaluate this biomarker in MGRS. Disclosures Kastritis: Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Amgen: Honoraria, Research Funding; Genesis: Honoraria. Gavriatopoulou:Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses. Papassotiriou:Roche: Employment. Terpos:Janssen: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Takeda: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding.

Serum plasminogen activator urokinase receptor predicts elevated risk of acute respiratory distress syndrome in patients with sepsis and is positively associated with disease severity, inflammation and mortality.

The present study aimed to evaluate the predictive value of serum soluble urokinase plasminogen activator receptor (suPAR) regarding the risk of acute respiratory distress syndrome (ARDS) in sepsis patients, and investigate its correlation/association with disease severity, inflammation and mortality in sepsis patients with ARDS. A total of 57 sepsis patients with ARDS and 58 sepsis patients without ARDS were recruited for the present case-control study. Laboratory tests, acute physiology and chronic health evaluation (APACHE) II score and sequential organ failure assessment (SOFA) score were evaluated, and mortality during hospitalization was recorded. Blood samples were collected and serum suPAR was detected by ELISA. Furthermore, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-17, as well as C-reactive protein (CRP) were detected. The results indicated that the serum levels of suPAR in sepsis patients with ARDS were higher than those in sepsis patients without ARDS. Receiver operating characteristics (ROC) curve analysis indicated that it was possible to distinguish sepsis patients with ARDS from sepsis patients without ARDS based on their serum suPAR levels, and multivariate logistic regression analysis suggested that serum suPAR levels were an independent predictor of the risk of ARDS in sepsis patients. In sepsis patients with ARDS, serum suPAR levels were positively correlated with the APACHE II score, SOFA score and the levels of CRP, TNF-α, IL-1β and IL-8. In addition, serum suPAR levels were lower in survivors compared with those in non-survivors, and ROC curve analysis suggested that serum suPAR was able to predict the probability of mortality. In conclusion, serum suPAR independently predicted an elevated risk of ARDS in patients with sepsis, and was correlated/associated with greater disease severity, higher inflammation and increased mortality in patients with sepsis and ARDS.

The clinical value of brain natriuretic peptide and soluble urokinase plasminogen activator receptor in the diagnosis and prognosis of bloodstream infection in the patients of Intensive Care Unit

Objective To study the clinical value of brain natriuretic peptide (BNP) and soluble urokinase plasminogen activator receptor (suPAR) in the diagnosis and prognosis of bloodstream infection. Methods Totally 165 patients suspected of bloodstream infection admitted in intensive care unit (ICU) of the Second Hospital Affiliated to Suzhou University were enrolled in this study. According to the diagnosis standard of bloodstream inflection, patients were divided into the bloodstream infection group and non-bloodstream infection group. According to the prognosis of the patients, the bloodstream infection group was further divided into the survival group and the death group. Serum levels of suPAR, BNP, CRP, PCT, and chronic health evaluation Ⅱ acute physiology score (APACHE Ⅱ ), and mortality of the patients were analyzed, and the possible relation of the above indexes between the two groups were compared. Based on the receiver operating characteristic curve (ROC) and the area under the curve (AUC), the early diagnostic value of suPAR, BNP, CRP, PCT, and APACHE Ⅱ score in the bloodstream infection patients was determined. Results Serum levels of suPAR, BNP, CRP, PCT and APACHE II score in the bloodstream infection group were higher than those in the non-bloodstream infection group (P<0.05); Serum levels of suPAR, BNP, CRP, PCT and APACHE Ⅱ score in the death group were higher than those in the survival group (P<0.05). There was a positive correlation between serum suPAR, BNP, PCT and APHCHE Ⅱscore in patients of bloodstream infection(r=0.503, 0.548, 0.781,all P<0.05). The levels of suPAR, BNP, PCT and APACHE Ⅱ in the patients of blood stream infection were related to significant the prognosis (P<0.05). And these indexes can provide good evaluation on the prognosis of the patients. Conclusion Detection of serum suPAR, BNP can evaluate the severity of bloodstream infection and preliminarily determine the prognosis of patients with bloodstream infection. Therefore, the method is worth applying in the clinical field. Key words: Bloodstream infection; Soluble urokinase plasminogen activator receptor; Brain natriuretic peptide; APACHE Ⅱ score