suPAR Concentration Research Articles

Soluble urokinase plasminogen activator receptor in vaginally collected amniotic fluid predicting fetal inflammatory response syndrome: a prospective cohort study

BackgroundImproving noninvasive antenatal diagnosis of fetal inflammatory response syndrome (FIRS) can assist in the evaluation of prenatal risk and reduce perinatal outcomes. This study aimed to determine whether soluble urokinase-type plasminogen activator receptor (suPAR) in vaginally collected amniotic fluid is significant in identifying FIRS after preterm premature rupture of membranes before 34 weeks of gestation.MethodsThis was a prospective cohort study of 114 pregnant women and their newborns after preterm premature rupture of membranes at 22–34+6 weeks of gestation. SuPAR was evaluated using an enzyme-linked immunosorbent assay in vaginally collected amniotic fluid. Patients were classified according to the presence or absence of FIRS. FIRS was defined by umbilical cord blood interleukin-6 level > 11 pg/mL or histological funisitis. The data were analyzed using the R package (R–4.0.5).ResultsSuPAR was detected in all amniotic fluid samples with a median of 26.23 ng/mL (interquartile range (IQR), 15.19–51.14). The median level of suPAR was higher in the FIRS group than in the non-FIRS group, 32.36 ng/mL (IQR, 17.27–84.16) vs. 20.46 ng/mL (IQR, 11.49–36.63) (P = 0.01), respectively. The presence of histological chorioamnionitis significantly increased the suPAR concentration in the FIRS group (P < 0.001). The areas under the curve for FIRS and FIRS with histological chorioamnionitis were 0.65 and 0.74, respectively, with an optimum cutoff value of 27.60 ng/mL. Controlling for gestational age, the cutoff of suPAR more than 27.60 ng/mL predicted threefold higher odds for FIRS and sixfold higher odds for FIRS with histologic chorioamnionitis.ConclusionSoluble urokinase-type plasminogen activator receptor in vaginally obtained amniotic fluid may assist in evaluating prenatal risk of FIRS in patients after preterm premature rupture of membranes before 34 weeks of gestation.

SuPAR and WT1 modify the adhesion of podocytes and are related to proteinuria in class IV lupus nephritis

IntroductionLupus nephritis (LN) affects up to 60 % of the patients with Systemic Lupus Erythematosus (SLE) and renal damage progression is associated with proteinuria, caused in part by the integrity of the glomerular basement membrane (GBM) and by podocyte injury. The soluble urokinase plasminogen activator receptor (suPAR) and Wilms Tumor 1 (WT1) have been related to podocyte effacement and consequently with proteinuria which raises questions about its pathogenic role in LN. ObjectiveDefine whether suPAR levels and WT1 expression influence in podocyte anchorage destabilization in LN class IV. Materials and methodsThis is a cross-sectional study of cases and controls. We studied patients with SLE without renal involvement (n = 12), SLE and LN class IV with proteinuria ≤0.5 g/24 h (n = 12), LN class IV with proteinuria ≥0.5 g/24 h (n = 12) and compared them with renal tissue control (CR) (n = 12) and control sera (CS) (n = 12). The CR was integrated by cadaveric samples without SLE or renal involvement and the CS was integrated by healthy participants. The expression and cellular localization of WT1, urokinase-type plasminogen activator receptor (uPAR), ac-α-tubulin, vimentin, and β3-integrin was assessed by immunohistochemistry (IHC). The concentration of suPAR in serum was analyzed by enzyme-linked immunosorbent assay (ELISA). ResultsIn patients with LN, the activation of anchoring proteins was increased, such as podocyte β3-integrin, as well as the acetylation of alpha-acetyl-tubulin and uPAR, in contrast to the decrease in vimentin; interestingly, the cellular localization of WT1 was cytoplasmic and the number of podocytes per glomerulus decreased. The concentrations of suPAR was increased in patients with LN. ConclusionThe destabilization of podocyte anchorage modulated by β3-integrin activation, and tubulin acetylation, associated with decreased WT1 cytoplasmic expression, and increased suPAR levels could be involved in kidney damage in patients with LN class IV.

Detection of Inflammatory Biomarker suPAR in COVID-19 Disease With CHORUS TRIO Instrument.

Deregulation in the urokinase-type plasminogen activator receptor (uPA/uPAR) system is reported in many diseases where the immune system is activated. During SARS-CoV-2 infection, a rise in soluble uPAR (suPAR) levels has been detected and its concentration above 6 µg/L predicts worsening to severe respiratory failure 14 days earlier, with a positive predictive value of 85.9%, and was the prerequisite for a treatment with anakinra, a recombinant IL-1 receptor antagonist that blocks the activity of both IL-1α and IL-1β. To compare suPAR concentrations measured by CHORUS suPAR on CHORUS TRIO instrument of DIESSE with the commercially available suPARnostic (ViroGates) ELISA assay. A single-centre, non-pharmacological, diagnostic study was performed. A total of 522 serum samples from patients with COVID-19 were tested for suPAR. CHORUS suPAR resulted accurate and reliable, with a high grade of specificity (97.9%), accuracy (97.3%) and sensitivity (96.9%). The median concentration of suPAR, as determined with CHORUS suPAR, was 6.8 µg/L (interquartile range 4.5-9.7) in patients with moderate disease (n = 465) and 8.5 µg/L (interquartile range 5.4-10.6) in patients with severe disease. Among patients with moderate and severe disease, 60.6% and 71.9%, respectively, reached the cut-off concentration of suPAR ⩾6 µg/L, defining their illness severity and suggesting eligibility to anakinra treatment. CHORUS suPAR kit resulted as sensitive, specific, accurate and able to quantify suPAR concentrations in patients with moderate and severe COVID-19.

The Clinical Significance of the Glomerular Biomarker Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) in Renal Function of Caucasian Patients with Compound Heterozygosity for Hb S and β-Thalassemia

Background: A wide spectrum of glomerular lesions has been described in patients with Sickle Cell Disease (SCD). The most frequently identified morphologic lesion associated with SCD is perihilar Focal Segmental Glomerulosclerosis (FSGS). Glomerular ischemia leads to a compensatory increase in renal blood flow and glomerular filtration rate (GFR); such hyperfiltration, combined with glomerular hypertrophy, probably contributes to glomerulosclerosis. As glomerulosclerosis becomes more extensive, GFR starts to decrease. The glomerular biomarker suPAR is the circulating form of a glycosyl-phosphatidylinositol-anchored three domain membrane protein that is expressed on a variety of cells, including immunologically active cells, endothelial cells, and podocytes. suPAR has been implicated in the pathogenesis of kidney disease, specifically FSGS, through interference with podocyte migration and apoptosis. Recently, suPAR was associated also with subsequent acute kidney injury. We aimed to investigate a possible link between suPAR serum levels and renal function decline for the first time in Caucasian patients with compound heterozygosity for HbS and β-thalassemia (HbS/βthal). Patients and Methods: Ιn the study were included 138 Caucasian adult patients with HbS/βthal at steady phase, and 20 healthy individuals of similar age and gender who served as controls. suPAR concentration was measured with an immunoenzymatic assay (ViroGates, Denmark) along with a series of other blood chemistry markers of erythropoiesis, renal, endothelial and cardiac function, such as: Neutrophil Gelatinase Associated Lipocalin (NGAL), Interleukin-18 (IL-18), Retinol Binding Protein-4 (RBP-4), Fatty Acid Binding Protein-4 (FABP-4), von Willebrand factor antigen (VWF:antigen), D-Dimers, Α Disintegrin and Metalloproteinase with Thrombospondin Type 1 Motif 13 (ADAMTS-13), hs-Troponin-T (hs-TnT), Placental Growth Factor (PlGF) and Growth Differentiation Factor-15 (GDF-15), measured with immunoenzymatic and electrochemiluminescence immunoassays. eGFR values were calculated using the CKD-EPI (Cystatin C and/or Creatinine equations. Results: We found that: a) suPAR levels were higher in patients with HbS/βthal compared to controls, 4.2±2.7pg/mL (1.2-18.2pg/mL) vs 1.9±0.4pg/mL (1.0-2.4pg/mL), p<0.001; b) No correlation was found with hydroxycarbamide treatment (p>0.1), while a weak correlation was found between suPAR levels and HbS/βthal genotype (r=-0.256, p=0.012). c) suPAR levels correlated significantly with eGFR values r=-0.657,p<0.001 and CKD stage (ANOVA p<0.001); 70% of the patients with hyperfiltration and stage-1 CKD had increased suPAR levels; d) suPAR levels correlated significantly with patients’ values of age r=0.477, p<0.001, Hb r= -0.493, p<0.001, Reticulocyte production Index r=0.367, p=0.002, ferritin r=0.459, p<0.001 and uric acid r=0.215, p<0.01, while no correlation was found with LDH r=0.149, p>0.1. e) Comparing the diagnostic significance of suPAR with other parameters of tubular-glomerular activation such as NGAL, IL-18, RBP-4, FABP-4, GDF-15, only the tubular marker NGAL has slightly superior significance, while none of these renal markers was increased in patients with hyperfiltration. f) Nevertheless, suPAR levels may reflect defects to more systems as correlated significance with markers of endothelial dysfunction-hemostatic system: vWF:antigen r=0.466, p<0.001, D-dimer r=0.344, p<0.001), ADAMTS-13/VWF ratio r=-0.485, p<0.001, cardiac injury and stress: hs-troponin-T r=0.519, p<0.001 and GDF-15 r=0.453, p<0.001) and angiogenesis: PlGF r=0.429, p<0.001 was found. Conclusions: To our knowledge this is the first report of the evaluation of a glomelurar biomarker such as suPAR in Caucasian patients with HbS/βthal, showing higher levels in these patients due to possible destruction of podocytes. As more than 70% of patients with hyperfiltration and stage-1 CKD, had increased suPAR levels, we suggest that suPAR could be a prognostic marker of renal injuries in patients with SCD particular in those patients with hyperfiltration and stage-1 CKD. However, this biomarker should be more investigated in order to determine its clinical significance.

Diagnostic and Prognostic Value of Deregulated Circulating Long Non-coding RNA TUG1 in Elderly Patients with Severe Pneumonia.

To investigate the expression pattern of long non-coding RNA TUG1 in elderly patients with severe community-acquired pneumonia (sCAP) and evaluate its diagnostic and prognostic value for sCAP. Serum TUG1 levels were detected in 130 sCAP patients and 122 healthy volunteers via qRT-PCR method. The receiver operating characteristic (ROC) curve and k-M plot were drawn for the diagnostic and prognostic value evaluation. A diminished trend of TUG1 was detected in the serum of sCAP cases, and negatively correlated with the concentration of TNF-α, CRP, suPAR and sTREM-1. Among the 130 cases, 30 cases died from sCAP within 30days after admission. Serum TUG1 had the diagnostic value for 30-day mortality prediction with the AUC of 0.823. In the non-survival group, more cases had old age, high CURB score and PSI score. K-M plot demonstrated that cases with low TUG1 levels showed poor survival than those carrying high TUG1 levels. Serum TUG1 was an independent risk factor for death in elderly patients with sCAP within 30days after admission. Serum TUG1 was at low expression in sCAP patients, and it had the predictive value for the clinical prognosis of elderly sCAP patients.

Soluble urokinase Plasminogen Activator Receptor (suPAR) levels are predictive of COVID-19 severity: an Italian experience

BackgroundThe soluble urokinase Plasminogen Activator Receptor (suPAR) has been identified as a reliable marker of COVID-19 severity, helping in personalizing COVID-19 therapy. This study aims to evaluate the correlation between suPAR levels and COVID-19 severity, in relation to the traditional inflammatory markers. MethodsSera from 71 COVID-19 patients were tested for suPAR levels using Chorus suPAR assay (Diesse Diagnostica Senese SpA, Italy). suPAR levels were compared with other inflammatory markers: IL-1β, IL-6, TNF-α, circulating calprotectin, neutrophil and lymphocyte counts, and Neutrophil/Lymphocytes Ratio (NLR). Respiratory failure, expressed as P/F ratio, and mortality rate were used as indicators of disease severity. ResultsA positive correlation of suPAR levels with IL-6 (r = 0.479, p = 0.000), TNF-α (r = 0.348, p = 0.003), circulating calprotectin (r = 0.369, p = 0.002), neutrophil counts (r = 0.447, p = 0.001), NLR (r = 0.492, p = 0.001) has been shown. Stratifying COVID-19 population by suPAR concentration above and below 6 ng/mL, we observed higher levels of circulating calprotectin (10.1 μg/mL, SD 7.9 versus 6.4 μg/mL, SD 7.5, p < 0.001), higher levels of P/F ratio (207.5 IQR 188.3 vs 312.0 IQR 127.8, p = 0.013) and higher mortality rate. Median levels of suPAR were increased in all COVID-19 patients requiring additional respiratory support (Nasal Cannula, Venturi Mask, BPAP and CPAP) (6.5 IQR = 4.9) compared to the group at room air (4.6 IQR = 4.2). ConclusionsuPAR levels correlate with disease severity and survival rate of COVID-19 patients, representing a promising prognostic biomarker for the risk assessment of the disease.

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.

Development and validation of SCOPE score: A clinical score to predict COVID-19 pneumonia progression to severe respiratory failure

SummaryMost patients infected with SARS-CoV-2 (COVID-19) experience mild, non-specific symptoms, but many develop severe symptoms associated with an excessive inflammatory response. Elevated plasma concentrations of soluble urokinase plasminogen activator receptor (suPAR) provide early warning of progression to severe respiratory failure (SRF) or death, but access to suPAR testing may be limited. The Severe COvid Prediction Estimate (SCOPE) score, derived from circulating concentrations of C-reactive protein, D- dimers, interleukin-6, and ferritin among patients not receiving non-invasive or invasive mechanical ventilation during the SAVE-MORE study, offers predictive accuracy for progression to SRF or death within 14 days comparable to that of a suPAR concentration of ≥6 ng/mL (area under receiver operator characteristic curve 0.81 for both). The SCOPE score is validated in two similar independent cohorts. A SCOPE score of 6 or more is an alternative to suPAR for predicting progression to SRF or death within 14 days of hospital admission for pneumonia, and it can be used to guide treatment decisions.

Impact of cardiopulmonary bypass and surgical complexity on plasma soluble urokinase-type plasminogen activator receptor levels after cardiac surgery

Background Circulating soluble urokinase plasminogen activator receptor (suPAR) is a marker of inflammation with prognostic value for elevated risk of morbidity and mortality. It has not yet been shown how the inflammatory process induced by cardiac surgery affects suPAR concentrations postoperatively Methods In a prospective observational study, plasma suPAR levels were measured in 30 patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), pre-, peri, post-operatively, and 3–5 days after surgery. Fifteen patients underwent coronary artery bypass grafting (CABG) and 15 underwent complex procedures with longer CPB duration. Concentrations of suPAR at each time point were compared to the preoperative levels and compared between the two groups. Results In both groups, plasma suPAR concentrations were significantly higher on the first postoperative day (3.27 (interquartile range (IQR) 2.75–3.86) µg/L compared to baseline (2.62 (1.98–3.86)) µg/L, p < .001. There were no significant differences in suPAR concentrations between the groups at any time point. Preoperatively, the median suPAR concentration was 2.57 (2.01–3.60) µg/L in the CABG group versus 2.67 (1.89–3.97) µg/L in the complex group (p = .567). At ICU arrival 2.48 (2.34–3.23) µg/L versus 2.73 (2.28–3.44) µg/L in CABG and complex patients, respectively (p = .914). There was no difference in suPAR concentrations between the groups on postoperative day 1 (3.34 (2.89–3.89) versus 3.19 (2.57–3.62) p = .967) or 3–5 days after surgery (2.72 (1.98–3.16) versus 2.96 (2.39–4.28) p = .085. Conclusions After a transient rise on the first postoperative day, the suPAR levels returned to the preoperative levels by the third postoperative day. There was no significant difference in suPAR levels between the routine CABG and complex group with longer CPB time.

RAGE and αVβ3-integrin are essential for suPAR signaling in podocytes

The soluble urokinase plasminogen activator receptor (suPAR) has been implicated in the pathogenesis of kidney diseases including primary and recurrent focal and segmental glomerulosclerosis (FSGS), diabetic nephropathy, and acute kidney injuries (AKI). Elevated serum suPAR concentration is a negative prognostic indicator in multiple critical clinical conditions. This study has examined the initial transduction steps used by suPAR in cultured mouse podocytes. We now report that the receptor for advanced glycation end-products (RAGE) co-immunoprecipitates with αV and β3 integrin subunits, which have been previously shown to initiate suPAR signal transduction at the podocyte cell surface. siRNA knock-down of RAGE attenuated Src phosphorylation evoked by either suPAR or by glycated albumin (AGE-BSA), a prototypical RAGE agonist. suPAR effects on Src phosphorylation were also blocked by the structurally dissimilar RAGE antagonists FPS-ZM1 and azeliragon, as well as by cilengitide, an inhibitor of outside-in signaling through αV-integrins. FPS-ZM1 also blocked Src phosphorylation evoked by AGE-BSA. FPS-ZM1 blocked increases in cell surface TRPC6 abundance, cytosolic reactive oxygen species (ROS) and activation of the small GTPase Rac1 evoked by either suPAR or AGE-BSA. In addition, FPS-ZM1 inhibited Src phosphorylation evoked by serum collected from a patient with recurrent FSGS during a relapse. The magnitude of this inhibition was indistinguishable from the effect produced by a neutralizing antibody against suPAR. These data suggest that orally bioavailable small molecule RAGE antagonists could represent a useful therapeutic strategy for a wide range of clinical conditions associated with elevated serum suPAR, including primary FSGS and AKI.

MO948CHANGES OF SOLUBLE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR (SUPAR) AFTER CADAVERIC KIDNEY TRANSPLANTATION AND ASSOCIATION WITH KIDNEY FUNCTION

Abstract Background and Aims The soluble urokinase plasminogen activator receptor (suPAR), a marker of podocyte injury, has been implicated in pathogenesis of various kidney diseases, especially in focal segmental glomerulosclerosis. It correlates to the activation level of immune system. SuPAR predicted all course mortality in hemodialysis patients, but was not tested as a prognostic biomarker in kidney transplant patients. The aim of this study was to evaluate changes of suPAR concentration after kidney transplantation and to test its relation to graft function. Method We examined patients, who underwent cadaveric kidney transplantation (Tx) from 2019/05/23 to 2020/07/30 in the Hospital of Lithuanian University of Health Sciences. We evaluated level of suPAR biomarker before Tx, 12 days after Tx and 3 months after Tx. We used the suPARnostic Quick Triage test by ViroGates (Medtech, Denmark) for testing suPAR concentration. The suPARnostic Quick Triage test is based on the lateral flow principle. The device consists of a nitrocellulose membrane with two immobilized antibody zones and a running buffer with gold particles. The quantitative results are read by the aLF Reader with a detection interval of 2-15 ng/mL suPAR. Data on serum creatinine level and eGFR were collected at the same time points. Creatinine was tested using Analyzer AU680, Beckman Coulter, USA (Kinetic Jaffe traceable to the IDMS reference method). The statistical data analysis was performed using SPSS 23.0 software. Results 35 patients were included into the study, 57% of men and 43% of woman. Mean age of patients - 47±13.5 years. Mean suPAR level before transplantation was 8.7±4.2 ng/ml. It was a trend towards lower mean suPAR level 12 days after Tx (5.9±2.8 ng/ml, p=0.1) as compared to before Tx. It was significant decrease of suPAR level 3 months after Tx (3.9±1.1 ng/ml, p=0.003) as compared to before Tx. There was no suPAR relation to patient’s age. Serum creatinine and eGFR did not correlate with suPAR levels measured at the same time (before Tx, 12 days, and 3 months after Tx). We did not find relation between suPAR level before transplantation and creatinine level and eGFR 12 days after Tx. We found a significant negative correlation between suPAR level before transplantation and creatinine level 3 months after transplantation (r = -0.4, p = 0.049), but not eGFR 3 months after Tx. In a group of patients with eGFR ≥45 ml/min/1.73m2 3 months after transplantation mean suPAR level before Tx (9.5±4.3 ng/ml), after 12 days (5.8±2.6 ng/ml), and 3 months after Tx (3.8±0.87 ng/ml) was not different than in group of patients with eGFR &amp;lt; 45 ml/min/1.73m2 (8±4.1 ng/ml, 5.2±3.5 ng/ml, 3.9±1.5 ng/ml accordingly), p&amp;gt;0.05. Conclusion There was a significant gradual decrease of suPAR levels during 3 months after transplantation. No correlation of suPAR levels and transplanted kidney function was confirmed. A larger study is needed to assess whether suPAR could predict long term outcomes in kidney transplantation.

Soluble urokinase-type plasminogen activator receptor (suPAR) is a risk indicator for eGFR loss in kidney transplant recipients

The prognostic significance of suPAR in various kidney diseases has recently been demonstrated. Its role in transplantation-specific outcomes is still largely unknown. Therefore, we prospectively investigated the prognostic relevance of suPAR in patients before and one year after kidney transplantation (KTx). We included 100 patients who had received a kidney transplantation between 2013 and 2015. The plasma concentration of suPAR was measured by ELISA assay. In recipients of living donations (LD), pre-transplant suPAR levels were significantly lower than those of recipients of deceased donations (DD). After KTx, suPAR levels significantly declined in LD and DD recipients, without a detectable difference between both groups any more. Higher suPAR levels in recipients one year after KTx were associated with a more severe eGFR loss in the following three years in multivariable cox-regression (n = 82, p = 0.021). suPAR-levels above 6212 pg/ml one year after KTx are associated with eGFR loss > 30%, which occurred almost twice as fast as in patients with suPAR ≤ 6212 pg/ml (p < 0.001). Hence, suPAR level at one year mark might be a risk indicator of increased eGFR loss.

Biomarkers of Immune Activation and Incident Kidney Failure With Replacement Therapy: Findings From the African American Study of Kidney Disease and Hypertension

Immune activation is fundamental to the pathogenesis of many kidney diseases. Innate immune molecules such as soluble urokinase-type plasminogen activator receptor (suPAR) have been linked to the incidence and progression of chronic kidney disease (CKD). Whether other biomarkers of immune activation are associated with incident kidney failure with replacement therapy (KFRT) in African Americans with nondiabetic kidney disease is unclear. Prospective cohort. African American Study of Kidney Disease and Hypertension (AASK) participants with available baseline serum samples for biomarker measurement. Baseline serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1), sTNFR2, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). Incident KFRT, all-cause mortality. Cox proportional hazards models. Among 500 participants with available samples, mean glomerular filtration rate was 44.7mL/min/1.73m2, and median urinary protein-creatinine ratio was 0.09g/g at baseline. Over a median follow up of 9.6 years, there were 161 (32%) KFRT and 113 (23%) death events. In models adjusted for demographic and clinical factors and baseline kidney function, each 2-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was associated with 3.66-fold (95% CI, 2.31-5.80), 2.29-fold (95% CI, 1.60-3.29), and 1.35-fold (95% CI, 1.07-1.71) greater risks of KFRT, respectively; in comparison, each doubling of baseline suPAR concentration was associated with 1.39-fold (95% CI, 1.04-1.86) greater risk of KFRT. sTNFR1, sTNFR2, and TNF-α were also significantly associated with death (up to 2.2-fold higher risks per 2-fold higher baseline levels; P≤0.01). IFN-γ was not associated with either outcome. None of the biomarkers modified the association of APOL1 high-risk status (genetic risk factors for kidney disease among individuals of African ancestry) with KFRT (P>0.05 for interaction). Limited generalizability to other ethnic groups or causes of CKD. Among African Americans with CKD attributed to hypertension, baseline levels of sTNFR1, sTNFR2, and TNF-α but not IFN-γ were associated with KFRT and mortality.

Soluble urokinase plasminogen activator receptor as a long-term prognostic biomarker in acute coronary syndromes

Purpose: The aim of our study was to analyse the long-term prognostic value of soluble urokinase plasminogen activator receptor (suPAR) in the setting of an acute coronary syndrome (ACS).Methods: We included 340 patients with an ACS who underwent coronary angiography and plasma suPAR concentration was measured. Patients were classified into low suPAR concentrations (<2.6 ng/mL) and high suPAR concentrations (≥2.6 ng/mL) and long-term events were evaluated. suPAR prognostic value was assessed beyond a clinical model that included age, GRACE score, estimated glomerular filtration rate, cardiac troponin-I peak and left ventricular ejection fraction <40%.Results: Higher suPAR concentrations were associated with an increased prevalence of cardiovascular risk factors. After multivariate adjustment, suPAR ≥2.6 ng/mL were independently associated with an increased risk of all-cause death (HR 2.3; 95%CI 1.2–4.4; p = .017), major adverse cardiovascular events (MACE) (HR 1.7; 95%CI 1.1–2.5; p = .020) and heart failure (HR 4.1; 95%CI 1.3–12.6; p = .015), but not with myocardial infarction. For long-term all-cause death significant improvement of reclassification and discrimination were seen after addition of suPAR to a clinical model.Conclusions: In the setting of an ACS, suPAR is associated with long-term all-cause death, heart failure and MACE, and provides incremental prognostic value beyond traditional risks factors.

SuPAR is associated with death and adverse cardiovascular outcomes in patients with suspected coronary artery disease

Background The inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is associated with presence and severity of coronary artery disease (CAD) and incident death and myocardial infarction (MI). We sought to validate this finding in a further cohort of patients with suspected CAD. Methods Plasma suPAR was available in 1635 patients (73% with CAD) undergoing coronary angiography at a single regional Danish hospital between 2003 and 2005. Patients were followed for adverse cardiovascular outcomes of death, cardiac death and MI over a median follow-up of 4.2 years. Results In multivariate Cox models, adjusted for established cardiovascular risk factors, the biomarkers C-reactive protein, troponin-T and N-terminal-pro brain natriuretic peptide and the number of stenotic vessels, suPAR was independently associated with the combined endpoint of death/MI, hazard ratio (HR) 1.88; cardiovascular death, HR 2.01; and non-fatal MI, HR 1.53; (all p ≤ .037) per doubling of suPAR concentration. A plasma cutoff for suPAR ≥ 3.5 ng/mL was also significantly associated with death/MI, HR 1.51; p = .005. The C-statistic for the multivariate model predicting death/MI improved from 0.712 to 0.730 (p for difference .008) after inclusion of suPAR. However, suPAR was not associated with presence or extent of CAD (p > .05). Conclusion These results validate previous findings that demonstrate suPAR to be an independent predictor of death/MI in patients with suspected or known CAD, however suPAR was not associated with presence or extent of CAD in our cohort. Probably because suPAR reflects end organ damage rather than the degree of atherosclerosis. BRIEF SUMMARY We demonstrate that the inflammatory biomarker soluble urokinase plasminogen activator receptor is an independent predictor of death/myocardial infarction in patients with suspected or known coronary artery disease, but is not associated with the presence or severity of coronary artery disease.

SuPAR is a Bad Omen for Chronic Kidney Disease Progression

The rationale for considering serum soluble- urokinase plasminogen activator receptor (s-uPAR) concentration as a potential biomarker for incipient CKD was primarily based on reports that increased levels of this receptor will serve as a circulating permeability variable that may be impaired at the start of FSGS and DN, a crucial explanation for CKD. So in early stages(1-3) of CKD, suPAR was evaluated. The aims of present paper are to investigate whether patients with CKD have distinct circulating suPAR, that could lead to a potential development of noninvasive diagnostic biomarkers of the disease. And finally using healthy subjects as a control group to determine specificity and sensitivity . 135 subjects were incorporated in this study, 30 were healthy control, with mean age 48.7±9.7years, and they were 14 males and 16 females. 105CKD patient , with mean age 50.1±10.0years, they were 54 males and 51 females. Blood samples were collected. Serum after centrifugation was isolated for estimation of suPAR by Enzyme linked immune sorbent assay , creatinine, and urea by enzymatic method . Early morning urine sample was collected to be used for determination albumin creatinine ratio in patient . suPAR level was higher in CKD patients than in healthy control, 6.179±2.221 versus 2.303±0.475, respectively; the difference was highly significant (P &lt; 0.001) .To study the potential role of suPAR in diagnosis of patients with CKD, ROC showed that the cutoff value of suPAR was &gt; 3.5 ng / ml fold shift with sensitivity and specificity; the AUC was 0.826 (95 % confidence interval: 0.690-0.920) and therefore 82.6 % precision and significance level of (P &lt; 0.001). In conclusion, The suPAR is significantly more effective and also more comprehensive to CKD clinical assessment and can be supported with creatinine blood analysis.

Increased level of circulating cell-free mitochondrial DNA due to a single bout of strenuous physical exercise

PurposePhysical exercise is reported to affect the immune response in various ways. Thus, the levels of pro-inflammatory cytokines as well as the abundance of circulating leukocytes are changed. In this study, the occurence of circulating cell-free mitochondrial DNA (cfmtDNA) and nuclear DNA (nDNA) was investigated in connection with a single bout of strenuous physical exercise.MethodsHealthy volunteers performed a controlled ergo-spirometry cycle test and venous blood samples were taken at different time-points to analyze the concentration of blood components before, during and after the test. The number of circulating leukocytes was measured, as well as secretion of the soluble urokinase activator receptor (suPAR).ResultsCf-mtDNA significantly increased during exercise, compared to baseline values and after 30 and 90 min of rest. Circulating leukocytes increased during exercise, but returned to baseline levels afterwards. Surface expression of the urokinase plasminogen activating receptor (uPAR) on neutrophils decreased significantly during exercise. The concentration of suPAR tended to increase during exercise but only significantly after 90 min of rest.ConclusionIncreased concentration of cf-mtDNA indicates that cell damage takes place during high intensity training. Hypoxia and tissue damage are likely causes of cf-mtDNA from muscle cells. The levels of cf-mtDNA remain high during the initial rest, due to the decreasing numbers of leukocytes normally clearing the plasma from cf-mtDNA. The increased levels of suPAR further emphasize that strenuous physical exercise causes a reaction similar to inflammation. Further studies are needed to detect the source of increased cf-mtDNA and the corresponding increase of suPAR liberation.

Association between Soluble Urokinase-Type Plasminogen Activator Receptor Levels and Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

Background Chronic kidney disease (CKD) has become a global public health problem with a high prevalence and mortality. There is no sensitive and effective markers for chronic kidney disease. Previous studies proposed suPAR as an early predict biomarker for chronic kidney disease, but the results are controversial. Therefore, the purpose of the current meta-analysis is to evaluate the association between suPAR and CKD. Methods We searched the PubMed, Embase, Cochrane Library databases, and Web of Science before May 1, 2019. The search was based on the key words including suPAR and CKD. Data are extracted independently according to standard format, and quality analysis is performed. We extracted the concentration of suPAR and hazard rate (HR) values of mortality, cardiovascular disease, and end-stage renal disease. Results There were 14 studies fulfilling the criteria. The concentration of suPAR was higher in patients with CKD than that in the control group (P < 0.001; SMD: −2.17; 95% CI: −2.71, −1.63; I2 = 67.4%). SuPAR had a higher risk of mortality (P=0.001; HR: 1.72; 95% CI: 1.24, 2.39; I2 = 68.0%). The higher suPAR level increased the risk of cardiovascular disease (P < 0.001; HR: 3.06; 95% CI: 2.21, 4.22; I2 = 0.0%) and the risk of end-stage renal disease (P < 0.001; HR: 1.40; 95% CI: 1.22, 1.60; I2 = 0.0%). Conclusions Monitoring suPAR concentrations may be used for early diagnosis and prognosis for patients with CKD, and the higher suPAR increased the risk of mortality, cardiovascular events, and end-stage renal disease.

Serum soluble urokinase type plasminogen activated receptor and focal segmental glomerulosclerosis: a systematic review and meta-analysis

ObjectivesSoluble urokinase plasminogen activated receptor (suPAR) is a biomarker that may predict the occurrence of focal segmental glomerulosclerosis (FSGS); however, there is still controversy about whether suPAR can predict FSGS....

Kinetics of the soluble urokinase plasminogen activator receptor (suPAR) in cirrhosis.

BackgroundThe soluble urokinase plasminogen activator receptor (suPAR) is related to hepatic inflammation and fibrosis and has been suggested to participate in the development of liver cirrhosis. Therefore, the aim of the current study was to measure the concentration of suPAR in the hepatic vein of cirrhotic patients during a liver vein catheterization to identify a possible hepatic suPAR generation. Furthermore, we explored if suPAR levels were associated with the degree of cirrhosis and liver dysfunction.Methods and patientsWe included 105 cirrhotic patients and 19 liver-healthy controls. Blood was sampled from the hepatic vein and the femoral artery and suPAR was measured by enzyme-linked immunosorbent assay.ResultsWe identified significantly higher median suPAR concentrations among the cirrhotic patients (7.2 ng/ml in the hepatic vein; 6.8 ng/ml in the femoral artery) compared to the controls (2.6 ng/ml, respectively, p-values <0.001). However, the median hepatic suPAR formation was 0.0 ng/ml in both groups. We observed significantly increasing suPAR levels according to higher Child classes (4.5 ng/ml, 6.9 ng/ml and 9.0 ng/ml, Child A, B, C respectively; p-value<0.001), and significantly higher median suPAR concentrations in patients with ascites versus patients without ascites (8.1 ng/ml versus 5.3 ng/ml, respectively, p-value<0.001). suPAR levels were significantly related to bilirubin (r = 0.48, p<0.001), the hepatic venous pressure gradient (r = 0.39, p<0.001), the cardiac index (r = 0.24, p = 0.02) and the plasma volume (r = 0.33, p = 0.001), whereas suPAR levels were significantly inversely related to albumin (r = -0.59, p<0.001), plasma coagulation factors (r-0.39, p<0.001), the mean arterial pressure (r = -0.28, p = 0.004), the systemic vascular resistance (r = 0.26, p = 0.007), the indocyanine green clearance (r = -0.51, p<0,001) and the galactose elimination capacity (r = -0.39, p<0.001).ConclusionWe identified elevated suPAR concentration in cirrhotic patients, which correlated significantly with the degree of cirrhosis and liver failure, but we were not able to demonstrate hepatic suPAR generation per se. This suggests that further investigations of the source of suPAR in cirrhotic patients need to be undertaken.