Soluble Urokinase Plasminogen Activator Receptor Research Articles

Soluble Urokinase Plasminogen Activator Receptor (suPAR) Promotes Cardioprotective Intracellular Signalling in Myocardial Ischaemia

Soluble urokinase Plasminogen Activator Receptor (suPAR) is an emerging biomarker of inflammation capable of predicting cardiovascular outcomes. However, the biological activity of suPAR on the heart is poorly understood. Potential cardiac intracellular signalling pathways triggered by suPAR were explored. Isolated Langendorff rat hearts undergoing global ischaemia received treatment with either suPAR infusion or perfusion buffer (controls). Proteins were extracted from hearts for each treatment group, and Troponin T in rat outflow perfusates following ischaemia were measured. The phosphorylation status of each kinase was characterised using a phospho-specific antibody and a ratio of phosphorylation to the total protein was calculated. Analysis between treatment groups was performed with unpaired t-test with Welch’s correction. Hearts receiving suPAR treatment after ischaemia showed a 1.4-fold increase in Akt phosphorylation, and a 1.6-fold increase in Akt phosphorylation if suPAR was given before ischaemia. The ratio of p-Akt/Akt was 1.83±0.14 (n=7) in the post-ischaemic suPAR treatment group vs 1.3±0.04 (n=6) in controls (p=0.007). Pre-ischaemic suPAR treatment gave a p-Akt/Akt ratio of 1.08±0.03 (n=8) vs 0.67±0.11 (n=5) in controls (p=0.01). Upstream signalling ERK1 and ERK2 phosphorylation also increased at 2.6-fold (p=0.009) and 1.9-fold (p=0.01), respectively, in suPAR treated heart vs controls. Finally, suPAR treated hearts obtained lower Troponin T values compared with controls after recovery from ischaemia (p<0.001). suPAR infusion promoted the phosphorylation of ERK and Akt kinases in isolated rat heart tissue and reduced related cardiac troponin release after a period of global no-flow ischaemia. These actions suggest that suPAR is a novel activator of the reperfusion injury salvage kinase (RISK) pathway.

Protein Glycosylation Influences Soluble Urokinase Plasminogen Activator Receptor (suPAR) Measurements

Elevated plasma levels of the biomarker soluble urokinase plasminogen activator receptor (suPAR) are prognostic of adverse outcomes in cardiovascular disease (CVD). This novel inflammatory protein has five known N-linked glycosylation sites, but the contribution of glycosylation to disease progression is unknown. This study aimed to assess the impact of glycosylation on suPAR measurements. Bio-banked plasma samples from healthy volunteers and patients with CVD were treated with deglycosylation enzymes. suPAR was measured for all treated and untreated samples using the Virogates suPARnostic ELISA. Percentage change in suPAR concentrations following treatment were compared using paired t-test, and differences between patient cohorts were examined using the Mann-Whitney test. In healthy subjects, suPAR concentrations increased after pre-treatment with deglycosylation enzymes (median 1.8 vs 2.4 ng/mL; p<0.001; n=15). In patients diagnosed with myocardial infarction (MI), a percentage increase in suPAR concentrations was also obtained after deglycosylation treatment, and this increment was higher than acute chest pain patients without MI (58% vs 44%; p=0.02; n=15). In patients with acute decompensated heart failure, a higher percentage change in suPAR concentrations was also observed following deglycosylation, compared with that of healthy subjects (38% vs 30%; p=0.04; n=33). suPAR immunoreactivity increased for the ViroGates ELISA after removal of protein glycosylation, as demonstrated by higher concentrations observed after treatment. This suggests that the current clinical assay for suPAR is influenced by its N-linked glycosylation. As glycosylation alterations are associated with CVD, further investigations are required to assess this implication with respect to the prognostic accuracy of suPAR in cardiovascular disease progression.

Serum levels of soluble urokinase plasminogen activator receptor in juvenile idiopathic arthritis: a single-center Swedish case-control study

ObjectivesReliable biomarkers in the early stages of idiopathic arthritis (JIA) are scarce and the disease heterogeneity makes it clinically challenging to predict the risk of joint damage. Biomarkers with prognostic potential are warranted in order to individualize treatment and follow-up in JIA. The soluble urokinase plasminogen activator receptor (suPAR) has been reported as an easily measurable biomarker for prognosis and severity in several rheumatic diseases but it has never been studied in JIA.MethodsSera from 51 well-characterized patients with JIA and 50 age- and sex-matched control subjects were collected and stored for later analysis of suPAR. Patients were carefully followed clinically over 3 years and analysis of erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (anti-CCP) were analyzed as part of clinical routine. Signs of joint erosions were evaluated by radiography.ResultsOverall, the levels of suPAR did not differ significantly between JIA patients and controls but those with polyarticular involvement showed higher suPAR (p = 0.013). In addition, elevated suPAR were associated with joint erosions (p = 0.026). Two RF/anti-CCP negative individuals with erosions showed high levels of suPAR.ConclusionsWe present new data on the biomarker suPAR in JIA. Our results indicate that, apart from RF and anti-CCP, analysis of suPAR could be of additional value in assessing the risk of erosions. Analysis of suPAR early could potentially guide treatment decision-making in JIA, but our observations should be confirmed in prospective studies.

Risk Estimation of Gestational Diabetes Mellitus in the First Trimester.

There is no early, first-trimester risk estimation available to predict later (gestational week 24-28) gestational diabetes mellitus (GDM); however, it would be beneficial to start an early treatment to prevent the development of complications. We aimed to identify early, first-trimester prediction markers for GDM. The present case-control study is based on the study cohort of a Hungarian biobank containing biological samples and follow-up data from 2545 pregnant women. Oxidative-nitrative stress-related parameters, steroid hormone, and metabolite levels were measured in the serum/plasma samples collected at the end of the first trimester from 55 randomly selected control and 55 women who developed GDM later. Pregnant women who developed GDM later during the pregnancy were older and had higher body mass index. The following parameters showed higher concentration in their serum/plasma samples: fructosamine, total antioxidant capacity, testosterone, cortisone, 21-deoxycortisol; soluble urokinase plasminogen activator receptor, dehydroepiandrosterone sulfate, dihydrotestosterone, cortisol, and 11-deoxycorticosterone levels were lower. Analyzing these variables using a forward stepwise multivariate logistic regression model, we established a GDM prediction model with a specificity of 96.6% and sensitivity of 97.5% (included variables: fructosamine, cortisol, cortisone, 11-deoxycorticosterone, SuPAR). Based on these measurements, we accurately predict the development of later-onset GDM (24th-28th weeks of pregnancy). Early risk estimation provides the opportunity for targeted prevention and the timely treatment of GDM. Prevention and slowing the progression of GDM result in a lower lifelong metabolic risk for both mother and offspring.

Urinary cytokine measurements do not reflect surgery-induced inflammation in rhesus macaques.

Measurement of the health and disease status of free-ranging primates is often limited by a lack of available biomarkers of immune activation and inflammation that can be applied noninvasively via the measurement of urine or fecal samples. Here, we evaluate the potential usefulness of noninvasive urinary measurements of a number of cytokines, chemokines, and other markers of inflammation and infection. We took advantage of surgery-associated inflammation in seven captive rhesus macaques, collecting urine samples before and after the medical interventions. We measured these urine samples for 33 different markers of inflammation and immune activation that are known to be responsive to inflammation and infection in rhesus macaque blood samples, via the Luminex platform. We also measured all samples for concentrations of the soluble urokinase plasminogen activator receptor (suPAR),which we had validated in a prior study as an effective biomarker of inflammation. Despite urine samples being collected in captivity under ideal conditions (clean, no contamination with feces or soil, frozen quickly), 13/33 biomarkers measured via Luminex were found at concentrations below detection limits in >50% of samples. Of the remaining 20 markers, only 2 showed significant increases in response to surgery-IL18 and MPO (myeloperoxidase). However, suPAR measurements of the same samples show a consistent marked increase in response to surgery that is absent from the patterns of IL18 and MPO measurement. Given that our samples were collected under conditions that are greatly preferable to those usually encountered in the field, urinary cytokine measurements via the Luminex platform seem overall unpromising for primate field studies.

Soluble urokinase plasminogen activator receptor is associated with cardiovascular calcification in peritoneal dialysis patients.

Cardiovascular disease (CVD) is an important cause of morbidity and mortality in peritoneal dialysis (PD) patients. Cardiovascular calcification (CVC) is highly prevalent in PD patients and could predict their cardiovascular mortality. Soluble urokinase plasminogen activator receptor (suPAR) is closely associated with coronary artery calcification in hemodialysis patients and is an important predictor of CVD. However, the role of suPAR in PD patients is poorly understood. We investigated the relationship between serum suPAR and CVC in PD patients. Abdominal aortic calcification (AAC) was assessed by lateral lumbar radiography, coronary artery calcification (CAC) by multi-slice computed tomography, and cardiac valvular calcification (ValvC) by echocardiography. CVC was defined as confirmed presence of calcification in one site (AAC, CAC, or ValvC). Patients were divided into CVC group and non-CVC group. Demographic characteristics, biochemical variables, comorbidities, PD regimen, serum suPAR, and medication were compared between the two groups. Logistic regression was conducted to determine association between serum suPAR and presence of CVC. The receiver-operator curve (ROC) was plotted to calculate the area under the curve (AUC) for suPAR to identify CVC and ValvC. Of 226 PD patients, 111 (49.1%) had AAC, 155 (68.6%) had CAC, and 26 (11.5%) had ValvC. There were significant differences in age, BMI, diabetes, white blood cell, phosphorus, hs-CRP, suPAR, time on dialysis, total volume of dialysate, ultrafiltration, volume of urine, and Kt/V between CVC and non-CVC group. Serum suPAR was associated with CVC by multivariate logistic regression analysis in PD patients, especially in elderly patients. The levels of serum suPAR were closely related to the degree of AAC, CAC, and ValvC in PD patients. The incidence of CVC was higher in patients with higher levels of suPAR. The ROC curve showed that serum suPAR had a predictive value for CVC (AUC = 0.651), especially for ValvC (AUC = 0.828). Cardiovascular calcification is prevalent in PD patients. High levels of serum suPAR are associated with cardiovascular calcification in PD patients, especially in elderly patients.

Alterations in inflammatory markers after a 12-week exercise program in individuals with schizophrenia-a randomized controlled trial.

In individuals with schizophrenia, inflammation is associated with depression, somatic comorbidity and reduced quality of life. Physical exercise is known to reduce inflammation in other populations, but we have only limited knowledge in the field of schizophrenia. We assessed inflammatory markers in plasma samples from individuals with schizophrenia participating in an exercise intervention randomized controlled trial. We hypothesized that (i) physical exercise would reduce levels of inflammatory markers and (ii) elevated inflammatory status at baseline would be associated with improvement in cardiorespiratory fitness (CRF) following intervention. Eighty-two individuals with schizophrenia were randomized to a 12-week intervention of either high-intensity interval training (HIIT, n = 43) or active video gaming (AVG, n = 39). Participants were assessed at baseline, post intervention and four months later. The associations between exercise and the inflammatory markers soluble urokinase plasminogen activator receptor, c-reactive protein, tumor necrosis factor (TNF), soluble TNF receptor 1 and interleukin 6 (IL-6) were estimated using linear mixed effect models for repeated measures. For estimating associations between baseline inflammation and change in CRF, we used linear regression models. Our main findings were (i) TNF and IL-6 increased during the intervention period for both groups. Other inflammatory markers did not change during the exercise intervention period; (ii) baseline inflammatory status did not influence change in CRF during intervention, except for a positive association between baseline IL-6 levels and improvements of CRF to post intervention for both groups. In our study, HIIT and AVG for 12-weeks had no reducing effect on inflammatory markers. Patients with high baseline IL-6 levels had a positive change in CRF during intervention. In order to increase our knowledge regarding association between inflammatory markers and exercise in individuals with schizophrenia, larger studies with more frequent and longer exercise bout duration are warranted.

Association of Kidney Tubule Biomarkers With Cardiac Structure and Function in the Multiethnic Study of Atherosclerosis

Markers of glomerular disease, estimated glomerular filtration rate (eGFR) and albuminuria, are associated with cardiac structural abnormalities and incident cardiovascular disease (CVD). We aimed to determine whether biomarkers of kidney tubule injury, function, and systemic inflammation are associated with cardiac structural abnormalities. Among 393 Multi-Ethnic Study of Atherosclerosis participants without diabetes, CVD, or chronic kidney disease, we assessed the association of 12 biomarkers of kidney tubule injury, function, and systemic inflammation with the left ventricular mass/volume ratio (LVmvr) and left ventricular ejection fraction (LVEF) on cardiac magnetic resonance imaging using linear regression. The average age was 60 ± 10years; 48% were men; mean eGFR was 96±16ml/min/1.73m2; mean LVmvr was 0.93±0.18g/ml, and mean LVEF was 62±6%. Each twofold greater concentration of plasma soluble urokinase plasminogen activator receptor was associated with a 0.04g/ml (95% confidence interval [CI] 0.01 to 0.08 g/ml) higher LVmvr and 2.1% (95% CI 0.6 to 3.5%) lower LVEF, independent of risk factors for CVD, eGFR, and albuminuria. Each twofold greater plasma monocyte chemoattractant protein 1 was associated with higher LVmvr with a similar coefficient to that of plasma soluble urokinase plasminogen activator receptor. Each twofold greater concentration of plasma chitinase-3-like protein 1 and urine alpha-1-microglobulin was associated with a 1.1% (95% CI 0.4 to 1.7%) and 1.2% (95% CI 0.2 to 2.2%) lower LVEF, respectively. In conclusion, abnormal kidney tubule health may lead to cardiac dysfunction above and beyond eGFR and albuminuria.

Soluble Urokinase Plasminogen Activator Receptor (suPAR) in Autoimmune Rheumatic and Non Rheumatic Diseases.

The soluble urokinase plasminogen activator receptor (suPAR) is the bioactive form of uPAR, a membrane-bound glycoprotein, and it is primarily expressed on the surface of immunologically active cells. Mirroring local inflammation and immune activation, suPAR has gained interest as a potential prognostic biomarker in several inflammatory diseases. Indeed, in many diseases, including cancer, diabetes, cardiovascular diseases, kidney diseases, and inflammatory disorders, higher suPAR concentrations have been associated with disease severity, disease relapse, and mortality. Our review describes and discusses the supporting literature concerning the promising role of suPAR as a biomarker in different autoimmune rheumatic and non-rheumatic diseases.

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.

SuPAR links a dysregulated immune response to tissue inflammation and sepsis-induced acute kidney injury.

Acute kidney injury (AKI) secondary to sepsis results in poor outcomes and conventional kidney function indicators lack diagnostic value. Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune-derived molecule implicated in inflammatory organ damage. We characterized the diagnostic ability of longitudinal serum suPAR levels to discriminate severity and course of sepsis-induced AKI (SI-AKI) in 200 critically ill patients meeting Sepsis-3 criteria. The pathophysiologic relevance of varying suPAR levels in SI-AKI was explored in a polymicrobial sepsis model in WT, (s)uPAR-knockout, and transgenic suPAR-overexpressing mice. At all time points studied, suPAR provided a robust classification of SI-AKI disease severity, with improved prediction of renal replacement therapy (RRT) and mortality compared with established kidney biomarkers. Patients with suPAR levels of greater than 12.7 ng/mL were at highest risk for RRT or death, with an adjusted odds ratio of 7.48 (95% CI, 3.00-18.63). suPAR deficiency protected mice against SI-AKI. suPAR-overexpressing mice exhibited greater kidney damage and poorer survival through inflamed kidneys, accompanied by local upregulation of potent chemoattractants and pronounced kidney T cell infiltration. Hence, suPAR allows for an innate immune-derived and kidney function-independent staging of SI-AKI and offers improved longitudinal risk stratification. suPAR promotes T cell-based kidney inflammation, while suPAR deficiency improves SI-AKI.

Associations between plasma inflammatory markers and psychotic disorder, depressive disorder and generalised anxiety disorder in early adulthood: A nested case-control study

BackgroundLow-grade inflammation may occur in association with several mental disorders of early adulthood, though associations with markers of chronic inflammation such as soluble urokinase plasminogen activator receptor (suPAR) are less well-established. We aimed to examine associations between acute and chronic inflammatory markers and mental disorders, as well as psychiatric co-morbidity, in young adults aged 24 years in the Avon Longitudinal Study of Parents and Children. MethodsIncluded were 781 participants (of 4019 who attended at age 24 years) who completed psychiatric assessments and provided plasma samples. Of these, 377 met criteria for psychotic disorder, depressive disorder or generalised anxiety disorder and 404 did not. Plasma concentrations of IFN-γ, IL-6, IL-8, IL-10, TNF-α, CRP, sVCAM1, sICAM1, suPAR and alpha-2-macroglobulin were measured using immunoassays. Logistic regression compared standardised inflammatory marker levels in cases and controls. Negative binomial regression evaluated associations between inflammatory markers and co-morbidity (number of mental disorders). Models were adjusted for sex, body mass index, cigarette smoking, cannabis use and employment status, then additionally for childhood trauma. ResultsFor psychotic disorder, there was evidence for associations with IL-6 (odds ratio[OR] 1.68, 95 %CI 1.20–2.34) and suPAR (OR 1.74, 95 %CI 1.17–2.58). There was weaker evidence for an association between suPAR and depressive disorder (OR 1.31, 95 %CI 1.05–1.62). There was little evidence for associations between inflammatory markers and generalised anxiety disorder. There was weak evidence for an association between suPAR and co-morbidity (β 0.10, 95 %CI 0.01–0.19). There was little evidence for additional confounding by childhood trauma. ConclusionsThere was evidence that 24-year-olds with psychotic disorder had raised plasma IL-6 and suPAR concentrations compared to controls. These findings have implications regarding the role of inflammation in mental disorders in early adulthood.

Socioenvironmental Adversity and Adolescent Psychotic Experiences: Exploring Potential Mechanisms in a UK Longitudinal Cohort.

Children exposed to socioenvironmental adversities (eg, urbanicity, pollution, neighborhood deprivation, crime, and family disadvantage) are more likely to subsequently develop subclinical psychotic experiences during adolescence (eg, hearing voices, paranoia). However, the pathways through which this occurs have not been previously investigated. We hypothesized that cognitive ability and inflammation would partly explain this association. Data were utilized from the Environmental-Risk Longitudinal Twin Study, a cohort of 2232 children born in 1994-1995 in England and Wales and followed to age 18. Socioenvironmental adversities were measured from birth to age 10 and classified into physical risk (defined by high urbanicity and air pollution) and socioeconomic risk (defined by high neighborhood deprivation, neighborhood disorder, and family disadvantage). Cognitive abilities (overall, crystallized, fluid, and working memory) were assessed at age 12; and inflammatory markers (C-reactive protein, interleukin-6, soluble urokinase plasminogen activator receptor) were measured at age 18 from blood samples. Participants were interviewed at age 18 regarding psychotic experiences. Higher physical risk and socioeconomic risk were associated with increased odds of psychotic experiences in adolescence. The largest mediation pathways were from socioeconomic risk via overall cognitive ability and crystallized ability, which accounted for ~11% and ~19% of the association with psychotic experiences, respectively. No statistically significant pathways were found via inflammatory markers in exploratory (partially cross-sectional) analyses. Cognitive ability, especially crystallized ability, may partly explain the association between childhood socioenvironmental adversity and adolescent psychotic experiences. Interventions to support cognitive development among children living in disadvantaged settings could buffer them against developing subclinical psychotic phenomena.

Diagnostic and prognostic value of lipopolysaccharide binding protein and soluble urokinase plasminogen activator receptor in dogs with parvoviral enteritis

Amaç: Bu çalışmada, parvoviral enteritisli köpeklerde lipopolisakkarit bağlayıcı protein (LBP) ve soluble ürokinaz plazminojen aktivatör reseptörünün (suPAR) tanısal ve prognostik değerlendirilmesi amaçlanmıştır. Gereç ve Yöntem: Bu çalışmanın hayvan materyalini 1-6 ay yaşlar arasında farklı ırk ve cinsiyette kanlı ishal semptomu gösteren hızlı test kiti yardımıyla parvoviral enteritis teşhisi konulan 20 köpek hasta grubunu oluşturdu. Kontrol amacıyla kliniğe getirilen ve yapılan fiziksel muayeneler sonucunda sağlıklı olduğu belirlenen 10 köpek kontrol grubunu oluşturdu. Çalışmadaki köpeklerin tamamından bir defa Vena cephalica antebrachi’den 5 mL jelli serum tüplerine ve 2 mL K2EDTA’lı tüplere kan örnekleri alındı. EDTA’lı kan örneklerinden tam kan sayımı yapıldı. Bulgular: Serum örnekleri ise biyokimyasal ölçümler yapılana kadar -20°C’de muhafaza edildi. Hematoloji bulgularında hasta grupta total lökosit sayısı, eritrosit sayısı, hemoglobin sayısı ve hematokrit yüzdesi kontrol grubuna kıyasla istatistiksel olarak anlamlı düşük bulundu (P&lt;0,05). Hasta grupta kreatinin (P=0,040), üre (P=0,036), total bilirubin (P=0,011), seruloplazmin (P=0,008), haptoglobin (P&lt;0,001) ve LBP (P=0,011) konsantrasyonları kontrol grubuna göre istatistiksel olarak anlamlı yüksek bulurken, albümin (P=0,005) ve suPAR (P=0,012) konsantrasyonları düşük bulunmuştur. Sonuç: Sonuç olarak parvoviral enteritisli köpeklerde seruloplazmin, haptoglobin, LBP ve suPAR diagnostik ve prognostik olarak önemli bulunmuştur.

Inflammatory burden of adolescents with childhood maltreatment: results from baseline data of a school cohort.

Increasing studies have investigated inflammatory burden of adults with childhood adversity, but less is known about how childhood maltreatment affects the inflammation level of adolescents. Baseline data of a school cohort of physical and mental health status and life experience survey on primary and secondary school students in Anhui Province, China was used. Childhood maltreatment of children and adolescents was assessed by Chinese version of Childhood Trauma Questionnaire-Short Form (CTQ-SF). Urine samples were collected to assess levels of soluble urokinase Plasminogen Activator Receptor (suPAR), C-reactive protein (CRP) and cytokines interleukin-6 (IL-6) by enzyme-linked immunosorbent assay (ELISA). Logistic regression was conducted to examine the association between childhood maltreatment exposure and risk of high inflammation burden. A total of 844 students were included with mean age 11.41 ± 1.57years old. Adolescents with emotional abuse were significantly more likely to have high level of IL-6 (OR = 3.59, 95% CI 1.16-11.14). In addition, adolescents with emotional abuse were more likely to show high IL-6 and high suPAR combination (OR = 33.41, 95% CI 1.69-659.22), and high IL-6 and low CRP combination (OR = 4.34, 95% CI 1.29-14.55). Subgroup analyses showed that emotional abuse was associated with high IL-6 burden among boys or adolescents with depression. Childhood emotional abuse was positively associated with higher burden of IL-6. Early detection and prevention of emotional abuse for children and adolescents, especially for boys or adolescents with depression status, may be helpful for preventing elevated inflammatory burden and related health problems.

Anakinra as a potential treatment for COVID-19.

On November 8, 2022, the United States Food and Drug Administration (FDA) issued an emergency use authorization for the interleukin-1 (IL-1) inhibitor anakinra for the treatment of patients with COVID-19 pneumonia. The authorization was specifically intended for patients requiring supplemental oxygen who are at risk of progression to respiratory failure and are likely to have an elevated plasma soluble urokinase plasminogen activator receptor. Anakinra is a modified, recombinant human IL-1 receptor antagonist used to treat rheumatoid arthritis, neonatal-onset multisystem inflammatory disease and other inflammatory diseases. This manuscript examines what is known about the role of IL-1 receptor antagonism in the treatment of patients with COVID-19 and examines how anakinra may be used in the future to address the SARS-CoV-2 infection pandemic.

Serum HMGB1 and Soluble Urokinase Plasminogen Activator Receptor Levels Aid Diagnosis and Prognosis Prediction of Sepsis with Acute Respiratory Distress Syndrome

Objective: To study the clinical application of serum HMGB1 and soluble urokinase plasminogen activator receptor (suPAR) expression in sepsis with acute respiratory distress syndrome (ARDS). Methods: Clinical data of 303 septic patients with/without ARDS were documented. Levels of serum inflammatory markers and HMGB1/suPAR were measured. ARDS patients were subdivided into high and low HMGB1/suPAR expression groups and followed up. Results: Serum HMGB1 and suPAR were upregulated in ARDS patients and positively correlated with inflammatory markers. The combination of HMGB1 with suPAR surpassed HMGB1 or suPAR alone in aiding diagnosis of sepsis with ARDS. CRP, PCT, IL-6, HMGB1 and suPAR were independent risk factors for ARDS. High HMGB1/suPAR expression might be linked to poor prognosis. Conclusion: Serum HMGB1/suPAR levels might aid diagnosis and predict poor prognosis of septic patients with ARDS.

Soluble urokinase plasminogen activator receptor and survival in elective cardiac surgery.

The study investigated the prognostic value of soluble urokinase plasminogen activator receptor (suPAR) in patients undergoing cardiac surgery and calculated a simplified biomarker score comprising suPAR, N-terminal pro B-type natriuretic peptide (NT-proBNP) and age. Biomarkers were assessed in a cohort of 478 patients undergoing elective cardiac surgery. After a median follow-up of 4.2 years, a total of 72 (15.1%) patients died. SuPAR, NT-proBNP and age were independent prognosticators of mortality in a multivariable Cox regression model after adjustment for EuroScoreII. We then calculated a simplified biomarker score comprising age, suPAR and NT-proBNP, which had a superior prognostic value compared to EuroScoreII (Harrel's C of 0.76 vs. 0.72; P for difference=0.02). Besides long-term mortality, the biomarker score had an excellent performance predicting one-year mortality and hospitalization due to heart failure. The biomarker suPAR and NT-proBNP were strongly and independently associated with mortality in patients undergoing cardiac surgery. A simplified biomarker score comprising only three variables (age, suPAR and NT-proBNP) performed better than the established EuroScoreII with respect to intermediate and long-term outcome as well as hospitalization due to heart failure. As such, integration of established and upcoming biomarkers in clinical practice may provide improved decision support in cardiac surgery.

Interferon gamma-induced protein 10 (IP-10) for the early prognosis of the risk for severe respiratory failure and death in COVID-19 pneumonia.

Elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) predict progression to severe respiratory failure (SRF) or death among patients with COVID-19 pneumonia and guide early anakinra treatment. As suPAR testing may not be routinely available in every health-care setting, alternative biomarkers are needed. We investigated the performance of C-reactive protein (CRP), interferon gamma-induced protein-10 (IP-10) and TNF-related apoptosis-inducing ligand (TRAIL) for predicting SRF or death in COVID-19. Two cohorts were studied; one discovery cohort with 534 patients from the SAVE-MORE clinical trial; and one validation cohort with 364 patients from the SAVE trial including also 145 comparators. CRP, IP-10 and TRAIL were measured by the MeMed Key® platform in order to select the biomarker with the best prognostic performance for the early prediction of progression into SRF or death. IP-10 had the best prognostic performance: baseline concentrations 2000pg/ml or higher predicted equally well to suPAR (sensitivity 85.0%; negative predictive value 96.6%). Odds ratio for poor outcome among anakinra-treated participants of the SAVE-MORE trial was 0.35 compared to placebo when IP-10 was 2,000pg/ml or more. IP-10 could divide different strata of severity for SRF/death by day 14 in the validation cohort. Anakinra treatment decreased this risk irrespective the IP-10 concentrations. IP-10 concentrations of 2,000pg/ml or higher are a valid alternative to suPAR for the early prediction of progression into SRF or death the first 14days from hospital admission for COVID-19 and they may guide anakinra treatment. gov, NCT04680949 and NCT04357366.

Levels of peri-implant sulcular fluid levels of soluble urokinase plasminogen activator receptor and TNF-α among cigarette smokers and non-smokers with peri-implantitis.

Soluble urokinase plasminogen activator receptor (suPAR) and tumor necrosis factor-alpha (TNF-α) are inflammatory biomarkers. No studies have yet assessed the suPAR levels in relation with TNF-α in the peri-implant sulcular fluid (PISF) among cigarette smokers and non-smokers with peri-implantitis. The aim was to evaluate PISF levels of suPAR, and TNF-α among cigarette smokers and non-smokers with and without peri-implantitis. Sixty male patients with peri-implantitis were included. There were 20 cigarette smokers and 20 and non-smokers with peri-implantitis (Groups 1 and 2), and 20 non-smokers without peri-implantitis (Group 3). Demographic data and information related to cigarette smoking was recorded. Peri-implant clinicoradiographic parameters (plaque index [PI], gingival index [GI], probing depth [PD] and crestal bone loss [CBL]) were assessed. The PISF samples were collected and levels of suPAR and TNF-α were measured. Sample-size estimation was performed and all parameters were statistically assessed. Level of significance was set at P< 0.05. Sixty individuals were included in Groups 1, 2 and 3 (20 in each). Peri-implant PI (P< 0.01), PD (P< 0.01) and mesial (P< 0.01) and distal (P< 0.01) CBL were significantly higher in Group 1 than in Groups 2 and 3. The PISF volume (P< 0.01) and suPAR (P< 0.01) and TNF-α levels (P< 0.01) were significantly higher in Groups 1 and 2 than in Group 3. There was no difference in PISF volume and suPAR and TNF-α levels between patients in Groups 1 and 2. In Group 2, there was a statistically significant correlation between peri-implant PD and PISF suPAR and TNF-α levels (P< 0.01). The suPAR and TNF-α levels are expressed in high concentrations in the PISF of smokers and non-smokers with peri-implantitis compared with non-smokers without peri-implantitis. In non-smokers, PISF suPAR and TNF-α levels are correlated with peri-implant PD.