Elevated suPAR Levels Research Articles

Abstract 4132351: Soluble Urokinase Plasminogen Activator Receptor Levels Predict Incident Cardio-Kidney-Metabolic Disease Risk

Introduction: Given the rising global incidence of cardio-kidney-metabolic (CKM) syndrome, there is an urgent need for novel risk prediction strategies for CKM disease. Hypothesis: As soluble urokinase plasminogen activator receptor (suPAR) levels have been associated with the development of cardio-kidney disease, we hypothesized that elevated suPAR levels would predict incident CKM disease risk. Methods: A total of 25,596 UK Biobank participants without CKM disease at enrollment were analyzed for the association of suPAR levels and incident CKM disease. CKM disease was defined as the first occurrence of CVD (heart failure, atrial fibrillation/flutter, coronary heart disease, stroke, and peripheral artery disease), chronic kidney disease (CKD), or metabolic disease (type 2 diabetes mellitus and obesity). Incident CVD, CKD, and metabolic disease were also analyzed separately as secondary outcomes. Kaplan-Meier analysis was performed to visualize the association between suPAR levels and the primary composite CKM outcome. Competing-risk regression, while accounting for competing non-CKM disease death, was performed to examine the association between suPAR levels and the primary composite CKM outcome. Models were adjusted for demographics, traditional risk factors, and CRP levels. Results: The mean age was 56.0 (SD 8.3) years, 44% were male, and 94% were White. suPAR levels were associated with a significantly higher rate of composite CKM events (P<0.001) (Figure 1). During a median follow-up of 13.5 [IQR 1.7] years, 5,012 (20.0%) composite CKM events, 3,599 (8.3%) incident CVD events, 863 (3.4%) incident CKD events, and 1,397 (4.7%) incident metabolic disease events occurred. suPAR levels (per SD) significantly predicted the primary composite CKM outcome (sHR 1.23, 95% CI 1.19-1.27) after adjustment. suPAR levels (per SD) also significantly predicted incident CVD (sHR 1.24, 95% CI 1.19-1.29), incident CKD (sHR 1.41, 95% CI 1.30-1.53), and incident metabolic disease (sHR 1.17, 95% CI 1.10-1.24) after adjustment. Conclusion(s): In this large, longitudinal cohort study of UKB participants, plasma suPAR levels were a significant predictor of CKM disease risk, independent of demographics, traditional risk factors, and CRP levels.

Prognostic value of soluble urokinase plasminogen activator receptor (suPAR) in patients admitted with acute heart failure

Abstract Introduction The inflammatory marker, soluble urokinase plasminogen activator receptor (suPAR), has emerged as a promising prognostic biomarker of heart failure (HF). Higher levels of suPAR in plasma are indicative of hospital readmissions and mortality. Currently little is known about suPAR-values upon admission in patients with acute heart failure (AHF). Purpose This study investigates the prevalence of elevated suPAR and prognostic value in patients hospitalized with AHF. Methods In this prospective cohort study, all patients ≥ 18 years old admitted at the Emergency Department at a large University Hospital in Denmark, were consecutively included from March 10, 2020, to March 31, 2022. The follow-up period was 365 days. The biomarker suPAR was measured in all patients upon admission (median time from admission to suPAR measurement was two hours (IQR 3: 3,9-6,9)). Patient data was extracted from the electronic patient record system, and a cardiologist adjudicated whether the patients had AHF. Patients were stratified according to validated cut-off values of suPAR above or below 6 ng/mL. Kaplan-Meier survival analysis and Cox Regression were used to assess the association between suPAR levels and one-year mortality outcomes. Results A total of 408 (5%) AHF patients, from a total population of 6,715, were included in the study. 40 patients were excluded due to missing suPAR-values and the final analysis comprised of 368 AHF patients. Among AHF patients upon admission, the mean suPAR value was 6.2 ng/mL (standard deviation [SD] = 4.8 ng/mL), and non-AHF patients had a mean value of 4.5 ng/mL (SD = 3.1 ng/mL). A suPAR level above 6 ng/mL was significantly associated with mortality (figure 1), log-rank test p-value < 0.0001. Furthermore, Cox regression analysis demonstrated that elevated suPAR levels were independently associated with increased risk of mortality with a hazard ratio (HR): 2.09 (95% CI: 1.59-2.90), p-value < 0.001 after adjusting for potential confounders: age, sex, atrial fibrillation, Chronic Obstructive Pulmonary Disease, and Creatinine levels. Conclusion The inflammatory biomarker suPAR measured upon hospital admission in AHF patients is significantly associated with one-year mortality in patients admitted with AHF. The potential of suPAR as a valuable prognostic marker in AHF is offering clinicians a tool to identify high-risk patients and tailor management strategies, accordingly, thereby improving patient outcomes.Figure 1 - 1 year mortality

Interleukin-6 and suPAR are associated with diastolic function in type 1 diabetes: The Thousand & 1 Study

Abstract Background Heart failure (HF) is a common complication in individuals with type 1 diabetes (T1D). Inflammation is an important contributor to the pathogenesis and progression of both T1D and HF – especially HF with preserved ejection fraction (HFpEF). Diastolic dysfunction is a hallmark of HFpEF. Despite this, the association between diastolic function and inflammatory biomarkers is not well-known in individuals with T1D. Methods The Thousand & 1 study of individuals with T1D without known heart disease was studied. Diastolic parameters, including E/e’, was obtained by echocardiography and associated with Interleukin-6 (IL-6), soluble urokinase-type plasminogen activator receptor (suPAR) and high-sensitivity C-reactive protein (hsCRP). These inflammatory biomarkers were analysed as continuous variables and dichotomized in above/below 3 pg/mL (IL-6), 4 ng/mL (suPAR), and 4 mg/L (hsCRP). In multivariable regression analysis, adjustments were made for age, gender, body mass index, duration of diabetes, HbA1c, systolic blood pressure, left ventricular ejection fraction, glomerular filtration rate, albuminuria status, use of statins, tobacco use and physical activity levels. In an additional analyse, we also adjusted for N-terminal pro–B-type natriuretic peptide (NT-proBNP). Results We included 1,014 individuals (52% male, mean age 50±15). IL-6 was elevated in 207 individuals, suPAR in 182 individuals, and hsCRP in 863 individuals. Mean E/e’ was 7.6 and mean left ventricular ejection fraction was 58±5%. In fully adjusted models, inflammatory biomarkers were significantly associated with diastolic function. Thus, individuals with IL-6 > 3 pg/mL had 0.6 (95% confidence intervals: 0.2 to 1.0), P=0.001) higher E/e’ compared to individuals with IL-6 < 3 pg/mL. For every doubling of suPAR levels, E/e’ increased by 0.5 (0.2 to 0.9, P=0.003). For every doubling of hsCRP levels, E/e’ increased by 0.1 (0.02 to 0.2, P=0.022). Individuals with elevated levels of all three biomarkers had 1.9 (0.5 to 3.2, P=0.006) higher E/e’ compared to low levels of all three biomarkers. Including NTproBNP to the model did essentially not change the estimates. Conclusions Firstly, in T1D, elevated levels of IL-6, suPAR and hsCRP are associated with diastolic function assessed by E/e’, independent of traditional risk factors including NT-proBNP. Secondly, IL-6, suPAR and hsCRP may contain information about diastolic function in T1D which is not detected by NT-proBNP.Figure 1Figure 2

Evaluation of Soluble Urokinase Plasminogen Activator Receptor in COVID-19 Patients

Background/Objectives: This retrospective study analyzed soluble urokinase plasminogen activator receptor (suPAR) plasma levels alongside routine inflammatory markers, including the neutrophil-to-lymphocyte count ratio, C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), and D-dimers in COVID-19 patients hospitalized during the Omicron wave of the pandemic. Methods: We measured plasma suPAR levels using a suPARnostic® Quick Triage kit. We divided COVID-19 patients into two groups based on the severity of SARS-CoV-2 infection according to the National Institutes of Health (NIH) criteria. The logistic regression analysis tested the predictive value of the biomarkers. Results: We evaluated 160 consecutive COVID-19 patients hospitalized between January and August 2022. The cohort exhibited a high incidence of comorbidities, with an in-hospital mortality rate of 5.6%. Upon admission, the median suPAR plasma levels were not significantly different between patients with mild COVID-19 (n = 110) and those with moderate/severe disease (n = 50), with 7.25 ng/mL and 7.55 ng/mL, respectively. We observed significant differences (p < 0.01) between the groups for CRP and IL-6 levels that were higher in moderate/severe disease than in mild infection. Additionally, suPAR plasma levels were above the normal range (0–2.00 ng/mL) in all patients, with a significant positive correlation identified between suPAR levels and serum IL-6, PCT, and creatinine levels. Conclusions: These findings indicate that COVID-19 during the Omicron wave is strongly associated with elevated suPAR levels; however, these levels do not directly correlate with the severity of SARS-CoV-2 infection.

B-070 Supar: what UACR and GFR don't say…

Abstract Background Soluble urokinase-type plasminogen activator receptor (suPAR) is the circulating form of a three domain membrane protein expressed on a variety of cells, including immunologically active cells, endothelial cells, and podocytes. Diabetic nephropathy (DN) typically manifests with impaired glomerular filtration and microalbuminuria and progresses to end-stage renal disease. The study investigated whether high levels of suPAR may be added to KDIGO models that includes estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) to give more information about diabetic patients at higher risk of DN occurrence. Methods We measured plasma suPAR levels in 142 patients (67F/75M, median age 67 years) admitted to our hospital to check their glucose and glycated A1c hemoglobin (HbA1c) levels. We also recorded information about UACR and eGFR, and the relationship between suPAR levels and these parameters was investigated together with the distribution of suPAR levels according to KDIGO category risk of CKD. Results Among our study population, according to KDIGO risk category, 80 patients were at low risk, 47 were at moderate risk and 13 were at high risk of CKD. Mean plasma suPAR levels are 4.613±3.331 ng/mL, and significant correlation between suPAR and eGFR (P=0.0001) and between suPAR and HbA1c (P=0.0026) were found, while there is not a significant correlation with UACR (p=0.207) . According to KDIGO category risk, suPAR levels significantly increased from low to high risk, in particular, the increase is higher between the first two category (4.176 vs 6.285 ng/mL) risk compared to the highest (7.557 vs 7.427 ng/mL). We classified the 80 patients at low risk for KDIGO according suPAR levels divided into 4 quartiles according to literature (S. Salim Hayek et Al 2015) and 52 of them had suPAR levels in the third and fourth quartiles. Moreover, among these 52 patients, only 5 had HbA1c levels over the therapeutic target of 53 mmol/mol. Conclusions We identified an association between elevated plasma suPAR levels and a decline in the eGFR. However, we did not find a correlation with UACR, this is because suPAR levels are associated with a prospective membrane damage through interference with podocyte migration and apoptosis. According to this analysis, suPAR is a possible best candidate marker to stratify those patients who, according to the KDIGO criteria, are at low risk and have good glycemic compensation, but suPAR levels suggest a more careful follow-up.

A characterization of patients with low soluble urokinase plasminogen activator receptor who died within 90 days of hospital discharge.

Soluble urokinase plasminogen activator receptor (suPAR) is a marker of systemic chronic inflammation. Elevated suPAR levels are associated with adverse clinical outcomes, but a small subset of patients with low suPAR also experience poor outcomes. Therefore, we aimed to characterize patients presenting to the emergency department with low suPAR (<3 ng/mL) who died within 90 days after discharge in a registry-based study. Compared to patients with low suPAR who survived (n = 15 122), those who died within 90 days (n = 87) had higher age (75.4 years), higher medication use (7.0; 71.3% with polypharmacy) and more blood tests outside reference intervals (5.0) (including C-reactive protein, neutrophils and albumin), and the most common diagnoses were chronic pulmonary disease (27.6%), cerebrovascular disease (18.4%) and dementia (11.5%). Patients with low suPAR were more morbid than what was reflected by suPAR alone. Future studies must determine which factors that contribute the most to potential algorithms when stratifying patients based on their risk of adverse clinical outcomes. These data indicate that inclusion of medication data could be relevant.

Mechanism matters: mortality and endothelial cell damage marker differences between blunt and penetrating traumatic injuries across three prehospital clinical trials.

Injury mechanism is an important consideration when conducting clinical trials in trauma. Mechanisms of injury may be associated with differences in mortality risk and immune response to injury, impacting the potential success of the trial. We sought to characterize clinical and endothelial cell damage marker differences across blunt and penetrating injured patients enrolled in three large, prehospital randomized trials which focused on hemorrhagic shock. In this secondary analysis, patients with systolic blood pressure < 70 or systolic blood pressure < 90 and heart rate > 108 were included. In addition, patients with both blunt and penetrating injuries were excluded. The primary outcome was 30-day mortality. Mortality was characterized using Kaplan-Meier and Cox proportional-hazards models. Generalized linear models were used to compare biomarkers. Chi squared tests and Wilcoxon rank-sum were used to compare secondary outcomes. We characterized data of 696 enrolled patients that met all secondary analysis inclusion criteria. Blunt injured patients had significantly greater 24-h (18.6% vs. 10.7%, log rank p = 0.048) and 30-day mortality rates (29.7% vs. 14.0%, log rank p = 0.001) relative to penetrating injured patients with a different time course. After adjusting for confounders, blunt mechanism of injury was independently predictive of mortality at 30-days (HR 1.84, 95% CI 1.06-3.20, p = 0.029), but not 24-h (HR 1.65, 95% CI 0.86-3.18, p = 0.133). Elevated admission levels of endothelial cell damage markers, VEGF, syndecan-1, TM, S100A10, suPAR and HcDNA were associated with blunt mechanism of injury. Although there was no difference in multiple organ failure (MOF) rates across injury mechanism (48.4% vs. 42.98%, p = 0.275), blunt injured patients had higher Denver MOF score (p < 0.01). The significant increase in 30-day mortality and endothelial cell damage markers in blunt injury relative to penetrating injured patients highlights the importance of considering mechanism of injury within the inclusion and exclusion criteria of future clinical trials.

Role of Soluble Urokinase-Type Plasminogen Activator Receptor in Cardiovascular Disease.

Chronic inflammation is a major contributor to cardiovascular disease (CVD) risk. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived glycoprotein that is strongly associated with atherosclerotic disease. This review summarizes evidence on suPAR's role in CVD pathogenesis and its potential as a prognostic indicator and therapeutic target. Clinical, genetic, and experimental evidence supports suPAR's role as a pathogenic factor in atherosclerosis. suPAR promotes atherosclerosis through modulation of monocyte activation and function. Clinically, elevated suPAR levels are linked to increased cardiovascular risk across diverse populations. Ongoing clinical trials are evaluating therapies targeting suPAR signaling. Current evidence positions suPAR as a regulator of myeloid cell function that contributes to vascular inflammation and subsequent cardiovascular events. Additional research is needed to determine whether suPAR measurement can improve CVD risk prediction and enable personalized management. Overall, suPAR is a promising immune-derived biomarker and target for reducing inflammation and cardiovascular risk.

Soluble urokinase Plasminogen Activator Receptor (suPAR) is associated with educational attainment in patients with coronary artery disease

Abstract Background Biological mediators of adverse social determinants of health may include chronic low-grade inflammation. Elevation of circulating soluble urokinase Plasminogen Activator Receptor (suPAR) levels indicates activation of inflammatory and immune pathways and is associated with cardiovascular outcomes, independent of C-reactive protein (CRP) levels. Purpose We investigated whether the adverse impact of lower educational attainment on all-cause and cardiovascular mortality is mediated by elevated suPAR levels in patients with coronary artery disease (CAD). Methods In 3,164 patients undergoing coronary angiography, we investigated multivariable associations, including demographic characteristics, behavioral and clinical risk factors, between suPAR levels collected at the time of angiography and self-reported educational attainment, and assessed the relationship between lower educational level (defined as high school degree or less as highest educational qualification) and outcomes using Cox proportional hazard and Fine and Gray’s sub-distribution competing risk models. Mediation analyses were performed to assess the total effect of education on mortality, and the indirect effects through hs-CRP and suPAR on survival stratified by education using accelerated failure time models under exponential distribution. Results Mean age of the cohort was 64.5±11.9 years, with 32% women and 8.1±3.8 years follow-up. SuPAR levels were 9.0% [95% CI 6.3–11.8, p &amp;lt;0.0001] higher in patients achieving a lower (≤high school) compared to a higher (≥college) education after full covariate adjustment including hs-CRP levels. Lower educational attainment was associated with a higher risk of cardiovascular death (HR 1.39 [95% CI 1.15–1.68, p=0.0008]). After adjustment for demographic, clinical and behavioral covariates, and hs-CRP levels, this effect remained significant (HR 1.29 [95% CI 1.06–1.57, p=0.01]). However, after adjustment for suPAR levels, the effect of a lower educational level on cardiovascular mortality became insignificant. Values were similar for all-cause death. SuPAR levels mediated 49% and hs-CRP levels 17% of the association between lower educational attainment and cardiovascular mortality. Conclusion SuPAR importantly mediates the effects of lower educational attainment on mortality, indicating the importance of systemic inflammation and immune dysregulation as biologic mediators of adverse social determinants of health.Figure 1Central Illustration

Soluble urokinase Plasminogen Activator Receptor (suPAR) mediates the effect of a lower education level on adverse outcomes in patients with coronary artery disease.

To investigate whether the adverse impact of lower educational attainment on mortality risk in patients with coronary artery disease (CAD) is mediated by the activation of inflammatory and immune pathways, estimated as elevated soluble urokinase plasminogen activator receptor levels. In 3164 patients undergoing coronary angiography, we investigated multivariable associations between suPAR and educational attainment and assessed the relationship between a lower educational level (defined as a high-school degree or less as the highest educational qualification) and outcomes using Cox proportional hazard and Fine and Gray's subdistribution competing risk models. The potential mediating effect through suPAR and high-sensitivity C-reactive protein (hs-CRP) was assessed using mediation analysis. A total of 1814 patients (57.3%) had achieved a higher (≥college) education level and 1350 patients (42.7%) a lower (≤high school) education level. Soluble urokinase plasminogen activator receptor levels were 9.0% [95% confidence interval (CI) 6.3-11.8, P ≤ 0.0001] higher in patients with lower educational qualifications than in those with higher educational qualifications after covariate adjustment. Lower educational attainment was associated with a higher risk of cardiovascular death after adjustment for demographic, clinical, and behavioural covariates, including CAD severity and heart failure history, medication use, and hs-CRP levels [hazard ratio 1.26 (95% CI 1.02-1.55, P = 0.03)]. However, after adjustment for suPAR levels, the effect of a lower educational level on cardiovascular death became insignificant. Values were similar for all-cause death. Soluble urokinase plasminogen activator receptor levels mediated 49% and hs-CRP levels 17% of the cardiovascular death risk attributable to lower educational attainment. Circulating suPAR levels importantly mediate the effects of lower educational attainment on mortality, indicating the importance of systemic inflammation and immune dysregulation as biologic mediators of adverse social determinants of health.

Plasma Biomarkers and Incident CKD Among Individuals Without Diabetes

Biomarkers of kidney disease progression have been identified in individuals with diabetes and underlying chronic kidney disease (CKD). Whether or not these markers are associated with the development of CKD in a general population without diabetes or CKD is not well established. Prospective observational cohort. In the Atherosclerosis Risk in Communities) study, 948 participants were studied. The baseline plasma biomarkers of kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), soluble urokinase plasminogen activator receptor (suPAR), tumor necrosis factor receptor 1 (TNFR-1), tumor necrosis factor receptor 2 (TNFR-2), and human cartilage glycoprotein-39 (YKL-40) measured in 1996-1998. Incident CKD after 15 years of follow-up defined as≥40% estimated glomerular filtration rate decline to<60mL/min/1.73m2 or dialysis dependence through United States Renal Data System linkage. Logistic regression and C statistics. There were 523 cases of incident CKD. Compared with a random sample of 425 controls, there were greater odds of incident CKD per 2-fold higher concentration of KIM-1 (OR, 1.49; 95% CI, 1.25-1.78), suPAR (OR, 2.57; 95% CI, 1.74-3.84), TNFR-1 (OR, 2.20; 95% CI, 1.58-3.09), TNFR-2 (OR, 2.03; 95% CI, 1.37-3.04). After adjustment for all biomarkers, KIM-1 (OR, 1.42; 95% CI, 1.19-1.71), and suPAR (OR, 1.86; 95% CI, 1.18-2.92) remained associated with incident CKD. Compared with traditional risk factors, the addition of all 6 biomarkers improved the C statistic from 0.695-0.731 (P<0.01) and using the observed risk of 12% for incident CKD, the predicted risk gradient changed from 5%-40% (for the 1st-5th quintile) to 4%-44%. Biomarkers and creatinine were measured at one time point. Higher levels of KIM-1, suPAR, TNFR-1, and TNFR-2 were associated with higher odds of incident CKD among individuals without diabetes. For people with diabetes or kidney disease, several biomarkers have been shown to be associated with worsening kidney disease. Whether these biomarkers have prognostic significance in people without diabetes or kidney disease is less studied. Using the Atherosclerosis Risk in Communities study, we followed individuals without diabetes or kidney disease for an average of 15 years after biomarker measurement to see if these biomarkers were associated with the development of kidney disease. We found that elevated levels of KIM-1, suPAR, TNFR-1, and TNFR-2 were associated with the development of kidney disease. These biomarkers may help identify individuals who would benefit from interventions to prevent the development of kidney disease.

Abstract 419: Liberation Of Soluble Urokinase Plasminogen Receptor (supar) Occurs In Response To Coronavirus Infection But Not To Influenza Virus Infection

Objectives: Urokinase (uPA), and its receptor, uPAR, mediate fibrinolysis and matrix remodeling. Liberation of monocyte/macrophage (MO/Mϕ) bound uPAR to yield soluble uPAR (suPAR) occurs after infection with coronaviruses (CoVs) such as SARS-CoV-2, and suPAR levels correlate with systemic inflammation and degree of end organ injury. How suPAR liberation from MO/Mϕs occurs after CoV infection, and whether suPAR induction occurs after pneumotropic viral infections such as influenza A (IAV) is unclear. Methods: Murine bone marrow derived Mϕs (BMDMs) and immortalized Mϕs (RAW264.7) were infected with CoV [MHVA59 (murine model for SARS-CoV-2 infection) or MHV1] or with IAV (A/PR/8/34) and levels of mRNA and protein were measured using qRT-PCR and ELISA, respectively. uPA activity of cell supernatants was quantitated using a commercially available assay. uPA knockdown of Mϕs was performed using siRNA transfection. C57BL6/J mice underwent intranasal inoculation of either 2x10 5 pfu of MHVA59, 25 pfu of IAV, or with PBS (sham). Plasma levels of suPAR and splenic Mϕ (surrogate for circulating MOs) levels of mRNA and protein were analyzed at post-infection day 3. Results: Though both CoV or IAV infection resulted in induction of mRNA and protein levels of cellular uPAR and uPA, and uPA activity, only CoV infection yielded liberation of suPAR from Mϕs (Fig. 1A-C). Indicating a functional role in suPAR liberation, infection of uPA-silenced Mϕs yielded a blunted induction of suPAR release despite not affecting mRNA levels of uPAR (Fig 1D). Finally, inoculation of mice with MHVA59, but not with IAV, resulted in elevated plasma levels of suPAR, despite inducing a robust induction of uPAR in splenic Mϕs (Fig. 1E). Conclusions: suPAR induction results after CoV infection, but not IAV infection, and occurs through a uPA-dependent pathway. Antagonism of co-regulators of uPAR and uPA may prove to be a therapeutic strategy to combat post-CoV tissue injury mediated by Mϕs.

INCREASED SUPAR SERUM CONCENTRATIONS IN PATIENTS WITH LEFT AND RIGHT VENTRICULAR REMODELING DUE TO PRESSURE OVERLOAD IS ASSOCIATED WITH MYOCARDIAL MASS

<h3>Background</h3> Soluble urokinase plasminogen activator receptor (suPAR) is a novel biomarker, which has been investigated as a screening tool for risk stratification and to monitor therapeutic responses in various cardiovascular diseases.1 However, it has never been investigated whether suPAR plasma levels differ in left compared to right heart dysfunction. Therefore, we investigated suPAR in patients with right ventricular remodelling due to pressure overload resulting from chronic thromboembolic pulmonary hypertension (CTEPH) and compared it with suPAR in patients with left ventricular remodelling due to pressure-overload resulting from aortic valve stenosis (AS). In addition, we monitored the time course of suPAR after transcatheter- and surgical aortic valve replacement (TAVR) and (SAVR). <h3>Methods</h3> We analyzed blood samples of 78 CTEPH patients with pulmonary hypertension and 42 patients with left ventricular remodeling due to severe AS. Blood samples were drawn prior to pulmonary endarterectomy in CTEPH and prior to either SAVR or TAVR in patients with AS. Further, we investigated the therapeutic response of SAVR and TAVR 10 days and 3 months after surgery or intervention. ELISA testing of suPAR was performed according to manufacturers` instructions. <h3>Results</h3> Patients diagnosed with severe AS had significantly higher suPAR levels compared to patients with CTEPH and healthy volunteers [median 3.6 ng/ml (2.6, 7.3); p<0.05], [median 2.8 ng/ml (2.0, 3.9); p<0.05] and [median 1.5 ng/ml (1.0; 2.4); p<0.05] (Figure). Three months after TAVR, suPAR serum concentrations further increased compared to baseline levels prior to the intervention [median 4.7 (2.7; 8.5) to median 6.0 (3.9; 17.9); p<0.05]. In contrast, AS patients undergoing SAVR showed significantly decreased suPAR serum concentrations 10 days after surgery [median 3.3 ng/ml (2.5; 3.9) to median 2.3 ng/ml (2.0; 4.4); p<0.05]. <h3>Conclusion</h3> suPAR serum concentrations are more elevated in left compared to right heart pressure-overload and healthy volunteers, suggesting that suPAR is rather associated with myocardial mass than with pulmonary hypertension. The exact mechanisms leading to elevated suPAR levels in this context still have to be evaluated.

Association of Preoperative Basal Inflammatory State, Measured by Plasma suPAR Levels, with Intraoperative Sublingual Microvascular Perfusion in Patients Undergoing Major Non-Cardiac Surgery.

It remains unknown whether chronic systemic inflammation is associated with impaired microvascular perfusion during surgery. We evaluated the association between the preoperative basal inflammatory state, measured by plasma soluble urokinase-type plasminogen activator receptor (suPAR) levels, and intraoperative sublingual microcirculatory variables in patients undergoing major non-cardiac surgery. Plasma suPAR levels were determined in 100 non-cardiac surgery patients using the suPARnostic® quick triage lateral flow assay. We assessed sublingual microcirculation before surgical incision and every 30 min during surgery using Sidestream Darkfield (SDF+) imaging and determined the De Backer score, the Consensus Proportion of Perfused Vessels (Consensus PPV), and the Consensus PPV (small). Elevated suPAR levels were associated with lower intraoperative De Backer score, Consensus PPV, and Consensus PPV (small). For each ng mL−1 increase in suPAR, De Backer score, Consensus PPV, and Consensus PPV (small) decreased by 0.7 mm−1, 2.5%, and 2.8%, respectively, compared to baseline. In contrast, CRP was not significantly correlated with De Backer score (r = −0.034, p = 0.36), Consensus PPV (r = −0.014, p = 0.72) or Consensus PPV Small (r = −0.037, p = 0.32). Postoperative De Backer score did not change significantly from baseline (5.95 ± 3.21 vs. 5.89 ± 3.36, p = 0.404), while postoperative Consensus PPV (83.49 ± 11.5 vs. 81.15 ± 11.8, p < 0.001) and Consensus PPV (small) (80.87 ± 13.4 vs. 78.72 ± 13, p < 0.001) decreased significantly from baseline. In conclusion, elevated preoperative suPAR levels were associated with intraoperative impairment of sublingual microvascular perfusion in patients undergoing elective major non-cardiac surgery.

Soluble Urokinase Plasminogen Activator Receptor Levels Are Associated with Severity of Fibrosis in Patients with Primary Sclerosing Cholangitis.

The soluble urokinase-type plasminogen activator receptor (suPAR) has evolved as a useful biomarker for different entities of chronic liver disease. However, its role in patients with primary sclerosing cholangitis (PSC) is obscure. We analyzed plasma levels of suPAR in 84 patients with PSC and compared them to 68 patients with inflammatory bowel disease (IBD) without PSC and to 40 healthy controls. Results are correlated with clinical records. suPAR concentrations were elevated in patients with PSC compared to patients with IBD only and to healthy controls (p < 0.001). Elevated suPAR levels were associated with the presence of liver cirrhosis (p < 0.001) and signs of portal hypertension (p < 0.001). suPAR revealed a high accuracy for the discrimination of the presence of liver cirrhosis comparable to previously validated noninvasive fibrosis markers (area under the curve (AUC) 0.802 (95%CI: 0.702–0.902)). Further, we demonstrated that suPAR levels may indicate the presence of acute cholangitis episodes (p < 0.001). Finally, despite the high proportion of PSC patients with IBD, presence of IBD and its disease activity did not influence circulating suPAR levels. suPAR represents a previously unrecognized biomarker for diagnosis and liver cirrhosis detection in patients with PSC. However, it does not appear to be confounded by intestinal inflammation in the context of IBD.

Inflammatory burden in adolescents with prolonged parent-child separation

BackgroundProlonged parent–child separation is associated with a broad array of poor developmental outcomes. A potential pathway may be through changes in inflammatory processes. However, relatively little is known about the relationship between parent–child separation pattern (timing and duration) and inflammatory burden. The aim of this study was to investigate whether parent–child separation since birth is associated with inflammatory burden in adolescents. MethodsA total of 574 adolescents (mean age 12.07 years, SD: 0.62) were enrolled from rural areas of Chizhou, Anhui Province, China. Parent-child separation was reported mainly by primary caregivers, and other adverse childhood adversities (ACEs) were derived from adolescents semi-structured interview or questionnaire. Blood samples were collected from venepuncture for C-reactive protein (CRP) as well as soluble urokinase plasminogen activator receptor (suPAR). ResultsNearly 40% (232/574) participants experienced parent–child separation, among which more than 1 of 4 persistently separated from both parents since birth. Both CRP and suPAR levels were significantly higher among adolescents persistently separated from both parents, compared with those who did not separate from both parents (CRP: 1.75 vs. 1.36 mg/L, P < 0.001; suPAR: 2.85 ng/mL vs. 2.55 ng/mL, P < 0.001). After adjusted for demographic covariates, body mass index, ACEs as well as parental characteristics, persistent parent–child separation was associated with elevated suPAR (B = 0.30; 95% CI, 0.12–0.48) and CRP (B = 1.34; 95% CI, 1.02–1.75). No similar associations were observed between inflammatory burden with current or early childhood parent–child separation groups. Adolescents who exposed to persistent parent–child separation were more likely to have elevated suPAR levels even if they did not have elevated CRP levels (aOR, 4.26, 95% CI, 1.23–14.80; P = 0.022). ConclusionElevated inflammatory burden observed in persistent parent–child separation adolescents highlights the need to support children and adolescents undergoing separation from both parents in order to minimize the long-term impact on disease vulnerability.

Associations between childhood victimization, inflammatory biomarkers and psychotic phenomena in adolescence: A longitudinal cohort study

Exposure to victimization in childhood has been linked to the development of psychosis. However, little is known about how childhood victimization is translated into biological risk for psychosis. One possibility is via increased inflammation. This study aimed to investigate the association between childhood victimization, psychotic experiences (PEs) in adolescence and inflammatory markers using data from a general population cohort. Participants were 1,419 British-born children followed from birth to age 18 years as part of the Environmental Risk Longitudinal Twin Study. Childhood victimization was measured prospectively using multiple sources from birth to age 12 years. PEs were assessed during private interviews with participants at age 18 years for the period since age 12. Plasma C-reactive protein (CRP), interleukin-6 (IL-6), and soluble urokinase plasminogen activator receptor (suPAR) levels were measured from plasma samples collected from participants at 18 years. Young people with both PEs and childhood victimization were more likely to belong to a group with elevated suPAR, CRP and IL-6 levels at 18 years of age (OR = 3.34, 95% CI 1.69–6.59, p = 0.001) than those with no childhood victimization and without PEs. However, this association was attenuated when adjusted for other risk factors for elevated inflammation at age 18 (OR = 1.94, 95% CI 0.94–4.04, p = 0.075). In contrast, presence of PEs without childhood victimization was not significantly associated with age-18 inflammatory markers and neither was childhood victimization without PEs (all p’s greater than 0.05). The current study highlights that inflammatory dysregulation is mostly present in adolescents reporting PEs who also experienced childhood victimization, though this seemed to be largely due to concurrent inflammation-related risk factors.

Prognostic Impact of Preoperative Plasma Levels of Urokinase Plasminogen Activator Proteins on Disease Outcomes after Radical Cystectomy.

We sought to validate the association of plasma levels of urokinase-type plasminogen activator (uPA), its soluble receptor (SuPAR) and its inhibitor (PAI-one) with oncologic outcomes in a large cohort of patients treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). We collected preoperative blood samples from 1,036 consecutive patients treated with RC for UCB. Plasma specimens were assessed for levels of uPA, SuPAR and PAI-one. Retrospective logistic and Cox regression analyses were performed to assess their correlation with clinical outcomes. The additional clinical net benefit provided by the biomarkers was evaluated using decision curve analysis. Preoperative plasma uPA, SuPAR and PAI-one levels were significantly elevated in patients harboring adverse pathological features. Higher levels of all biomarkers were independently associated with an increased risk of lymph node metastasis; uPA levels were also independently associated with ≥pT3 disease. Preoperative uPA and SuPAR were independently associated with recurrence-free and cancer-specific survival. The addition of these biomarkers to standard pre-treatment and post-treatment models improved the discriminatory power for prediction of lymph node metastasis, ≥pT3 disease, and recurrence-free and cancer-specific survival by a prognostically significant margin. We confirmed that elevated preoperative plasma levels of uPA, SuPAR and PAI-one are associated with features of aggressive disease and worse survival outcomes in patients treated with RC for UCB. These biomarkers hold potential in identifying patients who are likely to benefit from intensified/multimodal therapy. They also demonstrated the ability to improve the discriminatory power of predictive/prognostic models, thus refining personalized clinical decision-making.

Prognostic value of suPAR and hsCRP on acute kidney injury after cardiac surgery

BackgroundAcute kidney injury (AKI) represents a serious complication following cardiac surgery. Adverse outcome after cardiac surgery has been observed in the presence of elevated levels of soluble urokinase-type plasminogen activator receptor (suPAR) and high-sensitivity C-Reactive Protein (hsCRP). The aim of study was (i) to investigate the relationship between preoperative elevated levels of suPAR and hsCRP and postoperative AKI in unselected cardiac surgery patients and (ii) to assess whether the concentration of the biomarkers reflected severity of AKI.MethodsIn a retrospective observational study, biobank blood plasma samples (n = 924) from patients admitted for elective on-pump cardiac surgery were analysed for suPAR and hsCRP levels. The relation between suPAR and hsCRP-values and AKI (any stage), defined by the KDIGO (Kidney Disease: Improving Global Outcomes) criteria, was assessed using adjusted logistic regression. Further, the association between biomarkers and severity (KDIGO 1, KDIGO 2–3 and renal replacement therapy (RRT)) was assessed using adjusted logistic regression.ResultsPostoperative AKI (any stage) was observed in 327 patients (35.4 %). A doubling of preoperative suPAR corresponded to an adjusted odds ratio (OR) for postoperative AKI (any stage) of 1.62 (95 % CI 1.26–2.09, p < 0.001). Furthermore, a doubling of suPAR had an adjusted OR of 1.50 (95 % CI 1.16–1.93, p = 0.002), 2.44 (95 % CI 1.56–3.82, p < 0.001) and 1.92 (95 % CI 1.15–3.23, p = 0.002), for KDIGO 1, KDIGO 2–3 and need for RRT, respectively. No significant association was found between elevated levels of hsCRP and any degree of AKI.ConclusionsIncreasing levels of suPAR, but not hsCRP, were associated with development and severity of AKI following on-pump cardiac surgery.

Soluble Urokinase-Type Plasminogen Activator Receptor, Changes of 24-Hour Blood Pressure, and Progression of Chronic Kidney Disease.

BackgroundSoluble urokinase‐type plasminogen activator receptor (suPAR) is associated with cardiovascular risks and poor renal outcomes. However, whether elevated suPAR levels are associated with 24‐hour blood pressure patterns or kidney disease progression in patients with chronic kidney disease (CKD) is unclear.Methods and ResultsA total of 751 patients with CKD stage 1 to 5 were recruited from CMERC‐HI (Cardiovascular and Metabolic Disease Etiology Research Center–High Risk) cohort study (2013–2018). The relationship of serum suPAR levels to 24‐hour blood pressure parameters and CKD progression was analyzed. The median serum suPAR level was 1439.0 (interquartile range, 1026.2–2150.1) pg/mL, and the mean estimated glomerular filtration rate was 52.8±28.5 mL/min per 1.73 m2 at baseline. Patients with higher suPAR levels had significantly higher levels of office, 24‐hour, daytime, and nighttime systolic blood pressure and nighttime diastolic blood pressure than those with lower suPAR levels. The highest suPAR tertile was associated with an increased risk of a reverse dipping pattern (odds ratio, 2.93; 95% CI, 1.27–6.76; P=0.01). During a follow‐up of 43.2 (interquartile range, 27.0–55.6) months, the CKD progression occurred in 271 (36.1%) patients. The highest suPAR tertile was significantly associated with higher risk of CKD progression than the lowest tertile (hazard ratio [HR], 2.09; 95% CI, 1.37–3.21; P=0.001). When the relationship was reevaluated with respect to each dipping pattern (dipper, extreme dipper, nondipper, and reverse dipper), this association was consistent only in reverse dippers in whom the risk of CKD progression increased (HR, 1.43; 95% CI, 1.02–2.01; P=0.03) with every 1‐unit increase in serum suPAR levels.ConclusionsElevated suPAR levels are independently associated with CKD progression, and this association is prominent in reverse dippers.