Plasma Soluble Urokinase Plasminogen Activator Research Articles

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial

BackgroundEndotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial.MethodsAdult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of ≥ 6 ng/ml in the SAVE-MORE trial (NCT04680949) were characterized at baseline and days 4 and 7 of treatment using a previously defined 33-messenger RNA classifier to assign an immunological endotype in blood. Endpoints were changes in endotypes and progression to severe respiratory failure (SRF) associated with anakinra treatment.ResultsAt baseline, 23.2% of 393 patients were designated as inflammopathic, 41.1% as adaptive, and 35.7% as coagulopathic. Only 23.9% were designated as the same endotype at days 4 and 7 compared to baseline, while all other patients transitioned between endotypes. Anakinra-treated patients were more likely to remain in the adaptive endotype during 7-day treatment (24.4% vs. 9.9%; p < 0.001). Anakinra also protected patients with coagulopathic endotype at day 7 against SRF compared to placebo (27.8% vs. 55.9%; p = 0.013).ConclusionWe identify an association between endotypes defined using blood transcriptome and anakinra therapy for COVID-19 pneumonia, with anakinra-treated patients shifting toward endotypes associated with a better outcome, mainly the adaptive endotype.Trial registration ClinicalTrials.gov, NCT04680949, December 23, 2020.

Using Machine Learning to Determine a Suitable Patient Population for Anakinra for the Treatment of COVID-19 Under the Emergency Use Authorization.

A randomized, double-blind, placebo-controlled study (SAVEMORE trial) provided data to support an Emergency Use Authorization (EUA) of anakinra in hospitalized adults with positive results of direct severe acute respiratory syndrome-coronavirus 2 viral testing with pneumonia requiring supplemental oxygen (low- or high-flow oxygen) who are at risk of progressing to severe respiratory failure and likely to have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR). Currently, the suPAR assay is not commercially available in the United States. An alternative method was needed to identify patients that best reflect the population in the clinical trial selected based on suPAR level ≥ 6 ng/mL at baseline. A machine learning approach based on data from the SAVEMORE trial was used to develop a scoring rule to identify patients who are likely to have a suPAR level ≥ 6 ng/mL at baseline. External validation of the scoring rule was conducted with data from a different trial (SAVE). This clinical scoring rule with high positive predictive value, high specificity, reasonable sensitivity, and biological relevance is expected to identify patients who are likely to have an elevated suPAR level ≥ 6 ng/mL at baseline. As such, it is included in the EUA to identify patients that fall within the authorized population for whom the known and potential benefits outweigh the known and potential risks of anakinra.

P-suPAR may reflect the inflammatory response after pancreatic surgery

BackgroundSeveral different scoring systems have been developed to predict post-pancreatectomy complications. Currently used inflammatory markers are of only limited value in predicting complications after pancreatic surgery. Plasma soluble urokinase plasminogen activator receptor (P-suPAR) is a prognostic biomarker associated with different inflammatory conditions. The aim of this study was to investigate P-suPAR levels before and after pancreatic surgery. MethodsOne hundred and seventy-six patients evaluated for pancreatic surgery due to suspected malignant or premalignant lesion were recruited for this study at Tampere University Hospital between 2016 and 2021. P-suPAR was analyzed before the planned operation and on postoperative days (PODs) one and three. ResultsOne hundred and thirty-three patients [median age 67 (range 33–84) years, 50 % male] underwent a pancreatic surgery procedure. Compared to preoperative values [median 3.7 (IQR 3.1–4.7) ng/mL], P-suPAR was significantly lower on PODs 1 [3.2 (2.5–3.9) ng/mL; p < 0.001] and 3 [3.2 (2.7–4.1) ng/mL; p < 0.001]. P-suPAR on POD 1 was significantly lower in patients with postoperative pancreatic fistula (POPF) [2.6 (2.1–3.4) ng/mL] than in patients with no POPF [3.2 (2.6–3.8) ng/mL; p = 0.007]. Similar decreases in P-suPAR values were seen in patients with postoperative acute pancreatitis (POAP) and surgical site infection (SSI). ConclusionsAfter pancreatic surgery, P-suPAR level on POD 1 is significantly lower in patients with POPF, POAP or SSI. P-suPAR is decreased after pancreatic resection in all patients. This type of postoperative P-suPAR profile has not previously been described, and may reflect the compensatory anti-inflammatory reaction following the initial systemic inflammatory reaction caused by surgical trauma.

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.

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.

Efficacy and safety of early soluble urokinase plasminogen receptor plasma-guided anakinra treatment of COVID-19 pneumonia: a subgroup analysis of the SAVE-MORE randomised trial

The SAVE-MORE trial demonstrated that anakinra treatment in COVID-19 pneumonia with plasma soluble urokinase plasminogen activator (suPAR) levels of 6ng/mL or more was associated with 0.36 odds for a worse outcome compared to placebo when expressed by the WHO-Clinical Progression Scale (CPS) at day 28. Herein, we report the results of subgroup analyses and long-term outcomes. This prospective, double-blind, randomised clinical trial, recruited patients with a confirmed SARS-CoV-2 infection, in need of hospitalisation, lower respiratory tract infection and plasma suPAR ≥6ng/mL from 37 academic and community hospitals in Greece and Italy. Patients were 1:2 randomised to subcutaneous treatment with placebo or anakinra (100mg) once daily for 10 days. Pre-defined subgroups of Charlson's comorbidity index (CCI), sex, age, level of suPAR, and time from symptom onset were analysed for the primary endpoint (overall comparison of distribution of frequencies of the scores from the WHO-CPS between treatments on day 28), by multivariable ordinal regression analysis in the intention to treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2020-005828-11) and ClinicalTrials.gov (NCT04680949). Patients were enrolled between 23 December 2020 and 31 March 2021; 189 patients in the placebo arm and 405 patients in the anakinra arm were the ITT population. Multivariable analysis showed that anakinra treatment was accompanied by significantly lower odds for worse outcome compared to placebo at day 28 for all studied subgroups (CCI ≥ 2, OR: 0.34, 95% confidence intervals [CI] 0.22-0.50; CCI < 2, OR: 0.38, 95% CI 0.21-0.68; suPAR > 9ng/mL, OR: 0.35, 95% CI 0.19-0.66; suPAR 6-9ng/mL, OR: 0.35, 95% CI 0.24-0.52; patients ≥65 years, OR: 0.41, 95% CI 0.25-0.66; and patients <65 years, OR: 0.29, 95% CI 0.19-0.45). The benefit was uniform, irrespective of the time from start of symptoms until the start of the study drug. At days 60 and 90, anakinra treatment had odds of 0.40 (95% CI 0.28-0.57) and 0.46 (95% CI 0.32-0.67) respectively, for a worse outcome compared to placebo. The costs of general ward stay, ICU stay, and drugs were lower with anakinra treatment. Anakinra represents an important therapeutic tool in the management of COVID-19 that may be administered in all subgroups of patients; benefits are maintained until day90. Hellenic Institute for the Study of Sepsis; Swedish Orphan Biovitrum AB.

Soluble urokinase plasminogen activator receptor is associated with short-term mortality and enhanced reactive oxygen species production in acute-on-chronic liver failure

BackgroundAcute-on-chronic liver failure (ACLF) is a comprehensive syndrome characterized by an acute deterioration of liver function and high short-term mortality rates in patients with chronic liver disease. Whether plasma soluble urokinase plasminogen activator receptor (suPAR) is a suitable biomarker for the prognosis of patients with ACLF remains unknown.MethodA prospective cohort of 282 patients with ACLF from three hospitals in China was included. 88.4% of the group was hepatitis B virus-related ACLF (HBV-related ACLF). Cox regression was used to assess the impact of plasma suPAR and other factors on 30- and 90-day mortality. Reactive oxygen species (ROS) production were detected to explore the role of suPAR in regulating neutrophil function in HBV-related ACLF.ResultThere was no difference in plasma suPAR levels between HBV-related and non-HBV-related ACLF. Patients with clinical complications had higher suPAR levels than those without these complications. A significant correlation was also found between suPAR and prognostic scores, infection indicators and inflammatory cytokines. Cox’s regression multivariate analysis identified suPAR ≥ 14.7 ng/mL as a predictor for both day 30 and 90 mortality (Area under the ROC curve: 0.751 and 0.742 respectively), independent of the MELD and SOFA scores in patients with ACLF. Moreover, we firstly discovered suPAR enhanced neutrophil ROS production under E.coli stimulation in patients with HBV-related ACLF.ConclusionssuPAR was a useful independent biomarker of short-term outcomes in patients with ACLF and might play a key role in the pathogenesis.Trial registration CNT, NCT02965560.

Elevated preoperative suPAR is a strong and independent risk marker for postoperative complications in patients undergoing major noncardiac surgery (SPARSE)

BackgroundPatients undergoing major surgery are often at risk of developing postoperative complications. We investigated whether a preoperative marker of chronic inflammation, soluble urokinase plasminogen activator receptor, can aid in identifying patients at high risk for postoperative complications, morbidity, and mortality. MethodsIn this prospective observational study (ClinicalTrials.gov identifier: NCT03851965), EDTA blood was collected from consecutive adult White patients scheduled for major noncardiac surgery with expected duration ≥2 hours under general anesthesia. Inclusion criteria were age ≥18 years and American Society of Anesthesiologists physical status I to IV. Plasma soluble urokinase plasminogen activator receptor levels were determined using the suPARnostic quick triage lateral flow assay. The primary endpoint was postoperative complications defined as presence of any complication and/or admission to intensive care unit and/or mortality within the first 90 postoperative days. ResultsPreoperative soluble urokinase plasminogen activator receptor had an odds ratio of 1.50 (95% confidence interval: 1.24–1.82) for every ng/mL increase. When including age, sex, American Society of Anesthesiologists score, C-reactive protein, and grouped soluble urokinase plasminogen activator receptor in multivariate analysis, patients with soluble urokinase plasminogen activator receptor between 5.5 and 10 ng/mL had an odds ratio of 11.2 (confidence interval: 3.1–40.8) and patients with soluble urokinase plasminogen activator receptor >10 ng/mL had an odds ratio of 19.9 (95% confidence interval: 4.3–92.9) compared to patients with soluble urokinase plasminogen activator receptor ≤5.5 ng/mL, respectively. Receiver operating characteristic analysis of soluble urokinase plasminogen activator receptor showed an area under the curve of 0.82 (confidence interval: 0.72–0.91). Receiver operating characteristic analysis combining age, sex, C-reactive protein levels, and American Society of Anesthesiologists score and had an area under the curve of 0.71 (95% confidence interval: 0.61–0.82). Adding soluble urokinase plasminogen activator receptor to this model increased the area under the curve to 0.83 (95% confidence interval: 0.74–0.92) (P = .033). ConclusionPreoperative soluble urokinase plasminogen activator receptor provided strong and independent predictive value on postoperative complications in White patients undergoing major noncardiac surgery.

Utility of suPAR and NGAL for AKI Risk Stratification and Early Optimization of Renal Risk Medications among Older Patients in the Emergency Department.

Diagnosis of acute kidney injury (AKI) based on plasma creatinine often lags behind actual changes in renal function. Here, we investigated early detection of AKI using the plasma soluble urokinase plasminogen activator receptor (suPAR) and neutrophil gelatinase-sssociated lipocalin (NGAL) and observed the impact of early detection on prescribing recommendations for renally-eliminated medications. This study is a secondary analysis of data from the DISABLMENT cohort on acutely admitted older (≥65 years) medical patients (n = 339). Presence of AKI according to kidney disease: improving global outcomes (KDIGO) criteria was identified from inclusion to 48 h after inclusion. Discriminatory power of suPAR and NGAL was determined by receiver-operating characteristic (ROC). Selected medications that are contraindicated in AKI were identified in Renbase®. A total of 33 (9.7%) patients developed AKI. Discriminatory power for suPAR and NGAL was 0.69 and 0.78, respectively, at a cutoff of 4.26 ng/mL and 139.5 ng/mL, respectively. The interaction of suPAR and NGAL yielded a discriminatory power of 0.80, which was significantly higher than for suPAR alone (p = 0.0059). Among patients with AKI, 22 (60.6%) used at least one medication that should be avoided in AKI. Overall, suPAR and NGAL levels were independently associated with incident AKI and their combination yielded excellent discriminatory power for risk determination of AKI.

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.

FC 043SOLUBLE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR (SUPAR) DETERMINES OUTCOMES IN CLINICAL AND EXPERIMENTAL SEPTIC ACUTE KIDNEY INJURY

Abstract Background and Aims Sepsis is the main contributor to the development of acute kidney injury (AKI) in critically ill patients. Plasma soluble urokinase plasminogen activator receptor (suPAR) is a circulating risk factor for AKI and a new prognostic marker for renal outcome prediction. We analyzed the pathophysiological role and kinetic properties of suPAR in septic AKI in critically ill patients and in a murine model of septic AKI. Method 200 critically ill patients were enrolled prospectively after meeting Sepsis-3 criteria. Serum suPAR levels were measured at 0, 12, 24, 48, 72, 96, 120 and 168-hour after enrollment (n=1440) and the need for RRT within 7 days (predefined criteria) was assessed as the primary outcome measure. Polybacterial sepsis was induced by cecal slurry injection in three mouse strains, respectively wild type (WT, N=16), uPAR-knockout (KO, N=15), and suPAR transgenic overexpression (OE, N=14). Results No or mild AKI occurred in 62 patients (31.0%), moderate or severe AKI without the need for RRT in 102 patients (51.0%), criteria for RRT were met in 36 patients (18.0%) and 7 patients (3.5%) died within the 7-day period. Compared to all other maximum AKI stages and AKI disease courses within 7 days, patients requiring RRT showed significantly higher suPAR levels at all time-points. Patients with suPAR levels ≥ 12.7 ng/mL (highest quartile) had an unadjusted odds ratio (OR) of 9.73 (95% confidence interval [CI], 4.31-21.98) and an adjusted odds ratio of 5.22 (95% CI, 2.16-12.65) for the need for RRT; and 7.47 (95% CI, 3.54-15.74) and 4.44 (95% CI, 1.98-9.97) for RRT or death within 7 days compared to patients with levels &amp;lt; 12.7 ng/mL. Compared to KO mice, WT and OE mice showed a significantly greater impairment of renal function, structure and tubular apoptosis 24 hours after induction of sepsis. The inflammation levels with respect to Interleukin 6 were comparable between different strains. Kaplan-Meier analysis revealed a survival benefit of KO mice over OE mice within 24h (86.7% vs. 50.0%, p=0.033). Conclusion SuPAR distinguishes between divergent AKI stages/courses and the need for RRT at any time within 7 days after sepsis diagnosis. Our experimental data suggest that suPAR is a pathophysiological driver of septic AKI and may serve as a target for future interventional strategies.

Evaluation of Plasma Urokinase-Type Plasminogen Activator Receptor and Interleukin 34 in Patients with Chronic Hepatitis C as Serological Fibrosis Markers

Background: Hepatitis C Virus (HCV) infection is a progressive disease that may result in chronic hepatitis, fibrosis and cirrhosis. Assessment of liver fibrosis is an essential factor in the management of chronic HCV. Objective: To evaluate plasma soluble Urokinase Plasminogen Activator Receptor (sUPAR) and interleukin-34 (IL-34) as serological markers of liver fibrosis in patients with chronic HCV. Methods: This case-control study enrolled 60 chronic HCV patients who were subdivided into three groups of mild, moderate and severe hepatic fibrosis depending on Fibrosis-4 score (FIB-4). Patients were compared with 20 age and sex-matched controls. Plasma sUPAR and IL-34 levels were measured by Enzyme Linked Immunosorbent Assay (ELISA). Results: Plasma sUPAR and IL-34 were significantly increased in HCV patients when compared with controls, and their increase was positively correlated with the progression of hepatic fibrosis. Plasma sUPAR and IL-34 positively correlated with Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT), and negatively correlated with hemoglobin concentration and platelet count. The output data of Receiver Operating Characteristic (ROC) curve to differentiate patients from controls revealed that sUPAR at cut-off > 186.2 ng/L and Area Under Curve (AUC) of 0.944 had (85%) sensitivity and (100%) specificity, and IL-34 at cut off > 16.4 ng/L and AUC of 0.942 had (75%) sensitivity and (100%) specificity. The output data of ROC curve to differentiate severe from mild to moderate hepatic fibrosis patients revealed that sUPAR at cut-off > 510 ng/L and AUC of 0.837 had (80%) sensitivity and (90%) specificity. While IL-34 at cut off > 55.3 ng/L and AUC of 0.844 had (85%) sensitivity and (80%) specificity. Conclusions: Increased plasma levels of sUPAR and IL-34 in chronic HCV patients with liver fibrosis and their increase was parallel to the degree of liver fibrosis. Plasma sUPAR and IL-34 can be used as serological markers of liver fibrosis in chronic HCV patients.

Clinical value of soluble urokinase-type plasminogen activator receptor (SuPAR) as a biomarker of disease activity in Behcet’s disease

Background: Behçet's disease (BD) is a chronic multisystemic vasculitic disease of unknown pathogenesis. Diagnosis and disease activity measurement has always been a challenge. Soluble urokinase plasminogen activator receptor (suPAR) is showing an increased utility as a promising diagnostic and prognostic inflammatory biomarker in different systemic inflammatory disorders. Objectives: To study the clinical value of plasma Soluble urokinase plasminogen activator receptor (suPAR) in patients with Behçet's disease, and if it can be used as a measure to disease activity. Methods: According to the International Criteria for Behcet's Disease (ICBD), fifty adult Behçet's disease patients were enrolled in the study, and forty healthy adult subjects were included in a case-control study. An enzyme-linked immunosorbent assay was used to obtain quantitative data. Results: The suPAR level was not statistically different between the patients with BD patients and the controls. No correlation was found between suPAR levels and disease activity (BDFAC). Conclusion: Very few studies analyzed the clinical value of suPAR level in patients with BD and its correlation with disease activity. Our results show that suPAR does not seem to play a role in the disease mechanism of BD.

The relationship between levels of plasma-soluble urokinase plasminogen activator receptor (suPAR) and presence of migraine attack and aura

Migraine is one of the most common types of pain associated with sterile inflammatory conditions. Soluble urokinase plasminogen activator receptor (suPAR) is a potential novel inflammatory marker. We aim to determine the association between serum values of suPAR, procalcitonin, fibrinogen, and high-sensitivity C-reactive protein (hs-CRP) and migraine disease characteristics. The study involved a total of 60 migraine patients (33 patients in the interictal period, 27 patients in the attack period) and 30 healthy individuals. The serum values of suPAR were found to be significantly higher in migraine patients in the attack period than in migraine patients in the interictal period, and in healthy individuals (p < .01 for both). In addition, levels of suPAR were determined to be higher in migraine with aura patients than in migraine without aura patients. When we subdivided migraine patients according to frequency of attack (attacks/month), significant differences were found between the suPAR and procalcitonin levels (measured during the attack period) of those in the frequent-attack group (4–5 or more) versus those in the less frequent attack group (less than 4). Serum levels of procalcitonin were shown to be significantly higher in migraine patients during the attack period compared with migraine patients in the interictal period and in control subjects (p = .001 for both). Significant differences were found between plasma levels of fibrinogen in migraine patients versus control subjects (p < .01). No statistically significant difference was found between levels of hs-CRP in migraine patients versus the control group. These findings may show that presenting a high level of suPAR in migraine patients with attack and aura results to predisposition to occurring on the symptoms and that high levels of suPAR, procalcitonin and fibrinogen in patients with migraine result in neurogenic inflammation during migraine headaches.

Soluble Urokinase Plasminogen Activator Receptor and Outcomes in Patients with Diabetes on Hemodialysis.

Soluble urokinase plasminogen activator receptor is a novel biomarker strongly predictive of cardiovascular outcomes implicated in the pathogenesis of kidney disease. Soluble urokinase plasminogen activator receptor levels, however, correlate with declining kidney function. It is unclear whether soluble urokinase plasminogen activator receptor levels remain associated with outcomes in patients with ESRD. We measured plasma soluble urokinase plasminogen activator receptor levels in 1175 patients (mean age =66±8 years old, 54% men) with type 2 diabetes mellitus on hemodialysis participating in the German Diabetes and Dialysis Study followed for a median of 4 years for outcomes including all-cause death, cardiovascular events, and infection-related mortality. Survival analysis was performed using stepwise Cox proportional hazards models adjusted for potential confounders. Also, adjustments were made for inflammatory markers (C-reactive protein and leukocyte count) and the oxidative stress marker asymmetric dimethyl arginine to investigate potential mediators of the relationship between soluble urokinase plasminogen activator receptor and outcomes. Median soluble urokinase plasminogen activator receptor levels were 10,521 pg/ml (interquartile range, 9105-12,543 pg/ml). When stratified by tertiles, patients with soluble urokinase plasminogen activator receptor >11,633 pg/ml (third tertile) had adjusted 1.6-fold higher mortality (hazard ratio, 1.60; 95% confidence interval, 1.27 to 2.03) compared with those with low soluble urokinase plasminogen activator receptor <9599 pg/ml (first tertile). Risks of sudden death and stroke were higher (adjusted hazard ratio, 1.98; 95% confidence interval, 1.27 to 3.09 and adjusted hazard ratio, 1.74; 95% confidence interval, 1.05 to 2.90, respectively), together accounting for higher incidence of cardiovascular events (adjusted hazard ratio, 1.48; 95% confidence interval, 1.15 to 1.89). Associations with outcomes persisted after adjusting for C-reactive protein, leukocyte count, and asymmetric dimethyl arginine. Addition of soluble urokinase plasminogen activator receptor to a risk factor model modestly improved risk discrimination for all-cause death (ΔC statistic, 0.02; 95% confidence interval, 0.00 to 0.03) and cardiovascular events (ΔC statistic, 0.02; 95% confidence interval, 0.00 to 0.05). The association of soluble urokinase plasminogen activator receptor levels with outcomes persists in patients on hemodialysis. Additional study is warranted to characterize the underlying pathways of that association, which may yield opportunities to develop new therapeutic strategies.

Abstract P261: HIV-positive Individuals With Undetectable Viral Loads Have suPAR Levels Comparable to HIV-negative Individuals

Introduction: Individuals with poorly-controlled HIV have high levels of plasma soluble urokinase plasminogen activator receptor (suPAR), a marker of immune activation associated with all-cause mortality, incident myocardial infarction and HIV-associated nephropathy in HIV-positive individuals. Data is conflicting regarding the effect of viral suppression on suPAR levels in HIV-positive individuals, or how these levels compare to individuals without HIV. Hypothesis: HIV-positive individuals with undetectable viral loads (VLs) will have similar levels of suPAR compared to individuals without HIV. Methods: Plasma suPAR was measured by ELISA in 273HIV-positive (70% Black [n=167], age 42 ± 8 years, 86% female [n=240], 56% detectable viral load [n=150]) and 276 HIV-negative (63% Black [n=169], age 40 ± 9 years, 96% female [n=265]) outpatients. Demographics, medical history and laboratory samples were collected. Results: Compared to HIV-negative individuals, HIV-positive subjects were older (p=0.01), less likely to be female (p&lt;0.001), had lower body mass index (28 ± 7 vs. 30 ± 8 kg/m 2 , p&lt;0.001) and worse renal function (eGFR 92 ± 19 vs. 97 ± 20 mL/min/1.73 m 2 , p=0.004). Median suPAR level was similar for HIV-negative and HIV-positive subjects with undetectable VLs (2436 [1908, 3380] vs. 2667 [1966, 4034] pg/mL, p=0.256), and both were significantly lower compared to HIV-positive subjects with detectable VLs (4252 [3099, 5369] pg/mL, p&lt;0.001). Within HIV-positive subjects, a detectable viral load was an independent predictor for high suPAR (OR 2.37 [95% CI 1.07-5.25], p=0.03) after controlling for age, race, sex, body mass, smoking history, hypertension, diabetes, eGFR and CD4+ count. Conclusions: In conclusion,HIV-positive individuals with undetectable VLs have similar levels of suPAR compared to those without HIV. Lower suPAR levels may account for the lower incidence of cardiovascular events and HIV nephropathy in patients with well-controlled HIV.

Low-dose growth hormone therapy reduces inflammation in HIV-infected patients: a randomized placebo-controlled study

Background: Combination antiretroviral therapy (cART) has drastically increased the life expectancy of HIV-infected patients. However, HIV-infected patients exhibit increased inflammation and 33–58% exhibit a characteristic fat re-distribution termed HIV-associated lipodystrophy syndrome (HALS). Recombinant human growth hormone (rhGH) has been tested as treatment of HALS. Low-dose rhGH therapy improves thymopoiesis and fat distribution in HIV-infected patients and appears to be well tolerated. However, since high-dose rhGH is associated with adverse events related to inflammation, we wanted to investigate the impact of low-dose rhGH therapy on inflammation in HIV-infected patients.Methods: Forty-six cART-treated HIV-infected men were included in the HIV-GH low-dose (HIGH/Low) study: a randomized, placebo-controlled, double-blinded trial. Subjects were randomized 3:2 to 0.7 mg/day rhGH, or placebo for 40 weeks. rhGH was self-administered between 1 pm and 3 pm. The primary outcome of this substudy was changes in inflammation measured by plasma C-reactive protein (CRP) and soluble urokinase plasminogen activator receptor (suPAR).Results: Both CRP (−66%, p = 0.002) and suPAR (−9.7%, p = 0.06) decreased in the rhGH group compared to placebo; however, only CRP decreased significantly. The effect of rhGH on inflammation was not mediated through rhGH-induced changes in insulin-like growth factor 1, body composition, or immune parameters.Conclusion: Daily 0.7 mg rhGH treatment for 40 weeks, administered at nadir endogenous GH secretion, significantly reduced CRP. The effect does not appear to be mediated by other factors. Our findings suggest that low-dose rhGH treatment may minimize long-term risks associated with high-dose rhGH therapy.

High level of plasma soluble urokinase plasminogen activator receptor (P-suPAR) on recovery predicts the long-term mortality after first acute alcohol-induced pancreatitis (AAP)

High level of plasma soluble urokinase plasminogen activator receptor (P-suPAR) on recovery predicts the long-term mortality after first acute alcohol-induced pancreatitis (AAP)

Prognostic significance of APACHE II score and plasma suPAR in Chinese patients with sepsis: a prospective observational study.

BackgroundTimely risk stratification is the key strategy to improve prognosis of patients with sepsis. Previous study has proposed to develop a powerful risk assessment rule by the combination of Acute Physiology and Chronic Health Evaluation II (APACHE II) score and plasma soluble urokinase plasminogen activator receptor (suPAR). That reaffirmation of suPAR as a prognostic marker in Chinese patients with severe sepsis is the aim of the study.MethodsA total of 137 consecutive Chinese patients with sepsis were enrolled in a prospective study cohort. Demographic and clinical characteristics, conventional risk factors and important laboratory data were prospectively recorded. Sequential plasma suPAR concentrations were measured by an enzymeimmunoabsorbent assay on days 1, 3, and 7 after admission to the intensive care unit (ICU). Receiver operating characteristic (ROC) curves and Cox regression analysis were used to examine the performance of suPAR in developing a rule for risk stratification.ResultsThe results showed that plasma suPAR concentrations remained relatively stable within survivors and non-survivors during the first week of disease course. Regression analysis indicated that APACHE II ≥15 and suPAR ≥10.82 ng/mL were independently associated with unfavorable outcome. With the above cutoffs of APACHE II and suPAR, strata of disease severity were determined. The mortality of each stratum differed significantly from the others.ConclusionsCombination of APACHE II score and suPAR may supply the powerful prognostic utility for the mortality of sepsis.

Increased plasma soluble urokinase plasminogen activator receptor levels in systemic sclerosis: possible association with microvascular abnormalities and extent of fibrosis.

Urokinase plasminogen activator receptor (uPAR) is a key component of the fibrinolytic system involved in extracellular matrix remodeling and angiogenesis. Novel animal models supported the key role of uPAR not only in fibrosis but also in systemic sclerosis (SSc)-related microvascular abnormalities. The aim of this study was to investigate plasma soluble uPAR (suPAR) levels in SSc, and their association with organ-specific involvement. suPAR concentrations were measured by ELISA in SSc patient (n=83) and in healthy controls (n=29). Simultaneously, CRP and ESR were assessed. Detailed clinical data including skin, lung, heart and microvascular characteristics were evaluated at sampling. suPAR values were higher in SSc patients than in controls. Subgroup analysis showed higher suPAR values in diffuse cutaneous- than in limited cutaneous SSc and correlated with anti-Scl-70+. suPAR levels also associated with pulmonary function test parameters of fibrosis, presence of microvascular lesions (e.g., Raynaud phenomenon, naifold capillaroscopic abnormalities and digital ulcers) and arthritis. Our data indicate that suPAR might be a valuable early diagnostic marker of SSc which also correlates with disease severity.