Serum suPAR Levels Research Articles

MO648SERUM SOLUBLE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR IN PATIENTS WITH DIABETIC KIDNEY DISEASE

Abstract Background and Aims Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide, associated with significant cardiovascular morbidity and mortality. Soluble urokinase plasminogen activator receptor (suPAR) is a novel biomarker associated with inflammation, endothelial dysfunction and kidney disease. There is a lack of studies that investigate the role of suPAR in patients with DKD. Our aim was to assess the level of serum suPAR and to evaluate its association with kidney function, proteinuria and histological lesions in patients with DKD. Method We performed a cross-sectional study on 75 patients with DKD evaluated in our department between 2019 and 2020. Inclusion criteria were: age> 18 years, diagnosis of type 1 or type 2 diabetes mellitus, DKD and absence of malignancy, autoimmune disease, infectious disease and liver disease. Demographical, clinical and laboratory parameters were collected at the time of admission. A subset analysis was performed on 28 patients with biopsy- proven diabetic nephropathy (DN) to investigate the association of serum suPAR with histological lesions. Kidney function was evaluated based on serum creatinine and estimated with CKD-EPI formula, proteinuria was reported as 24h proteinuria and albumin/creatinine ratio (ACR) and serum suPAR levels were measured with a solid-phase ELISA kit. The detection range of the kit was 12 -360 pg/ml (7.8- 500). Results Among the 75 patients, mean age was 57.9±12.2 years, male was the dominant gender (65.3%), mean BMI was 30.7±5.5 kg/m2, most patients had hypertension (97.3%) and 22.7% were active smokers. Sixty six out of 75 patients (88%) had type 2 diabetes and the median duration of diabetes was 180 months (120- 240). Median values of estimated glomerular filtration rate (eGFR), 24h proteinuria and ACR were 24.3 ml/min (15- 36), 4.8 g/24h (1.9- 7.1) and 2000 mg/g, respectively. Median serum level of suPAR at the time of evaluation was 2857.2 pg/ml (1916.4- 3700.1). Its level was positively correlated with duration of diabetes (r= 0.278, p= 0.01), eGFR (r= 0.634, p< 0.001), 24h proteinuria (r= 0.490, p< 0.001), ACR (r= 0.524, p< 0.001) and negatively correlated with urine specific gravity (r= -0.284, p= 0.01). In the subset analysis on 28 patients with biopsy-proven DN, median suPAR level was 2474 pg/ml (1782-3745) and was positively correlated with DN class (r= 0.493, p=0.008) and interstitial fibrosis and tubular atrophy (IFTA) score (r= 506, p=0.006), but not with interstitial inflammation, arteriolar hyalinosis or arteriolosclerosis. Conclusion Our study showed a high serum level of suPAR in patients with DKD and its association with duration of diabetes, urinary specific gravity, kidney function and proteinuria. We also found a positive correlation with severity of glomerular lesions and IFTA.

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 < 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.

The Unique Difference Between Serum Level of Soluble Urokinase Plasminogen Activator Receptor (suPAR) in Steroid-Resistant Nephrotic Syndrome Children Treated with an Alkylating Agent and Calcineurin Inhibitors

Background: Steroid-resistant nephrotic syndrome (SRNS) is a leading contributor to chronic kidney disease (CKD), and calcineurin inhibitors (CNIs) or monoclonal antibodies are currently the best identified therapy. Meanwhile, some developing countries still use alkylating agents (AA) such as cyclophosphamide (CPA) to treat SRNS due to economic reasons. Objectives: This study aims to determine the employability of soluble urokinase plasminogen activator receptor (suPAR) as a biomarker for monitoring therapy in SRNS children and compare the clinical improvement with those treated with an AA and CNIs. Methods: This was a retrospective cohort study conducted at Hasan Sadikin Hospital, Indonesia. The data was collected from July 2019 to July 2020 from 70 children with FSGS. Clinical signs were evaluated monthly, and serum suPAR level was measured at the third and sixth months following therapy. Two-way repeated measures ANOVA was carried out to compare the differences in suPAR level at baseline with the third and sixth months in SRNS patients who received AA and CNIs. Results: The mean age was nearly similar between the two groups based on the t-test (P = 0.140). Steroid-resistant nephrotic syndrome was more frequent in boys than in girls (P = 0.020), according to the Chi-square test. Baseline serum suPAR level was not significantly different between the two groups. In the third month, the daily urinary protein level was higher in SRNS patients that received the AA compared to the CNIs group (P < 0.001). There was a significant interaction between time and treatment (F(2,138) = 7.203, P = 0.001), with higher suPAR level in SRNS patients that received the AA compared to those administered with CNIs at the 3rd and 6th months, but this difference was not statistically significant (P > 0.05). Conclusions: As a noninvasive tool, suPAR is a promising modality in monitoring SRNS therapy, and CNIs have a tendency to achieve faster remission than the AA.

POS-452 SERUM LEVELS OF PLASMINOGEN ACTIVATOR UROKINASE RECEPTOR AND CARDIOTROPHIN-LIKE CYTOKINE FACTOR 1 IN PATIENTS WITH NEPHROTIC SYNDROME

The pathogenesis of primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) remains unknown to date. Some circulating permeability factors are discussed. This work assessed molecule candidates for permeability in serum samples of patients with nephrotic syndrome (NS). Forty-one patients with chronic glomerulonephritis (CGN) were included in our study. Seventeen patients had FSGS, 7 patients had MCD, 5 patients had membranoproliferative glomerulonephritis (MPGN), 6 patients had IgA nephropathy, and 6 patients had membranous nephropathy (MN). The laboratory data were compared with the clinical and histological features of nephritis. Serum levels of uPAR and CLCF-1 were measured by ELISA. Levels of uPAR in the serum of patients with CGN The levels of uPAR in serum did not correlate with daily proteinuria (Rs=-0.114, p=0.51), serum creatinine/eGFR (Rs=0.032, p=0.847 and Rs=-0.054, p=0.747, respectively), arterial hypertension (Rs=0.015, p=0.926), glomerulosclerosis percentage (Rs=0.364, p=0.07) or tubulointerstitial fibrosis (Rs=-0.189, p=0.517). There was no correlation with serum C-reactive protein levels (Rs = 0.226, p=0.173) Regarding the morphological forms of glomerulonephritis, the levels of uPAR were not significantly higher in FSGS patients than in MCD, IgA nephropathy, membranous nephropathy or membranoproliferative glomerulonephritis patients (Figure 1). However, the uPAR levels were significantly higher in FSGS patients before immunosuppressive treatment. In FSGS patients who already received immunosuppressive treatment, the uPAR levels were lower and comparable to those of the other groups (Figure 2). CLCF-1 in the serum of patients with CGN No correlations were found between the levels of CLCF-1 in serum and creatinine levels/glomerular filtration rate (Rs=0.285, p=0.079/Rs=-0.268, p=0.099), arterial hypertension (Rs=0.212, p=0.195), percentage of sclerosed glomeruli (Rs=0.28, p=0.127) or severity of tubulointerstitial fibrosis (Rs=0.238, p=0.413). There were no significant differences between the histological variants of nephritis (Figure 1). The levels of CLCF-1 did not depend on the therapy (Figure 2).However, we found correlations between CLCF-1 levels and proteinuria (Rs = 0. 397; p = 0.015) and lipid levels (Rs = 0. 475; p = 0.003). Additionally, correlations between CLCF-1 levels and triglyceride levels (Figure 3), very low-density lipoprotein (Rs = 0.467, p=0.045), and high-density lipoprotein levels (Rs = - 0.599, p=0.031) were found. View Large Image Figure ViewerDownload Hi-res image Download (PPT) Our data indicate a significant increase in the serum suPAR levels in untreated FSGS; immunosuppressive treatment can decrease the suPAR levels. CLCF-1 levels in serum did not depend on histological forms of nephritis or treatment, but it correlated with proteinuria and lipid levels in patients with nephrotic syndrome.

Soluble urokinase-type plasminogen activator receptor as a diagnostic biomarker for sepsis in intensive care unit patients

Background: Sepsis is one of the main causes of morbidity and mortality in the intensive care units (ICUs).It is difficult to differentiate it accurately and timely from other confusing conditions. So, it is of utmost importance to evaluate new biomarkers with a differentiation ability between sepsis and non-sepsis conditions. Soluble urokinase-type plasminogen activator receptor (suPAR) is a stable biomarker of inflammation. The aim of the study is to evaluate the value of suPAR in the diagnosis of septic ICU patients and to compare it (if present) with that of C-reactive protein (CRP) and procalcitonin (PCT).Methods: A case-control study was conducted at Zagazig University Hospitals from December 2017 to October 2019. A total of 90 subjects were enrolled in the study. Based on Systemic Inflammatory Response Syndrome (SIRS) criteria, they were divided into 2 groups: (i)Group A: 60 septic ICU admitted patients;(ii)Group B: 30 non-septic ICU admitted patients as control group.Single determination of level of serum suPAR was measured by enzyme-linked immunosorbent assay (ELISA) for all the participants.Results: Septic ICU patients had statistically significant higher serum suPAR, CRP and PCT levels than non-septic patients. suPAR had a sensitivity of 72%, specificity of 70% and AUC of 0.7 in sepsis diagnosis.Conclusion: Serum suPAR is a fair diagnostic test for septic ICU patients at cut-off 3.983 ng/ml but does not surpass that of PCT or CRP.

Index of Body Inflammation for Maxillofacial Surgery Purpose-to Make the Soluble Urokinase-Type Plasminogen Activator Receptor Serum Level Independent on Patient Age

Background: The serum suPAR level is affected in humans by it increases with age. Therefore it makes difficult interpretation and any comparison of age varied groups. The aim of this study is to find simple way to age independent presentation of suPAR serum level for maxillofacial surgery purpose. Methods: In generally healthy patients from 15 to 59 y.o. suPAR level was tested in serum before orthognathic or minor traumatologic procedures. Five ways to make the suPAR serum level assessment independent of age are proposed. Results: One way of making suPAR levels independent of age led to the result with the same statistical distribution as in the raw suPAR serum material and this distribution is the normal. Conclusion: The simple way for suPAR serum level analysis without its dependence on patient age is calculation of the index of body inflammation understood as square root of squared suPAR serum level divided by logarithm of patient age to base 10.

Combined suPAR and qSOFA for the prediction of 28-day mortality in sepsis patients

To determine the prognostic performance of soluble urokinase-type plasminogen activator receptor (suPAR) and quick Sequential Organ Failure Assessment (qSOFA) in predicting the 28-day mortality of sepsis patients admitted to the emergency department (ED). A prospective, single-center observational study was conducted between June 2018 and June 2019. In total, 175 patients with sepsis and septic shock admitted to the ED were enrolled based on the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). We assessed the qSOFA score on ED admission and measured serum suPAR levels by quantitative enzyme-linked immunosorbent assay. Univariate and multivariate analysis was performed to identify predictors of prognosis. Kaplan–Meier survival curves and areas under the receiver operating characteristic (ROC) curve for 28-day mortality were calculated. We estimated category-free net reclassification improvement (NRI) when suPAR was added to qSOFA. Increased suPAR levels were significantly associated with 28-day mortality [1.74 (1.24–2.51) ng/mL in survivors vs. 1.34 (0.96–2.00) ng/mL in non-survivors, p = 0.011] and with sepsis severity [1.34 (0.99–1.98) ng/mL in sepsis vs. 1.74 (1.22–2.65) ng/mL in septic shock, p = 0.039]. The area under the curve (AUC) for the prediction of 28-day mortality was 0.646 (95% confidence interval (CI): 0.553–0.740) for suPAR, 0.832 (95% CI: 0.692–0.923) for qSOFA and 0.864 (95% CI: 0.802–0.928) for combined suPAR and qSOFA. Serum suPAR did not significantly increase the AUC of the basic qSOFA, but a model containing suPAR and qSOFA had a continuous NRI of 11% (95% CI: 3.5–18.5%; p = 0.004). Serum suPAR was associated with sepsis severity and 28-day mortality. Adding suPAR to qSOFA increased the ROC curve area and improved its discrimination, suggesting that this might be a useful tool in sepsis mortality prediction models.

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.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) As a Biomarker of Renal Outcomes in AL Amyloidosis

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) As a Biomarker of Renal Outcomes in AL Amyloidosis

Serum level of soluble urokinase plasminogen activator receptor (suPAR) as a disease severity marker of myasthenia gravis: a pilot study.

Myasthenia gravis (MG) is an autoantibody-mediated inflammatory disease of the neuromuscular junction. Biomarkers indicating disease activity in MG are warranted. Recently, the soluble urokinase plasminogen activator receptor (suPAR) has been reported to be associated with inflammation, tissue damage, disease activity and prognosis in various diseases, including autoimmune diseases. In this study, serum suPAR levels were measured in 40patients with anti-acetylcholine receptor antibody-positive MG and 30controls, and their correlations with clinical variables and severity scale scores were investigated. We identified that serum suPAR levels significantly correlated with MG activities of daily living scale (Spearman's ρ=0·45; P=0·004) and MG Foundation of America classification (Spearman's ρ=0·37; P=0·02) at serum sampling, but not with anti-acetylcholine receptor antibody titers. In conclusion, serum suPAR levels can be a candidate for a novel biomarker of disease activity in anti-acetylcholine receptor antibody-positive MG.

Serum suPAR associated with disease severity and mortality in elderly patients with community-acquired pneumonia

Severe community-acquired pneumonia (SCAP) in elderly has more atypical clinical presentation compared to younger patients. Timely recognition could improve clinical care. This study investigated the value of soluble urokinase-type plasminogen activator receptor (suPAR) on severity assessment and outcome prediction in elderly patients with CAP. We conducted a prospective, observational study between January 2014 and December 2016. A total of 230 patients ≥65 were enrolled in this study, of which 151 were CAP and 79 were SCAP. Serum suPAR levels were determined by ELISA essays within 24 h after hospitalization. Thirty-day and 1-year mortalities were recorded as outcomes. Serum suPAR level was significantly increased in patients with SCAP. Positive correlation was found between suPAR levels with CURB-65 and PSI score (r = 0.423 and r = 0.489; p < .001 for both). The AUC for suPAR to discriminate SCAP patients from CAP was 0.783 at a cut-off value 4.27 ng/mL. AUCs of suPAR for predicting 30-day and 1-year mortalities were 0.815 (95% CI 0.746–0.866) and 0.820 (95% CI 0.770–0.870). Regression result shows suPAR (≥8.92 ng/mL) was independent factor for 30-day mortality (HR = 2.83, 95% CI 1.04–7.69) and suPAR with cut-off value 6.18 ng/mL could predict 1-year mortality (HR = 2.44, 95% CI 1.09–5.44). suPAR was strongly associated with CAP severity and could be a prognostic indicator for 1-year survival in elderly.

Serum soluble urokinase plasminogen activator receptor in adolescents: interaction of chronic pain and obesity.

Obesity in adolescents is increasing in frequency and is associated with short-term and long-term negative consequences that include the exacerbation of co-occurring chronic pain. To determine whether the interaction between chronic pain and obesity would be reflected in changes in serum soluble urokinase plasminogen activator receptor (suPAR) concentrations, a novel marker of systemic inflammation associated with obesity, insulin resistance, and cardiovascular disease. We measured serum suPAR levels in 146 adolescent males and females with no pain or obesity (healthy controls; n = 40), chronic pain with healthy weight (n = 37), obesity alone (n = 41), and the combination of chronic pain and obesity (n = 28). Serum suPAR (median [interquartile range]) was not increased by chronic pain alone (2.2 [1.8-2.4] ng/mL) or obesity alone (2.2 [2.0-2.4] ng/mL) but was increased significantly with the combination of chronic pain and obesity (2.4 [2.1-2.7] ng/mL; P < 0.019). This finding confirms the proposition that pain and obesity are inflammatory states that display a classic augmenting interaction. We propose that measurement of serum suPAR can be added to the armamentarium of serum biomarkers useful in the evaluation of mechanisms of inflammation in adolescent obesity and chronic pain.

Serum Copeptin, NLPR3, and suPAR Levels among Patients with Autosomal-Dominant Polycystic Kidney Disease with and without Impaired Renal Function

Background: The pathophysiology of renal disease progression in autosomal-dominant polycystic kidney disease (ADPKD) involves not only cystogenesis but also endothelial dysfunction, leading to the activation of inflammatory and fibrotic pathways. This study evaluated the levels of biomarkers related to osmoregulation, immune system activation, and tubular injury in ADPKD patients with impaired or preserved renal function. Methods: This study included 26 ADPKD patients with modestly impaired renal function (estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m²; Group A), 26 age- and sex-matched ADPKD patients with relatively preserved renal function (eGFR >70 mL/min/1.73 m²; Group B), and 26 age- and sex-matched controls (Group C). Serum levels of copeptin, the inflammasome nucleotide-binding and oligomerization domain-like receptors pyrin domain-containing protein 3 (NLRP3), and soluble urokinase-type plasminogen activator receptor (suPAR) were measured with ELISA techniques. Results: Patients in Group A had higher levels of copeptin (median [interquartile range]: 50.44 [334.85] pg/mL), NLRP3 (5.86 [3.89] ng/mL), and suPAR (390.05 [476.53] pg/mL) compared to patients in Group B (32.38 [58.33], p = 0.042; 2.42 [1.96], p < 0.001; and 313.78 [178.85], p = 0.035, respectively) and Group C (6.75 [6.43]; 1.09 [0.56]; and 198.30 [28.53], respectively; p < 0.001 for all comparisons). Levels of all studied markers were also significantly higher in Group B patients compared to controls (p < 0.001), despite having similar eGFR. In patients with ADPKD, all studied biomarkers were correlated positively with asymmetric-dimethylarginine (ADMA) and endocan levels, and negatively with eGFR. ADMA and endocan levels were the only parameters independently associated with increased copeptin levels. Conclusions: This study showed that ADPKD patients with impaired and preserved renal function had higher copeptin, NLRP3, and suPAR levels than controls. Such findings support that cystogenesis and inflammation are associated with endothelial dysfunction, even in the early stages of ADKPD.

Soluble urokinase-type plasminogen activator receptor represents exercise tolerance and predicts adverse cardiac events in patients with heart failure.

Soluble urokinase-type plasminogen activator receptor (suPAR) is a membrane-binding protein that is released into the blood stream by immune activation. Recent reports suggest that circulating suPAR levels are associated with adverse cardiovascular outcomes. Exercise tolerance is an independent predictor of prognosis in patients with heart failure (HF); however, the relationship between serum suPAR level and exercise tolerance is unclear. We prospectively enrolled 94 patients who were hospitalized for worsening of HF. All patients underwent a symptom-limited cardiopulmonary exercise test to evaluate exercise tolerance. The median value of serum suPAR was 4848pg/ml. During follow up, 44 patients (47%) were admitted for all-cause mortality and re-hospitalization for HF. Median serum suPAR was significantly higher in the patients with cardiac events than in the patients with non-event group. Patients were divided into two groups according to circulating suPAR levels. Kaplan-Meier analysis demonstrated that adverse cardiac events were significantly higher in the high suPAR group (log-rank p = 0.023). Multivariate analysis revealed that suPAR was independently correlated with the parameters of exercise tolerance such as anaerobic threshold (p = 0.007) and peak oxygen uptake (p = 0.005). suPAR levels predicted adverse cardiac events and independently correlated with the parameters of exercise tolerance. suPAR could be a useful surrogate biomarker of exercise tolerance in patients with HF.

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

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

Expression of Urokinase-type Plasminogen Activator Receptor and its Soluble Form in Type 2 Diabetic Kidney Disease

Urokinase-type plasminogen activator receptor (uPAR) and its soluble form (suPAR) are new injury biomarkers that have been recently suggested to play a vital role in renal diseases. We evaluated the expression of uPAR and the serum concentration of suPAR in type 2 diabetes (T2DM) patients with diabetic kidney disease (DKD) to determine the role of this molecule as a biomarker in DKD. The uPAR immunohistochemical staining was performed in biopsy-confirmed DKD renal tissues. Meanwhile, the serum suPAR, Interleukin-18 (IL-18) and C-reactive protein (CRP) levels of 70 diabetic patients with or without DKD and 15 healthy controls were measured. The uPAR expression in DKD patients was significantly increased compared to that in healthy controls and was widely colocalized with the podocyte marker WT1. Meanwhile, serum suPAR and IL-18 levels gradually increased as DKD progressed to the advanced stage. Moreover, serum suPAR and IL-18 levels were negatively correlated with eGFR (ρ=‒0.734, ρ=‒0.462, p <0.01) and positively correlated with the urine protein to creatinine ratio (UP/CR) (ρ=0.730, ρ=0.440, p <0.01). The suPAR AUC performed better than the IL-18 AUC for the diagnosis of proteinuria (0.845 vs. 0.753, p<0.01) and the decline of renal function (0.895 vs. 0.796, p <0.01). The uPAR expressed in the renal tissues of DKD patients. The soluble form of uPAR, suPAR, can be detected in the serum of DKD patients and has a better diagnostic efficiency in the diagnosis of proteinuria and renal dysfunction in patients with T2DM than that of IL-18.

Increased Serum Soluble Urokinase Plasminogen Activator Receptor Predicts Short-Term Outcome in Patients with Hepatitis B-Related Acute-on-Chronic Liver Failure.

Aims Soluble urokinase plasminogen activator receptor (suPAR) reflects the immune activation in circumstances of inflammation and infection. It has been considered as a risk biomarker associated with poor outcome in various low-grade inflammation and infectious diseases. The study is aimed at investigating whether suPAR has a predictive value with short-term survival in patients with hepatitis B-related acute-on-chronic liver failure (HB-ACLF). Methods Serum suPAR expression was compared among patients with different states of chronic hepatitis B virus infection. Sixty HB-ACLF patients were recruited as the training cohort and followed up for 90 days. Serum suPAR level and the clinical relevance with short-term outcome were investigated. The temporal dynamics of suPAR were evaluated in 50 HB-ACLF patients with available serum sequentially at baseline, week 2 and week 4. Another 167 HB-ACLF patients were enrolled to validate the predictive value of suPAR with respect to the prognosis. Results Serum suPAR level was significantly increased in HB-ACLF patients compared to non-ACLF patients. In the training set of HB-ACLF, we observed higher suPAR level, INR, MELD score, and more complications in nonsurvivors than survivors. Longitudinal analysis revealed an increased trend of suPAR level in nonsurvivors during week 0 to week 4 and the modest decline in survivors. It showed that the synchronous suPAR level was higher in nonsurvivors at all indicated time points. Elevated suPAR level at baseline was identified as a strong predictor of a 90-day mortality of HB-ACLF patients. It was confirmed suPAR > 16.26 ng/ml had a positive predictive value of 72.22% and a negative predictive value of 77.88% for poor outcome in the validation cohort. Conclusions Serum suPAR level increases significantly in HB-ACLF patients and associated with a 90-day mortality. It suggests that suPAR might be a potential biomarker to predict the prognosis of HB-ACLF patients.

Neutrophils are a main source of circulating suPAR predicting outcome in critical illness

BackgroundCirculating levels of soluble urokinase plasminogen activation receptor (suPAR) have been proposed as a prognostic biomarker in patients with critical illness and sepsis. However, the origin of suPAR in sepsis has remained obscure. We investigated the potential cellular sources of suPAR by analyzing membrane-bound urokinase plasminogen activator receptor (uPAR, CD87) and evaluated its clinical relevance in critically ill patients.MethodsWe studied 87 critically ill patients (44 with sepsis, 43 without sepsis) from the medical intensive care unit (ICU) in comparison to 48 standard care patients with infections and 27 healthy controls in a prospective single-center non-interventional cohort study. Cellular uPAR expression of different immune cell subsets (by flow cytometry from peripheral blood) and corresponding serum suPAR concentrations were determined upon ICU admission and at day 3. Furthermore, we analyzed the effects of serum from sepsis patients on the activation and uPAR cleavage of primary human neutrophils and macrophages in vitro.ResultsIn healthy controls, uPAR (CD87) expression was detected on nearly all blood neutrophils and monocytes, but only scarcely on lymphocytes. While uPAR expression on monocytes was maintained in ICU patients, only 58% of neutrophils from critically ill patients expressed uPAR, which was significantly lower than in healthy controls or standard care patients. Concomitantly, serum suPAR levels were significantly increased in ICU patients. We noted a clear inverse correlation between low neutrophilic uPAR and high serum suPAR in standard care and ICU patients, indicating that shedding of uPAR from activated neutrophils represents a main source of suPAR in systemic inflammation. Both low uPAR and high suPAR were closely associated with mortality in critically ill patients. Furthermore, serum from sepsis patients induced uPAR protein expression and subsequent receptor shedding on isolated primary neutrophils, but not on macrophages, in vitro.ConclusionsThe inverse correlation between low uPAR surface expression on neutrophils and high serum suPAR in critically ill patients supports that neutrophils are a main source of shed suPAR proteins in systemic inflammation. Furthermore, high suPAR levels and low neutrophilic uPAR expression predict mortality in ICU patients.

Increased Serum Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Levels in FSGS: A Meta-Analysis.

Introduction The soluble urokinase-type plasminogen activator receptor (suPAR) has been found to be elevated in primary focal segmental glomerulosclerosis (pFSGS). However, its usefulness as a biomarker for FSGS remains controversial. We conducted a meta-analysis aiming at investigating the significance of suPAR in diagnosing pFSGS. Methods Electronic databases (PubMed and EMBASE) were searched to identify studies comparing suPAR levels in FSGS patients and controls, from the earliest available date to May 1, 2018. A random-effects model with standardized mean difference (SMD) was used for meta-analyses. Risk of bias was assessed using the Newcastle-Ottawa quality assessment scale. Results A total of 187 articles were screened, and the final analysis included 13 articles. In comparison to healthy controls, serum suPAR levels were significantly increased in pFSGS patients (SMD, 1.07, 95% confidence interval (CI) 0.65 to 1.48; participants = 814; studies = 9, I 2 = 85%). Higher suPAR levels were also found in patients with pFSGS compared to those with minimal change disease (SMD 0.53, 95% CI 0.22 to 0.84). Of note, such a difference was not found in pediatric groups (SMD 0.42, 95% CI -0.13 to 0.96) while it was more evidently noted in adult patients (SMD 1.32, 95% CI 0.90 to 1.74). Serum suPAR levels did not differ between pFSGS patients in remission compared to those in active proteinuric state (SMD 0.29, 95% CI -0.30 to 0.88). Comparison with membranous nephropathy and IgA nephropathy showed no significant difference. Conclusions Our meta-analysis demonstrated that, in comparison to both healthy controls and controls with minimal change disease, suPAR levels were significantly higher in adult patients with pFSGS. suPAR levels did not differ between pFSGS patients during the initial period of diagnosis and those in remission.

Correlation of Serum and Ascitic Fluid Soluble Form Urokinase Plasminogen Activator Receptor Levels With Patient Complications, Disease Severity, Inflammatory Markers, and Prognosis in Patients With Severe Acute Pancreatitis.

Objectives The aim of the study was to investigate the correlation of serum and ascitic fluid soluble form urokinase plasminogen activator receptor (suPAR) levels with patients' complications, disease severity, inflammatory markers, and prognosis in patients with severe acute pancreatitis (SAP). Methods Fifty patients with SAP, 47 patients with mild acute pancreatitis, and 50 healthy controls were enrolled. Serum samples were obtained from all participants after enrollment; meanwhile, ascitic fluid samples were collected from 20 patients with SAP who developed ascites. Serum and ascitic fluid suPAR levels were determined by enzyme-linked immunosorbent assay. Results Serum suPAR level was greatly elevated in patients with SAP than patients with mild acute pancreatitis and healthy controls. Receiver operating characteristic curve showed that serum suPAR presented with good value in predicting risk of pancreatic necrosis, pancreatic infection, and multiple organ dysfunction syndrome, whereas serum suPAR did not predict mortality. Serum suPAR level was also positively correlated with Acute Physiology and Chronic Health Evaluation II score, Balthazar index, and Sequential Organ Failure Assessment score. As to ascitic fluid suPAR, it was positively correlated with serum suPAR level, Acute Physiology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment score, risk of pancreatic infection, and multiple organ dysfunction syndrome. Conclusions Serum and ascetic fluid suPAR levels could be served as markers for disease severity and risk of severe complications in patients with SAP.