Prognostic Significance of Proteomics-Discovered Circulating Inflammatory Biomarkers in Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) ultimately leads to right ventricular failure and premature death. The identification of circulating biomarkers with prognostic utility is considered a priority. As chronic inflammation is recognized as key pathogenic driver, we sought to identify inflammation-related circulating proteins that add incremental value to current risk stratification models for long-term survival in patients with PAH. METHODS AND RESULTS: Plasma levels of 384 inflammatory proteins were measured with the proximity extension assay technology in patients with PAH (n=60) and controls with normal hemodynamics (n=28). Among these, 51 analytes were significantly overexpressed in the plasma of patients with PAH compared with controls. Cox proportional hazard analyses and C-statistics were performed to assess the prognostic value and the incremental prognostic value of differentially expressed proteins. A panel of 6 proteins (CRIM1 [cysteine rich transmembrane bone morphogenetic protein regulator 1], HGF [hepatocyte growth factor], FSTL3 [follistatin-like 3], PLAUR [plasminogen activator, urokinase receptor], CLSTN2 [calsyntenin 2], SPON1 [spondin 1]) were independently associated with death/lung transplantation at the time of PAH diagnosis after adjustment for the 2015 European Society of Cardiology/European Respiratory Society guidelines, the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) 2.0 risk scores, and the refined 4-strata risk assessment. CRIM1, PLAUR, FSTL3, and SPON1 showed incremental prognostic value on top of the predictive models. As determined by Western blot, FSTL3 and SPON1 were significantly upregulated in the right ventricle of patients with PAH and animal models (monocrotaline-injected and pulmonary artery banding-subjected rats). CONCLUSIONS: In addition to revealing new actors likely involved in cardiopulmonary remodeling in PAH, our screening identified promising circulating biomarkers to improve risk prediction in PAH, which should be externally confirmed.

suPAR in cardiovascular disease.

Soluble urokinase plasminogen activator receptor (suPAR), the soluble counterpart of urokinase plasminogen activator receptor, is found in the circulation at various levels. suPAR and its parent molecule, cell surface uPAR, exhibit similar structure and extracellular functional roles facilitating fibrinolysis, cellular adhesion, and migration. Studies have assessed the correlation between suPAR in cardiovascular disease (CVD). It is postulated that suPAR may serve as an indicator of inflammatory activation and burden during CVD progression. Increased suPAR independently predicts poorer outcomes in acute coronary syndromes, in heart failure, as well as in coronary artery disease and atherosclerosis. To guide translation into clinical utization, suPAR has been assessed in numerous CVD settings for improved risk discrimination independently or in association with established traditional risk factors. Whilst the involvement of suPAR has been explored in other diseases such as kidney diseases and cancer, there is only emerging evidence of suPAR's mechanistic involvement in cardiovascular disease. In this review, we provide a background into suPAR and its potential role as a biomarker in CVD.

Dysregulated hemostasis in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is associated with a high incidence of early death, which occurs within 30 days of diagnosis. The major cause of early death in APL is severe bleeding, particularly intracranial bleeding. Although APL is known to be associated with activation of coagulation, hyperfibrinolysis, and thrombocytopenia, the precise mechanisms that cause bleeding have not yet been elucidated. I propose that a combination of four pathways may contribute to bleeding in APL: (1) tissue factor, (2) the urokinase plasminogen activator/urokinase plasminogen activator receptor, (3) the annexin A2/S100A100/tissue plasminogen activator, and (4) the podoplanin/C-type lectin-like receptor 2. A better understanding of these pathways will identify new biomarkers to determine which APL patients are at high risk of bleeding and allow the development of new treatments for APL-associated bleeding.

Urokinase Plasminogen Activator Receptor: An Important Focal Player in Chronic Subdural Hematoma?

Chronic subdural hematoma (CSDH) development involves inflammatory, angiogenetic, and fibrinolytic mechanisms, several components of which are now unraveled through intensive research. The urokinase plasminogen activator receptor (uPAR) is part of the plasminogen activator system and possesses inflammatory, angiogenetic, and fibrinolytic capabilities. As a first, this study aims to identify uPAR in the hematoma fluid, hematoma membrane, dura mater, and systemic blood from patients with CSDH and, if present, to investigate if the uPAR level at the time of surgery may be a predictor for later developing recurrent CSDH. uPAR expression in the hematoma membrane and dura mater was analyzed using immunohistochemistry and presented as the H-score of the positive immunostaining. The uPAR levels in the hematoma fluid and systemic blood were determined using a multiplex antibody bead kit (Luminex). Samples were collected at the time of the first CSDH surgery, and in the case of recurrent CSDH within 90 days, the samples were again collected at reoperation. A comparison of uPAR expression between the hematoma membrane and dura mater, as well as uPAR levels in systemic blood and hematoma fluid, was performed using the Wilcoxon rank sum test. We included 112 patients, 26 of whom had recurrent CSDH. The median hematoma uPAR level was 22,125 (14,845-33,237) and significantly higher than the median systemic blood level of 789 pg/L (465-2,088) (p < 0.001). Similarly, the uPAR level of the hematoma membrane was 14.3 (7.54-44.8) and significantly higher than the dural uPAR level of 0.81 (0.3-1.98) (p < 0.001). For the first time, we identified uPAR in the subdural fluid, hematoma membrane, dura mater, and systemic blood from patients with CSDH. The high expression of uPAR in the subdural fluid and hematoma membrane indicates that the mechanisms of CSDH are predominantly in the subdural fluid collection and surrounding hematoma membrane.

Rationale and design of the Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study.

INTRODUCTION: Disease subtyping and monitoring are essential for the management of nephrotic syndrome (NS). Although various biomarkers for NS have been reported, their clinical efficacy has not been comprehensively validated in adult Japanese patients. METHODS: The Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study is a nationwide, multicenter, and prospective cohort study in Japan, enrolling adult (≥18 years) patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), and lupus nephritis (LN). Baseline clinical information and plasma and urine samples will be collected at the time of immunosuppressive therapy initiation or biopsy. Follow-up data and plasma and urine samples will be collected longitudinally based on the designated protocols. Candidate biomarkers will be measured: CD80, cytotoxic T-lymphocyte antigen 4, and soluble urokinase plasminogen activator receptor for MCD and FSGS; anti-phospholipase A2 receptor and thrombospondin type-1 domain-containing protein 7A antibodies for MN; fragment Ba, C3a, factor I, and properdin for MPGN/C3G; and CD11b, CD16b, and CD163 for LN. Outcomes include complete and partial remission, relapse of proteinuria, a 30% reduction in estimated glomerular filtration rate (eGFR), eGFR decline, and initiation of renal replacement therapy. The diagnostic accuracy and predictive ability for clinical outcomes will be assessed for each biomarker. RESULTS: From April 2019 to April 2023, 365 patients were enrolled: 145, 21, 138, 10, and 51 cases of MCD, FSGS, MN, MPGN/C3G, and LN, respectively. CONCLUSION: This study will provide valuable insights into biomarkers for NS and serve as a biorepository for future studies.

Plasma IL-6, TREM1, uPAR, and IL6/IL8 biomarkers increment further witnessing the chronic inflammation in type 2 diabetes.

OBJECTIVES: Type 2 diabetes (T2D) is known to be associated with chronic inflammation, but the inflammatory regulators/markers are not exactly defined and the link between them remains undetermined. The objective of this study is to identify these markers by testing traditional (IL6 & IL8) and non-traditional (TREM1 & uPAR) inflammatory markers. METHODS: Data and blood samples were obtained from 114 T2D and 74 non-diabetic Kuwaiti subjects attending health facilities in Kuwait. Chemical analyzers were used to measure glycemic and lipid profiles, while ELISA was used to measure plasma levels of insulin and several inflammatory markers. RESULTS: Showed that the IL-6 and TREM1 were significantly higher in T2D compared to non-diabetic controls, and the uPAR level was borderline higher in T2D but significantly correlated with IL-6 levels. Unexpectedly, IL8 was significantly below normal in T2D and IL6/IL8 ratio was significantly higher in T2D patients. Unlike other tested markers, uPAR was in addition strongly correlated with insulin levels and HOMA-IR index. CONCLUSIONS: Raised levels of IL6, TREMI, IL6/IL8 ratio, and the strong positive correlation of plasma levels of uPAR with IL-6, insulin, and HOMA-IR index, are reliable spectators of chronic inflammation in T2D patients. The reduced level of IL-8 in T2D was a peculiar observation that needs further explanation. Finally, the consequences and impact of the sustained rise of these inflammatory regulators in diabetic tissues need to be meticulously explored.

Soluble Urokinase Plasminogen Activator Receptor (suPAR) as a Biomarker of Systemic Chronic Inflammation.

Systemic chronic inflammation (SCI) is persistent, health-damaging, low-grade inflammation that plays a major role in immunosenescence and in development and progression of many diseases. But currently, there are no recognized standard biomarkers to assess SCI levels alone, and SCI is typically measured by combining biomarkers of acute inflammation and infection, e.g., CRP, IL-6, and TNFα. In this review, we highlight 10 properties and characteristics that are shared by the blood protein soluble urokinase plasminogen activator receptor (suPAR) and SCI, supporting the argument that suPAR is a biomarker of SCI: (1) Expression and release of suPAR is upregulated by immune activation; (2) uPAR and suPAR exert pro-inflammatory functions; (3) suPAR is associated with the amount of circulating immune cells; (4) Blood suPAR levels correlate with the levels of established inflammatory biomarkers; (5) suPAR is minimally affected by acute changes and short-term influences, in contrast to many currently used markers of systemic inflammation; (6) Like SCI, suPAR is non-specifically associated with multiple diseases; (7) suPAR and SCI both predict morbidity and mortality; (8) suPAR and SCI share the same risk factors; (9) suPAR is associated with risk factors and outcomes of inflammation above and beyond other inflammatory biomarkers; (10) The suPAR level can be reduced by anti-inflammatory interventions and treatment of disease. Assessing SCI has the potential to inform risk for morbidity and mortality. Blood suPAR is a newer biomarker which may, in fact, be a biomarker of SCI since it is stably associated with inflammation and immune activation; shares the same risk factors as many age-related diseases; is both elevated by and predicts age-related diseases. There is strong evidence that suPAR is a prognostic marker of adverse events, morbidity, and mortality. It is associated with immune activity and prognosis across diverse conditions, including kidney disease, cardiovascular disease, cancer, diabetes, and inflammatory disorders. Thus, we think it likely represents a common underlying disease-process shared by many diseases; that is, SCI. We review the supporting literature and propose a research agenda that can help test the hypothesis that suPAR indexes SCI, with the potential of becoming the new gold standard for measuring SCI.

The levels of soluble urokinase plasminogen activator receptor (suPAR) in saliva are influenced by acute stress.

Although elevations in systemic suPAR levels have been associated with inflammatory conditions and with exposure to life stress and adversity, it is not yet clear whether acute psychological stress influences suPAR levels, either systemically and/or in saliva. The aim of this study was to investigate whether salivary suPAR levels are increased following exposure to acute psychological stress. Healthy subjects, aged 18-40 years, completed a laboratory psychological stressor and provided saliva samples before and after the stress test (60 min apart). Levels of suPAR as well as those of cytokines increased in the post-stress samples (all ps < .001). Baseline and post-stress IL-1ß and TNF-α as well as post-stress IL-6 correlated significantly with suPAR (all ps < .01), but IL-10 and baseline IL-6 did not. These results show that suPAR levels in saliva are stress-reactive and suggest a potential application as stress biomarkers in saliva, particularly given the advantage of easily detectable concentrations.

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

PURPOSE: 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). MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Eleven genomic loci affect plasma levels of chronic inflammation marker soluble urokinase-type plasminogen activator receptor.

Soluble urokinase-type plasminogen activator receptor (suPAR) is a chronic inflammation marker associated with the development of a range of diseases, including cancer and cardiovascular disease. The genetics of suPAR remain unexplored but may shed light on the biology of the marker and its connection to outcomes. We report a heritability estimate of 60% for the variation in suPAR and performed a genome-wide association meta-analysis on suPAR levels measured in Iceland (N = 35,559) and in Denmark (N = 12,177). We identified 13 independently genome-wide significant sequence variants associated with suPAR across 11 distinct loci. Associated variants were found in and around genes encoding uPAR (PLAUR), its ligand uPA (PLAU), the kidney-disease-associated gene PLA2R1 as well as genes with relations to glycosylation, glycoprotein biosynthesis, and the immune response. These findings provide new insight into the causes of variation in suPAR plasma levels, which may clarify suPAR's potential role in associated diseases, as well as the underlying mechanisms that give suPAR its prognostic value as a unique marker of chronic inflammation.

uPAR+ extracellular vesicles: a robust biomarker of resistance to checkpoint inhibitor immunotherapy in metastatic melanoma patients.

BACKGROUND: Emerging evidence has highlighted the importance of extracellular vesicle (EV)-based biomarkers of resistance to immunotherapy with checkpoint inhibitors in metastatic melanoma. Considering the tumor-promoting implications of urokinase-type plasminogen activator receptor (uPAR) signaling, this study aimed to assess uPAR expression in the plasma-derived EVs of patients with metastatic melanoma to determine its potential correlation with clinical outcomes. METHODS: Blood samples from 71 patients with metastatic melanoma were collected before initiating immunotherapy. Tumor-derived and immune cell-derived EVs were isolated and analyzed to assess the relative percentage of uPAR+ EVs. The associations between uPAR and clinical outcomes, sex, BRAF status, baseline lactate dehydrogenase levels and number of metastatic sites were assessed. RESULTS: Responders had a significantly lower percentage of tumor-derived, dendritic cell (DC)-derived and CD8+ T cell-derived uPAR +EVs at baseline than non-responders. The Kaplan-Meier survival curves for the uPAR+EV quartiles indicated that higher levels of melanoma-derived uPAR+ EVs were strongly correlated with poorer progression-free survival (p<0.0001) and overall survival (p<0.0001). We also found a statistically significant correlation between lower levels of uPAR+ EVs from both CD8+ T cells and DCs and better survival. CONCLUSIONS: Our results indicate that higher levels of tumor-derived, DC-derived and CD8+ T cell-derived uPAR+ EVs in non-responders may represent a new biomarker of innate resistance to immunotherapy with checkpoint inhibitors. Moreover, uPAR+ EVs represent a new potential target for future therapeutic approaches.

Predicting outcomes of COVID-19 from admission biomarkers: a prospective UK cohort study.

INTRODUCTION: COVID-19 has an unpredictable clinical course, so prognostic biomarkers would be invaluable when triaging patients on admission to hospital. Many biomarkers have been suggested using large observational datasets but sample timing is crucial to ensure prognostic relevance. The DISCOVER study prospectively recruited patients with COVID-19 admitted to a UK hospital and analysed a panel of putative prognostic biomarkers on the admission blood sample to identify markers of poor outcome. METHODS: Consecutive patients admitted to hospital with proven or clinicoradiological suspected COVID-19 were consented. Admission bloods were extracted from the clinical laboratory. A panel of biomarkers (interleukin-6 (IL-6), soluble urokinase plasminogen activator receptor (suPAR), Krebs von den Lungen 6, troponin, ferritin, lactate dehydrogenase, B-type natriuretic peptide, procalcitonin) were performed in addition to routinely performed markers (C reactive protein (CRP), neutrophils, lymphocytes, neutrophil:lymphocyte ratio). Age, National Early Warning Score (NEWS2), CURB-65 and radiographic severity score on initial chest radiograph were included as comparators. All biomarkers were tested in logistic regression against a composite outcome of non-invasive ventilation, intensive care admission or death, with area under the curve (AUC) (figures calculated). RESULTS: 187 patients had 28-day outcomes at the time of analysis. CRP (AUC: 0.69, 95% CI: 0.59 to 0.78), lymphocyte count (AUC: 0.62, 95% CI: 0.53 to 0.72) and other routine markers did not predict the primary outcome. IL-6 (AUC: 0.77, 0.65 to 0.88) and suPAR (AUC: 0.81, 0.72 to 0.88) showed some promise, but simple clinical features alone such as NEWS2 score (AUC: 0.70, 0.60 to 0.79) or age (AUC: 0.70, 0.62 to 0.77) performed nearly as well. DISCUSSION: Admission blood biomarkers have only moderate predictive value for predicting COVID-19 outcomes, while simple clinical features such as age and NEWS2 score outperform many biomarkers. IL-6 and suPAR had the best performance, and further studies should focus on the additive value of these biomarkers to routine care.

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

BACKGROUND: Acute 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. METHODS: In 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. RESULTS: Postoperative 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. CONCLUSIONS: Increasing levels of suPAR, but not hsCRP, were associated with development and severity of AKI following on-pump cardiac surgery.

An open label trial of anakinra to prevent respiratory failure in COVID-19.

Background: It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19. Methods: A total of 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100 mg once daily for 10 days. Primary outcome was SRF incidence by day 14 defined as any respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. Main secondary outcomes were 30-day mortality and inflammatory mediators; 28-day WHO-CPS was explored. Propensity-matched standard-of care comparators were studied. Results: 22.3% with anakinra treatment and 59.2% comparators (hazard ratio, 0.30; 95% CI, 0.20-0.46) progressed into SRF; 30-day mortality was 11.5% and 22.3% respectively (hazard ratio 0.49; 95% CI 0.25-0.97). Anakinra was associated with decrease in circulating interleukin (IL)-6, sCD163 and sIL2-R; IL-10/IL-6 ratio on day 7 was inversely associated with SOFA score; patients were allocated to less severe WHO-CPS strata. Conclusions: Early suPAR-guided anakinra decreased SRF and restored the pro-/anti-inflammatory balance. Funding: This study was funded by the Hellenic Institute for the Study of Sepsis, Technomar Shipping Inc, Swedish Orphan Biovitrum, and the Horizon 2020 Framework Programme. Clinical trial number: NCT04357366.

People infected with the SARS-CoV-2 virus, which causes COVID-19, can develop severe respiratory failure and require a ventilator to keep breathing, but this does not happen to every infected individual. Measuring a blood protein called suPAR (soluble urokinase plasminogen activator receptor) may help identify patients at the greatest risk of developing severe respiratory failure and requiring a ventilator. Previous investigations have suggested that measuring suPAR can identify pneumonia patients at highest risk for developing respiratory failure. The protein can be measured by taking a blood sample, and its levels provide a snapshot of how the body's immune system is reacting to infection, and of how it may respond to treatment. Anakinra is a drug that forms part of a class of medications called interleukin antagonists. It is commonly prescribed alone or in combination with other medications to reduce pain and swelling associated with rheumatoid arthritis. Kyriazopoulou et al. investigated whether treating COVID-19 patients who had developed pneumonia with anakinra could prevent the use of a ventilator and lower the risk of death. The findings show that treating COVID-19 patients with an injection of 100 milligrams of anakinra for ten days may be an effective approach because the drug combats inflammation. Kyriazopoulou et al. examined various markers of the immune response and discovered that anakinra was able to improve immune function, protecting a significant number of patients from going on a ventilator. The drug was also found to be safe and cause no significant adverse side effects. Administering anakinra decreased of the risk of progression into severe respiratory failure by 70%, and reduced death rates significantly. These results suggest that it may be beneficial to use suPAR as an early biomarker for identifying those individuals at highest risk for severe respiratory failure, and then treat them with anakinra. While the findings are promising, they must be validated in larger studies.

Preoperative Levels of the Soluble Urokinase-Type Plasminogen Activator Receptor as Predictor for New Episodes of Atrial Fibrillation After Vascular Surgery.

INTRODUCTION: The soluble urokinase-type plasminogen activator receptor (suPAR) in uPAR soluble form is produced when the uPAR is cleaved from the cell membrane during the inflammatory process. Postoperative atrial fibrillation (AF) is the most common perioperative cardiac arrhythmia. It is speculated that elevated suPAR has a role in the development of AF. The aim of our study was to investigate the predictive role of preoperative suPAR in the occurrence of AF during the first 6 months after major vascular surgery. METHODS: We included 119 male and 63 female patients with an average age of 67.19 ± 6.02 years, without permanent/persistent AF. Basic predictive model (BASIC) included traditional risk factors for AF: age, gender, body mass index-BMI, smoking status, presence of arterial hypertension, diabetes mellitus and dyslipidemia. RESULTS: Over the 6-month period, 19 (10.4%) patients had one new episode of atrial fibrillation and 2 patients (1.1%) had 2 episodes of paroxysmal atrial fibrillation. Paroxysms of AF were significantly more frequent in patients who had a resection of an abdominal aneurysm than in patients with other types of major vascular surgery. BASIC had good discriminatory ability in the prediction of AF paroxysms during the first 6 months after surgery (AUC = 0.715, 95%CI 0.590-0.840). Adding suPAR to the basic model significantly improved the discriminative ability of the predictive model for AF episodes (ΔAUC = 0.238, p < 0.001). The predictive performance of the model BASIC+CRP+suPAR, measured using AUC, NRI and IDI statistics, was very similar to the model BASIC+suPAR. CONCLUSION: AF is a common complication in surgical patients with high mortality and morbidity. suPAR could improve the ability of traditional risk factors to predict its occurrence up to 6 months after major vascular surgery.

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

Background Soluble 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 Results A 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. Conclusions Elevated suPAR levels are independently associated with CKD progression, and this association is prominent in reverse dippers.

Plasma levels of soluble urokinase plasminogen activator receptor (suPAR) and high-sensitivity C-reactive protein after Roux-en-Y gastric bypass or sleeve gastrectomy: a 1-year prospective observational study.

PURPOSE: Low-grade inflammation in obesity contributes to the development of cardiovascular disease, diabetes mellitus and cancer, and is associated with increased mortality. The purpose of this 1-year prospective observational study was to examine the weight loss effect of bariatric surgery on plasma concentrations of two inflammatory markers, namely high-sensitivity C-reactive protein (hsCRP) and soluble urokinase-type plasminogen activator receptor (suPAR), in patients with obesity. METHODS: Sixteen subjects without obesity and 32 patients with obesity class III, who had already settled upon Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) were included in the study. Subjects without obesity were examined once, at baseline; patients with obesity were examined preoperatively (baseline) and 3, 6 and 12 months postoperatively. RESULTS: Plasma suPAR and hsCRP concentrations at baseline were higher in patients with obesity than in lean participants (2.68 ± 0.86 vs 1.86 ± 0.34 ng/mL, p < 0.001 and 9.83 ± 9.55 vs 1.36 ± 1.95 mg/dL, p < 0.001). Levels of suPAR following bariatric surgery increased significantly 3 months after either RYGB or SG (3.58 ± 1.58 vs 3.26 ± 0.7 ng/mL, respectively) and declined at 6 (3.19 ± 1.75 vs 2.8 ± 0.84 ng/mL, respectively) and 12 months (2.6 ± 1.5 vs 2.22 ± 0.49 ng/mL, respectively; p < 0.05 for the effect of time on suPAR levels during the study), whereas those of hsCRP declined consistently after bariatric surgery (3 months: 5.44 ± 3.99 vs 9.47 ± 11.98 mg/dL, respectively; 6 months; 5.39 ± 5.6 vs 10.25 ± 17.22 mg/dL, respectively; and 12 months: 2.23 ± 2.5 vs 3.07 ± 3.63 mg/dL, respectively; p < 0.001 for the effect of time on hsCRP levels during the study). 1-year change in BMI was negatively associated with suPAR levels at 12 months. CONCLUSION: Our findings support an association between obesity and low-grade inflammation. Weight loss following bariatric surgery is associated with a consistent decline in plasma hsCRP, while plasma suPAR levels increase at 3 months and decline by 12 months.

Can soluble urokinase plasminogen receptor predict outcomes after cardiac surgery?

OBJECTIVES: Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker that has been implicated in several cardiac pathologies and has been shown to be elevated in critically ill populations. We measured plasma suPAR in a cohort of cardiac surgical patients to evaluate its ability to predict prolonged intensive care unit (ICU) and hospital length of stay and development of complications following surgery. We compared suPAR against EuroSCORE II and C-reactive protein (CRP). METHODS: Ninety patients undergoing cardiac surgery were recruited with samples taken preoperatively and on postoperative days 1, 2 and 3. suPAR was measured using enzyme-linked immunosorbent assay. Area under the receiver operator curve (AUROC) was used to test predictive capability of suPAR. Comparison was made with EuroSCORE II and CRP. RESULTS: suPAR increased over time (P < 0.001) with higher levels in patients requiring prolonged ICU and hospital stay, and prolonged ventilation (P < 0.05). suPAR was predictive for prolonged ICU and hospital stay, and prolonged ventilation at all time points (AUROC 0.66-0.74). Interestingly, this association was also observed preoperatively, with preoperative suPAR predicting prolonged ICU (AUROC 0.66), and hospital stay (AUROC 0.67) and prolonged ventilation (AUROC 0.74). The predictive value of preoperative suPAR compared favourably to EuroSCORE II and CRP. CONCLUSIONS: suPAR increases following cardiac surgery and levels are higher in those who require prolonged ICU stay, prolonged hospital stay and prolonged ventilation. Preoperative suPAR compares favourably to EuroSCORE II and CRP in the prediction of these outcomes. suPAR could be a useful biomarker in predicting outcome following cardiac surgery, helping inform clinical decision-making. CLINICAL REGISTRATION: West of Scotland Research Ethics Committee Reference: 12/WS/0179 (AM01).

Plasma suPAR may help to distinguish between chronic pancreatitis and pancreatic cancer.

OBJECTIVES: SuPAR (soluble urokinase-type plasminogen activator receptor) is a biomarker reflecting the inflammatory state of the human body. Earlier studies suggest that urinary suPAR/creatinine ratio levels are elevated in chronic pancreatitis (CP), and that plasma suPAR (P-suPAR) level is elevated in pancreatic cancer (PC). Our aim was to study the levels of P-suPAR in CP in a long-term prospective follow-up setting to explore the possibility of distinguishing between PC and CP. MATERIALS AND METHODS: Two patient groups were compared. The first group included 83 patients who were prospectively followed up after their first acute alcohol-induced pancreatitis (AAP) for median 7.0 (range 0.3-9.8) years. Twelve patients in this group developed CP during follow-up, and two patients were further excluded from the CP cohort. The second group consisted of 25 patients operated on for suspicion of pancreatic malignancy and final pathological diagnosis of PC. P-suPAR levels were measured and compared within and between these groups. RESULTS: P-suPAR levels remained low during follow-up despite the development of CP. P-suPAR was significantly higher in PC patients [median 3.7 (IQR 3.1-4.4) ng/mL] than in CP patients [2.6 (1.8-3.6) ng/mL]; p = .014. A cutoff value of 2.8 ng/mL resulted from a ROC curve with area under curve (AUC) of 0.79 (95% CI 0.61-0.97), p = .009 in differentiation between PC and CP with a sensitivity and a specificity of 88% and 70% respectively. CONCLUSION: P-suPAR is higher in patients with PC than in patients with CP, and it could thus be used in differentiating between PC and CP.

Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. METHODS: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. RESULTS: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. CONCLUSIONS: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.