SuPAR, biomarkers of inflammation, and severe outcomes in patients hospitalized for COVID-19: The International Study of Inflammation in COVID-19.

Severe coronavirus disease 2019 (COVID-19) is a hyperinflammatory syndrome. The biomarkers of inflammation best suited to triage patients with COVID-19 are unknown. We conducted a prospective multicenter observational study of adult patients hospitalized specifically for COVID-19 from February 1, 2020 to October 19, 2022. Biomarkers measured included soluble urokinase plasminogen activator receptor (suPAR), C-reactive protein, interleukin-6, procalcitonin, ferritin, and D-dimer. In-hospital outcomes examined include death and the need for mechanical ventilation. Patients admitted in the United States (US, n = 1962) were used to compute area under the curves (AUCs) and identify biomarker cutoffs. The combined European cohorts (n = 1137) were used to validate the biomarker cutoffs. In the US cohort, 356 patients met the composite outcome of death (n = 197) or need for mechanical ventilation (n = 290). SuPAR was the most important predictor of the composite outcome and had the highest AUC (0.712) followed by CRP (0.642), ferritin (0.619), IL-6 (0.614), D-dimer (0.606), and lastly procalcitonin (0.596). Inclusion of other biomarkers did not improve discrimination. A suPAR cutoff of 4.0 ng/mL demonstrated a sensitivity of 95.4% (95% CI: 92.4%-98.0%) and negative predictive value (NPV) of 92.5% (95% CI: 87.5%-96.9%) for the composite outcome. Patients with suPAR < 4.0 ng/mL comprised 10.6% of the cohort and had a 0.8% probability of the composite outcome. Applying this cutoff to the validation cohort yielded a sensitivity of 93.8% (90.4%-96.7%) and NPV of 95.5% (93.1%-97.8%) for the composite outcome. Among commonly measured biomarkers, suPAR offered stronger discriminatory ability and may be useful in triaging low-risk patients with COVID-19.

Social isolation, loneliness, and inflammation: A multi-cohort investigation in early and mid-adulthood.

Social isolation and loneliness have been associated with poor health and increased risk for mortality, and inflammation might explain this link. We used data from the Danish TRIAGE Study of acutely admitted medical patients (N = 6,144, mean age 60 years), and from two population-representative birth cohorts: the New Zealand Dunedin Longitudinal Study (N = 881, age 45) and the UK Environmental Risk (E-Risk) Longitudinal Twin Study (N = 1448, age 18), to investigate associations of social isolation with three markers of systemic inflammation: C-reactive protein (CRP), interleukin-6 (IL-6), and a newer inflammation marker, soluble urokinase plasminogen activator receptor (suPAR), which is thought to index systemic chronic inflammation. In the TRIAGE Study, socially isolated patients (those living alone) had significantly higher median levels of suPAR (but not CRP or IL-6) compared with patients not living by themselves. Social isolation prospectively measured in childhood was longitudinally associated with higher CRP, IL-6, and suPAR levels in adulthood (at age 45 in the Dunedin Study and age 18 in the E-Risk Study), but only suPAR remained associated after controlling for covariates. Dunedin Study participants who reported loneliness at age 38 or age 45 had elevated suPAR at age 45. In contrast, E-Risk Study participants reporting loneliness at age 18 did not show any elevated markers of inflammation. In conclusion, social isolation was robustly associated with increased inflammation in adulthood, both in medical patients and in the general population. It was associated in particular with systemic chronic inflammation, evident from the consistently stronger associations with suPAR than other inflammation biomarkers.

Childhood self-control forecasts the pace of midlife aging and preparedness for old age.

The ability to control one's own emotions, thoughts, and behaviors in early life predicts a range of positive outcomes in later life, including longevity. Does it also predict how well people age? We studied the association between self-control and midlife aging in a population-representative cohort of children followed from birth to age 45 y, the Dunedin Study. We measured children's self-control across their first decade of life using a multi-occasion/multi-informant strategy. We measured their pace of aging and aging preparedness in midlife using measures derived from biological and physiological assessments, structural brain-imaging scans, observer ratings, self-reports, informant reports, and administrative records. As adults, children with better self-control aged more slowly in their bodies and showed fewer signs of aging in their brains. By midlife, these children were also better equipped to manage a range of later-life health, financial, and social demands. Associations with children's self-control could be separated from their social class origins and intelligence, indicating that self-control might be an active ingredient in healthy aging. Children also shifted naturally in their level of self-control across adult life, suggesting the possibility that self-control may be a malleable target for intervention. Furthermore, individuals' self-control in adulthood was associated with their aging outcomes after accounting for their self-control in childhood, indicating that midlife might offer another window of opportunity to promote healthy aging.

Using soluble urokinase plasminogen activator receptor to stratify patients for medication review in the emergency department.

AIMS: To investigate whether the association between levels of medication use (including polypharmacy and potentially inappropriate medications [PIMs]) and health outcomes such as readmission and mortality is dependent on baseline soluble urokinase plasminogen activator receptor (suPAR). METHODS: This registry-based cohort study included medical patients admitted to the emergency department at Copenhagen University Hospital Hvidovre, Denmark. Patients were grouped according to their admission suPAR levels: low (0-3 ng/mL), intermediate (3-6 ng/mL), or high (>6 ng/mL). Hyper-polypharmacy was defined as ≥10 prescribed medications. PIMs were identified based on the EU(7)-PIM list, and data on admissions and mortality were obtained from national registries. Risk of 90-day readmission and mortality was assessed by Cox regression analysis adjusted for sex, age and Charlson comorbidity index. Results were reported as hazard ratios within 90 days of index discharge. RESULTS: In total, 26 291 patients (median age 57.3 y; 52.7% female) were included. Risk of 90-day readmission and mortality increased significantly for patients with higher suPAR or higher number of medications. Among patients with low suPAR, patients with ≥10 prescribed medications had a hazard ratio of 2.41 (95% confidence interval = 2.09-2.78) for 90-day readmission and 8.46 (95% confidence interval = 2.53-28.28) for 90-day mortality compared to patients with 0 medications. Patients with high suPAR generally had high risk of readmission and mortality, and the impact of medication use was less pronounced in this group. Similar, but weaker, association patterns were observed between suPAR and PIMs. CONCLUSION: The association between levels of medication use and health outcomes is dependent on baseline suPAR.

The effect of the employment of experienced physicians in the Emergency Department on quality of care and equality-a quasi-experimental retrospective cohort study.

BACKGROUND: Increasing acute admissions in Emergency Departments (EDs) negatively affect quality of care, safety and flow. Thus, the Danish Health Authorities recommend the presence of experienced physicians in the ED. In 2016, consultant-led triage and continuous presence of consultants were introduced at a larger ED in Copenhagen, Denmark. This study investigated whether the employment of consultants in a Danish ED affected the quality of care for acutely admitted medical patients in terms of length of admission, readmission and mortality, as well as socioeconomic equality in quality of care delivery. METHODS: Admission data were collected during two 7-month periods, one prior to and one after the organizational intervention, with 9869 adult medical patients admitted for up to 48 h in the ED. Linear regression and Cox proportional hazards regression analyses adjusted for age, sex, comorbidities, level of education and employment status were applied. RESULTS: Following the employment of consultants, an overall 11% increase in index-admissions was observed, and 90% of patients were discharged by a consultant with a reduced mean length of admission by 1.4 h (95% CI: 1.0-1.9). No change was found in in-hospital mortality, readmission or mortality within 90 days after discharge. No change in distribution of quality indicators across patients' socioeconomic status was found. CONCLUSIONS: Consultants in the ED was found to reduce length of hospitalization without a negative effect on the quality of care for ED-admitted medical patients in general or patients with lower socioeconomic status.

Soluble Urokinase Plasminogen Activator Receptor as a Decision Marker for Early Discharge of Patients with COVID-19 Symptoms in the Emergency Department.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (The Covid-19 pandemic) strains health care capacity. Better risk stratification, with discharge of patients with a predicted mild disease trajectory, can ease this burden. Elevated blood-soluble urokinase plasminogen activator receptor (suPAR) has previously been shown to be associated with risk of intubation in confirmed COVID-19 patients. OBJECTIVE: To evaluate whether point-of-care measures of suPAR in patients presenting to the emergency department (ED) with symptoms of COVID-19 can identify patients that can be safely discharged. METHODS: Observational cohort study including all patients in the ED with symptoms of COVID-19 from March 19 to April 3, 2020. SuPAR was measured at first presentation. Review of electronic patient records 14 days after admission was used to assess disease trajectory. Primary endpoints were mild, moderate, severe, or very severe trajectory. The predictive value of suPAR, National Early Warning Score (NEWS), C-reactive protein (CRP), and duration of symptoms was calculated using receiver operating characteristics (ROC). RESULTS: Of 386 patients, 171 (44%) had a mild disease trajectory, 79 (20%) a moderate, 63 (16%) a severe, and 73 (19%) a very severe disease trajectory. Low suPAR was a strong marker of mild disease trajectory. Results suggest a cut-off for discharge for suPAR < 2.0 ng/mL if suPAR is used as a single parameter, and <3.0 ng/mL when combined with NEWS ≤ 4 and CRP < 10 mg/L. CONCLUSION: suPAR is a potential biomarker for triage and safe early discharge of patients with COVID-19 symptoms in the ED. suPAR can be used even before SARS-CoV-2 status is known.

Alterations of monocyte NF-κB p65/RelA signaling in a cohort of older medical patients, age-matched controls, and healthy young adults.

BACKGROUND: Altered monocyte NF-κB signaling is a possible cause of inflammaging and driver of aging, however, evidence from human aging studies is sparse. We assessed monocyte NF-κB signaling across different aging trajectories by comparing healthy older adults to older adults with a recent emergency department (ED) admission and to young adults. METHODS: We used data from: 52 older (≥65 years) Patients collected upon ED admission and at follow-up 30-days after discharge; 52 age- and sex-matched Older Controls without recent hospitalization; and 60 healthy Young Controls (20-35 years). Using flow cytometry, we assessed basal NF-κB phosphorylation (pNF-κB p65/RelA; Ser529) and induction of pNF-κB following stimulation with LPS or TNF-α in monocytes. We assessed frailty (FI-OutRef), physical and cognitive function, and plasma levels of IL-6, IL-18, TNF-α, and soluble urokinase plasminogen activator receptor. RESULTS: Patients at follow-up were frailer, had higher levels of inflammatory markers and decreased physical and cognitive function than Older Controls. Patients at follow-up had higher basal pNF-κB levels than Older Controls (median fluorescence intensity (MFI): 125, IQR: 105-153 vs. MFI: 80, IQR: 71-90, p < 0.0001), and reduced pNF-κB induction in response to LPS (mean pNF-κB MFI fold change calculated as the log10 ratio of LPS-stimulation to the PBS-control: 0.10, 95% CI: 0.08 to 0.12 vs. 0.13, 95% CI: 0.10 to 0.15, p = 0.05) and TNF-α stimulation (0.02, 95% CI: - 0.00 to 0.05 vs. 0.10, 95% CI: 0.08 to 0.12, p < 0.0001). Older Controls had higher levels of inflammatory markers than Young Controls, but basal pNF-κB MFI did not differ between Older and Young Controls (MFI: 81, IQR: 70-86; p = 0.72). Older Controls had reduced pNF-κB induction in response to LPS and TNF-α compared to Young Controls (LPS: 0.40, 95% CI: 0.35 to 0.44, p < 0.0001; and TNF-α: 0.33, 95% CI: 0.27 to 0.40, p < 0.0001). In Older Controls, basal pNF-κB MFI was associated with FI-OutRef (p = 0.02). CONCLUSIONS: Increased basal pNF-κB activity in monocytes could be involved in the processes of frailty and accelerated aging. Furthermore, we show that monocyte NF-κB activation upon stimulation was impaired in frail older adults, which could result in reduced immune responses and vaccine effectiveness.

Cumulative childhood risk is associated with a new measure of chronic inflammation in adulthood.

BACKGROUND: Childhood risk factors are associated with elevated inflammatory biomarkers in adulthood, but it is unknown whether these risk factors are associated with increased adult levels of the chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR). We aimed to test the hypothesis that childhood exposure to risk factors for adult disease is associated with elevated suPAR in adulthood and to compare suPAR with the oft-reported inflammatory biomarker C-reactive protein (CRP). METHODS: Prospective study of a population-representative 1972-1973 birth cohort; the Dunedin Multidisciplinary Health and Development Study observed participants to age 38 years. Main childhood predictors were poor health, socioeconomic disadvantage, adverse childhood experiences (ACEs), low IQ, and poor self-control. Main adult outcomes were adulthood inflammation measured as suPAR and high-sensitivity CRP (hsCRP). RESULTS: Participants with available plasma samples at age 38 were included (N = 837, 50.5% male). suPAR (mean 2.40 ng/ml; SD 0.91) was positively correlated with hsCRP (r 0.15, p < .001). After controlling for sex, body mass index (BMI), and smoking, children who experienced more ACEs, lower IQ, or had poorer self-control showed elevated adult suPAR. When the five childhood risks were aggregated into a Cumulative Childhood Risk index, and controlling for sex, BMI, and smoking, Cumulative Childhood Risk was associated with higher suPAR (b 0.10; SE 0.03; p = .002). Cumulative Childhood Risk predicted elevated suPAR, after controlling for hsCRP (b 0.18; SE 0.03; p < .001). CONCLUSIONS: Exposure to more childhood risk factors was associated with higher suPAR levels, independent of CRP. suPAR is a useful addition to studies connecting childhood risk to adult inflammatory burden.

Soluble Urokinase Plasminogen Activator Receptor (suPAR) as an Added Predictor to Existing Preoperative Risk Assessments.

BACKGROUND: Risk assessment strategies, such as using the American Society of Anesthesiologists (ASA) physical status classification, attempt to identify surgical high-risk patients. Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker reflecting overall systemic inflammation and immune activation, and it could potentially improve the identification of high-risk surgical patients. METHODS: We included patients acutely admitted to the emergency department who subsequently underwent surgery within 90 days of admission. Patients were stratified into low-risk or high-risk groups, according to ASA classification (ASAlow: ASA I-II; ASAhigh: ASA III-VI) and suPAR level, measured at admission (suPARhigh above and suPARlow below 5.5 ng/ml), respectively. Pre-specified complications were identified in national registries and electronic medical records. The association between ASA classification, suPAR level, CRP and the rate of postoperative complications was analyzed with logistic regression and Cox regression analyses, estimating odds ratios and hazard ratios (HRs). RESULTS: During 90-day follow-up from surgery, 31 (7.0%) patients died and 158 (35.6%) patients had postoperative complications. After adjusting for age, sex, and ASA classification, the HR for 90-day postoperative mortality was 2.5 (95% CI 1.6-4.0) for every doubling of suPAR level. suPAR was significantly better than CRP at predicting mortality and all complications (P = 0.0036 and P = 0.0041, respectively). Combining ASA classification and suPAR level significantly improved prediction of mortality and the occurrence of a postoperative complication within 90 days after surgery (P < 0.0001). CONCLUSION: Measuring suPAR levels in acutely admitted patients may aid in identifying high-risk patients and improve prediction of postoperative complications.

Healthy lifestyles reduce suPAR and mortality in a Danish general population study.

BACKGROUND: The plasma level of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is a strong predictor of disease development and premature mortality in the general population. Unhealthy lifestyle habits such as smoking or unhealthy eating is known to elevate the suPAR level. We aimed to investigate whether change in lifestyle habits impact on the suPAR level, and whether the resultant levels are associated with mortality. RESULTS: Paired suPAR measurements from baseline- and the 5-year visit of the population-based Inter99 study were compared with the habits of diet, smoking, alcohol consumption, and physical activity. Paired suPAR measurements for 3225 individuals were analyzed by linear regression, adjusted for demographics and lifestyle habits. Compared to individuals with a healthy lifestyle, an unhealthy diet, low physical activity, and daily smoking were associated with a 5.9, 12.8, and 17.6% higher 5-year suPAR, respectively. During 6.1 years of follow-up after the 5-year visit, 1.6% of those with a low suPAR (mean 2.93 ng/ml) died compared with 3.8% of individuals with a high suPAR (mean 4.73 ng/ml), P <  0.001. In Cox regression analysis, adjusted for demographics and lifestyle, the hazard ratio for mortality per 5-year suPAR doubling was 2.03 (95% CI: 1.22-3.37). CONCLUSION: Lifestyle has a considerable impact on suPAR levels; the combination of unhealthy habits was associated with 44% higher 5-year suPAR values and the 5-year suPAR was a strong predictor of mortality. We propose suPAR as a candidate biomarker for lifestyle changes as well as the subsequent risk of mortality.

Risk assessment models for potential use in the emergency department have lower predictive ability in older patients compared to the middle-aged for short-term mortality - a retrospective cohort study.

BACKGROUND: Older patients is a complex group at increased risk of adverse outcomes compared to younger patients, which should be considered in the risk assessment performed in emergency departments. We evaluated whether the predictive ability of different risk assessment models for acutely admitted patients is affected by age. METHODS: Cohort study of middle-aged and older patients. We investigated the accuracy in discriminating between survivors and non-survivors within 7 days of different risk assessment models; a traditional triage algorithm, a triage algorithm with clinical assessment, vital signs, routine biomarkers, and the prognostic biomarker soluble urokinase plasminogen activator receptor (suPAR). RESULTS: The cohort included 22,653 (53.2%) middle-aged patients (age 40-69 years), and 19,889 (46.8%) older patients (aged 70+ years). Death within 7 days occurred in 139 patients (0.6%) in middle-aged patients and 596 (3.0%) of the older patients. The models based on vital signs and routine biomarkers had the highest area under the curve (AUC), and both were significantly better at discriminating 7-day mortality in middle-aged patients compared to older patients; AUC (95% CI): 0.88 (0.84-0.91), 0.75 (0.72-0.78), P < 0.01, and 0.86 (0.82-0.90), 0.76 (0.73-0.78), P < 0.001. In a subgroup of the total cohort (6.400 patients, 15.0%), the suPAR level was available. suPAR had the highest AUC of all individual predictors with no significant difference between the age groups, but further research in this biomarker is required before it can be used. CONCLUSION: The predictive value was lower in older patients compared to middle-aged patients for all investigated models. Vital signs or routine biomarkers constituted the best models for predicting 7-day mortality and were better than the traditional triage model. Hence, the current risk assessment for short-term mortality can be strengthened, but modifications for age should be considered when constructing new risk assessment models in the emergency department.

Inflammatory biomarkers and cancer: CRP and suPAR as markers of incident cancer in patients with serious nonspecific symptoms and signs of cancer.

In Denmark, patients with serious nonspecific symptoms and signs of cancer (NSSC) are referred to the diagnostic outpatient clinics (DOCs) where an accelerated cancer diagnostic program is initiated. Various immunological and inflammatory biomarkers have been associated with cancer, including soluble urokinase plasminogen activator receptor (suPAR) and the pattern recognition receptors (PRRs) pentraxin-3, mannose-binding lectin, ficolin-1, ficolin-2 and ficolin-3. We aimed to evaluate these biomarkers and compare their diagnostic ability to classical biomarkers for diagnosing cancer in patients with NSSC. Patients were included from the DOC, Department of Infectious Diseases, Copenhagen University Hospital Hvidovre. Patients were given a final diagnosis based on the combined results from scans, blood work and physical examination. Weight loss, Charlson score and previous cancer were registered on admission, and plasma concentrations of biomarkers were measured. The primary outcome was incident cancer within 1 year. Out of 197 patients included, 39 patients (19.8%) were diagnosed with cancer. Patients with cancer were significantly older and had a higher burden of comorbidities and previous cancer diagnoses compared to patients who were not diagnosed with cancer. Previous cancer, C-reactive protein (CRP) and suPAR were significantly associated with newly diagnosed cancer during follow-up in multiple logistic regression analyses adjusted for age, sex and CRP. Neither any of the PRRs investigated nor self-reported weight loss was associated with cancer. In this study, previous cancer, CRP and suPAR were significantly associated with cancer diagnosis in patients with NSSC. Ficolin-1-3, MBL and pentraxin-3 were not associated with cancer.

Soluble urokinase plasminogen activator receptor (suPAR) in acute care: a strong marker of disease presence and severity, readmission and mortality. A retrospective cohort study.

OBJECTIVE: Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker associated with presence and progression of disease and with increased risk of mortality. We aimed to evaluate the unspecific biomarker suPAR as a prognostic marker in patients admitted to acute care. METHODS: This registry-based retrospective cohort study included 4343 consecutively admitted patients from the Acute Medical Unit at a large Danish university hospital. Time to readmission and death were analysed by multiple Cox regression. Results were reported as HRs for 30-day and 90-day follow-up. RESULTS: During 30-day follow-up, 782 patients (18.0%) were readmitted and 224 patients (5.2%) died. Comparing 30-day readmission and mortality between patients in the highest and lowest suPAR quartiles yielded HRs of 2.11 (95% CI 1.70 to 2.62) and 4.11 (95% CI 2.46 to 6.85), respectively, when adjusting for age, sex, Charlson score and C reactive protein. Area under the curve for receiver operating characteristics curve analysis of suPAR for 30-day mortality was 0.84 (95% CI 0.81 to 0.86). Furthermore, in the entire cohort, women had slightly higher suPAR compared with men, and suPAR was associated with age, admission time, admission to intensive care unit and Charlson score. CONCLUSIONS: In this large unselected population of acute medical patients, suPAR is strongly associated with disease severity, readmission and mortality after adjusting for all other risk factors, indicating that suPAR adds information to established prognostic indicators. While patients with low suPAR levels have low risk of readmission and mortality, patients with high suPAR levels have a high risk of adverse events.

Osmotic shrinkage elicits FAK- and Src phosphorylation and Src-dependent NKCC1 activation in NIH3T3 cells.

The mechanisms linking cell volume sensing to volume regulation in mammalian cells remain incompletely understood. Here, we test the hypothesis that activation of nonreceptor tyrosine kinases Src, focal adhesion kinase (FAK), and Janus kinase-2 (Jak2) occurs after osmotic shrinkage of NIH3T3 fibroblasts and contributes to volume regulation by activation of NKCC1. FAK phosphorylation at Tyr397, Tyr576/577, and Tyr861 was increased rapidly after exposure to hypertonic (575 mOsm) saline, peaking after 10 (Tyr397, Tyr576/577) and 10-30 min (Tyr861). Shrinkage-induced Src family kinase autophosphorylation (pTyr416-Src) was induced after 2-10 min, and immunoprecipitation indicated that this reflected phosphorylation of Src itself, rather than Fyn and Yes. Phosphorylated Src and FAK partly colocalized with vinculin, a focal adhesion marker, after hypertonic shrinkage. The Src inhibitor pyrazolopyrimidine-2 (PP2, 10 µM) essentially abolished shrinkage-induced FAK phosphorylation at Tyr576/577 and Tyr861, yet not at Tyr397, and inhibited shrinkage-induced NKCC1 activity by ∼50%. The FAK inhibitor PF-573,228 augmented shrinkage-induced Src phosphorylation, and inhibited shrinkage-induced NKCC1 activity by ∼15%. The apparent role of Src in NKCC1 activation did not reflect phosphorylation of myosin light chain kinase (MLC), which was unaffected by shrinkage and by PP2, but may involve Jak2, a known target of Src, which was rapidly activated by osmotic shrinkage and inhibited by PP2. Collectively, our findings suggest a major role for Src and possibly the Jak2 axis in shrinkage-activation of NKCC1 in NIH3T3 cells, whereas no evidence was found for major roles for FAK and MLC in this process.

Integrin ß1, Osmosensing, and Chemoresistance in Mouse Ehrlich Carcinoma Cells.

BACKGROUND/AIMS: Altered expression of the integrin family of cell adhesion receptors has been associated with initiation, progression, and metastasis of solid tumors as well as in the development of chemoresistance. Here, we investigated the role of integrins, in particular integrin ß1, in cell volume regulation and drug-induced apoptosis in adherent and non-adherent Ehrlich ascites cell lines. METHODS: Adhesion phenotypes were verified by colorimetric cell-adhesion-assay. Quantitative real-time PCR and western blot were used to compare expression levels of integrin subunits. Small interfering RNA was used to silence integrin ß1 expression. Regulatory volume decrease (RVD) after cell swelling was studied with calcein-fluorescence-self-quenching and Coulter counter analysis. Taurine efflux was estimated with tracer technique. Caspase assay was used to determine apoptosis. RESULTS: We show that adherent cells have stronger fibronectin binding and a significantly increased expression of integrin α5, αv, and ß1 at mRNA and protein level, compared to non-adherent cells. Knockdown of integrin ß1 reduced RVD of the adherent but not of the non-adherent cells. Efflux of taurine was unaffected. In contrast to non-adherent, adherent cells exhibited chemoresistance to chemotherapeutic drugs (cisplatin and gemcitabine). However, knockdown of integrin ß1 promoted cisplatin-induced caspase activity in adherent cells. CONCLUSION: Our data identifies integrin ß1 as a part of the osmosensing machinery and regulator of cisplatin resistance in adherent Ehrlich cells.

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

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

Self-rated health and chronic inflammation are related and independently associated with hospitalization and long-term mortality in the general population.

The subjective indicator of health self-rated health (SRH) and the chronic inflammation biomarker soluble urokinase plasminogen activator receptor (suPAR) are both robust predictors of healthcare use and mortality. However, the possible relationship between SRH and suPAR in the assessment of hospitalization and mortality risk is unknown. We used data from the Danish population-based Inter99 cohort to examine the association between SRH and suPAR and test their individual and combined associations with 2-year risk of acute hospitalization and 5- and 15-year mortality. SRH and serum suPAR levels were measured in 5490 participants (median age 45.1 years, 48.7% men). Poorer SRH was associated with elevated suPAR. In unadjusted analyses, SRH and suPAR were individually associated with higher risks of acute hospitalization and mortality, and both measures remained independently associated with higher risks of hospitalization and 15-year mortality after mutual adjustments. The association of suPAR with mortality was stronger in poorer SRH categories, and when combined, SRH and suPAR could identify different groups of individuals with increased risk of acute hospitalization and mortality. Both SRH and suPAR were independently associated with risk of acute hospitalization and mortality, and different combinations of the two measures could identify different groups of individuals at increased risk.

Soluble urokinase plasminogen activator receptor and decline in kidney function among patients without kidney disease.

Background: Hospitalized patients are at an increased risk of developing kidney disease after discharge, often despite the absence of any clinical indicators during hospitalization. Soluble urokinase plasminogen activator receptor (suPAR) is a marker of systemic chronic inflammation that can be measured from routine blood samples. We determined whether elevated suPAR during hospitalization is associated with a decline in estimated glomerular filtration rate (eGFR) after discharge. Methods: This was a retrospective longitudinal cohort study of patients without detectable kidney disease presenting to the emergency department on two separate occasions during a 3-year period. The association between suPAR and a decline in eGFR was assessed by linear mixed models for repeated measures adjusting for age, sex, C-reactive protein, sodium, diabetes, hypertension and cardiovascular disease. Results: In total, 5124 patients (median age 65.9 years, 51.0% female) were included. The median suPAR was 2.9 ng/mL, the median time to readmission was 144 days and the expected rate of eGFR decline over this period was 5.1 mL/min/1.73 m2/year. Adjusting for other risk factors, patients with suPAR <3, 3-6 or ≥6 ng/mL had an expected eGFR decline of 4.3, 5.2 or 9.0 mL/min/1.73 m2/year, respectively. Similarly, patients with suPAR in the lowest (<2.4 ng/mL), middle (2.4-3.6 ng/mL) or highest (≥3.6 ng/mL) tertile had an expected eGFR decline of 4.2, 4.6 or 6.5 mL/min/1.73 m2/year, respectively. In both cases, a higher suPAR level was significantly and independently associated with a higher rate of eGFR decline (P < .001). Conclusions: A higher suPAR level was associated with accelerated eGFR decline among patients presenting to the emergency department, suggesting that routine suPAR measurements may have utility for the early detection of kidney disease.

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.