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1.
Front Immunol ; 12: 738093, 2021.
Article in English | MEDLINE | ID: covidwho-1518484

ABSTRACT

Disease caused by SARS-CoV-2 coronavirus (COVID-19) led to significant morbidity and mortality worldwide. A systemic hyper-inflammation characterizes severe COVID-19 disease, often associated with acute respiratory distress syndrome (ARDS). Blood biomarkers capable of risk stratification are of great importance in effective triage and critical care of severe COVID-19 patients. Flow cytometry and next-generation sequencing were done on peripheral blood cells and urokinase-type plasminogen activator receptor (suPAR), and cytokines were measured from and mass spectrometry-based proteomics was done on plasma samples from an Indian cohort of COVID-19 patients. Publicly available single-cell RNA sequencing data were analyzed for validation of primary data. Statistical analyses were performed to validate risk stratification. We report here higher plasma abundance of suPAR, expressed by an abnormally expanded myeloid cell population, in severe COVID-19 patients with ARDS. The plasma suPAR level was found to be linked to a characteristic plasma proteome, associated with coagulation disorders and complement activation. Receiver operator characteristic curve analysis to predict mortality identified a cutoff value of suPAR at 1,996.809 pg/ml (odds ratio: 2.9286, 95% confidence interval 1.0427-8.2257). Lower-than-cutoff suPAR levels were associated with a differential expression of the immune transcriptome as well as favorable clinical outcomes, in terms of both survival benefit (hazard ratio: 0.3615, 95% confidence interval 0.1433-0.912) and faster disease remission in our patient cohort. Thus, we identified suPAR as a key pathogenic circulating molecule linking systemic hyperinflammation to the hypercoagulable state and stratifying clinical outcomes in severe COVID-19 patients with ARDS.


Subject(s)
COVID-19/blood , Receptors, Urokinase Plasminogen Activator/blood , SARS-CoV-2 , Adult , Aged , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/immunology , Blood Proteins/analysis , COVID-19/immunology , Cytokines/blood , Humans , Inflammation/blood , Inflammation/immunology , Middle Aged , Myeloid Cells/immunology , Proteome/analysis , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/immunology , Severity of Illness Index , Young Adult
2.
J Am Soc Nephrol ; 32(1): 115-126, 2021 01.
Article in English | MEDLINE | ID: covidwho-1496665

ABSTRACT

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.


Subject(s)
Biomarkers/blood , Diabetic Nephropathies/genetics , Kidney Failure, Chronic/genetics , Renal Insufficiency, Chronic/genetics , Adult , Aged , Chemokine CCL2/blood , Chitinase-3-Like Protein 1/blood , Cohort Studies , Diabetic Nephropathies/blood , Disease Progression , Female , Glomerular Filtration Rate , Hepatitis A Virus Cellular Receptor 1/blood , Humans , Kidney Failure, Chronic/blood , Male , Middle Aged , Phenotype , Prevalence , Receptors, Tumor Necrosis Factor, Type I/blood , Receptors, Tumor Necrosis Factor, Type II/blood , Receptors, Urokinase Plasminogen Activator/blood , Renal Insufficiency, Chronic/blood , Risk , Young Adult
3.
Sci Rep ; 11(1): 17476, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1392881

ABSTRACT

Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker and risk factor for kidney diseases, with a potential prognostic value in critically ill patients. In this monocentric prospective study, we measured plasma suPAR levels immediately after ICU admission in unselected 237 consecutive patients using a turbidimetric assay. Primary objective was the prognostic value for ICU- and 28-day mortality. Secondary objectives were association with sequential organ failure assessment (SOFA) score, coagulation and inflammation markers, AKI-3 and differences in prespecified subgroups. Median suPAR levels were 8.0 ng/mL [25th-75th percentile 4.3-14.4], with lower levels in ICU survivors than non-survivors (6.7 vs. 11.6 ng/mL, p < 0.001). SuPAR levels were higher in COVID-19, kidney disease, moderate-to-severe liver disease, and sepsis. ICU mortality increased by an odds ratio (OR) of 4.7 in patients with the highest compared to lowest quartile suPAR. Kaplan-Meier overall survival estimates at 3 months were 63% and 49%, in patients with suPAR below/above 12 ng/mL (log-rank p = 0.027). Due to an observed interaction between SOFA score and suPAR, we performed a random forest method identifying cutoffs. ICU mortality was 53%, 17% and 2% in patients with a SOFA score > 7, SOFA ≤ 7 & suPAR > 8 ng/mL, and SOFA score ≤ 7 & suPAR ≤ 8 ng/mL, respectively. suPAR was a significant predictor for AKI-3 occurrence (OR per doubling 1.89, 95% CI: 1.20-2.98; p = 0.006). suPAR levels at ICU admission may offer additional value for risk stratification especially in ICU patients with moderate organ dysfunction as reflected by a SOFA score ≤ 7.


Subject(s)
COVID-19/blood , Critical Illness/mortality , Kidney Diseases/blood , Receptors, Urokinase Plasminogen Activator/blood , Renal Insufficiency/mortality , Aged , Female , Humans , Immunoturbidimetry , Intensive Care Units , Male , Middle Aged , Mortality , Odds Ratio , Organ Dysfunction Scores , Prognosis , Prospective Studies , Renal Insufficiency/blood , Survival Analysis
4.
Nat Med ; 27(10): 1752-1760, 2021 10.
Article in English | MEDLINE | ID: covidwho-1392877

ABSTRACT

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/ß inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml-1, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.


Subject(s)
COVID-19/drug therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Receptors, Urokinase Plasminogen Activator/blood , Aged , COVID-19/virology , Double-Blind Method , Female , Humans , Interleukin 1 Receptor Antagonist Protein/adverse effects , Male , Middle Aged , Placebos , SARS-CoV-2/isolation & purification
5.
J Med Virol ; 93(9): 5568-5573, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1363700

ABSTRACT

Coronavirus disease 2019 (COVID-19) is one of the most pressing health problems of this century, but our knowledge of the disease is still limited. In this study, we aimed to examine serum-soluble urokinase plasminogen activator receptor (suPAR) and kidney injury molecule 1 (KIM-1) levels based on the clinical course of COVID-19. Our study included 102 patients over the age of 18 who were diagnosed as having COVID-19 between September 2020 and December 2020 and a control group of 50 health workers over the age of 18 whose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR results were negative. KIM-1 was measured by ELISA and suPAR by suPARnostic™ assay. Analysis of previously identified variables of prognostic significance in COVID-19 revealed high neutrophil to lymphocyte ratio, lactose dehydrogenase, prothrombin time, C-reactive protein, PaO2 /FiO2 , D-dimer, ferritin, and fibrinogen levels in patients with severe disease (p < 0.05 for all). KIM-1 and suPAR levels were significantly higher in COVID-19 patients compared to the control group (p = 0.001 for all). KIM-1 level was higher in severe patients compared to moderate patients (p = 0.001), while suPAR level was lower (p = 0.001). KIM-1, which is believed to play an important role in the endocytosis of SARS-CoV-2, was elevated in patients with severe COVID-19 and may be a therapeutic target in the future. SuPAR may have a role in defense mechanism and fibrinolysis, and low levels in severe patients may be associated with poor prognosis in the early period.


Subject(s)
COVID-19/blood , Hepatitis A Virus Cellular Receptor 1/blood , Receptors, Urokinase Plasminogen Activator/blood , SARS-CoV-2 , Adult , Aged , Biomarkers/blood , COVID-19/diagnosis , Female , Humans , Male , Middle Aged , Multivariate Analysis , Prognosis , Severity of Illness Index
6.
Int J Infect Dis ; 107: 188-194, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1275363

ABSTRACT

OBJECTIVE: To examine the association between plasma levels of the soluble urokinase plasminogen activator receptor (suPAR) and the incidence of severe complications of COVID-19. METHODS: 403 RT-PCR-confirmed COVID-19 patients were recruited and prospectively followed-up at a major hospital in the United Arab Emirates. The primary endpoint was time from admission until the development of a composite outcome, including acute respiratory distress syndrome (ARDS), intensive care unit (ICU) admission, or death from any cause. Patients discharged alive were considered as competing events to the primary outcome. Competing risk regression was used to quantify the association between suPAR and the incidence of the primary outcome. RESULTS: 6.2% of patients experienced ARDS or ICU admission, but none died. Taking into account competing risk, the incidence of the primary outcome was 11.5% (95% confidence interval [CI], 6.7-16.3) in patients with suPAR levels >3.91 ng/mL compared to 2.9% (95% CI, 0.4-5.5) in those with suPAR ≤3.91 ng/mL. Also, an increase by 1 ng/mL in baseline suPAR resulted in a 58% rise in the hazard of developing the primary outcome (hazard ratio 1.6, 95% CI, 1.2-2.1, p = 0.003). CONCLUSION: suPAR has an excellent prognostic utility in predicting severe complications in hospitalised COVID-19 patients.


Subject(s)
COVID-19/complications , Receptors, Urokinase Plasminogen Activator/blood , SARS-CoV-2 , Adult , Aged , COVID-19/blood , Female , Humans , Intensive Care Units , Male , Middle Aged , Patient Admission , Prospective Studies
8.
Sci Rep ; 10(1): 19117, 2020 11 05.
Article in English | MEDLINE | ID: covidwho-1242032

ABSTRACT

Podocyte injury has recently been described as unifying feature in idiopathic nephrotic syndromes (INS). Puumala hantavirus (PUUV) infection represents a unique RNA virus-induced renal disease with significant proteinuria. The underlying pathomechanism is unclear. We hypothesized that PUUV infection results in podocyte injury, similar to findings in INS. We therefore analyzed standard markers of glomerular proteinuria (e.g. immunoglobulin G [IgG]), urinary nephrin excretion (podocyte injury) and serum levels of the soluble urokinase plasminogen activator receptor (suPAR), a proposed pathomechanically involved molecule in INS, in PUUV-infected patients. Hantavirus patients showed significantly increased urinary nephrin, IgG and serum suPAR concentrations compared to healthy controls. Nephrin and IgG levels were significantly higher in patients with severe proteinuria than with mild proteinuria, and nephrin correlated strongly with biomarkers of glomerular proteinuria over time. Congruently, electron microcopy analyses showed a focal podocyte foot process effacement. suPAR correlated significantly with urinary nephrin, IgG and albumin levels, suggesting suPAR as a pathophysiological mediator in podocyte dysfunction. In contrast to INS, proteinuria recovered autonomously in hantavirus patients. This study reveals podocyte injury as main cause of proteinuria in hantavirus patients. A better understanding of the regenerative nature of hantavirus-induced glomerulopathy may generate new therapeutic approaches for INS.


Subject(s)
Glomerular Filtration Barrier/pathology , Hemorrhagic Fever with Renal Syndrome/pathology , Kidney Glomerulus/pathology , Nephrotic Syndrome/pathology , Puumala virus , Adolescent , Adult , Female , Hemorrhagic Fever with Renal Syndrome/blood , Hemorrhagic Fever with Renal Syndrome/urine , Humans , Male , Membrane Proteins/urine , Middle Aged , Nephrotic Syndrome/blood , Nephrotic Syndrome/urine , Podocytes/pathology , Receptors, Urokinase Plasminogen Activator/blood , Young Adult
9.
Emerg Med J ; 38(7): 543-548, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1238541

ABSTRACT

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.


Subject(s)
Biomarkers/blood , COVID-19/mortality , Age Factors , Aged , Cohort Studies , Early Warning Score , Female , Hospitalization , Humans , Interleukin-6/blood , Male , Middle Aged , Prognosis , Receptors, Urokinase Plasminogen Activator/blood , United Kingdom/epidemiology
10.
Elife ; 102021 03 08.
Article in English | MEDLINE | ID: covidwho-1121691

ABSTRACT

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.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , COVID-19/drug therapy , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Respiratory Insufficiency/prevention & control , Aged , Aged, 80 and over , Antigens, CD/blood , Antigens, Differentiation, Myelomonocytic/blood , COVID-19/mortality , Female , Humans , Incidence , Injections, Subcutaneous , Interleukin-10/blood , Interleukin-6/blood , Male , Middle Aged , Receptors, Cell Surface/blood , Receptors, Urokinase Plasminogen Activator/blood , Receptors, Urokinase Plasminogen Activator/metabolism , Respiration, Artificial , Respiratory Insufficiency/epidemiology , SARS-CoV-2 , Standard of Care , Treatment Outcome
11.
J Am Soc Nephrol ; 31(11): 2725-2735, 2020 11.
Article in English | MEDLINE | ID: covidwho-789004

ABSTRACT

BACKGROUND: AKI commonly occurs in patients with coronavirus disease 2019 (COVID-19). Its pathogenesis is poorly understood. The urokinase receptor system is a key regulator of the intersection between inflammation, immunity, and coagulation, and soluble urokinase plasminogen activator receptor (suPAR) has been identified as an immunologic risk factor for AKI. Whether suPAR is associated with COVID-19-related AKI is unknown. METHODS: In a multinational observational study of adult patients hospitalized for COVID-19, we measured suPAR levels in plasma samples from 352 adult patients that had been collected within 48 hours of admission. We examined the association between suPAR levels and incident in-hospital AKI. RESULTS: Of the 352 patients (57.4% were male, 13.9% were black, and mean age was 61 years), 91 (25.9%) developed AKI during their hospitalization, of whom 25 (27.4%) required dialysis. The median suPAR level was 5.61 ng/ml. AKI incidence rose with increasing suPAR tertiles, from a 6.0% incidence in patients with suPAR <4.60 ng/ml (first tertile) to a 45.8% incidence of AKI in patients with suPAR levels >6.86 ng/ml (third tertile). None of the patients with suPAR <4.60 ng/ml required dialysis during their hospitalization. In multivariable analysis, the highest suPAR tertile was associated with a 9.15-fold increase in the odds of AKI (95% confidence interval [95% CI], 3.64 to 22.93) and a 22.86-fold increase in the odds of requiring dialysis (95% CI, 2.77 to 188.75). The association was independent of inflammatory markers and persisted across subgroups. CONCLUSIONS: Admission suPAR levels in patients hospitalized for COVID-19 are predictive of in-hospital AKI and the need for dialysis. SuPAR may be a key component of the pathophysiology of AKI in COVID-19.


Subject(s)
Acute Kidney Injury/etiology , Betacoronavirus , Coronavirus Infections/complications , Pneumonia, Viral/complications , Receptors, Urokinase Plasminogen Activator/blood , Acute Kidney Injury/blood , Acute Kidney Injury/epidemiology , Adult , Aged , Aged, 80 and over , COVID-19 , Female , Humans , Incidence , Male , Middle Aged , Pandemics , SARS-CoV-2
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