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.

Associations between soluble urokinase plasminogen activator receptor (suPAR) concentration and psychiatric disorders - A systematic review and meta-analysis.

BACKGROUND: There is some evidence of an association between inflammation in the pathogenesis of mental disorders. Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of chronic inflammation, which provides a more stable index of systemic inflammation than more widely used biomarkers. This review aims to synthesise studies that measured suPAR concentrations in individuals with a psychiatric disorder, to determine if these concentrations are altered in comparison to healthy participants. METHOD: Comprehensive literature searches from inception to October 2023 were conducted of five relevant databases (PubMed, Web of Science, Embase, Scopus, APA PsychInfo). Random-effects meta-analyses were performed to compare the standardised mean difference of blood suPAR levels (i.e. plasma or serum) for individuals with any psychiatric disorder relative to controls. Separate meta-analyses of suPAR levels were conducted for individuals with schizophrenia or other psychotic disorder and depressive disorder. Risk of bias was assessed using the Newcastle Ottawa Scale. Post-hoc sensitivity analyses included excluding studies at high risk of bias, and analyses of studies that measured suPAR concentrations either in serum or in plasma separately. RESULTS: The literature search identified 149 records. Ten full-text studies were screened for eligibility and 9 studies were included for review. Primary analyses revealed no significant difference in suPAR levels between individuals with any psychiatric disorder compared to controls (k = 7, SMD = 0.42, 95 % CI [-0.20, 1.04]). However, those with depressive disorder had elevated suPAR levels relative to controls (k = 3, SMD = 0.61, 95 % CI [0.34, 0.87]). Similarly, secondary analyses showed no evidence of a significant difference in suPAR levels in individuals with any psychiatric disorder when studies at high risk of bias were excluded (k = 6, SMD = 0.54, 95 % CI [-0.14, 1.22]), but elevated suPAR concentrations for those with schizophrenia or other psychotic disorder were found (k = 3, SMD = 0.98, 95 % CI [0.39, 1.58]). Furthermore, studies that analysed plasma suPAR concentrations found elevated plasma suPAR levels in individuals with any psychiatric disorder relative to controls (k = 5, SMD = 0.84, 95 % CI [0.38, 1.29]), while studies measuring serum suPAR levels in any psychiatric disorder did not find a difference (k = 2, SMD = -0.61, 95 % CI [-1.27, 0.04]). For plasma, elevated suPAR concentrations were also identified for those with schizophrenia or other psychotic disorder (k = 3, SMD = 0.98, 95 % CI [0.39, 1.58]). DISCUSSION: When studies measuring either only serum or only plasma suPAR were considered, no significant difference in suPAR levels were observed between psychiatric disorder groups, although significantly elevated suPAR levels were detected in those with moderate to severe depressive disorder. However, plasma suPAR levels were significantly elevated in those with any psychiatric disorder relative to controls, while no difference in serum samples was found. A similar finding was reported for schizophrenia or other psychotic disorder. The plasma findings suggest that chronic inflammatory dysregulation may contribute to the pathology of schizophrenia and depressive disorder. Future longitudinal studies are required to fully elucidate the role of this marker in the psychopathology of these disorders.

Soluble urokinase plasminogen activator receptor (suPAR) in bronchoalveolar fluid and blood in critically ill patients-a prospective cohort study.

INTRODUCTION: Soluble urokinase plasminogen activator receptor (suPAR) is a biologically active protein and increased levels are associated with worse outcomes in critically ill patients. suPAR in bronchoalveolar fluid (BALF) may be helpful to differentiate between types of acute respiratory distress syndrome (ARDS) and may have potential for early detection of fungal infection. METHODS: We prospectively investigated levels of suPAR in BALF and serum in critically ill patients who underwent bronchoscopy for any reason at the ICU of the Department of Internal Medicine, Medical University of Graz, Graz, Austria. RESULTS: Seventy-five patients were available for analyses. Median age was 60 [25th-75th percentile: 50-69] years, 27% were female, and median SOFA score was 12 [11-14] points. Serum suPAR levels were significantly associated with ICU mortality in univariable logistic regression analysis. There was no correlation between BALF and serum suPAR. Serum suPAR was higher in ARDS patients at 11.2 [8.0-17.2] ng/mL compared to those without ARDS at 7.1 [3.7-10.1] (p < 0.001). BALF-suPAR was significantly higher in patients with evidence of fungal lung infection compared to patients without fungal infection both in the general cohort (7.6 [3.2-9.4] vs 2.5 [1.1-5.3], p = 0.013) and in the subgroup of ARDS (7.2 [3.1-39.2] vs 2.5 [1.0-5.2], p = 0.022). All patients were classified as putative/probable invasive aspergillosis. CONCLUSION: We found significant higher levels of serum suPAR in ARDS patients compared to those not fulfilling ARDS criteria. Serum and BALF-suPAR were significantly higher in those patients with evidence for invasive pulmonary aspergillosis. These findings may suggest testing this biomarker for early diagnosis of fungal infection in a greater cohort.

qSOFA combined with suPAR for early risk detection and guidance of antibiotic treatment in the emergency department: a randomized controlled trial.

BACKGROUND: Sepsis guidelines suggest immediate start of resuscitation for patients with quick Sequential Organ Failure Assessment (qSOFA) 2 or 3. However, the interpretation of qSOFA 1 remains controversial. We investigated whether measurements of soluble urokinase plasminogen activator receptor (suPAR) may improve risk detection when qSOFA is 1. METHODS: The study had two parts. At the first part, the combination of suPAR with qSOFA was analyzed in a prospective cohort for early risk detection. At the second part, the double-blind, randomized controlled trial (RCT) SUPERIOR evaluated the efficacy of the suPAR-guided medical intervention. SUPERIOR took place between November 2018 and December 2020. Multivariate stepwise Cox regression was used for the prospective cohort, while univariate and multivariate logistic regression was used for the RCT. Consecutive admissions at the emergency department (ED) with suspected infection, qSOFA 1 and suPAR ≥ 12 ng/mL were allocated to single infusion of placebo or meropenem. The primary endpoint was early deterioration, defined as at least one-point increase of admission Sequential Organ Failure Assessment (SOFA) score the first 24 h. RESULTS: Most of the mortality risk was for patients with qSOFA 2 and 3. Taking the hazard ratio (HR) for death of patients with qSOFA = 1 and suPAR < 12 ng/mL as reference, the HR of qSOFA = 1 and suPAR ≥ 12 ng/mL for 28-day mortality was 2.98 (95% CI 2.11-3.96). The prospective RCT was prematurely ended due to pandemia-related ED re-allocations, with 91 patients enrolled: 47 in the placebo and 44 in the meropenem arm. The primary endpoint was met in 40.4% (n = 19) and 15.9% (n = 7), respectively (difference 24.5% [5.9-40.8]; odds ratio 0.14 [0.04-0.50]). One post hoc analysis showed significant median changes of SOFA score after 72 and 96 h equal to 0 and - 1, respectively. CONCLUSIONS: Combining qSOFA 1 with the biomarker suPAR improves its prognostic performance for unfavorable outcome and can help decision for earlier treatment. Trial registration EU Clinical Trials Register (EudraCT, 2018-001008-13) and Clinical-Trials.gov (NCT03717350). Registered 24 October 2018.

Soluble urokinase plasminogen activator receptor in vaginally collected amniotic fluid predicting fetal inflammatory response syndrome: a prospective cohort study.

BACKGROUND: Improving noninvasive antenatal diagnosis of fetal inflammatory response syndrome (FIRS) can assist in the evaluation of prenatal risk and reduce perinatal outcomes. This study aimed to determine whether soluble urokinase-type plasminogen activator receptor (suPAR) in vaginally collected amniotic fluid is significant in identifying FIRS after preterm premature rupture of membranes before 34 weeks of gestation. METHODS: This was a prospective cohort study of 114 pregnant women and their newborns after preterm premature rupture of membranes at 22-34+6 weeks of gestation. SuPAR was evaluated using an enzyme-linked immunosorbent assay in vaginally collected amniotic fluid. Patients were classified according to the presence or absence of FIRS. FIRS was defined by umbilical cord blood interleukin-6 level > 11 pg/mL or histological funisitis. The data were analyzed using the R package (R-4.0.5). RESULTS: SuPAR was detected in all amniotic fluid samples with a median of 26.23 ng/mL (interquartile range (IQR), 15.19-51.14). The median level of suPAR was higher in the FIRS group than in the non-FIRS group, 32.36 ng/mL (IQR, 17.27-84.16) vs. 20.46 ng/mL (IQR, 11.49-36.63) (P = 0.01), respectively. The presence of histological chorioamnionitis significantly increased the suPAR concentration in the FIRS group (P < 0.001). The areas under the curve for FIRS and FIRS with histological chorioamnionitis were 0.65 and 0.74, respectively, with an optimum cutoff value of 27.60 ng/mL. Controlling for gestational age, the cutoff of suPAR more than 27.60 ng/mL predicted threefold higher odds for FIRS and sixfold higher odds for FIRS with histologic chorioamnionitis. CONCLUSION: Soluble urokinase-type plasminogen activator receptor in vaginally obtained amniotic fluid may assist in evaluating prenatal risk of FIRS in patients after preterm premature rupture of membranes before 34 weeks of gestation.

The Role of Soluble Urokinase Plasminogen Activator Receptor (suPAR) as an Early Indicator of Mortality in Pediatric Septic Shock.

BACKGROUND: Despite advancements in antibiotic therapy and resuscitation protocols, sepsis and septic shock remain major contributors to morbidity and mortality in children. We aimed to investigate the utility of soluble urokinase plasminogen activator receptor (suPAR) for the early detection of septic shock and to evaluate its accuracy in predicting mortality. METHODS: A prospective study was conducted in a tertiary pediatric emergency department (ED), enrolling patients diagnosed with the sepsis, severe sepsis, or septic shock. In addition to assessing infection biomarkers such as C-reactive protein and procalcitonin, suPAR levels were quantified upon admission using enzyme-linked immunosorbent assay. The primary outcome measure was 30-day mortality. RESULTS: Overall 72 patients and 80 healthy children included. Plasma suPAR levels demonstrated a statistically significant elevation in the sepsis, severe sepsis, and septic shock groups compared with the control group (p < 0.001 for all). The septic shock group exhibited the highest suPAR levels upon admission, surpassing both the sepsis and severe sepsis groups (p = 0.009 and 0.042). ROC analysis underscored the promising potential of suPAR with an AUC of 0.832 for septic shock. Analysis of mortality prediction revealed significantly higher suPAR levels in nonsurvivors than survivors (9.7 ng/mL vs. 4.2 ng/mL; p < 0.001). Employing plasma suPAR levels to discriminate between mortality and survival, a threshold of ≥7.0 ng/mL demonstrated a sensitivity of 90.9% and specificity of 71.0%. CONCLUSION: Plasma suPAR levels have the potential as a biomarker for predicting mortality in children with septic shock. In pediatric septic shock, the presence of plasma suPAR ≥7 ng/mL along with an underlying disease significantly increases the risk of mortality.

Comparison of Integrase Strand Transfer Inhibitors (INSTIs) and Protease-Boosted Inhibitors (PIs) on the Reduction in Chronic Immune Activation in a Virally Suppressed, Mainly Male Population Living with HIV (PLWH).

Background and Objectives: The success of combined antiretroviral therapy (cART) has led to a dramatic improvement in the life expectancy of people living with HIV (PLWH). However, there has been an observed increase in cardiometabolic, bone, renal, hepatic, and neurocognitive manifestations, as well as neoplasms, known as serious non-AIDS events/SNAEs, compared to the general population of corresponding age. This increase is linked to a harmful phenomenon called inflammaging/immunosenescence, which is driven by chronic immune activation and intestinal bacterial translocation. In this study, we examined immunological and metabolic parameters in individuals receiving current cART. Materials and Methods: The study was conducted at Laiko General Hospital in Athens, Greece. Plasma concentrations of sCD14, IL-6, SuPAR, I-FABP, and LBP were measured in virally suppressed PLWH under cART with at least 350 CD4 lymphocytes/µL. We compared these levels between PLWH receiving integrase strand transfer inhibitors (INSTIs) and protease inhibitors (PIs) and attempted to correlate them with chronic immune activation and metabolic parameters. Results: Data from 28 PLWH were analyzed, with a mean age of 52 and 93% being males. Among the two comparison groups, IL-6 levels were higher in the PIs group (5.65 vs. 7.11 pg/mL, p = 0.03). No statistically significant differences were found in the other measured parameters. A greater proportion of PLWH under INSTIs had normal-range LBP (33% vs. 0%, p = 0.04). When using inverse probability of treatment weighting, no statistically significant differences in the measured parameters were found between the two groups (sCD14 p = 0.511, IL-6 p = 0.383, SuPAR p = 0.793, I-FABP p = 0.868, and LBP p = 0.663). Glucose levels were found to increase after viral suppression in the entire sample (92 mg/dL vs. 98 mg/dL, p = 0.009). Total (191 mg/dL vs. 222 mg/dL, p = 0.005) and LDL cholesterol (104 mg/dL vs. 140 mg/dL, p = 0.002) levels were higher in the PIs group. No significant differences were observed in liver and renal function tests. Conclusions: Further investigation is warranted for PLWH on cART-containing INSTI regimens to explore potential reductions in chronic immune activation and intestinal bacterial translocation.

Soluble Urokinase Plasminogen Activator Receptor Levels and Outcomes in Patients with Heart Failure.

BACKGROUND: Soluble urokinase-type plasminogen activator receptor (suPAR) is a marker of immune activation and pathogenic factor for kidney disease shown to predict cardiovascular outcomes including heart failure (HF) in various populations. We characterized suPAR levels in patients with HF and compared its ability to discriminate risk to that of B-type natriuretic peptide (BNP). METHODS AND RESULTS: We measured plasma suPAR and BNP levels in 3,437 patients undergoing coronary angiogram and followed for a median of 6.2 years. We performed survival analyses for the following outcomes: all-cause death, cardiovascular death, and hospitalization for HF. We then assessed suPAR's ability to discriminate risk for the aforementioned outcomes. We identified 1116 patients with HF (age 65±12, 67.2% male, 20.0% Black, 67% with reduced ejection fraction). The median suPAR level was higher in HF compared to those without HF (3370 [IQR 2610-4371] vs. 2880 [IQR 2270-3670] pg/mL, respectively, P<0.001). In patients with HF, suPAR levels (log-base 2) were associated with outcomes including all-cause death (adjusted hazard ratio aHR 2.30, 95%CI[1.90-2.77]), cardiovascular death (aHR 2.33 95%CI[1.81-2.99]) and HF hospitalization (aHR 1.96, 95%CI[1.06-1.25]) independently of clinical characteristics and BNP levels. The association persisted across subgroups and did not differ between patients with reduced or preserved ejection fraction, or those with ischemic or non-ischemic cardiomyopathy. Addition of suPAR to a model including BNP levels significantly improved the C-statistic for death (Δ0.027), cardiovascular death (Δ0.017) and hospitalization for HF (Δ0.017). CONCLUSIONS: SuPAR levels are higher in HF compared to non-HF, are strongly predictive of outcomes, and combined with BNP, significantly improved risk prediction.

Soluble urokinase plasminogen activator receptor and survival in elective cardiac surgery.

BACKGROUND: The study investigated the prognostic value of soluble urokinase plasminogen activator receptor (suPAR) in patients undergoing cardiac surgery and calculated a simplified biomarker score comprising suPAR, N-terminal pro B-type natriuretic peptide (NT-proBNP) and age. METHODS AND RESULTS: Biomarkers were assessed in a cohort of 478 patients undergoing elective cardiac surgery. After a median follow-up of 4.2 years, a total of 72 (15.1%) patients died. SuPAR, NT-proBNP and age were independent prognosticators of mortality in a multivariable Cox regression model after adjustment for EuroScoreII. We then calculated a simplified biomarker score comprising age, suPAR and NT-proBNP, which had a superior prognostic value compared to EuroScoreII (Harrel's C of 0.76 vs. 0.72; P for difference = 0.02). Besides long-term mortality, the biomarker score had an excellent performance predicting one-year mortality and hospitalization due to heart failure. CONCLUSION: The biomarker suPAR and NT-proBNP were strongly and independently associated with mortality in patients undergoing cardiac surgery. A simplified biomarker score comprising only three variables (age, suPAR and NT-proBNP) performed better than the established EuroScoreII with respect to intermediate and long-term outcome as well as hospitalization due to heart failure. As such, integration of established and upcoming biomarkers in clinical practice may provide improved decision support in cardiac surgery.

Predictive value of suPAR in AKI: a systematic review and meta-analysis.

BACKGROUND: Some clinical trials have shown that soluble urokinase-type plasminogen activator receptor (suPAR) has good predictive value for acute kidney injury (AKI), but there is still a lack of evidence-based proof. Therefore, we conducted this systematic review and meta-analysis to evaluate the predictive value of suPAR for AKI. METHODS: Pubmed, EMBASE, Cochrane Library, and Web of Science databases were searched until December 2021 to obtain the literature on the prediction of suPAR for AKI. The quality of the included studies was assessed using the QUADAS-2 scoring system, and a bivariate random-effect model was used for the meta-analysis. The present study has been registered on PROSPERO (Registration No. CRD42022324978). RESULTS: Seven articles were included, involving 2,319 patients, 635 of whom were AKI patients. The meta-analysis results showed that the combined sensitivity of suPAR in predicting AKI was 0.77 (95% CI 0.67-0.84); the specificity was 0.64 (95% CI 0.53-0.75); the odds ratio of diagnosis was 6 (95% CI 3-10); the pooled positive likelihood ratio was 2.2 (95% CI 1.6-2.9); the pooled negative likelihood ratio was 0.36 (95% CI 0.26-0.52); and the area under the summary receiver-operating characteristic (SROC) curve was 0.77 (95% CI 0.12~0.99). Deek's funnel plot suggested no potential publication bias among included studies. CONCLUSION: suPAR is a valuable biomarker for the prediction of AKI with relatively high predictive accuracy, but its clinical application needs improvements. SuPAR should be considered as an indicator in the subsequent development of more effective predictive tools for AKI.

Role of Soluble Urokinase-Type Plasminogen Activator Receptor in Cardiovascular Disease.

PURPOSE OF REVIEW: Chronic inflammation is a major contributor to cardiovascular disease (CVD) risk. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived glycoprotein that is strongly associated with atherosclerotic disease. This review summarizes evidence on suPAR's role in CVD pathogenesis and its potential as a prognostic indicator and therapeutic target. RECENT FINDINGS: Clinical, genetic, and experimental evidence supports suPAR's role as a pathogenic factor in atherosclerosis. suPAR promotes atherosclerosis through modulation of monocyte activation and function. Clinically, elevated suPAR levels are linked to increased cardiovascular risk across diverse populations. Ongoing clinical trials are evaluating therapies targeting suPAR signaling. Current evidence positions suPAR as a regulator of myeloid cell function that contributes to vascular inflammation and subsequent cardiovascular events. Additional research is needed to determine whether suPAR measurement can improve CVD risk prediction and enable personalized management. Overall, suPAR is a promising immune-derived biomarker and target for reducing inflammation and cardiovascular risk.

Circulating Soluble Urokinase Plasminogen Activator Receptor as a Predictive Indicator for COVID-19-Associated Acute Kidney Injury and Mortality: Clinical and Bioinformatics Analysis.

Urokinase receptors regulate the interplay between inflammation, immunity, and blood clotting. The soluble urokinase plasminogen activator system is an immunologic regulator affecting endothelial function and its related receptor; the soluble urokinase plasminogen activator receptor (suPAR) has been reported to impact kidney injury. This work aims to measure serum levels of suPAR in COVID-19 patients and correlate the measurements with variable clinicolaboratory parameters and patient outcomes. In this prospective cohort study, 150 COVID-19 patients and 50 controls were included. The circulating suPAR levels were quantified by Enzyme-linked immunosorbent assay (ELISA). Routine COVID-19 laboratory assessments, including CBC, CRP, LDH, serum creatinine, and estimated glomerular filtration rates, were performed. The need for oxygen therapy, CO-RAD score, and survival rates was assessed. Bioinformatic analysis and molecular docking were run to explore the urokinase receptor structure/function and to characterize molecules as potential anti-suPAR therapeutic targets, respectively. We found higher circulating suPAR levels in COVID-19 patients vs. controls (p < 0.001). Circulating suPAR levels positively correlated with COVID-19 severity, the need for O2 therapy, the total leukocytes count, and the neutrophils to lymphocyte ratio, while they were negatively correlated with the O2 saturation level, albumin, blood calcium, lymphocytic count, and GFR. In addition, the suPAR levels were associated with poor prognostic outcomes such as a high incidence of acute kidney injury (AKI) and mortality rate. Kaplan-Meier curves showed a lower survival rate with higher suPAR levels. The logistic regression analysis confirmed the significant association of suPAR levels with the occurrence of AKI related to COVID-19 and with increased mortality probability within three months of COVID-19 follow-up. Some compounds that can act similarly to uPAR were discovered and tested by molecular docking to identify the possible ligand-protein interactions. In conclusion, higher circulating suPAR levels were associated with COVID-19 severity and could be considered a putative predictor of AKI development and mortality.

Plasminogen System in the Pathophysiology of Sepsis: Upcoming Biomarkers.

Severe hemostatic disturbances and impaired fibrinolysis occur in sepsis. In the most serious cases, the dysregulation of fibrinolysis contributes to septic shock, disseminated intravascular coagulation (DIC), and death. Therefore, an analysis of circulating concentrations of pro- and anti-fibrinolytic mediators could be a winning strategy in both the diagnosis and the treatment of sepsis. However, the optimal cutoff value, the timing of the measurements, and their combination with coagulation indicators should be further investigated. The purpose of this review is to summarize all relevant publications regarding the role of the main components of the plasminogen activation system (PAS) in the pathophysiology of sepsis. In addition, the clinical value of PAS-associated biomarkers in the diagnosis and the outcomes of patients with septic syndrome will be explored. In particular, experimental and clinical trials performed in emergency departments highlight the validity of soluble urokinase plasminogen activator receptor (suPAR) as a predictive and prognostic biomarker in patients with sepsis. The measurements of PAI-I may also be useful, as its increase is an early manifestation of sepsis and may precede the development of thrombocytopenia. The upcoming years will undoubtedly see progress in the use of PAS-associated laboratory parameters.

Longitudinal Follow-Up of Serum and Urine Biomarkers Indicative of COVID-19-Associated Acute Kidney Injury: Diagnostic and Prognostic Impacts.

In patients hospitalized for severe COVID-19, the incidence of acute kidney injury (AKI) is approximately 40%. To predict and understand the implications of this complication, various blood and urine biomarkers have been proposed, including neutrophil gelatinase-associated lipocalin (NGAL), chemokine (C-C motif) ligand 14 (CCL14), cystatin C, leucine aminopeptidase (LAP), and soluble urokinase plasminogen activator (suPAR). This study, conducted between mid-January and early May 2021, aimed to assess the diagnostic and prognostic capabilities of these biomarkers in a cohort of COVID-19 patients monitored during the initial two weeks of hospitalization. Among the 116 patients included in this study, 48 developed AKI within the first three days of hospitalization (41%), with 29 requiring intensive care unit (ICU) admission, and the overall mortality rate was 18%. AKI patients exhibited a statistically significant increase in urinary LAP levels, indicating acute tubular injury as a potential mechanism underlying COVID-19-related renal damage. Conversely, urinary NGAL and CCL-14 excretion rates did not differ significantly between the AKI and non-AKI groups. Importantly, elevated plasma suPAR and cystatin C levels upon admission persisted throughout the first week of hospitalization and were associated with unfavorable outcomes, such as prolonged ICU stays and increased mortality, irrespective of AKI development. In conclusion, this study underscores the early predictive value of urinary LAP levels in identifying acute tubular injury in COVID-19-induced AKI. Moreover, elevated plasma suPAR and cystatin C levels serve as valuable prognostic markers, offering insights into the short-term morbidity and mortality risks among COVID-19 patients, regardless of AKI occurrence. These findings shed light on the complex interplay between COVID-19, renal injury, and biomarkers with diagnostic and prognostic potential.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) and Growth Differentiation Factor-15 (GDF-15) Levels Are Significantly Associated with Endothelial Injury Indices in Adult Allogeneic Hematopoietic Cell Transplantation Recipients.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GvHD) represent life-threatening syndromes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In both conditions, endothelial dysfunction is a common denominator, and development of relevant biomarkers is of high importance for both diagnosis and prognosis. Despite the fact that soluble urokinase plasminogen activator receptor (suPAR) and growth differentiation factor-15 (GDF-15) have been determined as endothelial injury indices in various clinical settings, their role in HSCT-related complications remains unexplored. In this context, we used immunoenzymatic methods to measure suPAR and GDF-15 levels in HSCT-TMA, acute and/or chronic GVHD, control HSCT recipients, and apparently healthy individuals of similar age and gender. We found considerably greater SuPAR and GDF-15 levels in HSCT-TMA and GVHD patients compared to allo-HSCT and healthy patients. Both GDF-15 and suPAR concentrations were linked to EASIX at day 100 and last follow-up. SuPAR was associated with creatinine and platelets at day 100 and last follow-up, while GDF-15 was associated only with platelets, suggesting that laboratory values do not drive EASIX. SuPAR, but not GDF-15, was related to soluble C5b-9 levels, a sign of increased HSCT-TMA risk. Our study shows for the first time that suPAR and GDF-15 indicate endothelial damage in allo-HSCT recipients. Rigorous validation of these biomarkers in many cohorts may provide utility for their usefulness in identifying and stratifying allo-HSCT recipients with endothelial cell impairment.

Soluble urokinase Plasminogen Activator Receptor (suPAR) levels are predictive of COVID-19 severity: an Italian experience.

BACKGROUND: The soluble urokinase Plasminogen Activator Receptor (suPAR) has been identified as a reliable marker of COVID-19 severity, helping in personalizing COVID-19 therapy. This study aims to evaluate the correlation between suPAR levels and COVID-19 severity, in relation to the traditional inflammatory markers. METHODS: Sera from 71 COVID-19 patients were tested for suPAR levels using Chorus suPAR assay (Diesse Diagnostica Senese SpA, Italy). suPAR levels were compared with other inflammatory markers: IL-1ß, IL-6, TNF-α, circulating calprotectin, neutrophil and lymphocyte counts, and Neutrophil/Lymphocytes Ratio (NLR). Respiratory failure, expressed as P/F ratio, and mortality rate were used as indicators of disease severity. RESULTS: A positive correlation of suPAR levels with IL-6 (r = 0.479, p = 0.000), TNF-α (r = 0.348, p = 0.003), circulating calprotectin (r = 0.369, p = 0.002), neutrophil counts (r = 0.447, p = 0.001), NLR (r = 0.492, p = 0.001) has been shown. Stratifying COVID-19 population by suPAR concentration above and below 6 ng/mL, we observed higher levels of circulating calprotectin (10.1 µg/mL, SD 7.9 versus 6.4 µg/mL, SD 7.5, p < 0.001), higher levels of P/F ratio (207.5 IQR 188.3 vs 312.0 IQR 127.8, p = 0.013) and higher mortality rate. Median levels of suPAR were increased in all COVID-19 patients requiring additional respiratory support (Nasal Cannula, Venturi Mask, BPAP and CPAP) (6.5 IQR = 4.9) compared to the group at room air (4.6 IQR = 4.2). CONCLUSION: suPAR levels correlate with disease severity and survival rate of COVID-19 patients, representing a promising prognostic biomarker for the risk assessment of the disease.

Associations of Plasma Biomarkers of Inflammation, Fibrosis, and Kidney Tubular Injury With Progression of Diabetic Kidney Disease: A Cohort Study.

RATIONALE & OBJECTIVE: Most circulating biomarkers of chronic kidney disease (CKD) progression focus on factors reflecting glomerular filtration. Few biomarkers capture nonglomerular pathways of kidney injury or damage, which may be particularly informative in populations at high risk for CKD progression such as individuals with diabetes. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 594 participants (mean age, 70 years; 53% women) of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who had diabetes and an estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 at baseline. EXPOSURES: Plasma biomarkers of inflammation/fibrosis (TNFR1 and TNFR2, suPAR, MCP-1, YKL-40) and tubular injury (KIM-1) measured at the baseline visit. OUTCOMES: Incident kidney failure with replacement therapy (KFRT). ANALYTICAL APPROACH: Cox proportional hazards regression and least absolute shrinkage and selection operator regression adjusted for established risk factors for kidney function decline, baseline eGFR, and urinary albumin-creatinine ratio (UACR). RESULTS: A total of 98 KFRT events were observed over a mean of 6.2±3.5 (standard deviation) years of follow-up. Plasma biomarkers were modestly associated with baseline eGFR (correlation coefficients ranging from-0.08 to-0.65) and UACR (0.14 to 0.56). In individual biomarker models adjusted for eGFR, UACR, and established risk factors, hazard ratios for incident KFRT per 2-fold higher biomarker concentrations were 1.52 (95% CI, 1.25-1.84) for plasma KIM-1, 1.54 (95% CI, 1.08-2.21) for TNFR1, 1.91 (95% CI, 1.16-3.14) for TNFR2, and 1.39 (95% CI, 1.05-1.84) for YKL-40. In least absolute shrinkage and selection operator regression models accounting for biomarkers in parallel, plasma KIM-1 and TNFR1 remained associated with incident KFRT. LIMITATIONS: Single biomarker measurement, lack of follow-up eGFR assessments. CONCLUSIONS: Individual plasma markers of inflammation/fibrosis (TNFR1, TNFR2, YKL-40) and tubular injury (KIM-1) were associated with risk of incident KFRT in adults with diabetes and an eGFR<60mL/min/1.73m2 after adjustment for established risk factors.

Circulating suPAR associates with severity and in-hospital progression of COVID-19.

BACKGROUND: COVID-19 disease progression is characterized by hyperinflammation and risk stratification may aid in early aggressive treatment and advanced planning. The aim of this study was to assess whether suPAR and other markers measured at hospital admission can predict the severity of COVID-19. METHODS: The primary outcome measure in this international, multi-centre, prospective, observational study with adult patients hospitalized primarily for COVID-19 was the association of WHO Clinical Progression Scale (WHO-CPS) with suPAR, ferritin, CRP, albumin, LDH, eGFR, age, procalcitonin, and interleukin-6. Admission plasma suPAR levels were determined using the suPARnostic® ELISA and suPARnostic® Turbilatex assays. RESULTS: Seven hundred and sixty-seven patients, 440 (57.4%) males and 327 (42.6%) females, were included with a median age of 64 years. Log-suPAR levels significantly correlated with WHO-CPS score, with each doubling of suPAR increasing the score by one point (p < .001). All the other markers were also correlated with WHO-CPS score. Admission suPAR levels were significantly lower in survivors (7.10 vs. 9.63, 95% CI 1.47-3.59, p < .001). A linear model (SALGA) including suPAR, serum albumin, serum lactate dehydrogenase, eGFR, and age can best estimate the WHO-CPS score and survival. Combining all five parameters in the SALGA model can improve the accuracy of discrimination with an AUC of 0.80 (95% CI: 0.759-0.836). CONCLUSIONS: suPAR levels significantly correlated with WHO-CPS score, with each doubling of suPAR increasing the score by one point. The SALGA model may serve as a quick tool for predicting disease severity and survival at admission.

Soluble urokinase plasminogen activator receptor and functionally relevant coronary artery disease: a prospective cohort study.

BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is an emerging biomarker associated with anatomical CAD burden and cardiovascular outcomes including myocardial infarction (MI) and death. We aimed to validate previous findings of the prognostic value of suPAR and to evaluate its diagnostic potential for functional relevant CAD (fCAD). METHODS: Consecutive patients with suspected fCAD were enrolled. Adjudication of fCAD was performed blinded to suPAR concentrations by myocardial perfusion single-photon emission tomography (MPI-SPECT) and coronary angiography. Prognostic outcome measures included all-cause death, cardiovascular death, and incident MI during 2-year follow-up. RESULTS: Among consecutive 968 patients, suPAR concentrations were higher in patients with fCAD compared to those without (3.45 vs. 3.20 ng/mL, p = 0.007), but did not provide acceptable diagnostic accuracy (area under the curve [AUC]: 0.56, 95%CI 0.52-0.60). SuPAR correlated with high-sensitivity cardiac-troponin T (Spearman's rho (ρ) 0.393, p < 0.001), NT-proBNP (ρ = 0.327, p < 0.001), age (ρ = 0.364, p < 0.001) and very weakly with coronary atherosclerosis (ρ = 0.123, p < 0.001). Prognostic discrimination of suPAR was moderate for cardiovascular death (AUC = 0.72, 95%CI 0.62-0.81) and all-cause death (AUC = 0.72, 95%CI 0.65-0.79) at 2-years. SuPAR remained a significant predictor for all-cause death in multivariable Cox regression (HR = 1.96, p = 0.001). CONCLUSIONS: SuPAR was an independent predictor of all-cause death, without diagnostic utility for fCAD. CLINICAL TRIAL REGISTRATION: NCT01838148.

Soluble urokinase plasminogen activator receptor and its complicated role in hemodialysis (HD) patients with Covid-19 infection.

BACKROUND: Soluble urokinase plasminogen receptor (suPAR) is a protein in the blood that has been described to reflect the severity status of systemic inflammation. AIMS AND OBJECTIVE: We investigated the association between admission suPAR levels and severity and outcome of HD patients with Covid-19 infection. MATERIALS AND METHODS: In an observational study of adult HD patients hospitalized for Covid-19, we measured suPAR levels in plasma samples. The time table for those measurements were as follows: at the beginning of admission, after a hemoperfusion (HP) session for those patients that received them, and just before discharge. RESULTS: Of the 17 patients (7 were male), 13 patients received HP (mean age: 74 years old). The median suPAR level was 12.94 ng/ml. For those who undertook HP in HD unit the median suPAR level before the session was 12.95 ng/mil and 6.2 ng/ml at the end of each session (p < 0.05). 3 patients had a suPAR level below 7 ng/ml. 2 of them survived without developing pleural effusions. 7 patients were discharged from the hospital with median suPAR level 12.08 ng/ml which did not differ significantly from the median suPAR level of the deceased ones (13.68 ng/ml). CONCLUSION: Admission levels of suPAR in HD patients hospitalized for Covid-19 do not seem to be predictive for their clinical course in general. Chronic Kidney Disease and its relation to suPAR independently of patients' inflammation status may be the key component for our notice. Despite that, in patients where low levels of suPAR combined with absence of pleural effusions the prognosis was excellent.