Dataset Information

Soluble Urokinase Plasminogen Activator Receptor (suPAR) and All-Cause and Cardiovascular Mortality in Diverse Hemodialysis Patients.

ABSTRACT:

Introduction

The soluble receptor of urokinase plasminogen activator (suPAR) is an innate immunity/inflammation biomarker predicting cardiovascular (CV) and non-CV events in various conditions, including type 2 diabetic patients on dialysis. However, the relationship between suPAR and clinical outcomes in the hemodialysis population at large has not been tested.

Methods

We measured plasma suPAR levels (R&D enzyme-linked immunosorbent assay [ELISA]) in 1038 hemodialysis patients with a follow-up of 2.9 years (interquartile range = 1.7-4.2) who were enrolled in the PROGREDIRE study, a cohort study involving 35 dialysis units in 2 regions in Southern Italy.

Results

suPAR was strongly (P < 0.001) and independently related to female gender (? = -0.160), age (? = 0.216), dialysis vintage (? = 0.264), CV comorbidities (? = 0.105), alkaline phosphatase (? = 0.136), albumin (? = -0.147), and body mass index (BMI; ? = 0.174) (all P < 0.006). In fully adjusted analyses, suPAR tertiles predicted the risk of all-cause mortality (third tertile vs. first tertile hazard ratio (HR) = 1.91, 95% confidence interval (CI) = 1.47 - 2.48, P < 0.001), CV mortality (HR = 1.47, 95% CI = 1.03-2.09, P = 0.03), and non-CV mortality (HR = 1.94, 95% CI = 1.28-2.93, P = 0.002); these relationships were not modified by diabetes or other risk factors. suPAR added only modest prognostic risk discrimination and reclassification power for these outcomes to parsimonious models based on simple clinical variables.

Conclusion

In conclusion, suPAR robustly predicted all-cause and both CV and non-CV mortality in a large unselected hemodialysis population. Intervention studies are needed to definitively test the hypothesis that suPAR is causally implicated in clinical outcomes in this population.

SUBMITTER: Torino C

PROVIDER: S-EPMC6127402 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Soluble Urokinase Plasminogen Activator Receptor (suPAR) and All-Cause and Cardiovascular Mortality in Diverse Hemodialysis Patients.

Torino Claudia C Pizzini Patrizia P Cutrupi Sebastiano S Postorino Maurizio M Tripepi Giovanni G Mallamaci Francesca F Reiser Jochen J Zoccali Carmine C

Kidney international reports 20180522 5

<h4>Introduction</h4>The soluble receptor of urokinase plasminogen activator (suPAR) is an innate immunity/inflammation biomarker predicting cardiovascular (CV) and non-CV events in various conditions, including type 2 diabetic patients on dialysis. However, the relationship between suPAR and clinical outcomes in the hemodialysis population at large has not been tested.<h4>Methods</h4>We measured plasma suPAR levels (R&D enzyme-linked immunosorbent assay [ELISA]) in 1038 hemodialysis patients wi ...[more]

PMID: 30197976

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Project description:BackgroundThe soluble urokinase plasminogen activator receptor (suPAR) is related to hepatic inflammation and fibrosis and has been suggested to participate in the development of liver cirrhosis. Therefore, the aim of the current study was to measure the concentration of suPAR in the hepatic vein of cirrhotic patients during a liver vein catheterization to identify a possible hepatic suPAR generation. Furthermore, we explored if suPAR levels were associated with the degree of cirrhosis and liver dysfunction.Methods and patientsWe included 105 cirrhotic patients and 19 liver-healthy controls. Blood was sampled from the hepatic vein and the femoral artery and suPAR was measured by enzyme-linked immunosorbent assay.ResultsWe identified significantly higher median suPAR concentrations among the cirrhotic patients (7.2 ng/ml in the hepatic vein; 6.8 ng/ml in the femoral artery) compared to the controls (2.6 ng/ml, respectively, p-values <0.001). However, the median hepatic suPAR formation was 0.0 ng/ml in both groups. We observed significantly increasing suPAR levels according to higher Child classes (4.5 ng/ml, 6.9 ng/ml and 9.0 ng/ml, Child A, B, C respectively; p-value<0.001), and significantly higher median suPAR concentrations in patients with ascites versus patients without ascites (8.1 ng/ml versus 5.3 ng/ml, respectively, p-value<0.001). suPAR levels were significantly related to bilirubin (r = 0.48, p<0.001), the hepatic venous pressure gradient (r = 0.39, p<0.001), the cardiac index (r = 0.24, p = 0.02) and the plasma volume (r = 0.33, p = 0.001), whereas suPAR levels were significantly inversely related to albumin (r = -0.59, p<0.001), plasma coagulation factors (r-0.39, p<0.001), the mean arterial pressure (r = -0.28, p = 0.004), the systemic vascular resistance (r = 0.26, p = 0.007), the indocyanine green clearance (r = -0.51, p<0,001) and the galactose elimination capacity (r = -0.39, p<0.001).ConclusionWe identified elevated suPAR concentration in cirrhotic patients, which correlated significantly with the degree of cirrhosis and liver failure, but we were not able to demonstrate hepatic suPAR generation per se. This suggests that further investigations of the source of suPAR in cirrhotic patients need to be undertaken.

Project description: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.

Project description:Background and objectivesSoluble urokinase plasminogen activator receptor is a novel biomarker strongly predictive of cardiovascular outcomes implicated in the pathogenesis of kidney disease. Soluble urokinase plasminogen activator receptor levels, however, correlate with declining kidney function. It is unclear whether soluble urokinase plasminogen activator receptor levels remain associated with outcomes in patients with ESRD.Design, setting, participants, & measurementsWe measured plasma soluble urokinase plasminogen activator receptor levels in 1175 patients (mean age =66±8 years old, 54% men) with type 2 diabetes mellitus on hemodialysis participating in the German Diabetes and Dialysis Study followed for a median of 4 years for outcomes including all-cause death, cardiovascular events, and infection-related mortality. Survival analysis was performed using stepwise Cox proportional hazards models adjusted for potential confounders. Also, adjustments were made for inflammatory markers (C-reactive protein and leukocyte count) and the oxidative stress marker asymmetric dimethyl arginine to investigate potential mediators of the relationship between soluble urokinase plasminogen activator receptor and outcomes.ResultsMedian soluble urokinase plasminogen activator receptor levels were 10,521 pg/ml (interquartile range, 9105-12,543 pg/ml). When stratified by tertiles, patients with soluble urokinase plasminogen activator receptor >11,633 pg/ml (third tertile) had adjusted 1.6-fold higher mortality (hazard ratio, 1.60; 95% confidence interval, 1.27 to 2.03) compared with those with low soluble urokinase plasminogen activator receptor <9599 pg/ml (first tertile). Risks of sudden death and stroke were higher (adjusted hazard ratio, 1.98; 95% confidence interval, 1.27 to 3.09 and adjusted hazard ratio, 1.74; 95% confidence interval, 1.05 to 2.90, respectively), together accounting for higher incidence of cardiovascular events (adjusted hazard ratio, 1.48; 95% confidence interval, 1.15 to 1.89). Associations with outcomes persisted after adjusting for C-reactive protein, leukocyte count, and asymmetric dimethyl arginine. Addition of soluble urokinase plasminogen activator receptor to a risk factor model modestly improved risk discrimination for all-cause death (?C statistic, 0.02; 95% confidence interval, 0.00 to 0.03) and cardiovascular events (?C statistic, 0.02; 95% confidence interval, 0.00 to 0.05).ConclusionsThe association of soluble urokinase plasminogen activator receptor levels with outcomes persists in patients on hemodialysis. Additional study is warranted to characterize the underlying pathways of that association, which may yield opportunities to develop new therapeutic strategies.

Dataset Information

Soluble Urokinase Plasminogen Activator Receptor (suPAR) and All-Cause and Cardiovascular Mortality in Diverse Hemodialysis Patients.

Introduction

Methods

Results

Conclusion

Publications

Soluble Urokinase Plasminogen Activator Receptor (suPAR) and All-Cause and Cardiovascular Mortality in Diverse Hemodialysis Patients.

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