Soluble urokinase plasminogen activator receptor is compartmentally regulated in decompensated cirrhosis and indicates immune activation and short-term mortality

Authors

  • H. W. Zimmermann,

    1. Department of Medicine III, University Hospital Aachen, Aachen, Germany
    2. NIHR Biomedical Research Unit and Centre for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, UK
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  • P. A. Reuken,

    1. Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    2. Integrated Research and Treatment Center – Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
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  • A. Koch,

    1. Department of Medicine III, University Hospital Aachen, Aachen, Germany
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  • M. Bartneck,

    1. Department of Medicine III, University Hospital Aachen, Aachen, Germany
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  • D. H. Adams,

    1. NIHR Biomedical Research Unit and Centre for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, UK
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  • C. Trautwein,

    1. Department of Medicine III, University Hospital Aachen, Aachen, Germany
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  • A. Stallmach,

    1. Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    2. Integrated Research and Treatment Center – Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
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  • F. Tacke,

    1. Department of Medicine III, University Hospital Aachen, Aachen, Germany
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  • T. Bruns

    Corresponding author
    1. NIHR Biomedical Research Unit and Centre for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, UK
    2. Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    3. Integrated Research and Treatment Center – Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    • Department of Medicine III, University Hospital Aachen, Aachen, Germany
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  • F. Tacke and T. Bruns contributed equally.

Correspondence: Tony Bruns, NIHR Biomedical Research Unit and Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. (fax: +44 121 415 8701; e-mail: t.bruns@bham.ac.uk).

Abstract

Objective

Patients with decompensated cirrhosis are susceptible to bacterial infections, which are associated with organ failure and a high mortality rate. Reliable biomarkers are needed to identify patients who require intensified treatment. Our objective was to study the regulation and prognostic relevance of elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) in patients with advanced cirrhosis.

Design, setting and participants

We examined the associations between serum and ascitic fluid (AF) suPAR and liver function, bacterial infection, and short-term mortality in 162 consecutive patients with decompensated cirrhosis undergoing diagnostic paracentesis in a tertiary health care centre in Germany.

Main outcome measure

Twenty-eight-day mortality.

Results

Circulating suPAR levels were increased in patients with decompensated cirrhosis and correlated with the severity of liver dysfunction and systemic inflammation but were not indicative of bacterial infection. Circulating suPAR levels >14.4 ng mL−1 predicted 28-day mortality, even after adjustment for liver function and confounders [HR = 3.05 (1.35–6.90); P = 0.0076] equal to the MELD score (AUC = 0.71; 95% CI = 0.61–0.81; P < 0.001). Cut-off levels derived from cohorts without liver disease were not applicable due to the low specificity. AF suPAR levels were elevated during spontaneous bacterial peritonitis (SBP), but not during episodes in which bacteria or bacterial DNA was translocated into the ascites. AF suPAR levels correlated poorly with systemic suPAR but were associated with a more severe course of SBP and a worse outcome. In vitro experiments revealed that monocytes, and to a lesser extent neutrophils, secrete suPAR after Toll-like-receptor ligation, which led to rapid urokinase plasminogen activator receptor cleavage followed by increased synthesis.

Conclusion

Blood and ascitic suPAR levels provide distinct, but relevant prognostic information on the severity of complications in patients with end-stage liver disease.

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