Soluble urokinase plasminogen activator receptor levels predict survival in patients with portal hypertension undergoing TIPS
Sven H. Loosen,
Fabian Benz,
Raphael Mohr,
Philipp A. Reuken,
Theresa H. Wirtz,
Lioba Junker,
Christian Jansen,
Carsten Meyer,
Michael Praktiknjo,
Alexander Wree,
Johanna Reißing,
Münevver Demir,
Wenyi Gu,
Mihael Vucur,
Robert Schierwagen,
Andreas Stallmach,
Anselm Kunstein,
Johannes Bode,
Christian Trautwein,
Frank Tacke,
Tom Luedde,
Tony Bruns,
Jonel Trebicka,
Christoph Roderburg
Affiliations
Sven H. Loosen
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Fabian Benz
Department of Gastroenterology and Hepatology, Campus Virchow Klinikum and Campus Charité Mitte, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
Raphael Mohr
Department of Gastroenterology and Hepatology, Campus Virchow Klinikum and Campus Charité Mitte, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; Department of Internal Medicine I, University Clinic Bonn, Bonn, Germany
Philipp A. Reuken
Department of Internal Medicine IV, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
Theresa H. Wirtz
Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
Lioba Junker
Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
Christian Jansen
Department of Internal Medicine I, University Clinic Bonn, Bonn, Germany
Carsten Meyer
Department of Radiology, University Clinic Bonn, Bonn, Germany
Michael Praktiknjo
Department of Internal Medicine B, University of Münster, Münster, Germany
Alexander Wree
Department of Gastroenterology and Hepatology, Campus Virchow Klinikum and Campus Charité Mitte, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
Johanna Reißing
Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
Münevver Demir
Department of Gastroenterology and Hepatology, Campus Virchow Klinikum and Campus Charité Mitte, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
Wenyi Gu
Department of Internal Medicine B, University of Münster, Münster, Germany
Mihael Vucur
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Robert Schierwagen
Department of Internal Medicine B, University of Münster, Münster, Germany
Andreas Stallmach
Department of Internal Medicine IV, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
Anselm Kunstein
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Johannes Bode
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Christian Trautwein
Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
Frank Tacke
Department of Gastroenterology and Hepatology, Campus Virchow Klinikum and Campus Charité Mitte, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
Tom Luedde
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Tony Bruns
Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
Jonel Trebicka
Department of Internal Medicine B, University of Münster, Münster, Germany; European Foundation for the Study of Chronic Liver Failure - EF CLIF, Barcelona, Spain; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
Christoph Roderburg
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany; Department of Gastroenterology and Hepatology, Campus Virchow Klinikum and Campus Charité Mitte, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; Corresponding author. Address: Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, 40225 Düsseldorf, Germany; Tel.: +49-211-81-16330.
Background & Aims: Transjugular intrahepatic portosystemic shunt (TIPS) is the most effective therapy for complications of portal hypertension. However, clinical outcomes following TIPS placement vary widely between patients and identifying ideal candidates remains a challenge. Soluble urokinase plasminogen activator receptor (suPAR) is a circulating marker of immune activation that has previously been associated with liver inflammation, but its prognostic value in patients receiving TIPS is unknown. In the present study, we evaluated the potential clinical relevance of suPAR levels in patients undergoing TIPS insertion. Methods: suPAR concentrations were measured by ELISA in hepatic vein (HV) and portal vein (PV) blood samples from 99 patients (training cohort) as well as peripheral venous blood samples from an additional 150 patients (validation cohort) undergoing TIPS placement. The association between suPAR levels and patient outcomes was assessed using Kaplan-Meier methods and Cox-regression analyses. Results: suPAR concentrations were significantly higher in HV samples compared to PV samples and correlated with PV concentration, the presence of ascites, renal injury, and consequently with the Child-Pugh and MELD scores. Patients with lower suPAR levels had significantly better short- and long-term survival after TIPS insertion, which remained robust after adjustment for confounders in multivariate Cox-regression analyses. Sensitivity analysis showed an improvement in risk prediction in patients stratified by Child-Pugh or MELD scores. In an independent validation cohort, higher levels of suPAR predicted poor transplant-free survival after TIPS, particularly in patients with Child-Pugh A/B cirrhosis. Conclusion: suPAR is largely derived from the injured liver and its levels are predictive of outcome in patients undergoing TIPS. suPAR, as a surrogate of hepatic inflammation, may be used to stratify care in patients following TIPS insertion. Impact and implications: Transjugular intrahepatic portosystemic shunt (TIPS) is the most effective therapy for complications of portal hypertension. However, clinical outcomes following TIPS placement vary widely between patients and identification of the ideal candidates remains challenging. We show that soluble urokinase plasminogen activator receptor (suPAR), a circulating marker of immune activation that can easily be measured in routine clinical practice, is a novel marker to identify patients who will benefit from TIPS and those who will not.
