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

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 shortterm 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 À1 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.

Genetic variants of TRAF6 modulate peritoneal immunity and the risk of spontaneous bacterial peritonitis in cirrhosis: A combined prospective-retrospective study

“…To assess whether the TRAF6 haplotype 2 is associated with altered peritoneal macrophage (PMϕ) function, we first determined the macrophage activation marker soluble urokinase-type plasminogen activator receptor (suPAR) in non-infected ascites 21 . Patients with the TRAF6 risk haplotype 2 had lower AF suPAR concentrations as compared to other haplotypes (Fig.…”

“…In the absence of SBP, the identified TRAF6 risk haplotype 2 was accompanied by a less proinflammatory state of peritoneal macrophages as shown by reduced concentrations of suPAR, a soluble marker of peritoneal and systemic immune activation 21 and lower expression of inflammatory cytokines and chemokines. The lower expression of the neutrophil-recruiting chemokine CXCL8 by PMϕ in patients carrying the TRAF6 risk haplotype 2 suggests an impaired neutrophil recruitment to the peritoneal cavity during viable bacterial translocation resulting in a higher risk for SBP accompanied by a reduced state of peritoneal inflammation.…”

SuPAR, an emerging biomarker in kidney and inflammatory diseases

“…Decompensated liver cirrhosis is the deterioration of liver function in a cirrhotic patient with a 1-year mortality rate reaching 50% 39. Spontaneous bacterial peritonitis (SBP), bacteraemia and pneumonia can occur in one-third of decompensated patients and contribute to the high mortality through sepsis and multiorgan failure.…”

Elevation of serum urokinase plasminogen activator receptor and liver stiffness in postoperative biliary atresia

“…uPAR is expressed by a wide range of immune cells and endothelial cells, which contribute to the etiopathogenesis of hepatic inflammation and liver fibrogenesis[7,8]. Once inflammation is activated, uPAR is released from the cell membrane by proteolytic enzymes to produce soluble uPAR[9]. In recent years, previous studies have investigated that elevated circulating uPAR levels have been observed in acute liver failure, chronic liver diseases, and nonalcoholic fatty liver diseases [10-12].…”