Soluble urokinase plasminogen activator receptor is a prognostic biomarker in decompensated cirrhosis

TL;DR

This study shows that suPAR, a protein linked to inflammation, can predict severe outcomes in patients with advanced liver disease.

Contribution

suPAR is identified as an independent biomarker for mortality and disease progression in decompensated cirrhosis.

Findings

suPAR levels ≥14.0 ng/ml independently predict 90-day mortality in decompensated cirrhosis.

suPAR correlates with disease severity markers like MELD score, bilirubin, and ICU treatment.

suPAR reflects systemic and liver-specific inflammation, providing prognostic value beyond existing scoring systems.

Abstract

Cirrhosis poses a significant healthcare burden, with decompensation and acute-on-chronic liver failure (ACLF) resulting in high morbidity and mortality. Reliable biomarkers of disease progression are urgently needed. Urokinase plasminogen activator receptor (uPAR) and its soluble form (suPAR) are linked to systemic inflammation in liver disease. This study aims to evaluate suPAR as a prognostic marker and its role in chronic liver disease.

SuPAR levels were measured in a derivation cohort (n = 178) and a validation cohort (n = 197) from two centers, including healthy controls and patients with cirrhosis, acute decompensation, and ACLF. In a mouse model using carbon tetrachloride and lipopolysaccharide, suPAR levels correlated with liver uPAR expression. Single-cell RNA sequencing was used to analyze uPAR expression in immune cells from healthy controls and from patients with HBV-related cirrhosis.

SuPAR levels correlated with disease severity markers, including creatinine, bilirubin, albumin, international normalized ratio, MELD score, and hospitalization duration (all p <0.001). They were associated with higher in-hospital mortality (p = 0.02), intensive care unit treatment (p <0.001), 90-day mortality (p = 0.003), and ACLF progression (p = 0.014). SuPAR levels ≥14.0 ng/ml independently predicted 90-day mortality in decompensated cirrhosis (hazard ratio [HR] 5.295, p = 0.015). The validation cohort confirmed these correlations, with increased 28-day (HR 9.589, p <0.001) and 90-day (HR 7.899, p <0.001) mortality. In mice, suPAR and liver uPAR expression were significantly higher in acute-on-chronic injury compared with chronic injury and control groups. Single-cell RNA sequencing in human liver immune cells revealed increased PLAUR expression in monocytes, macrophages, and dendritic cells in HBV-induced cirrhosis.

SuPAR is a potential biomarker for predicting outcomes in acute decompensation, reflecting both systemic and liver-specific inflammation. Further studies are needed to clarify the role of uPAR-expressing cells in disease progression.

Our study identifies soluble urokinase plasminogen activator receptor (suPAR) as a biomarker of liver-derived systemic inflammation that is clinically relevant for predicting adverse outcomes in decompensated cirrhosis and is associated with disease progression, organ dysfunction, and mortality. Systemic suPAR levels ≥14.0 ng/ml independently predicted 90-day mortality in patients with decompensated cirrhosis across two independent cohorts. Accurate outcome prediction is crucial for developing tailored, personalized treatments in advanced chronic liver disease, and suPAR, as an independent predictor of short-term mortality and disease progression, may complement established scoring systems such as MELD.

Image 1

•suPAR is a robust biomarker for predicting 90-day mortality and ACLF in decompensated cirrhosis.•suPAR ≥14.0 ng/ml independently predicts 90-day mortality in decompensated cirrhosis, regardless of MELD score.•suPAR is mainly derived from hepatic neutrophils and myeloid cells, as shown in mouse models and scRNA-seq data.•suPAR provides prognostic value beyond MELD, CRP, and CLIF-C AD, reflecting the inflammatory trajectory of liver disease.

suPAR is a robust biomarker for predicting 90-day mortality and ACLF in decompensated cirrhosis.

suPAR ≥14.0 ng/ml independently predicts 90-day mortality in decompensated cirrhosis, regardless of MELD score.

suPAR is mainly derived from hepatic neutrophils and myeloid cells, as shown in mouse models and scRNA-seq data.

suPAR provides prognostic value beyond MELD, CRP, and CLIF-C AD, reflecting the inflammatory trajectory of liver disease.

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