Sven Lamatsch, Mohsin Hassan, Kai Kappert, Hilmar Berger, Qingquan Bai, Zhengyang Zhao, Nirbaanjot Walia, Carlos De La Peña-Ramirez, Raphael Mohr, Münevver Demir, Juan Wang, Fabian Artusa, Richard Sittner, Fausto Andreola, Rhea Veelken, Florian van Boemmel, Jonas Schumacher, Niklas Aehling, Janett Fischer, Rajeshwar Mookerjee, Tianhui Hu, Thomas Berg, Rajiv Jalan, Frank Tacke, Pavitra Kumar, Cornelius Engelmann
- Liver cirrhosis poses a significant healthcare burden, with decompensation and 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.
Methods
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 carbontetrachloride and lipopolysaccharides, SuPAR levels correlated with liver uPAR expression. Single-cell RNA sequencing analysed uPAR expression in immune cells from healthy controls and HBV-related cirrhosis patients.
Results
SuPAR levels correlated with disease severity markers, including creatinine, bilirubin, albumin, INR, MELD-score, andLiver cirrhosis poses a significant healthcare burden, with decompensation and 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.
Methods
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 carbontetrachloride and lipopolysaccharides, SuPAR levels correlated with liver uPAR expression. Single-cell RNA sequencing analysed uPAR expression in immune cells from healthy controls and HBV-related cirrhosis patients.
Results
SuPAR levels correlated with disease severity markers, including creatinine, bilirubin, albumin, INR, MELD-score, and hospitalization duration (all p < 0.001). They were associated with higher in-hospital mortality (p=0.02), ICU 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 (HR=5.295, p=0.015). The validation cohort confirmed correlations with increased 28-day (HR=9.589, p < 0.001) and 90-day mortality (HR=7.899, p < 0.001). In mice, suPAR and liver uPAR expression were higher in acute-on-chronic injury versus chronic injury and controls. Single-cell RNA sequencing in human liver immune cells revealed increased PLAUR expression in monocytes, macrophages, and dendritic cells in HBV-induced cirrhosis.
Conclusions
SuPAR is a potential biomarker for predicting outcomes in acute decompensation, reflecting systemic and liver-specific inflammation. Further research is needed to clarify the role of uPAR-expressing cells in disease progression.
Impact and Implications
Our study identifies suPAR as a biomarker of liver-derived systemic inflammation, clinically relevant for predicting adverse outcomes in decompensated cirrhosis, and associates it 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.…
