The issue

Acute decompensation is the most frequent cause of non-elective hospital admission of patients with cirrhosis, and its most severe form, acute-on-chronic liver failure (ACLF), is characterized by hepatic and/or extrahepatic organ failures and high risk of short-term death. These patients exhibit intense systemic inflammation, indicated by leukocytosis, elevated blood levels of cytokines, inflammatory lipid mediators and C-reactive protein. These patients also exhibit immunosuppression, indicated by decreased responses of specific monocyte subsets to bacterial products, decreased capacity to kill microbes, and reduced lymphocyte function. Immunosuppression predisposes patients with acutely decompensated (AD) cirrhosis to secondary infections and re-escalation of end-organ dysfunction and mortality.

Albumin therapy is common in patients with AD cirrhosis, including patients treated by large-volume paracentesis and patients with spontaneous bacterial peritonitis (SBP) or hepatorenal syndrome–acute kidney injury (HRS–AKI). Recently, the ANSWER trial has demonstrated lower incidence of SBP and other infections in patients with AD cirrhosis receiving long-term weekly administration of albumin. In addition, albumin administration has emerged as efficacious anti-inflammatory therapy, reducing cytokine levels in patients with AD cirrhosis and ACLF. Although albumin pleiotropic effects have classically been attributed to its oncotic and antioxidant properties, recent data in leukocytes from patients with AD cirrhosis have proved that albumin modulates cytokine production in response to bacterial DNA by interacting with the endosomal Toll-like receptor 9 signaling pathway. However, at present, a comprehensive and deep understanding of the immunomodulatory actions of albumin in the setting of AD cirrhosis is still lacking.

The approach

The mechanisms by which albumin exerts immunomodulatory properties (i.e., to ameliorate systemic inflammation and boost the host immune response against pathogens) are at present unknown. Over the years, the Grifols Chair has consolidated a robust translational research program investigating the cellular and molecular pathways involved in the immune restorative functions of the albumin molecule. This program includes in its portfolio studies functional assays in peripheral blood mononuclear cells and neutrophils from patients with AD cirrhosis as well as in animal models of chronic liver disease. The Grifols Chair program has a strong involvement of cutting-edge technologies such as bulk and single-cell RNA-sequencing, targeted and untargeted metabolomics and lipidomics, and high-dimensional immunophenotyping.