Biomarkers

Chronic liver diseases often progress silently, leading to steatosis, fibrosis, or even cirrhosis before patients experience symptoms. Early detection is therefore essential, especially for transplant patients, as appropriate management can slow the progression of the disease. Traditional biomarkers, such as liver enzymes (ALT, AST) and bilirubin, lack specificity and do not provide information about the nature of liver damage. Post-translational modifications (PTMs) of human serum albumin (HSA) present promising biomarkers due to their early onset and specificity.

Our research explores the detection and quantification of specific albumin isoforms as indicators of liver damage. We have developed the “Serum Enhanced Binding” (SEB) test, which detects structural changes in albumin through ligand-binding models measured by mass spectrometry. In preclinical research, this method has successfully detected liver dysfunction at early stages.

Our project relies on several approaches: analytical chemistry to characterize albumin modifications, ex vivo studies on hepatocyte cell lines to understand the mechanisms of damage, preclinical models to monitor the appearance of PTMs, clinical studies to assess the predictive value of these biomarkers, in silico simulations to analyze binding behaviors, and data analysis through machine learning to link these biomarkers to the nature and severity of the disease. Our goal is to improve the diagnosis of liver diseases and complications of liver transplants, paving the way for more precise care.

 

To address the shortage of available organs for liver transplantation, the use of so-called “extended criteria” grafts has become fairly common. These grafts, while generally viable, carry an increased risk of primary graft dysfunction or early graft dysfunction (EAD), a complication that may require another transplant or lead to death.

The primary goal of this project is to explore the performance of post-translational modifications (PTMs) of albumin (HSA) as a very early, simple, and reliable biomarker for the onset of EAD, thereby facilitating the rapid management of patients with liver transplant failure. HSA is produced exclusively by the liver, and its post-translational modifications (glycosylations and others) appear to differ in liver damage. Therefore, post-translational modifications of HSA could serve as valuable indicators of the condition of the transplanted liver in the days following transplantation. Using advanced high-resolution mass spectrometry techniques (LC-HR-MS), the variations and distribution of HSA isoforms will allow us to identify patients at risk of graft rejection and thus improve the prediction and management of post-transplant complications. The SEB test described above will also be evaluated for this purpose and adapted if necessary.

The European research program BIOMARGIN (FP7 No. 305499), coordinated by P&T, has already led to the detection of tissue and blood biomarkers for immune rejection reactions against the graft. Research on potential urinary biomarkers, which are less invasive and more accessible, is continuing locally. Furthermore, after studying the nephrotoxic mechanisms of cyclosporine and tacrolimus (Figure) using multi-omics methods, the team is now focusing on the potential nephrotoxicity of some of their metabolites. Additionally, a combined liver + renal tubule-on-chip model is being developed for another unit focus (titled ????) to study the toxicity of drug metabolites produced by the liver, as well as the influence of interactions between drugs or between endogenous substances and drugs on liver and kidney functions.

The influx and efflux membrane transporters of the proximal renal tubules regulate the active excretion and reabsorption of many endogenous and drug molecules. The team has previously demonstrated the vulnerability of these transporters to ischemia-reperfusion injury related to transplantation. As part of scientific collaborations within and outside the FHU SUPORT, this research is evolving towards the search for specific endogenous biomarkers of tubular transport to more precisely assess proximal tubular damage, with early applications in the management of post-transplant complications.