Biomarkers in Kidney Transplantation

Last modifications: 02/08/2019 by FDM

Coordinator: Dr. Chantal Barin-Le Guellec – Dr. Roland Lawson

Injury factors in kidney transplantation (nephrotoxicity of immunosuppressants, ischemia-reperfusion (I/R), alloimmune reaction …) induce tubular dysfunction, which in turn has a negative impact on the homeostasis of major physiological functions (not only of the kidney itself but also of other organs, as a consequence of the accumulation of deleterious substances), and on the pharmacokinetics of drugs used in transplant patients. Transporters of the SLC and ABC families are involved in the fine regulation of these equilibria through renal secretion and reabsorption of small molecules (metabolites) generated by the cell metabolism or arising from the environment. They also regulate systemic and/or intracellular exposure of CNIs and other drugs used in transplantation.

The aim of our research is to find biomarkers which specifically reflect the function of transporters, to study (i) if and how they are impacted by graft injury, (ii) the kinetics of their modulation, (iii) the clinical and pharmacological impact of such effects, and (iv) the possibility to restore normal transporter function thus limiting deleterious consequences for the patients.

The tools and methods used to address these questions are:

• Metabolomics analyses (1H-RMN, LC-MS/MS) targeted on organic anions and cations
• Expression studies of transporters on tubular cells or renal biopsies
• Transport studies across renal tubular cells
• Ex vivo and clinical studies in kidney transplant patients

If our research is successful, it will contribute to improve patient care by providing new monitoring tools and by opening the way to innovative therapeutic interventions targeting membrane transporters.

Coordinator: Prof. Pierre Marquet

The European FP7 programme BIOMARGIN « BIOMarkers or Renal Graft INjuries » (2012-2018, coordinator: Pierre Marquet) has identified several urine proteomic/peptidomic biomarkers of graft rejection, for which patents will be filed. The prospective follow-up of a large cohort of >600 KTR is currently being carried out to evaluate their prognostic performance.

Our future objectives are to:

• Collaborate with the industry to develop prototypes of IVD tests for the urine analysis of these biomarkers in routine clinical and laboratory conditions in a large panel of renal transplantation centres.
• Organize and coordinate a national, randomized, interventional clinical trial in which the diagnostic and therapeutic strategies will be adjusted or not, based on these IVD tests. The aim of this trial is to further increase the level of evidence of these tests regarding the improvement of graft survival and patient quality-of-life, and to convince the transplantation community.

Coordinator: Prof. Pierre Marquet

The aim is to complete the deciphering of toxicity of CNIs and their metabolites, on different cell lines, using an integrated omics approach associating epigenomics, transcriptomics, proteomics and metabolomics.

The pathways identified are then explored by classic techniques of biochemistry, histology, molecular and cellular biology as well as through functional tests on selected cell lines as well as in animal models.

Figure from Burat et al., FASEB Bioadvances