Validation of a specific miR profile in kidney transplant patients with rejection and identification of the mechanisms of action involved.

Kidney transplantation is the treatment of choice for patients with end-stage renal disease.However 15% of the transplanted patients develop acute kidney rejection: T-cell mediated rejection (TCMR) or antibody-mediated rejection (ABMR). At the other end of this spectrum, exceptional patients maintain a prolonged allograft function without rejection after the discontinuation, either through noncompliance or medically-driven, of all immunosuppressive drugs. These patients are designated as "operationally tolerant" in reference to the lack of immune allo-reponse. This condition is extremely rare, as only 0.03% of kidney recipients was proven to be tolerant in a recent European-wide survey.MicroRNAs (miRNA) are non-coding RNAs with a central role in cell biology by binding tocomplementary target mRNAs, resulting in translational inhibition or degradation. Furthermore miRNAs form complexes with RNA binding proteins protecting them from RNAse-dependent degradation. As a consequence, miRNAs are highly stable in both plasma and urine. Several miRNAs have been suggested to be involved in the pathophysiology of TCMR, ABMR and tolerance. Given their role in pathophysiology, in vivo modulation of miRNA expression as a therapeutic strategy is widely explored in chronic kidney disease (CKD), like autosomal dominant polycystic disease and Alport syndrome. Currently, trials with miRNA targeting therapy in the field of transplantation have not entered the clinical phase yet. However, recent work on miRNA in kidney transplantation in humans, both in the pathophysiology and biomarker field, provides evidence for the therapeutic potential of miRNA targeting therapies.In this prospective, longitudinal observational clinical study we will investigate the role of miRNA in the development of acute rejection (both TCMR and ABMR) as well as the induction of tolerance after kidney transplantation. Pilot experiments with 28 kidney transplant patients confirmed the feasibility of isolating miRNA from plasma and kidney tissue. miRNA was sequenced with a NGS approach at Oxford Genome Centre. Unravelling the clinically relevant pathophysiological pathways might represent novel preventive and therapeutic targets. Besides, the comparison of miRNA profiles in both tolerogenic patients and rejection adds a scientifically interesting perspective at the extremes of the immune reaction towards a graft. In this project, we start from clinically relevant miRNA profiles in three groups of kidney transplant patients: rejection, matched stable graft patients and tolerant patients. Therefore, we intend to expand the discovery cohort data firstly and confirm the profiles found in a validation cohort secondly; while in parallel we will try to unravel the pathophysiological pathways involved in an experimental set-up.

Keywords:KIDNEY TRANSPLANTATION

Disciplines:Pathophysiology, Kidney transplantation