Mise en évidence et validation de biomarqueurs de la survie des greffes : Caractérisation des mécanismes

Investigateur Principal : Dr Sophie Brouard, PhD

Inserm, UMR 1064, ITUN, CHU de Nantes


Chronic Antibody Mediated Rejection (CABMR) is one of the major causes of graft loss at distance from surgery. As addressed before, CABMR is defined by the association of specific histological lesions associated with diffuse C4d deposits in peritubular capillaries and circulating Donor-Specific anti-HLA Antibodies. To date, no treatment exists for this pathology. Moreover its diagnosis which requires an invasive biopsy is concomitant from already irreversible lesions. From the patient perspective, the late graft loss results in a return in transplantation long-waiting list and often a hyperimmunization status that make difficult a future transplantation. The presence of DSA is a well defined marker of risk, however many patients with DSA will not develop chronic rejection and other markers are needed. Thus, one of our objectives was to identify biomarkers of CABMR in order to detect the lesions earlier, offering thus some possibilities of prevention. The next step is now their validation. Efforts have to be done to study larger cohorts of patients, rather than performing individual analyses that are difficult to interpret on a wider scale. The objectives are thus 1) to validate our potential diagnostic biomarkers of graft survival on large cohorts of patients, 2) to discover and validate new predictive tools and biomarkers that may detect CABMR earlier and may have a potential prognostic role in transplantation and finally, 3) to test and validate these biomarkers in protocol of drug withdrawal in parallel of tolerance markers. This approach is transversal with a major aim to combine clinical and biological markers to obtain discriminative biomarkers with high specificity and sensitivity.

This validation will be performed through 2 different studies:

Validation of blood diagnostic markers of graft survival on one year biopsy

The objective is to validate, on 625 patients our collection of blood biomarkers of CABMR. The blood biomarker levels will be correlated to the results of the systematic kidney biopsies at 1 year post transplantation.

Discovery of early and prognostic biomarkers of CABMR

Because the majority of the biomarkers described in the literature and by our own group, are able to diagnose CABMR but does not allow predicting it, we design a specific protocol to identify early predictive biomarkers in a prospective study. The objective is to correlate the blood transcriptional pattern at 3 months to one year systematic graft histology. In this program, we have already prospectively enrolled a cohort of 125 patients in whom blood has been harvested at 3 months after surgery.

Prediction at 3 months of  immunological event at 1 year