Grant: Operating Grant

Approximately 5000 kidney transplants in the USA fail each year with return to dialysis, an incidence approximately 4%, and making renal allograft failure, the fourth leading cause of end-stage renal disease. Antibody-mediated rejection is a major cause of late kidney transplant loss. Anti-HLA alloantibody is a risk factor, but does not indicate which kidneys are experiencing rejection. We recently showed that endothelial gene set expression in kidney transplants with donor specific antibodies is indicator of active antibody-mediated rejection and poor graft survival. However, only 40% of kidney transplant biopsies with high endothelial gene set expression and histopathology of chronic antibody-mediated rejection or graft loss were diagnosed by current immunohistologic criteria. Thus a large number of failing kidney transplants - at least 50-60% - have antibody-mediated rejection, much of it missed by current criteria. Molecular changes of endothelium in biopsies represent a sensitive approach for detecting kidney transplants at risk for antibody-mediated deterioration. We aim to develop a sensitive and specific, PCR or immunohistochemistry based test for identifying which kidney transplants are being damaged by alloantibody using individual endothelial genes/proteins. We will explore whether expression of individual endothelial genes/proteins would identify antibody-mediated graft injury and predict graft survival. This is more than of diagnostic importance: it will change clinical practice and transplant outcomes.