Evaluation of Angiopoietins as Prognostic Markers of Kidney Allograft Structure and Function

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Project Summary/Abstract Kidney transplantation is the main therapy for end stage kidney disease (ESKD),1 however, 3-5% of grafts fail yearly and only 50% remain functioning at ten years.2,3 The most common manifestations of graft loss are poorly characterized histologic findings of interstitial fibrosis and tubular atrophy (IFTA), 4-7 which are present in up to a third of biopsies 6-month after transplant.8 Furthermore, endothelial cell injury is common in kidney transplantation due to ischemic injury during procurement,9 and leads to impaired vessel integrity and peritubular capillary loss, which have been shown to lead to IFTA.9-12 In addition, vessel integrity has been proposed to have a protective impact on kidney function by reducing microvascular leakage of albumin13, and reducing the recipient alloimmune response to damaged endothelial cells.9, 10, 14, 15 For this reason, we propose to evaluate two vascular markers in the Angiopoietin family capturing blood vessel integrity [Angiopoietin-1 (Angpt-1), and -2 (Angpt-2)] in the setting of deceased-donor kidney transplantation. Activation of the Angpt-1 receptor, Tie-2, maintains vessel stability and integrity, but Angpt-2, a competitive antagonist to Angpt-1, interferes with the Angpt-1-Tie-2 axis, and promotes vessel leakage.16 The balance of Angpt-1: Angpt-2 production determines the integrity of blood vessels.17 The goal of this proposal is to evaluate if blood vessel integrity as measured by Angiopoietins will be prognostic of short and long-term graft function in an effort to identify pathways for future intervention. The candidate hypothesizes that maintaining vessel integrity (as measured by Angpt-1 and Angpt-2) will be associated with less fibrosis, and better graft outcomes. In aim 1, we will prospectively enroll deceased donor transplant recipients as well as use a pre- existing cohort of recipients to evaluate and externally validate the associations of perioperative Angiopoietins with 1-year graft function. In aim 2, we will evaluate if Angiopoietins measured at a single time point are associated with long-term graft failure (mean follow up of about four years) by using bio-specimens from the pre-existing FAVORIT trial. In aim 3, we will test the associations of perioperative Angiopoietins with tissue pathology on 6-month graft biopsies using our prospective enrollment cohort. More specifically, we will evaluate if Angpt-1 and -2 are associated with 6-month IFTA, peritubular capillary loss and vessel permeability on histology. Understanding the role of vessel integrity as measured by Angiopoietins in allograft outcomes may help identify pathways for future intervention and risk stratify recipients for more targeted trials and clinical care.