Despite the improved short-term outcomes in kidney transplantation (KT), comparable progress in long-term allograft survival has not been achieved. Chronic allograft dysfunction (CAD) characterized by interstitial fibrosis and tubular atrophy (IFTA), accounts for one quarter of transplant kidneys lost within 5 years. Preventing kidney graft dysfunction and loss is a critical unmet need in transplantation. From reported evidence, posttransplant graft survival is determined by the complex interplay of donor factors, acute peri-transplantation injury, and kidney transplant recipient factors. We recently reported that the transcriptome of deceased donor kidneys encompasses a gene signature at the time of KT that predicts long-term graft function. These signatures shed light on the inherent donor mechanisms responsible for triggering and likely sustaining posttransplant injury. Furthermore, although a recipient peripheral blood transcriptional signature was recently reported as a predictor of early acute rejection, the effect of pretransplant KT recipient peripheral blood transcriptional profiles on long- term outcomes has not been previously tested. Moreover, there are no comprehensive biological markers from donors and recipients that can be used pretransplant to predict graft outcomes. Given the multifactorial nature of CAD, our preliminary data, and the gaps in our knowledge, we have the unique ability to fill these unmet needs by studying the early stressors that lead to kidney graft fibrosis deploying an unbiased comprehensive approach. Towards this goal, we have already established a cohort with prospective sequential sampling of kidney allografts. In our studies, donor kidneys were evaluated at pre-implantation and recipient pretransplant peripheral blood mononuclear cells (PBMCs) were collected. The recipient cohort also includes longitudinal PBMCs, protocol biopsies, and detailed clinical metadata, allowing for the correlation of gene expression profiles with histological features and clinical parameters. In this exploratory proposal, we hypothesize that early cellular and molecular events in the donor kidney trigger local inflammatory responses that, when combined with recipient immune state, propagate and sustain posttransplant kidney injury leading to graft loss. Specific aims (SA) include: SA1 (1) Identify kidney transplant recipient preimplantation peripheral blood molecular profiles that associate with immune activation vs quiescence and determine posttransplant graft function. (2) Discern longitudinal posttransplant molecular variations in patient's PBMCs that associate with long-term graft function. SA2 Integrate kidney donor and recipient peripheral blood gene expression profiles in association with donor/recipient clinical characteristics for constructing a composite score to predict long-term outcomes. IMPACT: Results of these studies will provide a unique understanding of the early molecular triggers that determine graft outcomes and ultimately lead to CAD. Novel prognostic biomarkers will enable the early identification of patients at higher risk for progression to CAD, allowing for the development of new therapeutic modalities that have the potential to avoid irreversible graft injury and improve long-term outcomes.

Despite the improved short-term outcomes in kidney transplantation (KT), comparable progress in long-term allograft survival has not been achieved with chronic allograft dysfunction (CAD) accounting for most cases of graft loss. Results from our proposed studies will provide a unique understanding of the early molecular triggers that determine graft outcomes and ultimately lead to CAD. Novel prognostic biomarkers will enable the early identification of patients at higher risk for progression to CAD, such that their use in patient monitoring as well as the development of new therapeutic modalities targeting our identified molecular triggers have the potential to avoid irreversible graft injury and improve long-term outcomes in KT recipients.