The PI is a pediatric transplant nephrologist whose long-term career goal is to elucidate the role of vascular injury in chronic allograft nephropathy, the primary cause of kidney transplant failure in adults and children. Chronic allograft nephropathy has no effective treatment and is prevalent in nearly all functioning kidney transplants within 10 years. Novel pathogenic biomarkers that can detect early (and perhaps reversible) forms of disease will provide new therapeutic targets that are needed to improve kidney transplant survival. Chronic allograft nephropathy is a vascular disease resulting from time-dependent immune and non-immune vascular injury that begins early post-transplant. Since therapies that reduce immune injury have not reduced the incidence of chronic allograft nephropathy, the contributions of non-immune vascular injury need further investigation. The proposed research training plan will investigate the central hypothesis that kidney transplant injury contributes to ongoing vascular injury that leads to chronic allograft nephropathy through non-immune pathogenic factors involved in the chronic kidney disease-mineral bone disorder (CKD-MBD). This hypothesis was formed by recent seminal discoveries (with critical contributions from the PI) in translational models of CKD. The research plan is a component of the proposed career development plan that has the following three goals: 1) to become an expert in kidney transplantation and mechanisms of transplant failure, including chronic allograft nephropathy; 2) to improve the PI's knowledge of vascular biology/pathology in kidney transplantation; 3) to become a productive independent clinical investigator who advances our understanding of vascular injury in chronic allograft nephropathy to improve kidney transplant outcomes. To achieve these goals the PI will receive advanced clinical research training by completing a Master of Science in Clinical Investigation degree. The PI will receive exceptional mentoring from a team of experts in transplant nephrology and vascular biology. The proposed research and career development plans will be carried out in a superior training environment supported by Southern Illinois University (PI's professional home) and Washington University (WU, his research training and CTSA home).
Aim 1 a/1b will establish and validate CKD-MBD factors as biomarkers of transplant vascular injury in a cross-sectional study of kidney transplant recipients (n=120) enrolled in our biorepository.
Aim 2 will evaluate CKD-MBD factors as biomarkers of kidney transplant outcomes in a prospective 3-year longitudinal study of incident kidney transplant recipients (n=40). A third exploratory aim will identify novel mechanistic pathways involved in transplant vascular injury using RNA-seq studies of subjects from aims 1 and 2 with transplant vascular injury. This will help the PI learn and apply emerging genomic technologies, available through the WU-CTSA core, to his studies of transplant vascular injury. The PI expects that completion of the proposed research and career development plans will advance our understanding of vascular injury in chronic allograft nephropathy and enable his transition to an independent clinical investigator.
All kidney transplants eventually fail due to chronic rejection, also known as chronic allograft nephropathy. Unfortunately there is no meaningful diagnostic, preventive, or treatment strategy for the disease. This project will develop a non-invasive predictive and diagnostic test for chronic allograft nephropathy that will also provide important insights into the mechanism of disease. We expect this will improve the health of adults and children with kidney transplants by allowing for earlier detection of the disease process and identifying novel targets for treatment of the disease.
| Seifert, Michael E; Gunasekaran, Muthukumar; Horwedel, Timothy A et al. (2017) Polyomavirus Reactivation and Immune Responses to Kidney-Specific Self-Antigens in Transplantation. J Am Soc Nephrol 28:1314-1325 |
| Seifert, Michael E; Ashoor, Isa F; Chiang, Myra L et al. (2016) Fibroblast growth factor-23 and chronic allograft injury in pediatric renal transplant recipients: a Midwest Pediatric Nephrology Consortium study. Pediatr Transplant 20:378-87 |
| Seifert, Michael E; Mannon, Roslyn B (2015) Modernization of Chronic Allograft Injury Research: Better Biomarkers, Better Studies, Better Outcomes. Clin Transpl 31:211-225 |
