Kidney transplantation is the preferred treatment modality for patients with end-stage renal disease (ESRD). Compared to dialysis, transplantation leads to improved quality of life, longer patient survival and considerable cost reductions. Progress in medical therapy has dramatically improved short-term survival of deceased donor kidney transplants (DDKT), 92% of grafts function beyond one year. However, long-term results remain poor with 10 year graft survival rates of 45% and 33.8% in European Americans (EAs) and African Americans (AAs), respectively. New tools to improve long-term graft survival are urgently needed. Risk variants in the apolipoprotein L1 (APOL1) nephropathy gene and caveolin-1 (CAV1) gene in kidney donors shorten graft survival after transplantation. This provides strong evidence that gene variants associated with kidney disease impact transplant outcomes. The overarching goal of this proposal is to systematically search for genetic and environmental factors impacting graft survival after DDKT. We propose to test variants in 56 replicated nephropathy susceptibility loci from kidney donors for association with long-term kidney transplant graft survival. Interactive effects of gene variants with each other and with environmental stressors associated with nephropathy will be performed. Finally, gene expression will be carried out in healthy human kidney cells that contain risk variants that associate with kidney graft survival to better understand how gene variants cause kidney disease. The present analyses will be conducted in two phases: a Discovery phase involving genetic data from 2,500 (2000 EAs, 500 AAs) independent donor-kidney DNA samples, followed by a Replication phase where an additional 1,000 samples (800 EAs, 200 AAs) will be analyzed. A combined analysis will be performed to finalize parameter estimates and identify variants to be followed up in gene expression analyses. The 56 tested variants all reached genome-wide statistical significance in prior studies and many have been replicated. They have improved our understanding of the pathogenesis of kidney disease. However, most have relatively weak effects and low predictive ability limiting their clinical utility. We propose a systematic approach, analyzing nephropathy genes identified in genome-wide association studies in kidney transplantation. After transplantation, kidneys are stressed by prolonged lack of organ perfusion and exposure to nephrotoxic medications. These factors likely provide the contrast necessary to detect contributors to kidney allograft survival. This work is likely to improve outcomes after kidney transplantation and would allow meaningful translation of genetic association results in an important clinical realm.
Despite recent medical advances, long-term kidney allograft failure rates remain unacceptably high after kidney transplantation, there is strong evidence that inherited factors (gene variants) are associated with the development of severe kidney disease requiring dialysis treatments or a kidney transplant. Gene variants also appear to impact kidney transplant survival when the donated kidney carries the risk variants. We propose to analyze variants in 56 known kidney disease genes in more than 3,500 deceased kidney donors, testing for genetic association with survival of transplanted kidneys, these analyses use information from anonymous kidney donors and transplant recipients in two large national kidney transplant registries; this study is likely to provide results useful to improve outcomes after kidney transplantation.
| Ma, Lijun; Divers, Jasmin; Freedman, Barry I (2018) Mechanisms of injury in APOL1-associated kidney disease. Transplantation : |
| Hughes, Timothy M; Sink, Kaycee M; Williamson, Jeff D et al. (2018) Relationships between cerebral structure and cognitive function in African Americans with type 2 diabetes. J Diabetes Complications 32:916-921 |
| Murea, Mariana; Brown, W Mark; Divers, Jasmin et al. (2017) Vascular Access Placement Order and Outcomes in Hemodialysis Patients: A Longitudinal Study. Am J Nephrol 46:268-275 |
| Julian, B A; Gaston, R S; Brown, W M et al. (2017) Effect of Replacing Race With Apolipoprotein L1 Genotype in Calculation of Kidney Donor Risk Index. Am J Transplant 17:1540-1548 |
| Ainsworth, Hannah C; Langefeld, Carl D; Freedman, Barry I (2017) Genetic epidemiology in kidney disease. Nephrol Dial Transplant 32:ii159-ii169 |
| Freedman, Barry I; Sink, Kaycee M; Hugenschmidt, Christina E et al. (2017) Associations of Early Kidney Disease With Brain Magnetic Resonance Imaging and Cognitive Function in African Americans With Type 2 Diabetes Mellitus. Am J Kidney Dis 70:627-637 |
| Ma, Lijun; Chou, Jeff W; Snipes, James A et al. (2017) APOL1 Renal-Risk Variants Induce Mitochondrial Dysfunction. J Am Soc Nephrol 28:1093-1105 |
| Freedman, Barry I; Locke, Jayme E; Reeves-Daniel, Amber M et al. (2017) Apolipoprotein L1 Gene Effects on Kidney Transplantation. Semin Nephrol 37:530-537 |
| George, Brandon J; Beasley, T Mark; Brown, Andrew W et al. (2016) Common scientific and statistical errors in obesity research. Obesity (Silver Spring) 24:781-90 |
| Ma, Lijun; Langefeld, Carl D; Comeau, Mary E et al. (2016) APOL1 renal-risk genotypes associate with longer hemodialysis survival in prevalent nondiabetic African American patients with end-stage renal disease. Kidney Int 90:389-395 |
Showing the most recent 10 out of 18 publications
