Chronic kidney disease is present in a large proportion of adults with sickle cell disease (SCD) and is associated with increased morbidity and early mortality. However, the pathways for sickle nephropathy are unfortunately poorly understood. This proposal will leverage robust preliminary data from the applicant's K23 award to innovatively address the mechanistic pathways and susceptibilities for acute kidney injury in patients with SCD. The underlying hypothesis is that genetic variation in cell-free hemoglobin and heme processing pathways is centrally involved in influencing the propensity to develop acute kidney injury during vaso- occlusive episodes, when concentrations of cell-free hemoglobin and heme increase several-fold and the clearance of these nephrotoxins is critical to protect the kidney. The applicant will apply exciting preliminary data to test this hypothesis via two specific aims. Specific aim #1 will utilize a genomic approach to identify polymorphisms in candidate genes involved in cell- free hemoglobin and heme scavenging and catabolism pathways associated with acute kidney injury risk in a longitudinal cohort of SCD patients. Specific aim #2 will determine whether functional variants in HP, the main scavenger of cell-free hemoglobin in circulation, and HMOX1, the rate limiting enzyme for degrading heme, are associated with acute kidney injury risk and with biomarkers of oxidative stress and kidney injury. The goals of this proposal are to enhance the hypothesis for the applicant's R01 proposal that impaired cell- free hemoglobin and heme processing are critical to the kidney damage observed in sickle cell disease. This proposal will investigate a new focus of the applicant's research, acute kidney injury, which is a strong predictor of incident chronic kidney disease and its progression in the general population but is an understudied phenotype in SCD. Integrating the genetic analyses with kidney injury and oxidative stress biomarkers leads to a deeper understanding for the mechanisms of kidney damage and will guide individualized and preventive therapeutic strategies for sickle cell nephropathy. The applicant is exceptionally positioned to achieving the goals outlined in this proposal through a strong history of productivity and the institutional environment, which includes the UIC Comprehensive Sickle Cell Center which cares for over 800 SCD patients and has a long-standing tradition of successful implementation of research studies. At the present time, there are only limited therapeutic options available to treat SCD. Developing a better understanding of the susceptibilities and pathways for kidney disease may potentially have a significant impact on this underserved high risk population and will facilitate the long-term goals of the applicant in becoming a successful and independent translational researcher focusing on sickle cell nephropathy.