The kidney is affected in several different ways in sickle cell anemia (SCA). Children, and even infants with SCA develop a urine concentrating defect (UCD), increased glomerular filtration rate (GFR), supranormal proximal tubular function and impaired ability to excrete potassium. Also seen is hematuria (gross or microscopic) from medullary tubulo-interstitial damage. With increasing age, glomerulopathy develops, manifest initially as micro-albuminuria, then macro- albuminuria, progressing to renal failure and end stage renal disease. Kidneys and glomeruli are enlarged and GFR increased in early stages. With time, focal and segmental glomerulosclerosis, reduced GFR and end stage renal disease develops. Sickle nephropathy (SN) is present in 40-50% of adults. We have strong preliminary data on novel biomarkers on SN and animal data that supports an interventional trial with losartan to ameliorate UCD, albuminuria and pulmonary hypertension in sickle cell disease. We propose to conduct critical pilot studies in patients with SCA to guide the design of a robust phase III randomized controlled trial of losartan; and to assemble the sites, Statistics and Data Management Center (SDMC), regulatory documents, study monitoring and data management plan to ensure effective execution of a phase III multi-center study. In aim 1, we will conduct pilot studies to study the progression of SN and the feasibility of reducing/preventing SN with losartan, in order to gather critical data necessary to design a phase III randomized control trial for SN and PH. The pilot studies will help estimate feasibility of accruing patients, determine a refined duration/dose and the sample size and response rate necessary in the first two years of funding. In aim 2, we will design a multi-center phase III randomized trial of losartan for SN in the third year of funding. In aim 3, we will assemble the infrastructure to carry out a well executed multi-center trial. in the third year of funding, we will identify additional clinical sites based on eligible patients, and engage a SDMC to develop the clinical protocol, consent and assent forms, manual of operations, investigators brochure, extend the IND and prepare documents for IRB submission, establish a DSMB, data management and study monitoring plan and training materials for the study staff. We have assembled four participating sites: two adult and two pediatric sites for the pilot studies: Cincinnati Childrens Hospital Medical Center, University Hospital at the University of Cincinnati in Cincinnati and Nationwide Childrens Hospital and the Ohio State University Hospital in Columbus, Ohio for the pilot studies. These sites will also participate in the phase III study, while additional sites are identified and recruited, as needed based on the pilot data obtained from this planning grant. The above aims are a focused approach in this planning grant to obtain data critical for the design of a robust phase III trial, apply for RO1 funding and amass the infrastructure necessary to execute a well-designed phase III study and effectively translate research discoveries made in our laboratory to the clinic to affect effective therapeutic approaches to sickle nephropathy.