Sickle cell nephropathy is a common complication of sickle cell disease that affects both children and adults, and may lead to kidney failure. The mechanisms that cause kidney damage in sickle cell disease are not well understood. We will study kidney damage in a murine model of sickle cell disease that develops kidney injury that resembles human disease. We will investigate how sickle cell disease damages different areas of the kidneys: the glomerulus, causing protein leakage in the urine, renal insufficiency and kidney failure, and the kidney medulla which causes an inability to concentrate the urine, making the patients prone to dehydration. In the same animal model, we will study whether the renal damage described in our preliminary data and further defined in the first Aim can be reversed, ameliorated, or prevented by fully or partially restoring normal hematopoiesis after bone marrow transplantation. We will extend these studies in patients with sickle cell disease to investigate the ability of two primary therapies for sickle cell disease to prevent or repair sickle cell nephropathy. First, we will study if replacement of sickle hematopoiesis by hematopietic stem cell transplant can reverse or improve kidney damage that was already present in patients with sickle cell disease, and whether kidney damage progresses after transplantation. Then we will study the effects of hydroxyurea treatment in pediatric and adult sickle cell patients with early kidney disease to assess the ability of this agent to repair kidney function. In these cohorts of children and adults, we will study the effect of treatment on parameters of renal dysfunction and whether certain biomarkers of renal injury improve with treatment of the disease. We believe that by studying the renal response to two therapeutic interventions that modify the underlying disease, we will be able to determine which potential pathophysiological pathways are involved in early disease and late manifestations. This may allow us to design strategies to treat or prevent certain complications of the disease. Our goal is to understand the mechanisms of kidney damage in sickle cell disease and to determine if current therapies can repair or prevent progression of sickle kidney disease. We believe the combination of basic and clinical studies will enable us to contribute to the clinical management of the disease and the prevention of sickle cell nephropathy.

Public Health Relevance

Sickle cell disease is one of the most common genetic diseases and affects ~100,000 individuals in the United States occurring in ~1:400 African-American and ~ 1:1200 Hispanic-American births each year. Kidney damage occurs early in life and worsens through adulthood with approximately 80% of patients over 40 years having renal disease. Even though sickle nephropathy is one of the most prevalent and potentially dangerous complications of sickle cell disease the mechanisms underlying its development are poorly understood and will thus be the focus of this proposal. Our goal is to find news treatment for this potentially devastating condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK081699-01A1
Application #
7731051
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Eggers, Paul Wayne
Project Start
2009-09-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$350,001
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322