The Pathogenesis of Sickle Cell Nephropathy

镰状细胞肾病的发病机制

基本信息

批准号：
7731051
负责人：
DAVID R ARCHER
金额：
$ 35万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7731051
关键词：
ATP phosphohydrolase Acids Adolescent Adult Affect African American Aftercare Age Albumins Albuminuria Animal Model Area Biological Markers Birth Blood Blood Vessels Bone Marrow Transplantation Child Childhood Clinic Clinical Clinical Management Clinical Research Complication Creatinine Data Dehydration Detection Development Dextrans Disease Disease Progression Excretory function Experimental Water Deprivation Extravasation Functional disorder Globin Glomerular Capillary Glomerular Filtration Rate Goals Hematopoiesis Hematopoietic Stem Cell Transplantation Hemoglobin Hemoglobin SS Hereditary Disease Hispanic Americans Histology Human Immunoglobulin G Individual Injury Kidney Kidney Diseases Kidney Failure Kidney Glomerulus Knowledge Lead Lesion Life Measures Microalbuminuria Modeling Molecular Mus Mutation Pathogenesis Pathway interactions Patients Permeability Plasma Proteins Population Prevalence Prevention Proteins Regulation Renal Blood Flow Renal function Renal glomerular disease Reporting Serum Severity of illness Sickle Cell Sickle Cell Anemia Sickle Hemoglobin Stem cell transplant Techniques Testing Therapeutic Therapeutic Intervention Transforming Growth Factor beta Transplantation Tubular formation United States Urine Water aged alpha-1-microglobulin aquaporin-2 base beta-2 Microglobulin cohort connective tissue growth factor design dextran disorder prevention fetal hemodynamics human disease hydroxyurea improved kidney medulla mouse model news peripheral blood podocyte prevent public health relevance repaired response restoration sickling solute treatment effect urea transporter urinary

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：镰状细胞肾病是镰状细胞疾病的常见并发症，会影响儿童和成人，并可能导致肾衰竭。尚未充分了解镰状细胞病中肾脏损伤的机制。我们将在镰状细胞疾病的鼠模型中研究肾脏损伤，该模型会发展出类似于人类疾病的肾脏损伤。我们将研究镰状细胞疾病如何损害肾脏的不同区域：肾小球，导致尿液中的蛋白质泄漏，肾功能不全和肾衰竭，以及导致尿液浓缩尿液并使患者容易脱水的肾脏髓质。在同一动物模型中，我们将研究我们的初步数据中描述的肾损害以及在第一个目标中进一步定义的肾脏损害是否可以通过完全或部分恢复骨髓移植后的正常造血作用来逆转，改善或预防。我们将在镰状细胞疾病患者中扩展这些研究，以研究两种主要疗法可预防或修复镰状细胞肾病的能力。首先，我们将研究由造血干细胞移植替换镰状造血作用，可以逆转或改善镰状细胞疾病患者已经存在的肾脏损伤，以及移植后肾脏损伤是否会发生。然后，我们将研究羟基脲治疗对早期肾脏疾病的小儿和成年镰状细胞患者的影响，以评估该药物修复肾脏功能的能力。在这些儿童和成人队中，我们将研究治疗对肾功能障碍参数的影响，以及某些肾脏损伤的生物标志物是否通过治疗该疾病来改善。我们认为，通过研究对两种改变潜在疾病的治疗干预措施的肾脏反应，我们将能够确定早期疾病和晚期表现涉及哪些潜在的病理生理途径。这可能使我们能够设计策略来治疗或预防疾病的某些并发症。我们的目标是了解镰状细胞疾病中肾脏损伤的机制，并确定当前的疗法是否可以修复或防止镰状肾脏疾病的进展。我们认为，基础研究和临床研究的结合将使我们能够为疾病的临床管理和预防镰状细胞肾病做出贡献。公共卫生相关性：镰状细胞疾病是最常见的遗传疾病之一，在美国大约1：400非裔美国人和〜1：1200西班牙裔美国人出生的美国遗传疾病之一。肾脏损害在生命的早期发生，并在成年期间恶化，大约80％的患者在40年内患有肾脏疾病。即使镰状肾病是镰状细胞疾病最普遍，最危险的并发症之一，其发展的机制也很熟悉，因此将成为该提议的重点。我们的目标是为这种潜在的毁灭性状况找到新闻疗法。