The Pathogenesis of Sickle Cell Nephropathy

描述（由申请人提供）：镰状细胞肾病是镰状细胞病的常见并发症，影响儿童和成人，并可能导致肾衰竭。镰状细胞病引起肾损害的机制还不清楚。我们将研究镰状细胞病小鼠模型的肾损伤，该模型的肾损伤类似于人类疾病。我们将研究镰状细胞病如何损害肾脏的不同区域：肾小球，导致尿液中的蛋白质渗漏，肾功能不全和肾衰竭，以及肾髓质，导致无法浓缩尿液，使患者容易脱水。在相同的动物模型中，我们将研究在我们的初步数据中描述并在第一个目标中进一步定义的肾损伤是否可以通过在骨髓移植后完全或部分恢复正常造血来逆转、改善或预防。我们将在镰状细胞病患者中扩展这些研究，以研究镰状细胞病的两种主要疗法预防或修复镰状细胞肾病的能力。首先，我们将研究造血干细胞移植替代镰状造血是否可以逆转或改善镰状细胞病患者已经存在的肾损伤，以及肾损伤是否在移植后进展。然后，我们将研究羟基脲治疗儿童和成人镰状细胞患者早期肾脏疾病的影响，以评估这种药物修复肾功能的能力。在这些儿童和成人队列中，我们将研究治疗对肾功能不全参数的影响，以及肾损伤的某些生物标志物是否随着疾病的治疗而改善。我们相信，通过研究肾脏对两种治疗干预措施的反应，我们将能够确定哪些潜在的病理生理途径参与早期疾病和晚期表现。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病肾损害的机制，并确定目前的治疗方法是否可以修复或预防镰状肾病的进展。我们相信基础和临床研究的结合将使我们能够为疾病的临床管理和镰状细胞肾病的预防做出贡献。公共卫生相关性：镰状细胞病是最常见的遗传性疾病之一，在美国影响约100，000人，每年发生在约1：400非洲裔美国人和约1：1200西班牙裔美国人中。肾损害发生在生命早期，并持续到成年，大约80%的40岁以上的患者患有肾脏疾病。尽管镰状肾病是镰状细胞病最普遍和潜在危险的并发症之一，但对其发展的机制知之甚少，因此将成为本提案的重点。我们的目标是为这种潜在的破坏性疾病找到新的治疗方法。

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.