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，可影响儿童和成人，并可能导致肾衰竭。镰状细胞病引起肾损害的机制尚不清楚。我们将在镰状细胞病的小鼠模型中研究肾脏损伤，该模型发展为类似于人类疾病的肾脏损伤。我们将探讨镰状细胞病如何损害肾脏的不同区域：肾小球，导致尿中的蛋白质泄漏，肾功能不全和肾衰竭，肾髓质，导致无法集中尿液，使患者容易脱水。在相同的动物模型中，我们将研究是否可以通过骨髓移植后完全或部分恢复正常造血功能来逆转、改善或预防我们的初步数据中描述的肾脏损害以及在第一个Aim中进一步定义的肾脏损害。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治疗方法预防或修复镰状细胞肾病的能力。首先，我们将研究用造血干细胞移植替代镰状细胞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害，以及移植后肾损害是否会进展。然后，我们将研究羟基脲治疗儿童和成人镰状细胞早期肾病患者的效果，以评估该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参数的影响，以及肾脏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改变潜在疾病的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了疾病的早期和晚期表现。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脏损害的机制，并确定当前的治疗方法是否可以修复或预防镰状细胞肾病的进展。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，在美国每年约有10万名非裔美国人和1200名西班牙裔美国人出生。肾脏损害发生在生命早期，并在成年期恶化，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，但其发展的机制尚不清楚，因此将成为本提案的重点。我们的目标是为这种潜在的毁灭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.