THE ASSOCIATION OF BIOMARKERS OF ENDOTHELIAL FUNCTION WITH PROSPECTIVE CHANGES IN KIDNEY FUNCTION IN SICKLE CELL ANEMIA

镰状细胞性贫血中内皮功能生物标志物与肾功能预期变化的关联

• 批准号: 9372894
• 负责人: Kenneth I Ataga
• 金额: $ 23.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9372894
• 关键词: ASSOCIATION; BIOMARKERS; ENDOTHELIAL; FUNCTION; PROSPECTIVE

Sickle cell disease (SCD) is a severe monogenic disorder which affects approximately 80,000 patients in the US. It is characterized by a vasculopathy with involvement of multiple organs and resulting in complications such as chronic kidney disease (CKD). Despite the high prevalence of CKD in patients with SCD and its known association with increased mortality, the natural history of CKD in this setting and the factors associated with changes in kidney function remain incompletely defined. Furthermore, the available treatment options for albuminuria, an early manifestation of CKD, in patients with SCD are limited. In fact, no controlled studies have confirmed the long-term efficacy of angiotensin-converting enzyme (ACE) inhibitors, the current “standard of care.” There is increasing evidence for a contribution of endothelial dysfunction to the pathophysiology of albuminuria in SCD. The association of biomarkers of endothelial function with albuminuria provides opportunities, not only to assess the effect of therapies which improve endothelial function, but also to evaluate the predictive value of these biomarkers for a decline in kidney function. Our overall hypothesis is that biomarkers of endothelial function will be predictive of patients with sickle cell anemia at high risk for a decline in kidney function (decrease in estimated glomerular filtration rate and increase in albuminuria). The analyses that we plan to perform would allow us to identify those patients who are most likely to benefit from early treatment and will facilitate the development of targeted therapies. In addition, this study will enable the development of a biorepository of urine and plasma samples for future evaluation of the associations of changes in metabolic profiles and other novel biomarkers with a decline in kidney function. In this application, we will evaluate the rate of change of kidney function (eGFR and albuminuria) over 36 – 48 months; evaluate the cross-sectional association of biomarkers of endothelial function and clinical characteristics with kidney function; and evaluate the cross-sectional association of urine and plasma metabolomics profiles with kidney function. Finally, we will identify biomarkers of endothelial function, metabolomic profiles and clinical characteristics for a worsening in kidney function and for a rapid decline in kidney function, based on a decrease in eGFR of ≥ 2.5 mL/min per 1.73 m2 per year. At the conclusion of our proposed work, we will have an improved understanding of the natural history of CKD in sickle cell anemia. There are limited available therapies for the treatment of early CKD in patients with SCD and there is a paucity of data on the long-term efficacy of available pharmacotherapies. Identification of biomarkers for the progression of CKD will facilitate the development of treatments which may be more effective than the current “standard of care.”

镰状细胞病（SCD）是一种严重的单基因疾病，影响约80,000 美国的患者。它的特征是血管病，并参与多个器官和 导致并发症，例如慢性肾脏疾病（CKD）。尽管CKD的患病率很高 在SCD患者及其与死亡率增加的已知关联中，CKD的自然病史 该设置以及与肾功能变化相关的因素仍未完全定义。 此外，蛋白尿的可用治疗选择，CKD的早期表现， SCD患者有限。实际上，尚无对照研究证实 血管紧张素转换酶（ACE）抑制剂，当前的“护理标准”。有在增加 内皮功能障碍对SCD中蛋白尿的病理生理的贡献的证据。 内皮功能与蛋白尿的生物标志物协会不仅提供机会 评估改善内皮功能的疗法的作用，但也评估 这些生物标志物的预测价值对于肾功能下降。 我们的总体假设是，内皮功能的生物标志物将预测 镰状细胞贫血有肾功能下降的高风险（估计肾小球降低 过滤率和蛋白尿的增加）。我们计划执行的分析将使我们能够 确定那些最有可能从早期治疗中受益的患者，并将促进 靶向疗法的开发。此外，这项研究将使 尿液和血浆样品的生物座位，以将来评估变化的关联 肾功能下降的代谢谱和其他新型生物标志物。 在此应用中，我们将评估肾功能的变化率（EGFR和蛋白尿） 36 - 48个月；评估内皮功能生物标志物的横截面关联和 具有肾功能的临床特征；并评估尿液和 具有肾功能的血浆代谢组学谱。最后，我们将确定内皮的生物标志物 功能，代谢组曲线和临床特征，可用于肾功能的令人担忧 肾功能的迅速下降，基于每年1.73 m2的EGFR≥2.5ml/min的降低。 在我们提出的工作结束时，我们将对自然历史有了改进的了解 镰状细胞贫血中的CKD。有限的可用疗法可用于治疗早期CKD SCD患者，有关可用的长期效率的数据很少 药物治疗。鉴定CKD进展的生物标志物将有助于 开发可能比当前“护理标准”更有效的治疗方法。