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 美国患者的特点是累及多个器官的血管病变。 尽管 CKD 患病率很高，但仍会导致慢性肾脏病 (CKD) 等并发症。 在 SCD 患者及其已知与死亡率增加的关系中，CKD 的自然史 这种情况以及与肾功能变化相关的因素仍未完全确定。 此外，白蛋白尿（CKD 的早期表现）的可用治疗方案 事实上，尚无对照研究证实 SCD 患者的长期疗效。 血管紧张素转换酶 (ACE) 抑制剂是当前的“护理标准”。 内皮功能障碍对 SCD 蛋白尿病理生理学影响的证据。 内皮功能生物标志物与蛋白尿的关联提供了机会，不仅 评估改善内皮功能的治疗效果，还评估 这些生物标志物对肾功能下降的预测价值。 我们的总体假设是内皮功能的生物标志物将预测患有以下疾病的患者 镰状细胞性贫血具有肾功能下降的高风险（估计肾小球减少） 我们计划进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 此外，这项研究将有助于开发一种靶向疗法。 尿液和血浆样本的生物储存库，用于未来评估变化之间的关联 代谢特征和其他与肾功能下降相关的新型生物标志物。 在此应用中，我们将评估肾功能（eGFR 和蛋白尿）的变化率 36 – 48 个月；评估内皮功能和生物标志物的横断面关联 临床特征与肾功能的关系；并评估尿液和肾功能的横截面关联性。 最后，我们将确定内皮细胞的生物标志物。 肾功能恶化和肾功能恶化的功能、代谢组学特征和临床特征 肾功能迅速下降，基于 eGFR 每年每 1.73 m2 下降 ≥ 2.5 mL/min。 在我们提议的工作结束时，我们将对自然历史有更好的了解 镰状细胞性贫血中 CKD 的治疗 治疗早期 CKD 的可用疗法有限。 SCD 患者的长期疗效缺乏数据 识别 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。