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

镰状细胞病(SCD)是一种严重的单基因疾病，影响约80,000人 在美国的病人。它的特点是血管病变累及多个器官和 导致慢性肾脏疾病(CKD)等并发症。尽管慢性肾脏病的发病率很高 在SCD患者及其与死亡率增加的已知关联中，CKD的自然病史 这一设定和与肾功能改变相关的因素仍未完全确定。 此外，蛋白尿是慢性肾脏病的早期表现，现有的治疗方案 SCD患者是有限的。事实上，还没有对照研究证实阿司匹林的长期疗效 血管紧张素转换酶(ACE)抑制剂，目前的“护理标准”。有越来越多的 内皮功能障碍在SCD蛋白尿病理生理学中的作用的证据。 内皮功能的生物标记物与蛋白尿的关联不仅提供了机会， 评估改善内皮功能的治疗的效果，同时也评估 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慢性阻塞性肺疾病患者 镰状细胞性贫血是肾功能下降的高危因素(估计肾小球减少 滤过率和蛋白尿增加)。我们计划执行的分析将使我们能够 确定哪些患者最有可能从早期治疗中受益，并将有助于 开发靶向治疗。此外，这项研究将使开发一种 尿和血浆样本的生物保存库，用于未来评估 代谢谱和其他新的肾功能下降的生物标志物。 在这项应用中，我们将评估肾功能(EGFR和蛋白尿)的变化率 36-48个月；评估内皮功能和血管内皮细胞功能的生物标志物的横断面相关性 临床特征与肾功能的关系；并评估尿液和肾功能的横断面相关性 血浆代谢组学与肾功能的关系。最后，我们将确定内皮细胞的生物标志物 肾功能恶化和慢性肾衰的功能、代谢特征和临床特征 肾功能迅速下降，其基础是每1.73m2每年每1.73m2≥的EGFR值减少2.5mL/分钟。 在我们拟议的工作结束时，我们将对自然历史有一个更好的理解 CKD在镰状细胞性贫血中的分布。可用于治疗早期慢性肾脏病的治疗方法有限 而关于SCD患者的长期疗效的可用数据很少 药物疗法。识别慢性肾脏病进展的生物标志物将有助于 开发可能比目前的“护理标准”更有效的治疗方法。

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.”