Serum Calcification Activity in Patients with Chronic Kidney Disease

描述(申请人提供)：慢性肾脏疾病(CKD)影响了11%的美国成年人，并大大增加了心血管疾病和过早死亡的风险。迫切需要新的工具来准确测量肾衰竭的不利代谢环境，以催化发现肾脏特有的心血管疾病机制。血管和软组织营养不良钙化在CKD患者中非常普遍，可能是连接肾脏和心血管疾病的一个关键机制。没有一个单独的生物标志物或一组标志物能够量化单个CKD患者的整体血清血管钙化活动。钙化的放射学测量变化太慢，不能指示治疗的反应，也不能区分内膜和中层血管钙化。在这笔赠款中，我们建议开发一种新的检测方法，用于测量CKD患者血清的总钙化活性。我们将利用来自一项前瞻性冠状动脉钙化研究的储存样本，将患者血清孵育在已建立的人主动脉平滑肌培养系统中，并测定相对于对照材料的血清钙化活性。我们将评估体外钙化活动是否可以预测临床获得的冠状动脉钙化评分的流行和进展，并将使用个别CKD患者血清来研究候选钙化机制。我们预计，拟议的钙化检测将成为一种新的转化性研究工具，其应用包括：(1)在临床钙化结果的流行病学研究中用作生物标记物；(2)在钙化抑制剂的临床试验中用作治疗反应的替代标记物；以及(3)用作筛选工具，以确定哪些人可能面临最大的钙化进展风险，并可能从新的治疗方法中受益最大。在肾病学、生物工程学和流行病学方面的跨学科合作将被用于实现研究目标。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) affects 11% of American adults and substantially increases the risks of cardiovascular disease and premature death. Novel tools are urgently needed to accurately measure the adverse metabolic milieu of kidney failure to catalyze discovery of kidney-specific cardiovascular disease mechanisms. Dystrophic calcification of the vasculature and soft tissues is highly prevalent among CKD patients and may represent one key mechanism linking kidney and cardiovascular diseases. No individual biomarker, or group of markers, is able to quantify the overall serum vascular calcification activity in individual CKD patients. Radiographic measurements of calcification change too slowly to indicate response to treatment and cannot distinguish intimal from medial vascular calcification. In this grant, we propose to develop a novel assay that will measure the total calcification activity of CKD patient serum. We will utilize stored samples from a prospective coronary artery calcification study, incubate patient serum in an established human aortic smooth muscle culture system, and determine the serum calcification activity relative to control material. We will evaluate whether in-vitro calcification activity can predict the prevalence and progression of clinically obtained coronary calcification scores, and will investigate candidate calcification mechanisms using individual CKD patient serum. We envision the proposed calcification assay will serve as a novel translational research tool with application that include (1) use as a biomarker in epidemiologic studies of clinical calcification outcomes, (2) use as a surrogate marker of treatment response in clinical trials of calcification inhibitors, and (3) use as a selection tool to identify individuals who may be at greatest risk of calcification progression and may benefit most from novel therapies. Interdisciplinary collaboration in Nephrology, Bioengineering, and Epidemiology will be used to achieve the study objectives.