Serum Calcification Activity in Patients with Chronic Kidney Disease

描述（由申请人提供）：慢性肾脏疾病（CKD）影响11%的美国成年人，并大大增加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功能衰竭的不良代谢环境，以催化发现肾脏特异性心血管疾病的机制。血管和软组织的营养不良钙化在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。没有单独的生物标志物或一组标志物能够量化CKD患者的整体血清血管钙化活性。钙化的x线测量变化太慢，不能表明对治疗的反应，也不能区分内膜钙化和内侧血管钙化。在这项资助中，我们建议开发一种新的检测方法来测量CKD患者血清的总钙化活性。我们将利用前瞻性冠状动脉钙化研究中储存的样本，在已建立的人主动脉平滑肌培养系统中培养患者血清，并确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性是否可以预测临床获得的冠状动脉钙化评分的患病率和进展，并将使用个体CKD患者血清研究候选钙化机制。我们设想拟议的钙化分析将作为一种新的转化研究工具，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志物，(2)在钙化抑制剂的临床试验中用作治疗反应的替代标志物，以及(3)用作选择工具，以识别可能处于最大钙化进展风险的个体，并可能从新疗法中获益最多。肾脏学、生物工程和流行病学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. PUBLIC HEALTH RELEVANCE: Vascular calcification is common in individuals with chronic kidney disease. Current testing is inadequate for identifying \ patients who are at risk for vascular calcification. We propose to develop a novel in-vitro assay that will predict calcification scores in humans with chronic kidney disease by utilizing patient serum in an established smooth muscle cell culture system. These experiments intend to lay groundwork for future research studies of vascular calcification.