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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-DKUS-C (81))
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Kusek, John W
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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de Boer, Ian H; Kestenbaum, Bryan (2013) Invited commentary: Quantifying salt in urine--a complex solution. Am J Epidemiol 177:1193-5; discussion 1196-8