Novel Diagnostics and Therapeutic Targets for Calcification in CKD

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PROJECT SUMMARY Chronic kidney disease (CKD) predisposes affected individuals to high rates of end stage renal disease (ESRD), cardiovascular disease (CVD) and premature death. Despite increasing utilization of interventions that target traditional risk factors, the frequency of adverse clinical events remains high. Novel strategies targeting non-traditional risk factors are urgently needed to improve outcomes. Vascular calcification is a non- traditional risk factor for CKD progression and CVD in CKD. Validation of novel screening tests to define high- risk individuals before they develop vascular calcification and insights into novel vascular calcification mechanisms in CKD would enhance risk stratification and CVD and CKD management and potentially prevent adverse clinical events. Backed by strong preliminary data, we will efficiently leverage the Chronic Renal Insufficiency Cohort (CRIC) Study to advance the vascular calcification field by evaluating the novel T50 assay as a candidate biomarker and elevated levels of deoxycholic acid as a possible modifiable disease mechanism. T50 is a novel serum assay that quantifies calcification propensity by measuring the net effect of calcification inhibitors and promoters. Our preliminary data from 184 patients with stage 3-4 CKD demonstrate that low T50, which reflects increased calcification propensity, is strongly and independently associated with progression of aortic stiffness and with mortality. We will comprehensively evaluate T50 in the CRIC Study, which has detailed clinical data, serial measures of left ventricular hypertrophy, arterial stiffness and coronary artery calcification, and adjudicated CKD and CVD events. In Aim 1, we will study T50 and its relationships with clinical characteristics, mineral metabolites, prevalence and progression of arterial stiffness, coronary artery calcification and left ventricular hypertrophy, and with risks of ESRD, CVD and death in the entire CRIC cohort (n=3472). In Aim 2, we will obtain 3 annual measurements of T50 in the randomly selected CRIC's longitudinal mineral metabolism subcohort (n=1200) to define change in T50 over time, relate this evolution in vascular calcification propensity to progression of disordered mineral metabolism and to loss of kidney function, and examine how changes in T50 affect risks of ESRD, CVD events and death. Deoxycholic acid is a bile acid metabolite derived from choline. Our preliminary data demonstrate that deoxycholic acid levels are elevated in CKD and induce vascular calcification by promoting endoplasmic reticulum stress in vascular smooth muscle cells. In our post-hoc analysis of a phosphate binder study (n=112, CKD 3-4), an elevated deoxycholic acid level was independently associated with greater coronary artery calcification. Deoxycholic acid levels may be lowered by targeting its generation and excretion. To advance this potentially modifiable mechanism of vascular calcification, in Aim 3, we will examine elevated deoxycholic acid as a risk factor for intermediate and hard outcomes in the entire CRIC cohort (n=3472). We anticipate that our results will have major clinical implications, lead to future interventional studies in CKD and catalyze further laboratory work.