The present proposal investigates the utility of a nontraditional risk factor, serum cLDL, as a risk factor associated with cardiac events and arteriosclerosis in patients with CKD utilizing the wealth of information from the CRIC Study. This proposal has been approved by the CRIC Ancillary Steering Committee and will include approximately 3,600 CRIC participants with mild to moderate renal disease who have been followed for up to five years or until death. Blood urea dissociates to form cyanate that may alter proteins including low-density lipoprotein (LDL) by a process known as carbamylation. Our recent studies demonstrate that cLDL has all of the biological effects relevant to atherosclerosis. In addition, we have demonstrated the development of aortic atherosclerosis in mice that have elevated plasma cLDL due either to chronic kidney failure or chronic urea consumption. Finally, in human studies, end-stage kidney disease (ESKD) patients have significantly elevated plasma cLDL concentration. Our hypothesis is that cLDL is associated with prevalent, recurrent, and incident cardiovascular disease and with measures of arteriosclerosis (carotid intima-media thickness [IMT] and coronary artery calcification [CAC]) in patients with CKD. A secondary objective is to determine the relationship between serum cLDL and serum urea and/or level of renal function (estimated glomerular filtration rate [eGFR]). We have raised the antibody to measure cLDL and have developed a sensitive and specific cLDL sandwich ELISA assay. This ancillary study will cause no burden on participating patients and will examine a potentially important non-traditional atherosclerotic risk factor in patients with CKD. This proposal is timely because the cardiovascular events in patients who have been enrolled during 2003-2007 are currently being evaluated and the data will be available by 2010.

PUBLIC HEALTH RELEVANCE: Patients with kidney disease have a high risk of developing heart disease. Traditional risk factors for heart disease like high cholesterol do not explain this risk. Patients with kidney disease have higher levels of blood urea nitrogen, which can be transformed into products that modify proteins by a process known as carbamylation. The overall goal of this proposal is to utilize the wealth of information that has been gathered as part of the NIH-funded Chronic Renal Insufficiency Cohort (CRIC) Study to evaluate the relevance of carbamylated LDL (cLDL), a nontraditional CV risk factor, to cardiovascular disease in patients with chronic kidney disease.

R01HL104071

2010-08-15

2013-12-31