Progression of chronic kidney disease (CKD) is associated with a progressive increase in the risk of cardiovascular disease (CVD) related nonfatal and fatal events as well as of all-cause mortality. In patients free of CKD, elevated concentration of total and low density lipoprotein cholesterol (TC and LDLc), triglycerides (TG) and low levels of high density lipoprotein cholesterol (HDLc) are associated with increased risk of CVD events and death. Consequently, one of the main interventions used in cardiovascular prevention is lipid lowering drug therapy, namely use of statins. High dose statins are recommended in high-risk patients based on strong study evidence. In CKD, the benefit and risk of high dose statin is not well documented. In addition, previous studies have suggested that with progression of CKD, the association between TC and LDLc with CVD events or mortality is weakened and that statin therapy is less effective, but this has not been sufficiently documented. Niacin and fen fibrate have been used for cardiovascular prevention in addition to statins in patients free of CKD with questionable results. They have never been used in treating patients with CKD, but there are reasons to believe that their use in these patients might result in clinical benefit. Furthermore, previous studies have documented differences in risk, outcome associations and disease development between race, age, and other demographic and comorbidity subgroups of CKD patients. Studies in CKD patients of racial-ethnic, age and other differences in associations of lipids and lipid altering drugs with outcomes are not available and are necessary. The applicant is proposing to study these associations in over half a million VA patients. This large cohort will enable separate study of each stage of CKD progression as well as each one of the subgroups. Basing the guidelines on solid epidemiological data from large cohorts could lead to a unifying concept for use of lipid modulating drugs and indicate direction for future clinical trials. The main training objective of this proposal is to provide Dr. Streja with experience and expertise in clinical research while expanding her knowledge in statistics, nephrology and lipidology. The scientific objectives of this career development award project are 1) to establish the associations between lipid and clinical outcomes in CKD patients 2) to do so in different stages of CKD progression, 3) to analyze the effectiveness and safety of statin therapy in moderate and high dose in all stages of CKD, 4) to analyze these associations in various demographic subgroups, and 5) to analyze the potential benefit of lipid lowering drugs other than statins in CKD patients. The proposed application is the first comprehensive study in clinical lipidology applied to non-dialysis dependent CKD (NDD-CKD) in a large cohort which should result in an authoritative answer in this unexplored area of physiology and therapeutics. The study should lead to a new rational paradigm in lipid management in NDD-CKD and to improve veterans' outcomes throughout the nation. This CDA project will be conducted in a supportive multi-disciplinary environment with a group of mentors who are renowned experts in different aspects of this proposal, including VA staff physicians and scientists. The mentorship and comprehensive training program proposed in this application are designed to build on the training and expertise that the applicant has acquired so far in her career. Furthermore, this novel and promising proposal will pave the way for future studies supported by VA Merit Awards, which examine the epidemiology of cardiovascular disease in the veteran patient population. Hence, the proposed project will also prepare and transition the applicant to a career as an independent investigator in the VA Healthcare System.
Approximately 8% of the United States population has chronic kidney disease (CKD). In veterans the percent is much higher (20%) given the high number of patients with diabetes and hypertension, both underlying causes of CKD. Patients with CKD have a high risk of death, which increases with the progression of the disease, and half of these deaths are attributed to cardiovascular disease (CVD). Treatment with drugs affecting cholesterol metabolism are effectively used in the general population to decrease the risk of CVD events and death, but their role is insufficiently studied in CKD. A comprehensive study of the relationship between cholesterol and cholesterol sub fractions with the risk of CVD and death in CKD patients is necessary in order to create a clear and unified view about the way drugs affecting cholesterol should be used in these patients. In addition, it is essential for veterans with CKD to individualize the treatment, using data obtained in different age and racial-ethnic subgroups.
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