The long-term objective of this proposal is to foster the scientific development of the candidate to ensure successful transition to an independent clinical investigator. A career development program will focus on didactic training, completion of a research project, and mentoring from a committee with diverse expertise. Didactic training will be of direct relevance to the research proposal including coursework on advanced longitudinal modeling, use of biomarkers, and clinical and translational research methods related to cognition and cognitive impairment. The goal of the research proposal will be to evaluate risk factors for cognitive impairment and cerebrovascular disease in chronic kidney disease (CKD). Cognitive impairment and cerebrovascular disease are highly prevalent in CKD and cannot be fully explained by traditional risk factors such as hypertension, dyslipidemia, and hyperglycemia. Levels of fibroblast growth factor 23 (FGF-23) increase as kidney function declines, while levels of soluble klotho decrease as kidney function declines. High FGF-23 and low klotho have each been associated with an increased risk for cardiovascular events and mortality, and high FGF-23 may cause microvascular disease in the brain while low klotho may result in direct neurological damage. The proposed study will investigate the cross-sectional and longitudinal association of FGF-23 and klotho with cognitive function and cerebrovascular disease using data from two cohort studies (Health Aging and Body Composition Study (Health ABC) and the Cognition and Dialysis Study) and one clinical trial (Systolic Blood Pressure Intervention Trial), spanning all stages of CKD as well those at high risk for CKD. The overall hypothesis is that CKD is characterized by an increase in levels of FGF-23 and a decrease in levels of klotho, and that higher levels of FGF 23 and lower levels of Klotho are associated with the development of cerebrovascular disease and impaired cognitive function.
The specific aims are as follows:
Aim 1) To determine the cross-sectional and longitudinal association of FGF-23 and klotho with cognitive function and cerebrovascular disease in Health ABC, Aim 2) To determine the cross-sectional and longitudinal association of FGF-23 with cognitive function, stroke, and MRI abnormalities in the CKD subgroup of SPRINT, Aim 3) To assay soluble Klotho in a cohort of maintenance hemodialysis patients and determine the cross- sectional and longitudinal association of FGF-23 and Klotho with cognitive function.
All Aims are feasible and have sufficient statistical power. The candidate has assembled a mentoring committee with expertise in clinical research in nephrology, cognition, mineral metabolism, as well as epidemiology and statistics. Dr. Mark Sarnak will serve as the Primary Mentor. He has a long track record of successfully mentoring fellows and junior faculty and has worked in the area of cardiovascular disease, cognition and its associated risk factors for many years. Dr. Joachim Ix will serve as the Co-Mentor. He has extensive expertise in translational and clinical research on mineral metabolism in CKD and has a significant track record of mentoring young investigators.

Public Health Relevance

Although it is known that stroke and cognitive impairment are common in patients with chronic kidney disease, the reasons for their development remain unclear. We will study the relationship between blood levels of fibroblast growth factor 23 (which rises in kidney disease) and soluble Klotho (which falls) with stroke and cognitive impairment. This research may identify two potentially modifiable risk factors for stroke and cognitive impairment

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
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Rankin, Tracy L
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Tufts University
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Drew, David A; Katz, Ronit; Kritchevsky, Stephen et al. (2018) Fibroblast Growth Factor 23: A Biomarker of Kidney Function Decline. Am J Nephrol 47:242-250
Drew, David A; Katz, Ronit; Kritchevsky, Stephen et al. (2017) Association between Soluble Klotho and Change in Kidney Function: The Health Aging and Body Composition Study. J Am Soc Nephrol 28:1859-1866
Drew, David A; Koo, Bang-Bon; Bhadelia, Rafeeque et al. (2017) White matter damage in maintenance hemodialysis patients: a diffusion tensor imaging study. BMC Nephrol 18:213
Drew, David A; Weiner, Daniel E; Tighiouart, Hocine et al. (2017) Cognitive Decline and Its Risk Factors in Prevalent Hemodialysis Patients. Am J Kidney Dis 69:780-787