Disordered mineral metabolism is a near-universal complication of chronic kidney disease (CKD) that is strongly linked to risks of cardiovascular disease (CVD), CKD progression, fractures, and death. Phosphate excess induces arterial calcification, which is an important phenotype of CVD in CKD. Elevated fibroblast growth factor 23 (FGF23) maintains serum phosphate in the normal range in CKD, but FGF23 excess contributes mechanistically to left ventricular hypertrophy (LVH). Together, the deleterious effects of phosphate and FGF23 excess on the cardiovascular system promote CVD events and death. Dietary phosphate absorption is a modifiable determinant of phosphate and FGF23 levels. In animals, a high phosphate diet promoted kidney failure, and, in our preliminary data, it raised phosphate and FGF23 levels and induced LVH. In contrast, reducing dietary phosphate absorption with phosphate binders, low phosphate diets or the nicotinamide precursor, niacin, which reduces gastrointestinal NPT2b expression, lowered phosphate and FGF23 levels in pilot studies of CKD stage 3-4 patients. Thus, targeting phosphate and FGF23 excess may represent a novel therapeutic paradigm to improve clinical outcomes in CKD. However, a key road block to advancing this approach is the lack of evidence on the effects of phosphate and FGF23 reduction on intermediate end points in CKD. The NIDDK U01-supported COMBINE Study provides a unique opportunity to fill this gap. In this randomized, double-blinded, 18-month, parallel-group study in 200 CKD stage 3-4 patients, the U01-funded parent study will test the hypothesis that combining nicotinamide and lanthanum carbonate will lower serum phosphate and FGF23 levels. The purpose of this time-sensitive ancillary proposal is to enrich the parent study by adding longitudinal assessments of bone and mineral metabolism and surrogate measures of CVD and renal risks at baseline and at 9 and 18 months post-randomization.
In Aim 1, by obtaining serial assessments of bone turnover markers and mineral metabolites, we will test the hypothesis that compared with placebo, active therapy will blunt the slope of PTH rise, attenuate the decline of calcitriol and klotho levels, and improve bone turnover markers.
In Aim 2, we will use serial measures of cardiac MRI and CVD biomarkers to test the hypothesis that compared with placebo, active therapy will reduce or blunt the increase in LV mass;attenuate LV diastolic dysfunction and reduce levels of CVD biomarkers.
In Aim 3, using serial serologic testing and gadolinium-free blood oxygenation level dependent MRI and diffusion-weighted MRI to monitor changes in intra-renal oxygenation and fibrosis, we will test the hypothesis that compared with placebo, active therapy will blunt the slope of decline in GFR and the rise in proteinuria and inflammatory markers, improve intra-renal oxygenation and stabilize or reduce progression of renal fibrosis. The results of this U01-approved ancillary study proposal will yield novel mechanistic insights and provide critical data needed to select the endpoints for the future definitive phase-III outcomes trial targeting phosphate and FGF23 excess in CKD.

Public Health Relevance

High phosphate and fibroblast growth factor 23 (FGF23) levels are strongly associated with increased risks of kidney failure, cardiovascular disease and death. The current proposal will investigate whether strategies to lower phosphate and FGF23 levels in patients with chronic kidney disease will improve markers of bone and mineral metabolism and cardiovascular and kidney disease. The results will inform the design of a future large trial to test whether these strategies can improve patients'clinical outcomes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZDK1-GRB-9 (M3))
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Flessner, Michael Francis
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Isakova, Tamara; Cai, Xuan; Lee, Jungwha et al. (2018) Longitudinal FGF23 Trajectories and Mortality in Patients with CKD. J Am Soc Nephrol 29:579-590
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