Browsing by Author "O'Neill, Kalisha"

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    445 The effects of dietary fiber based on fermentability and viscosity on phosphorus absorption and the gut microbiome in chronic kidney disease-mineral and bone disorder
    (Cambridge University Press, 2023-04-24) Biruete, Annabel; Chen, Neal X.; Srinivasan, Shruthi; O'Neill, Kalisha; Nelson, David; Hill Gallant, Kathleen M.; Moe, Sharon M.; Medicine, School of Medicine
    OBJECTIVES/GOALS: To compare the effects of dietary fiber supplementation based on fermentability and viscosity on phosphorus fractional absorption and the gut microbiome in a rat model of chronic kidney disease-mineral and bone disorder (CKD-MBD). METHODS/STUDY POPULATION: 25-week-old Cy/+ male rats (CKD hereafter) will be randomly assigned to receive one of four fiber treatments (10% w/w each) based on fermentability and viscosity: 1) Cellulose (-fermentability, -viscosity), 2) inulin (+fermentability, -viscosity), 3) psyllium husk (-fermentability, +viscosity), or 4) pectin (+ fermentability, +viscosity). Diets will be formulated with a semipurified diet containing 0.7% phosphorus. Treatments will last for 10 weeks, and rats will be euthanized at 35 weeks of age, where animals have reached kidney failure. Intravenous and oral 33P will be used for intestinal phosphorus fractional absorption and cecal/fecal samples will be obtained at euthanasia for microbiome assessment using shotgun metagenomics. RESULTS/ANTICIPATED RESULTS: Our preliminary data show that fermentable dietary fiber (inulin) impacted phosphorus homeostasis by increasing the circulating levels of fibroblast growth factor-23 (a bone-derived hormone that increases phosphorus excretion in urine) and lowering circulating levels of phosphorus in the Cy/+ male rat model of progressive chronic kidney disease. We hypothesize that dietary fiber impacts phosphorus absorption in gut microbiome-dependent and independent mechanisms. For example, fermentable fiber enhances the production of short-chain fatty acids, lowering the intraluminal pH, and enhancing mineral solubility and absorption. Meanwhile, viscous fibers may encapsulate minerals limiting their absorption if these fibers are non-fermentable. DISCUSSION/SIGNIFICANCE: Hyperphosphatemia, or high circulating phosphorus, is a major factor in the pathogenesis of CKD-MBD. Treatment of hyperphosphatemia is focused on reducing intestinal absorption. However, available therapies vary in their efficacy and focus on phosphorus absorption in the small intestine, ignoring the possible impact of the large intestine.
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    Effect of Advanced Glycation End‐Products (AGE) Lowering Drug ALT‐711 on Biochemical, Vascular, and Bone Parameters in a Rat Model of CKD‐MBD
    (Wiley, 2019) Chen, Neal X.; Srinivasan, Shruthi; O'Neill, Kalisha; Nickolas, Thomas L.; Wallace, Joseph M.; Allen, Matthew R.; Metzger, Corinne E.; Creecy, Amy; Avin, Keith G.; Moe, Sharon M.; Medicine, School of Medicine
    Chronic kidney disease–mineral bone disorder (CKD‐MBD) is a systemic disorder that affects blood measures of bone and mineral homeostasis, vascular calcification, and bone. We hypothesized that the accumulation of advanced glycation end‐products (AGEs) in CKD may be responsible for the vascular and bone pathologies via alteration of collagen. We treated a naturally occurring model of CKD‐MBD, the Cy/+ rat, with a normal and high dose of the AGE crosslink breaker alagebrium (ALT‐711), or with calcium in the drinking water to mimic calcium phosphate binders for 10 weeks. These animals were compared to normal (NL) untreated animals. The results showed that CKD animals, compared to normal animals, had elevated blood urea nitrogen (BUN), PTH, FGF23 and phosphorus. Treatment with ALT‐711 had no effect on kidney function or PTH, but 3 mg/kg lowered FGF23 whereas calcium lowered PTH. Vascular calcification of the aorta assessed biochemically was increased in CKD animals compared to NL, and decreased by the normal, but not high dose of ALT‐711, with parallel decreases in left ventricular hypertrophy. ALT‐711 (3 mg/kg) did not alter aorta AGE content, but reduced aorta expression of receptor for advanced glycation end products (RAGE) and NADPH oxidase 2 (NOX2), suggesting effects related to decreased oxidative stress at the cellular level. The elevated total bone AGE was decreased by 3 mg/kg ALT‐711 and both bone AGE and cortical porosity were decreased by calcium treatment, but only calcium improved bone properties. In summary, treatment of CKD‐MBD with an AGE breaker ALT‐711, decreased FGF23, reduced aorta calcification, and reduced total bone AGE without improvement of bone mechanics. These results suggest little effect of ALT‐711 on collagen, but potential cellular effects. The data also highlights the need to better measure specific types of AGE proteins at the tissue level in order to fully elucidate the impact of AGEs on CKD‐MBD. © 2019 American Society for Bone and Mineral Research.