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Elevated Fibroblast Growth Factor 23 Mediates Cardiac Fibrosis in the Setting of Chronic Kidney DiseaseBackground: CKD (chronic kidney disease) is a progressive disease with a global prevalence of 11-13% (Hill et al., 2016). CKD disrupts homeostasis resulting in large majority of patients with CKD also suffering from CVD (cardiovascular disease), with over 90% of CKD patients having cardiac fibrosis (Graham-Brown et al., 2017). FGF23, a phosphaturic hormone derived from bone, has been found to be elevated in patients with CKD and is associated with increased mortality in this patient population. Elevated serum FGF23 levels lead to LVH (left ventricular hypertrophy) and cardiac fibrosis, however, the mechanism by which fibrosis develops is unknown. We hypothesize that FGF23 mediates cardiac fibrosis by activation of the RAAS (renin-angiotensin-aldosterone-system), TGF-β (transforming growth factor-β), and wnt/β-catenin pathways in cardiac myocytes and fibroblasts. Methods:A literature review was conducted to identify the current literature on FGF23, CKD, cardiac fibrosis, RAAS, TGF-β, wnt/β-catenin and the molecular mechanisms leading to pathology. Search engines used were PubMed, Elsevier, NCBI (National Center for Biotechnology Information), University of Arizona Library, Google, and Wikipedia. Keywords included: CKD prevalence and mortality, bone and mineral metabolism, FGF23 mortality, angiotensin II (ANGII) and cardiac fibrosis, and phosphate homeostasis. Conclusion: In a series of steps, systemic FGF23 mediates cardiac fibrosis via non-conical signaling pathways by first activating the RAAS in cardiac myocytes. RAAS activation in cardiac myocytes increases ANGII expression. ANGII crosstalk with cardiac fibroblasts leads to activation of fibroblasts and TGF-β pathways. TGF-β and 5wnt3a/β-catenin in cardiac fibroblasts activate pro-fibrotic gene expression. TGFβ and wnt3a/β-catenin from cardiac fibroblasts crosstalk with cardiac myocytes to induce pro-fibrotic gene expression and augment RAAS signaling pathway, respectively.