Mentored Patient Oriented Research in Mineral Metabolism

描述(申请人提供)：以磷酸盐调节激素成纤维细胞生长因子23(FGF23)水平升高为标志的磷酸盐代谢紊乱是数百万慢性肾脏疾病(CKD)患者心血管疾病和死亡的新风险因素。高膳食磷酸盐摄入量和CKD的存在是FGF23分泌的主要刺激因素。在这些情况下，FGF23水平的逐渐增加是维持正常磷酸盐平衡的适当适应。然而，我们团队和其他研究人员的研究表明，FGF23升高是CKD进展和死亡率更快的一个强大的独立危险因素。作为死亡率增加的一个潜在机制，我们最近证实FGF23升高是CKD患者左心室肥厚频繁发生的原因。这些数据表明，升高的FGF23可能不仅是一个潜在的强大的风险分层生物标志物，而且也是一个改善CKD预后的新的治疗靶点。PI的主要科学职业目标是通过随机试验证明，早期提供基于FGF23测试的干预措施，或专门针对FGF23水平升高的干预措施，将减缓CKD的进展，减少心血管疾病事件，并提高存活率。要证明大规模临床试验的合理性，需要进一步了解FGF23的生物学、其毒性机制、在流行病学研究中验证其对结果的影响(随着时间的推移反复分析FGF23)，以及详细的以患者为导向的研究，以表征候选干预措施降低FGF23水平的有效性。在本K24应用程序的目标1中，我们将对非裔美国人肾脏疾病和高血压研究进行二次分析。我们将测试FGF23与超声心动图所确定的心脏结构和功能之间的关系~我们将检验FGF23作为肾脏和心血管不良结局的新的危险因素的单一和重复测量~我们将使用新兴的工具来量化FGF23检测作为CKD风险分层生物标志物的作用。在目标2中，我们将测试饮食磷限制和磷结合物单独和联合作为候选干预措施的效果，以降低CKD 3-4期患者的FGF23水平。这些研究将是PI学员的优秀培训工具，并将通过正在进行的翻译研究平行项目进一步加强，PI将继续培养该项目，作为该奖项期间他的职业发展活动之一。其他职业发展活动包括领导能力的正式课程，以及在肾病学司实施一项新的教育倡议，以吸引更多研究员从事以病人为导向的研究。K24将为PI提供极其重要的保护时间和专门资源，以扩大他的指导活动，发展他自己的研究计划，并进一步推进他作为以患者为导向的肾脏病研究的领导者的职业生涯。

DESCRIPTION (provided by applicant): Disordered phosphate metabolism, marked by elevated levels of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23), is a novel risk factor for cardiovascular disease and mortality in the millions of patients suffering from chronic kidney disease (CKD). High dietary phosphate intake and presence of CKD are major stimuli for FGF23 secretion. In these settings, a progressive increase in FGF23 levels is an appropriate adaptation to maintain normal phosphate balance. However, studies from our team and others demonstrate that elevated FGF23 is a powerful, independent risk factor for more rapid CKD progression and mortality. As a potential mechanism of increased mortality, we recently demonstrated that elevated FGF23 contributes causally to the frequent development of left ventricular hypertrophy in CKD patients. These data suggest that elevated FGF23 may represent not only a potentially powerful risk-stratifying biomarker but also a novel therapeutic target to improve outcomes in CKD. The PI's overarching scientific career goal is to demonstrate by randomized trial that early delivery of interventions based on FGF23 testing, or specifically targeting elevated FGF23 levels, will slow progression of CKD, reduce cardiovascular disease events and improve survival. Justifying a large-scale clinical trial requires further knowledge of FGF23 biology, the mechanisms of its toxicity, validation of its impact on outcomes in epidemiological studies that analyze FGF23 repeatedly over time, and detailed patient-oriented research studies to characterize the efficacy of candidate interventions on reducing FGF23 levels. In Aim 1 of this K24 application, we will perform a secondary analysis of the African American Study of Kidney Disease and Hypertension. We will test the association between FGF23 and cardiac structure and function as determined by echocardiography~ we will examine single and repeated measures of FGF23 as a novel risk factor for adverse renal and cardiovascular outcomes~ and we will use emerging tools to quantify the utility of FGF23 testing as a risk-stratifying biomarker in CKD. In Aim 2, we will tes the effect of dietary phosphate restriction and phosphate binders alone and in combination as candidate interventions to lower FGF23 levels in CKD stage 3-4 patients. These studies will be excellent training vehicles for the PI's trainees and will be further enhanced by an ongoing parallel program in translational research that the PI will continue to cultivate as one of his career development activities during this award. Other career development activities include formal coursework in leadership and the implementation of a new educational initiative in the Division of Nephrology to attract additional fellows to patient-oriented research. The K24 will provide the PI with critically important protected time and dedicated resources to expand his mentorship activities, grow his own research program and further advance his career as a leader in patient-oriented research in nephrology.