FGF-23 and clinical outcomes in ADPKD patients

描述(申请人提供)：常染色体显性遗传性多囊肾病(ADPKD)是最常见的威胁生命的遗传性疾病。虽然到第五个十年，进行性囊性增大会导致50%的患者发生终末期肾脏疾病，但心血管疾病是ADPKD的主要死亡原因。左心室肥厚是ADPKD心血管疾病的重要表现，ADPKD的发病率是高血压的两倍。了解ADPKD患者高左室肥厚、心血管事件和死亡率的可改变机制对于设计新的治疗策略以改善临床结果至关重要。磷酸盐调节激素成纤维细胞生长因子23(FGF23)水平的升高是慢性肾脏疾病(CKD)、心血管疾病和死亡的独立危险因素，我们小组发表的数据表明FGF23在左心室肥厚的发病机制中起因果作用。虽然一项对ADPKD患者的研究表明，FGF23水平在病程早期升高，但ADPKD患者FGF23升高的机制尚不清楚。此外，还没有关于FGF23作为ADPKD患者左心室肥厚、CKD进展和临床结果的危险因素的数据，以及这些关系与其他原因的CKD有何不同。在第一个目标中，我们将确定与CKD或健康受试者的其他病因相比，成人和儿童ADPKD患者的FGF23水平是否更早和更明显地升高。我们将HALT-PKD试验中约1000名ADPKD成人和他汀类PKD试验中107名ADPKD儿童的FGF23和其他矿物质代谢物与来自非ADPKD队列的可比数据进行比较，包括儿童慢性肾脏疾病(CKiD)和慢性肾功能不全队列(CRIC)研究，这些研究的频率与种族和估计的肾小球滤过率相匹配。在第二个目标中，我们将进行第一次专门针对ADPKD的骨活检研究，以研究骨对FGF23产生的调节。我们将评估标准的骨组织形态计量学，并使用骨研究的新转换技术来精确研究微细的骨微结构(使用CT)、总骨磷酸盐含量(使用拉曼光谱)以及FGF23和DMP1的表达，FGF23和DMP1是FGF23在骨骼中的关键分子调节因子。在第三个目标中，我们将研究FGF23作为肾囊肿增大、慢性肾脏病进展、左室肥厚和心血管疾病事件的新的危险因素。大量的初步数据支持我们的假设，我们的研究团队在临床研究、FGF23、骨活检数据分析和ADPKD方面拥有成功完成这些目标所需的专业知识。通过使用NIDDK支持的4项正在进行的研究的数据，我们将有效地描述ADPKD中FGF23的特征，以努力指导新的干预措施的设计，以改善ADPKD的结果。

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is the most common life threatening hereditary disorder. Although progressive cyst enlargement leads to end-stage renal disease in 50 percent of affected individuals by the fifth decade, cardiovascular disease is the leading cause of death in ADPKD. Left ventricular hypertrophy is an important manifestation of cardiovascular disease in ADPKD with an incidence that is twice as high in ADPKD compared with essential hypertension. Understanding modifiable mechanisms of the high rates of left ventricular hypertrophy, cardiovascular events and mortality in ADPKD is essential to designing novel therapeutic strategies to improve clinical outcomes. An elevated level of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23), is an independent risk factor for progression of chronic kidney disease (CKD), cardiovascular disease, and death, and published data by our group suggest a causal role for FGF23 in the pathogenesis of left ventricular hypertrophy. Although one study of ADPKD patients suggested that FGF23 levels are increased early in the course of disease, the mechanisms underlying FGF23 elevation in ADPKD are unknown. Furthermore, there are no data on FGF23 as a risk factor for left ventricular hypertrophy, CKD progression and clinical outcomes in ADPKD, and how these relationships differ versus other causes of CKD. In the first aim, we will determine whether FGF23 levels increase earlier and more markedly in adults and children with ADPKD compared with other etiologies of CKD or healthy subjects. We will compare FGF23 and other mineral metabolites from ~1000 adults with ADPKD in the HALT-PKD trial and 107 children with ADPKD in the statin-PKD trial with comparable data from non-ADPKD cohorts, including the Chronic Kidney Disease in Children (CKiD) and the Chronic Renal Insufficiency Cohort (CRIC) studies that are frequency matched by race and estimated glomerular filtration rate. In the second aim, we will perform the first ever bone biopsy study dedicated to ADPKD to investigate the regulation of FGF23 production by bone. We will assess standard bone histomorphometry and use novel translational techniques of bone research to precisely study subtle bone microarchitecture (using ¿CT), total bone phosphate content (using Raman spectroscopy), and expression of FGF23 and DMP1, which is a critical molecular regulator of FGF23 in bone. In the third aim, we will examine FGF23 as a novel risk factor for kidney cyst enlargement, progression of CKD, left ventricular hypertrophy, and cardiovascular disease events. Extensive preliminary data support our hypotheses and our research team has the requisite expertise in clinical research, FGF23, analysis of bone biopsy data, and ADPKD to successfully complete these aims. By using data from 4 ongoing NIDDK- supported studies, we will efficiently characterize FGF23 in ADPKD in an effort to guide the design of novel interventions to improve outcomes in ADPKD.