FGF-23 and clinical outcomes in ADPKD patients

描述（申请人提供）：常染色体显性多囊肾病（ADPKD）是最常见的危及生命的遗传性疾病。尽管进行性囊肿增大导致50%的患者在第5个10年出现终末期肾脏疾病，但心血管疾病是ADPKD患者死亡的主要原因。左心室肥厚是ADPKD中心血管疾病的重要表现，其发生率是原发性高血压的两倍。了解ADPKD左室肥厚、心血管事件和死亡率高发生率的可改变机制，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）水平升高，是慢性肾脏疾病（CKD）、心血管疾病和死亡进展的独立危险因素，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。尽管一项针对ADPKD患者的研究表明，FGF23水平在疾病早期升高，但FGF23在ADPKD中升高的机制尚不清楚。此外，没有数据表明FGF23是ADPKD左室肥厚、CKD进展和临床结果的危险因素，以及这些关系与其他原因的CKD有何不同。在第一个目标中，我们将确定与其他病因的CKD或健康受试者相比，成人和儿童ADPKD患者的FGF23水平是否更早、更显著地升高。我们将比较来自约1000名成人ADPKD患者（在HALT-PKD试验中）和107名儿童ADPKD患者（在他汀- pkd试验中）的FGF23和其他矿物质代谢物与来自非ADPKD队列的可比较数据，包括儿童慢性肾病（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，我们将进行有史以来第一次专门针对ADPKD的骨活检研究，以研究骨对FGF23产生的调节。我们将评估标准骨组织形态学，并使用新的骨研究翻译技术来精确研究细微的骨微结构（使用CT），总骨磷酸盐含量（使用拉曼光谱），以及FGF23和DMP1的表达，DMP1是骨中FGF23的关键分子调节剂。在第三个目标中，我们将研究FGF23作为肾囊肿扩大、CKD进展、左心室肥厚和心血管疾病事件的一个新的危险因素。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方面具有必要的专业知识，可以成功完成这些目标。通过使用正在进行的4项NIDDK支持的研究的数据，我们将有效地表征FGF23在ADPKD中的作用，以指导设计新的干预措施以改善ADPKD的预后。

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.