FGF-23 and clinical outcomes in ADPKD patients

FGF-23 和 ADPKD 患者的临床结果

• 批准号: 8437472
• 负责人: Michel Benjamin Chonchol
• 金额: $ 52.48万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437472
• 关键词: Adult; Affect; Age; Animal Model; Autosomal Dominant Polycystic Kidney; Biology; Biopsy; Biopsy Specimen; Blood; Bone Density; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Child; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Clinical Research; Cohort Studies; Cross-Sectional Studies; Cyst; Cystic kidney; Data; Disease; Disease Progression; End stage renal failure; Essential Hypertension; Etiology; Event; Excretory function; Fibroblast Growth Factor; Frequencies; Gender; Genotype; Glomerular Filtration Rate; Hereditary Disease; Hormones; Human; Hypertension; Incidence; Individual; Intervention; Kidney; Kidney Diseases; Left Ventricular Hypertrophy; Left Ventricular Mass; Life; Link; Magnetic Resonance Imaging; Messenger RNA; Metabolism; Minerals; Molecular; Morphology; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Osteoblasts; Osteocytes; Outcome; Outcome Study; Participant; Pathogenesis; Patients; Phenotype; Population; Prevalence; Process; Production; Proteins; Publishing; Race; Raman Spectrum Analysis; Regulation; Reporting; Research; Resources; Risk; Risk Factors; Role; Serum; Source; Staging; Techniques; Thick; adverse outcome; bone; bone turnover; cardiovascular disorder risk; cohort; dentin matrix protein 1; design; disease-causing mutation; fibroblast growth factor 23; healthy volunteer; improved; indexing; inhibitor/antagonist; inorganic phosphate; mortality; novel; novel therapeutics; polycystic kidney disease 1 protein; urinary

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. PUBLIC HEALTH RELEVANCE: Autosomal dominant polycystic kidney disease is the most common life-threatening hereditary disease. Despite emerging evidence that abnormalities of the fibroblast growth factor 23-phosphate axis are related to an increased incidence of cardiovascular disease and progression of renal disease in subjects with chronic kidney disease, similar studies in ADPKD are lacking. Hence, we propose to investigate the role of the fibroblast growth factor 23 on progression of kidney and cardiovascular disease in children and adults with ADPKD.

描述（由申请人提供）：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。虽然进行性囊肿扩大导致50%的受影响个体在第五个十年时发生终末期肾病，但心血管疾病是ADPKD死亡的主要原因。左心室肥厚是ADPKD心血管疾病的重要表现，其发生率是原发性高血压的2倍。了解ADPKD患者左心室肥大、心血管事件和死亡率高的可改变机制对于设计新的治疗策略以改善临床结局至关重要。磷酸盐调节激素成纤维细胞生长因子23（FGF 23）水平升高是慢性肾脏病（CKD）、心血管疾病和死亡进展的独立风险因素，我们小组发表的数据表明FGF 23在左心室肥大发病机制中的因果作用。尽管一项针对ADPKD患者的研究表明，FGF 23水平在病程早期升高，但ADPKD中FGF 23升高的潜在机制尚不清楚。此外，没有关于FGF 23作为ADPKD左心室肥大、CKD进展和临床结局的风险因素的数据，以及这些关系与其他CKD原因的差异。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，ADPKD成人和儿童的FGF23水平是否更早和更明显地增加。我们将比较来自HALT-PKD试验中约1000例ADPKD成人患者和他汀类药物-PKD试验中107例ADPKD儿童患者的FGF 23和其他矿物质代谢产物与来自非ADPKD队列的可比数据，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，以研究骨骼对FGF 23产生的调节。我们将评估标准的骨组织形态计量学，并使用新的骨研究转化技术来精确研究微妙的骨微结构（使用CT），总骨磷酸盐含量（使用拉曼光谱），以及FGF 23和DMP 1的表达，这是骨骼中FGF 23的关键分子调节剂。在第三个目标中，我们将研究FGF 23作为肾囊肿扩大，CKD进展，左心室肥大和心血管疾病事件的新风险因素。广泛的初步数据支持我们的假设，我们的研究团队在临床研究，FGF 23，骨活检数据分析和ADPKD方面拥有必要的专业知识，以成功完成这些目标。通过使用来自4项正在进行的NIDDK支持的研究的数据，我们将有效地描述ADPKD中的FGF 23，以指导新干预措施的设计，以改善ADPKD的结局。 公共卫生相关性：常染色体显性遗传性多囊肾病是最常见的危及生命的遗传性疾病。尽管有新的证据表明成纤维细胞生长因子23-磷酸轴异常与慢性肾脏疾病受试者心血管疾病发病率增加和肾脏疾病进展相关，但缺乏ADPKD的类似研究。因此，我们建议研究成纤维细胞生长因子23在ADPKD儿童和成人肾脏和心血管疾病进展中的作用。