Kidney Stone Disease In ADPKD

ADPKD 中的肾结石病

• 批准号: 10651868
• 负责人: Michel Benjamin Chonchol
• 金额: $ 45.32万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651868
• 关键词: Adult; Affect; Age; Antibiotic Therapy; Antibiotics; Automobile Driving; Autosomal Dominant Polycystic Kidney; Bacteria; Biochemical; Cessation of life; Chemistry; Clinical; Clinical Data; Clinical Trials; Cyst; Data; Data Analytics; Database Management Systems; Databases; Development; Diagnosis; Disease; Disease Progression; End stage renal failure; Exposure to; Family; Feces; Fibrosis; Future; Gene Mutation; Goals; Growth; Healthcare; Healthcare Systems; Human; Incidence; Individual; Infection; Inflammation; Inflammatory Response; Injury; Injury to Kidney; Interleukin-6; Intestines; Kidney; Kidney Calculi; Kidney Diseases; Link; Measures; Medical; Metabolic Pathway; National Institute of Diabetes and Digestive and Kidney Diseases; Nested Case-Control Study; Oral; Oxalates; Participant; Patients; Pharmacy facility; Play; Population; Prevention; Randomized, Controlled Trials; Renal function; Renin-Angiotensin-Aldosterone System; Resources; Risk; Risk Factors; Role; Sampling; Secondary to; Severity of illness; Testing; Time; Tubular formation; Urinary tract; Urine; cohort; comorbidity; disorder prevention; dysbiosis; economic impact; experience; gut dysbiosis; gut microbiome; high dimensionality; inflammatory marker; insight; member; metabolomics; microbiome; new therapeutic target; novel; novel therapeutics; prevent; recruit; sex; transcriptomics; urinary

ABSTRACT/SUMMARY Autosomal dominant polycystic kidney (ADPKD) affects an estimated 600,000 individuals in the US and accounts for 5% of patients with end-stage kidney disease (ESKD). At the current time there is only one approved therapy available for patients diagnosed with rapidly progressing disease. This underlines the need for identification of additional measures to slow kidney disease progression in ADPKD patients. Kidney stone disease is highly prevalent, increasingly common, and associated with considerable comorbidity among patients affected with ADPKD. In this proposal, we build on our preliminary data which demonstrates that patients with ADPKD and kidney stone disease have a more rapid loss of kidney function compared to ADPKD patients without kidney stone disease. We will leverage an interdisciplinary team that is uniquely poised to define kidney stone disease in ADPKD by combining expertise in large data analytics and high-dimensional microbiome and metabolomic data. The overall goal of this application is to demonstrate that kidney stone disease in patients with ADPKD represents a significant risk factor for faster kidney disease progression and that antibiotic exposure increases stone risk in this population. A secondary goal is to determine how dysbiosis of the gut microbiome contributes to kidney stone disease. We hypothesize that kidney stone disease contributes to more rapid decline in kidney function in ADPKD through worsening inflammation and that antibiotics contribute to kidney stone disease by perturbing the gut-PKD axis through alterations of the gut microbiome. We test this hypothesis in 3 specific aims. In aim 1, we seek to describe the distribution and composition of kidney stones by sex and age and to determine the link between kidney stone disease and decline in kidney function independent of markers of inflammation and other known risk factors for kidney disease progression. In Aim 2 we investigate the link between antibiotic exposure and kidney stone disease while in Aim 3 we will define the link between oral antibiotic exposure and change in urinary kidney stone risk factors resultant from changes in the microbiome. We will leverage the Intermountain Healthcare System database with medical and pharmacy coverage, and clinical data including stone analysis and the longitudinal data and samples from the NIDDK sponsored HALT-PKD clinical trials. These resources will provide access to 1,823 patients with ADPKD including 296 with kidney stones. We will recruit 100 patients with ADPKD with or without antibiotic exposure to facilitate microbiome and stone risk analysis in aim 3. A barrier to developing new therapies for stone prevention is a lack of understanding of how perturbations of the gut microbiome and downstream metabolite changes in the intestinal and urinary tracts contributes to kidney stone disease. Understanding the gut-PKD axis from the proposed studies will introduce a new paradigm for kidney stone prevention in ADPKD and will provide key insights into novel therapeutic targets for kidney stone disease in ADPKD.

摘要/总结 常染色体显性多囊肾 (ADPKD) 影响美国约 600,000 人 占终末期肾病（ESKD）患者的 5%。目前只有一个 批准的治疗可用于诊断患有快速进展性疾病的患者。这强调了需要 确定减缓 ADPKD 患者肾脏疾病进展的其他措施。肾结石 该疾病非常普遍、日益常见，并且与人群中相当多的合并症相关 患有 ADPKD 的患者。在本提案中，我们以初步数据为基础，这些数据表明 与 ADPKD 相比，ADPKD 合并肾结石患者的肾功能丧失速度更快 无肾结石疾病的患者。我们将利用一支具有独特优势的跨学科团队 通过结合大数据分析和高维专业知识来定义 ADPKD 中的肾结石疾病 微生物组和代谢组数据。该应用程序的总体目标是证明肾结石 ADPKD 患者的疾病是肾脏疾病进展加快的一个重要危险因素， 接触抗生素会增加该人群的结石风险。第二个目标是确定生态失调如何 肠道微生物组的变化会导致肾结石疾病。我们推测肾结石病 通过恶化炎症导致 ADPKD 肾功能更快下降 抗生素通过改变肠道来扰乱肠道-PKD 轴，从而导致肾结石疾病 微生物组。我们通过 3 个具体目标来检验这一假设。在目标 1 中，我们试图描述分布和 按性别和年龄划分的肾结石组成，并确定肾结石疾病与肾结石之间的联系 肾功能下降与炎症标志物和其他已知的肾脏危险因素无关 疾病进展。在目标 2 中，我们调查抗生素暴露与肾结石疾病之间的联系 而在目标 3 中，我们将定义口服抗生素暴露与尿路肾结石风险变化之间的联系 微生物组变化引起的因素。我们将利用山间医疗保健系统 涵盖医疗和药房的数据库以及包括结石分析和纵向分析在内的临床数据 来自 NIDDK 赞助的 HALT-PKD 临床试验的数据和样本。这些资源将提供对 1,823 名 ADPKD 患者，其中 296 名患有肾结石。我们将招募 100 名 ADPKD 患者，其中患有或 无需接触抗生素即可促进目标 3 中的微生物组和结石风险分析。发展的障碍 预防结石的新疗法缺乏对肠道微生物群的扰动和 肠道和泌尿道下游代谢物的变化导致肾结石疾病。 从拟议的研究中了解肠道-PKD 轴将为肾结石引入新的范例 ADPKD 的预防，并将为肾结石疾病的新治疗靶点提供重要见解 ADPKD。