Kidney Stone Disease In ADPKD

摘要/总结 常染色体显性遗传性多囊肾（ADPKD）在美国影响约60万人， 占终末期肾病（ESKD）患者的5%。目前，只有一个 经批准的治疗可用于诊断为快速进展疾病的患者。这突出表明， 用于确定减缓ADPKD患者肾脏疾病进展的其他措施。肾结石 疾病是高度流行的，越来越常见，并与相当多的合并症，其中 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，患有ADPKD和肾结石疾病的患者的肾功能丧失更快 无肾结石的患者。我们将利用一支跨学科的团队， 通过结合大数据分析和高维分析的专业知识， 微生物组和代谢组学数据。本申请的总体目标是证明肾结石 ADPKD患者的疾病是肾脏疾病进展更快的重要风险因素， 抗生素暴露会增加这一人群的结石风险。第二个目标是确定生态失调 导致肾结石的原因我们假设肾结石疾病 通过加重炎症导致ADPKD患者肾功能更快下降， 抗生素通过改变肠道而扰乱肠道-PKD轴，从而导致肾结石病 微生物组我们在3个具体目标中检验了这一假设。在目标1中，我们试图描述分布和 按性别和年龄分列的肾结石构成，并确定肾结石疾病与 肾功能下降，不依赖于炎症标志物和其他已知的肾损害风险因素 疾病进展。在目标2中，我们研究了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泌尿系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 数据库，包括医疗和药房覆盖，以及临床数据，包括结石分析和纵向 来自NIDDK申办的HALT-PKD临床试验的数据和样本。这些资源将提供访问 1，823例ADPKD患者，包括296例肾结石患者。我们将招募100例ADPKD患者， 无抗生素暴露，以促进aim 3中的微生物组和结石风险分析。发展的障碍 预防结石的新疗法是缺乏对肠道微生物组的扰动以及 肠道和泌尿道中的下游代谢物变化导致肾结石疾病。 从拟议的研究中了解肠道-PKD轴将为肾结石引入一个新的范例 预防ADPKD，并将为肾结石疾病的新治疗靶点提供关键见解， ADPKD。

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.