MRI Risk Classification in Children and Young Adults with ADPKD

项目摘要 常染色体显性多囊肾病（ADPKD）占终末期肾病的10% （ESKD）在那些<65岁。通过多囊卵巢综合征放射学研究联盟的重大努力， 肾病（CRISP）等，美国FDA已批准使用托伐普坦限制肾病 目前正在对成人ADPKD患者进行治疗进展，并对其他新疗法进行额外的临床试验。 正在进行中开发这些疗法的关键一步是验证身高校正后的总 从磁共振成像（MRI）获得的肾脏体积（htTKV）作为识别受试者的生物标志物 在高风险的进展，htTKV现在被用来作为一个关键指标，以评估个人的终身风险， 根据马约影像学分类（MIC）方案评估肾脏疾病进展。 儿童和年轻成人ADPKD的有效治疗方法的开发有可能限制 在较早的时间点发生疾病肾脏疾病进展，导致肾功能保留增加 并最终延长预期寿命。不幸的是，筛查无症状儿童（<18岁）， 受影响的ADPKD父母目前不推荐，所以即使是受影响的年轻人也可能不知道他们有 这种疾病此外，患有ADPKD的儿童通常不包括在临床试验中，主要是由于 对于<15岁的ADPKD患者，缺乏有效的疾病进展生物标志物。因此，我们认为， 尽管成人ADPKD患者的发展前景看好，但这些FDA批准的治疗和多种治疗方法， 正在进行的临床试验是不可用的和/或没有实施的儿童和许多年轻的成人与ADPKD。 我们的初步数据表明：1）父母-子女（年龄15-25岁）的MIC非常一致， 提示早期筛查的潜在原理;和2）临床成像（TKV标准化） 体表面积，TKV/BSA）和快速、定量MR指纹结合放射组学分析， 为6-14岁的ADPKD儿童提供风险分层评估的方法。整体 本多中心提案的目的（芝加哥大学和克利夫兰诊所/凯斯西储 大学）是通过以下方式改善儿科和年轻成人ADPKD患者的临床护理：1）定义 ADPKD父母及其受影响后代（年龄15-25岁）的MIC之间的关联（目标1）;以及 2)为15岁以下儿童（6-14岁）制定一个基于MRI的风险分类， 以支持该年龄组未来的临床试验（目标2）。我们将招募80名患有ADPKD的儿童和年轻人， 和一个已知的受影响的父母将获得临床、人口统计学和遗传学数据，受试者将接受 横断面（目标1）以及纵向成像评估（目标2），在整个过程中共进行3次访视 四年。我们的初步发现的确认将有助于早期识别儿童和年轻人 存在肾脏疾病快速进展高风险的成人ADPKD患者，支持增加筛查， 扩大纳入正在进行和未来的临床试验，并在更早的年龄获得维持生命的治疗。

PROJECT SUMMARY Autosomal dominant polycystic kidney disease (ADPKD) accounts for 10% of end stage kidney disease (ESKD) in those <65 years of age. Through a major effort of the Consortium for Radiologic studies in Polycystic Kidney Disease (CRISP) and others, the US FDA has approved the use of tolvaptan to limit kidney disease progression in adult ADPKD patients, and additional clinical trials of other novel therapies are currently underway. A key step in the development of these therapies has been the validation of height-corrected total kidney volume (htTKV) obtained from magnetic resonance imaging (MRI) as a biomarker for identifying subjects at high risk for progression, and htTKV is now used to as a key metric to assess an individual’s lifetime risk for kidney disease progression though the Mayo Imaging Classification (MIC) schema. The development of effective therapies for children and young adults with ADPKD has the potential to limit disease kidney disease progression at an earlier timepoint resulting in increased preservation of kidney function and ultimately a longer life expectancy. Unfortunately, screening asymptomatic children (<18 years) with an affected ADPKD parent is not currently recommended, so even affected young adults may not know they have the disease. Further, children with ADPKD are generally not included in clinical trials, primarily due to the absence of a validated biomarker for disease progression for ADPKD patients <15 years of age. Therefore, despite the promising developments for adult ADPKD patients, these FDA-approved treatments and multiple ongoing clinical trials are unavailable and/or not implemented for children and many young adults with ADPKD. Our preliminary data suggests that: 1) parent-offspring (ages 15-25 years) MICs are in close agreement, suggesting a potential rationale for earlier screening; and 2) a combination of clinical imaging (TKV standardized to body surface area, TKV/BSA) and rapid, quantitative MR Fingerprinting coupled with radiomics analysis can provide the means to develop a risk stratification assessment for ADPKD children 6-14 years of age. The overall objective of this multi-center proposal (University of Chicago and Cleveland Clinic / Case Western Reserve University) is to improve the clinical care for pediatric and young adult ADPKD patient by: 1) defining the association between the MIC of an ADPKD parent and their affected offspring (age 15-25 years) (Aim 1); and 2) developing an MRI-based risk classification for children <15 years of age (age 6-14 years) that can be used to support future clinical trials in this age group (Aim 2). We will recruit 80 children and young adults with ADPKD and a known affected parent. Clinical, demographic and genetic data will be obtained and subjects will undergo cross sectional (Aim 1) as well longitudinal imaging assessments (Aim 2) for a total of 3 visits over the course of 4 years. Confirmation of our preliminary findings would facilitate early identification of pediatric and young adult ADPKD patients at high risk for rapid kidney disease progression, supporting increased screening, expanded inclusion in ongoing and future clinical trials, and access to life-sustaining therapies at an earlier age.