Multi-parametric MRI of ARPKD liver disease

项目摘要/摘要 常染色体隐性遗传性多囊肾病(ARPKD)的肝脏损害包括肝内胆管 扩张、先天性肝纤维化和门脉高压。一些患者需要肝移植或 因严重并发症造成的门体分流，如复发性上行性胆管炎或难治性 静脉曲张出血。尽管有很大的发病率负担，但目前还没有批准的疾病- 修改ARPKD的治疗方法。尽管几种药物在临床前研究中显示了有希望的结果，但一种 推进临床试验的关键障碍是缺乏敏感的ARPKD进展生物标志物作为 功效终点。目前衡量ARPKD肝病严重程度的临床方法是不够的，因为 肝脏炎症和合成功能的标准血液测试一般正常，即使在严重感染的情况下也是如此。 个人。门脉高压症患者可能会出现脾增大或血小板计数减少，但这些 结果不能检测出肝纤维化的早期阶段。肝活检是侵入性的，缺乏预后价值。 作为临床试验终点是不可行或不可接受的。ARPKD新的非侵入性影像生物标志物 因此，肝脏疾病的进展是必要的，并将是推进潜在临床试验的先决条件。 在申请人的K23支持的工作中，超声(US)弹性成像和二维(2D)磁性 磁共振弹性成像(MRE)似乎有助于量化ARPKD肝病的严重程度。然而， 这两种方法都只能测量肝纤维化，而不能直接捕捉到 ARPKD相关性肝病，即胆管扩张和门脉高压。因此，这项提议 旨在研究两种新的非对比磁共振方法，以提供更全面的评估 ARPKD肝病严重程度：定量磁共振胆胰管成像(MRCP+)，可以 量化胆管扩张，以及肝和脾的三维MRE(3D-MRE)，这些测量 多项组织力学特性以量化组织纤维化和门脉高压。这项研究的发现 将为未来对ARPKD成像生物标志物进行更大规模的多中心研究的建议的设计提供信息 进展，长期目标是开发有效的生物标记物作为ARPKD的替代终点 促进ARPKD疗法发展的临床试验。

PROJECT SUMMARY/ABSTRACT Liver involvement in autosomal recessive polycystic kidney disease (ARPKD) consists of intrahepatic biliary duct dilatation, congenital hepatic fibrosis, and portal hypertension. Some patients require liver transplantation or portosystemic shunting due to severe complications such as recurrent ascending cholangitis or refractory variceal bleeding. Despite this substantial burden of morbidity, there are currently no approved disease- modifying therapies for ARPKD. Although several agents have shown promising results in pre-clinical studies, a critical barrier to advancing clinical trials is the lack of sensitive biomarkers of ARPKD progression for use as efficacy endpoints. Current clinical methods to measure ARPKD liver disease severity are inadequate, because standard blood tests of liver inflammation and synthetic function are generally normal even in severely affected individuals. Patients with portal hypertension may develop an enlarged spleen or low platelet counts, but these findings cannot detect earlier stages of liver fibrosis. Liver biopsies are invasive and lack prognostic value, and would not be feasible or acceptable as a clinical trial endpoint. New non-invasive imaging biomarkers of ARPKD liver disease progression are therefore needed, and will be a prerequisite for advancing potential clinical trials. In the applicant's K23-supported work, ultrasound (US) elastography and two-dimensional (2D) magnetic resonance elastography (MRE) appeared to be helpful to quantify the severity of ARPKD liver disease. However, both of these methods can only measure liver fibrosis, and do not directly capture other important elements of ARPKD-related liver disease, namely biliary duct dilatation and portal hypertension. Therefore, this proposal seeks to investigate two novel non-contrast MR methods to provide a more comprehensive assessment of ARPKD liver disease severity: quantitative magnetic resonance cholangiopancreatography (MRCP+), which can quantify biliary duct dilatation, and three-dimensional MRE (3D-MRE) of the liver and spleen, which measures multiple tissue mechanical properties to quantify tissue fibrosis and portal hypertension. Findings from this study will inform the design of future proposals for a larger multicenter investigation of imaging biomarkers of ARPKD progression, with a long-term goal of developing validated biomarkers for use as surrogate endpoints in ARPKD clinical trials to advance the development of ARPKD therapies.