Multi-parametric MRI of ARPKD liver disease

ARPKD 肝病的多参数 MRI

• 批准号: 10380806
• 负责人: Erum Aftab Hartung
• 金额: $ 12.62万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380806
• 关键词: 3-Dimensional; Advanced Development; Affect; Age; Ascending Cholangitis; Autoimmune; Autosomal Recessive Polycystic Kidney; Biliary; Biological Markers; Blinded; Blood Tests; Childhood; Clinical; Clinical Trials; Cross-Sectional Studies; Data; Development; Dilatation - action; Disease; Disease Progression; Duct (organ) structure; Elements; Fibrosis; Funding; Future; Goals; Grant; Hemorrhage; Image; Individual; Investigation; Kidney Diseases; Liver; Liver Fibrosis; Liver diseases; Magnetic Resonance Cholangiopancreatography; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Measures; Methods; Modulus; Morbidity - disease rate; Octreotide; Operative Surgical Procedures; Patients; Platelet Count measurement; Portal Hypertension; Prospective Studies; Recording of previous events; Recurrence; Refractory; Research; Research Personnel; Rodent Model; Scanning; Severities; Severity of illness; Shunt Device; Spleen; Splenomegaly; Surgical Portosystemic Shunt; Surrogate Endpoint; Syndrome; Tissues; Triad Acrylic Resin; Work; bile duct; biliary tract; cohort; congenital hepatic fibrosis; design; elastography; imaging biomarker; imaging modality; intrahepatic; liver biopsy; liver inflammation; liver stiffness; liver transplantation; mechanical properties; non-invasive imaging; novel; phase I trial; preclinical study; prognostic value; radiologist; two-dimensional; ultrasound

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.

项目概要/摘要 常染色体隐性多囊肾病 (ARPKD) 的肝脏受累包括肝内胆管 扩张、先天性肝纤维化和门静脉高压。有些患者需要进行肝移植或 由于严重并发症（例如复发性上行性胆管炎或难治性胆管炎）而导致的门体分流 静脉曲张出血。尽管发病率负担很大，但目前还没有批准的疾病 修改 ARPKD 的治疗方法。尽管多种药物在临床前研究中显示出有希望的结果， 推进临床试验的关键障碍是缺乏 ARPKD 进展的敏感生物标志物 功效终点。目前测量 ARPKD 肝病严重程度的临床方法不足，因为 即使在严重受影响的情况下，肝脏炎症和合成功能的标准血液检查通常也正常 个人。门静脉高压症患者可能会出现脾肿大或血小板计数低，但这些 研究结果无法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，并且 作为临床试验终点是不可行或不可接受的。 ARPKD 的新非侵入性成像生物标志物 因此，肝脏疾病的进展是必要的，并且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 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程度，并不能直接捕捉肝纤维化的其他重要元素。 ARPKD相关的肝脏疾病，即胆管扩张和门静脉高压。因此，本提案 旨在研究两种新颖的非对比 MR 方法，以提供更全面的评估 ARPKD 肝病严重程度：定量磁共振胰胆管造影 (MRCP+)，可 量化胆管扩张以及肝脏和脾脏的三维 MRE (3D-MRE)，可测量 多种组织机械特性来量化组织纤维化和门静脉高压。这项研究的结果 将为 ARPKD 影像生物标志物的更大规模多中心研究的未来提案设计提供信息 进展，长期目标是开发经过验证的生物标志物作为 ARPKD 的替代终点 推进 ARPKD 疗法开发的临床试验。