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.

项目总结/摘要 常染色体隐性遗传性多囊肾病（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。有些病人需要肝移植， 由于严重并发症（如复发性上行性胆管炎或难治性）导致的门体分流 静脉曲张出血尽管发病率很高，但目前还没有批准的疾病- ARPKD的改良疗法。尽管几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， 疗效终点。目前的临床方法来衡量ARPKD肝病的严重程度是不够的，因为 肝脏炎症和合成功能的标准血液测试通常是正常的，即使在严重受影响的情况下， 个体门静脉高压症患者可能会出现脾脏肿大或血小板计数降低，但这些 这些发现不能检测肝纤维化的早期阶段。肝活检是侵入性的，缺乏预后价值， 作为临床试验终点不可行或不可接受。ARPKD的新的非侵入性成像生物标志物 因此，肝病进展是必要的，这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，使用了超声（US）弹性成像和二维（2D）磁共振成像。 共振弹性成像（MRE）似乎有助于量化ARPKD肝病的严重程度。然而，在这方面， 这两种方法都只能测量肝纤维化，而不能直接捕获肝纤维化的其他重要因素。 ARPKD相关肝病，即胆管扩张和门静脉高压。因此，这项建议 旨在研究两种新的非对比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+），可以 量化胆管扩张，以及肝脏和脾脏的三维MRE（3D-MRE）， 多种组织机械特性，以量化组织纤维化和门静脉高压。从这个研究结果 将为未来更大规模的ARPKD影像学生物标志物多中心研究提案的设计提供信息 进展，长期目标是开发经验证的生物标志物，用作ARPKD的替代终点 临床试验，以推进ARPKD疗法的发展。