MRI Imaging Biomarkers of ARPKD Kidney and Liver Disease

描述（由申请人提供）：常染色体隐性多囊肾病（ARPKD）是一种遗传性多器官疾病，影响1/20，000的儿童。这种疾病的特征是多囊肾和先天性肝纤维化（CHF）。肾脏疾病的特征是肾脏增大，伴有弥漫性显微镜下的集合管囊肿，通常在出生时就很明显。40 - 50%的受影响儿童在10岁时发生肾衰竭。ARPKD肝病（CHF）是一种以胆管增生、扩张以及门静脉周围纤维化为特征的胆道病变。CHF通常进展缓慢，在15 - 20%的患者中具有临床意义。然而，随着越来越多的患者存活到成年期，它可能会变得越来越普遍。CHF可导致危及生命的并发症，并导致接受肾移植的ARPKD患者的发病率和死亡率。 不幸的是，目前还没有确定的方法来监测ARPKD的肾脏或肝脏疾病进展。传统的肾功能或胆功能指标（如血清肌酐或胆红素）可能正常和/或稳定，尽管疾病正在进展。而且，与ADPKD不同，传统的诊断成像技术也是有限的，因为肾脏大小也可能随着时间的推移而稳定。侵入性肾脏和肝脏活检也不能用于ARPKD进展的纵向监测。在这种多器官疾病中缺乏可量化的进展指标不仅限制了我们评估肾脏和/或肝脏疾病进展的能力，而且严重限制了研究治疗干预的能力。这是特别有问题的，因为几种疗法已被证明在ARPKD动物模型中有效减缓肾脏或肝脏疾病进展。 拟定研究将在ARPKD的PCK大鼠模型中进行。具体目标是：（1）开发ARPKD肾病进展中囊性负荷的MRI成像测量;（2）开发ARPKD肝病进展中胆管扩张和门静脉周围纤维化的MRI成像评估;（3）测试纵向MRI评估监测疾病进展和治疗反应的适用性。目的1和2中开发的扩散和磁化传递MRI技术将分别通过ARPKD肾脏和肝脏疾病的组织学测量进行验证。在目标3中，这些MRI技术将用于纵向评估疾病进展和对新疗法的反应。这些影像学研究是高度可翻译的，可能为ARPKD患者未来的影像学和治疗研究提供重要数据。 公共卫生相关性：目前没有可用的治疗或方法来测量常染色体隐性多囊肾病（ARPKD）的肾脏和肝脏疾病进展。本研究旨在开发新的临床适用的ARPKD肾脏和肝脏疾病的磁共振成像（MRI）措施，以监测疾病进展和对治疗的反应。本项目中的动物MRI成像研究可高度转化为人类ARPKD，并将提供在ARPKD患者中开展临床试验所需的关键缺失元素。

DESCRIPTION (provided by applicant): Autosomal Recessive Polycystic Kidney Disease (ARPKD) is an inherited, multi-organ disorder that affects 1/20,000 children. The disease is characterized by both polycystic kidneys and congenital hepatic fibrosis (CHF). The kidney disease, characterized by enlarged kidneys with diffuse microscopic collecting duct cysts, is usually evident at birth. Kidney failure develops in 40-50% of affected children by age 10. ARPKD liver disease (CHF) is a biliary tract lesion characterized by both bile duct proliferation and dilatation as well periportal fibrosis. CHF is typically more slowly progressive and is clinically significant in 15-20% of patients. However, it is likely to become increasingly prevalent as more patients survive into adulthood. CHF can result in life-threatening complications and contributes to morbidity and mortality in ARPKD patients who have undergone kidney transplantation. Unfortunately, there are currently no established methods for monitoring kidney or liver disease progression in ARPKD. Traditional measures of kidney or biliary function (such as serum creatinine or bilirubin) may be normal and/or stable despite ongoing disease progression. And, unlike ADPKD, conventional diagnostic imaging techniques are also limited as kidney size may also be stable over time. Invasive kidney and liver biopsies are also not useful for longitudinal monitoring of ARPKD progression. The absence of quantifiable indicators of progression in this multi-organ disease not only limits our ability to assess kidney and/or liver disease progression, but also severely limits the ability to study therapeutic interventions. This is particularly problematic because several therapies have been shown to be effective in slowing kidney or liver disease progression in ARPKD animal models. The proposed studies will be conducted in the PCK rat model of ARPKD. The Specific Aims are: (1) to develop MRI imaging measures of cystic burden in ARPKD kidney disease progression; (2) to develop MRI imaging assessments of biliary expansion and periportal fibrosis in ARPKD liver disease progression; and (3) to test the applicability of longitudinal MRI assessments to monitor disease progression and response to therapy. The Diffusion and Magnetization Transfer MRI techniques developed in Aims 1 and 2 will be validated with histological measures of ARPKD kidney and liver disease, respectively. In Aim 3, these MRI techniques will be used longitudinally assess disease progression and response to novel therapies. These imaging studies are highly translatable and may provide important data for future imaging and therapeutic studies in ARPKD patients. PUBLIC HEALTH RELEVANCE: There are currently no available treatments or means to measure kidney and liver disease progression for Autosomal Recessive Polycystic Kidney Disease (ARPKD). This study seeks to develop novel clinically- applicable Magnetic Resonance Imaging (MRI) measures of ARPKD kidney and liver disease to monitor disease progression and response to therapies. The animal MRI imaging studies in this project are highly translatable to human ARPKD, and will provide a critical missing element needed for the development of clinical trials in ARPKD patients.