MRI Imaging Biomarkers of ARPKD Kidney and Liver Disease

描述(申请人提供)：常染色体隐性遗传性多囊肾病(ARPKD)是一种遗传性多器官疾病，影响1/20,000名儿童。这种疾病的特点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，弥漫的显微镜下集合管囊肿，通常在出生时就很明显。40-50%的受累儿童在10岁前发生肾功能衰竭。ARPKD肝病(CHF)是一种胆道病变，以胆管增殖和扩张以及门静脉周围纤维化为特征。充血性心力衰竭通常进展较慢，在15%-20%的患者中具有临床意义。然而，随着更多的患者活到成年，它可能会变得越来越普遍。慢性心力衰竭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中肾脏或肝脏疾病的进展。传统的肾或胆道功能指标(如血清肌酐或胆红素)可能是正常和/或稳定的，尽管疾病仍在继续发展。而且，与ADPKD不同，传统的诊断成像技术也受到限制，因为肾脏大小也可能随着时间的推移而稳定。侵袭性肾和肝活检对于ARPKD进展的纵向监测也没有用处。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。这尤其有问题，因为在ARPKD动物模型中，已有几种疗法被证明在减缓肾脏或肝脏疾病进展方面有效。拟议的研究将在ARPKD的PCK大鼠模型中进行。具体目标是：(1)开发ARPKD肾脏疾病进展中囊性负担的MRI成像方法；(2)开发ARPKD肝病进展中胆管扩张和门脉周围纤维化的MRI成像评估；以及(3)测试纵向MRI评估在监测疾病进展和治疗反应方面的适用性。AIMS 1和AIMS 2中开发的扩散和磁化转移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，这些核磁共振技术将用于纵向评估疾病进展和对新疗法的反应。这些影像研究具有很高的可译性，可能为未来ARPKD患者的影像和治疗研究提供重要数据。

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.