Imaging Assessments of ARPKD Kidney Disease Progression

修改后的项目摘要/摘要部分 常染色体隐性遗传性多囊肾病(ARPKD)是一种潜在的致命性遗传性疾病，影响大约20,000名儿童，并与显著的发病率和死亡率有关；ARPKD儿童中只有70%的新生儿存活，40%的儿童在15岁前进展为终末期肾脏疾病。目前还没有针对ARPKD的疾病特异性、临床可用的治疗方法，治疗主要针对慢性肾脏疾病并发症的管理。然而，一些新的治疗方法在ARPKD动物模型和成人常染色体显性遗传性PKD(ADPKD)患者中都显示出前景。不幸的是，在ARPKD患者中实施临床试验的主要障碍是缺乏对ARPKD肾脏疾病进展的敏感措施。肾脏疾病进展的常规指标，例如估计肾小球滤过率(EGFR)的下降，在ARPKD中是可变的，尽管肾脏持续受损，但GFR可能保持不变。已成功用于ADPKD临床试验的肾脏体积的成像评估在ARPKD中的适用性有限，因为尽管囊性疾病不断恶化，但肾脏大小随着时间的推移而稳定下来。因此，需要替代标记物来分期和监测ARPKD肾脏疾病的进展。我们的多学科成像团队已经确定T2-MRI是ARPKD进展的敏感指标。在ARPKD动物模型的研究中，我们利用高分辨率T2-MRI建立了肾囊性负荷作为ARPKD进展和治疗反应的准确和敏感的标志物。在ARPKD患者的初步研究中，我们显示与健康对照组相比，肾脏平均T2-MRI值增加，平均T2值的变化与肾脏疾病严重程度的差异一致。我们的团队还开创了新颖的磁共振指纹(MRF)技术，该技术可以抵抗运动伪影，并允许快速、同时采集多个成像参数。该项目的总体目标是建立肾脏平均T2值作为一种灵敏的、定量的MRI生物标志物来分期和纵向监测ARPKD肾脏疾病。我们将利用这些技术对从美国各地招募的儿童和年轻成人ARPKD患者的肾脏疾病进行横断面和纵向评估。拟议的研究将首次系统地应用这些定量MRI技术来评估ARPKD患者的肾囊负荷，长期目标是开发ARPKD肾脏疾病的MRI生物标记物，可用于识别疾病进展的高风险患者，并作为ARPKD患者最终临床试验的结果衡量标准。

Modified Project Summary/Abstract Section Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a potentially lethal inherited disorder that affects approximately 1/20,000 children and is associated with significant morbidity and mortality; only 70% of ARPKD children survive the neonatal period and 40% progress to end- stage kidney disease by age 15 years. There are currently no disease-specific, clinically-available therapies for ARPKD and treatment is directed at management of chronic kidney disease complications. Several novel therapies have, however, shown promise in both ARPKD animal models and adult autosomal dominant PKD (ADPKD) patients. Unfortunately, the major roadblock for implementing clinical trials in ARPKD patients is the absence of sensitive measures of ARPKD kidney disease progression. Conventional measures of kidney disease progression, e.g., declines in estimated glomerular filtration rate (eGFR), are variable in ARPKD and GFR may remain unchanged despite ongoing kidney damage. Imaging assessments of kidney volume, which have been successfully utilized in ADPKD clinical trials, have limited applicability to ARPKD, as kidney size stabilizes over time despite worsening cystic disease. Therefore, alternative markers are needed to stage and monitor ARPKD kidney disease progression. Our multidisciplinary imaging team has identified T2-MRI as a sensitive measure of ARPKD progression. In studies in ARPKD animal models, we utilized high resolution T2-MRI to establish renal cystic burden as an accurate and sensitive marker for ARPKD progression and therapeutic response. In preliminary studies in ARPKD patients, we showed increased mean kidney T2-MRI values in comparison to healthy controls, with mean T2 values variations consistent with differences in kidney disease severity. Our team has also pioneered novel Magnetic Resonance Fingerprinting (MRF) technologies that are resistant to motion artifacts and allow for rapid, simultaneous acquisition of multiple imaging parameters. The overall objective of this project is to establish mean kidney T2 values as a sensitive, quantitative MRI biomarker to stage and longitudinally monitor ARPKD kidney disease. We will utilize these techniques to obtain both cross-sectional and longitudinal assessments of kidney disease in pediatric and young adult ARPKD patients recruited from across the U.S. The proposed studies will be the first to systematically apply these quantitative MRI techniques to assess renal cystic burden in ARPKD patients, with the long-term goal of developing MRI biomarkers for ARPKD kidney disease that can be used to identify patients at high risk for disease progression and to serve as outcome measures for eventual clinical trials for ARPKD patients.