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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Flessner, Michael Francis
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Case Western Reserve University
Schools of Medicine
United States
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Donnola, Shannon B; Dasenbrook, Elliott C; Weaver, David et al. (2017) Preliminary comparison of normalized T1 and non-contrast perfusion MRI assessments of regional lung disease in cystic fibrosis patients. J Cyst Fibros 16:283-290
Gao, Ying; Erokwu, Bernadette O; DeSantis, David A et al. (2016) Initial evaluation of hepatic T1 relaxation time as an imaging marker of liver disease associated with autosomal recessive polycystic kidney disease (ARPKD). NMR Biomed 29:84-9
Dell, Katherine M; Matheson, Matthew; Hartung, Erum A et al. (2016) Kidney Disease Progression in Autosomal Recessive Polycystic Kidney Disease. J Pediatr 171:196-201.e1
Gao, Ying; Chen, Yong; Ma, Dan et al. (2015) Preclinical MR fingerprinting (MRF) at 7 T: effective quantitative imaging for rodent disease models. NMR Biomed 28:384-94
Dell, Katherine M (2015) The role of cilia in the pathogenesis of cystic kidney disease. Curr Opin Pediatr 27:212-8
Lu, Lan; Donnola, Shannon B; Koontz, Michaela et al. (2015) Lipid elimination with an echo-shifting N/2-ghost acquisition (LEENA) MRI. Magn Reson Med 73:711-7
Gao, Ying; Goodnough, Candida L; Erokwu, Bernadette O et al. (2014) Arterial spin labeling-fast imaging with steady-state free precession (ASL-FISP): a rapid and quantitative perfusion technique for high-field MRI. NMR Biomed 27:996-1004
Lu, Lan; Erokwu, Bernadette; Lee, Gregory et al. (2012) Diffusion-prepared fast imaging with steady-state free precession (DP-FISP): a rapid diffusion MRI technique at 7 T. Magn Reson Med 68:868-73
Shah, T; Lu, L; Dell, K M et al. (2011) CEST-FISP: a novel technique for rapid chemical exchange saturation transfer MRI at 7 T. Magn Reson Med 65:432-7
Dell, Katherine MacRae (2011) The spectrum of polycystic kidney disease in children. Adv Chronic Kidney Dis 18:339-47