The candidate for this K23 Patient Oriented Research Career Development Award is a pediatric nephrologist with a background in basic and clinical/translational research in autosomal recessive polycystic kidney disease (ARPKD). The proposed project seeks to develop new ultrasound (US) and magnetic resonance imaging (MRI) biomarkers to measure severity and progression of kidney and liver disease in ARPKD. Current clinical methods of measuring disease severity in ARPKD are not precise or sensitive enough to be used as endpoints in clinical trials. The lack of reliable endpoints is a critical barrier to th conduct of any potential future clinical trials in ARPKD. The candidate seeks to overcome this barrier by developing novel imaging biomarkers to measure kidney cyst burden, liver fibrosis, and portal hypertension in children with ARPKD.
Aim 1 will establish a quantitative method to measure kidney cyst burden using diffusion MRI and quantitative T2 MRI.
Aim 2 will establish quantitative methods to measure liver fibrosis and portal hypertension, using acoustic radiation force impulse imaging (an US-based technique), and magnetic resonance elastography to measure liver and spleen stiffness. The candidate's long-term career goal is to become an independent investigator with unique expertise in developing novel imaging biomarkers for ARPKD and other hepatorenal diseases. The proposed mentored research and career development plan facilitates this career goal by allowing the candidate to obtain further training and experience in imaging data analysis and biostatistics (including clinical trial outcomes, evaluation of surrogate endpoints, and longitudinal data analysis), in the outstanding research environment of the Children's Hospital of Philadelphia and University of Pennsylvania. The candidate has assembled an exceptional multidisciplinary mentorship team. The candidate's primary mentor, Susan Furth, MD, PhD is an internationally recognized expert in clinical investigation in pediatric nephrology and has an outstanding record of mentorship. Her co-mentor, Kassa Darge, MD, PhD, has an excellent record of multidisciplinary research in pediatric radiology, including novel US and MRI methods. These mentors, along with a multidisciplinary Advisory Committee that includes senior investigators in radiology, ARPKD, hepatology, and biostatistics, will help to guide the candidate's career development and will provide content expertise to ensure success of the proposed research. The proposed research, along with the structured mentoring, coursework, and training that comprise the candidate's career development plan, will provide the candidate with the skills and experience necessary to ensure her success as an independent investigator with a unique skill set in developing imaging biomarkers for ARPKD and other hepatorenal diseases.
Autosomal recessive polycystic kidney disease (ARPKD) is a genetic disorder that often causes kidney failure requiring dialysis or kidney transplant, and sometimes causes severe liver complications requiring liver transplant. No treatments are currently available to prevent progression of ARPKD; several therapies have appeared promising in animal studies, but a major barrier to performing human clinical trials is that curren methods of measuring progression of kidney and liver disease are not reliable. This application seeks to overcome this barrier by developing new ultrasound and magnetic resonance imaging methods to measure ARPKD severity and progression, and these methods may become valuable tools for future clinical trials of potential ARPKD therapies.
