MRI Risk Classification in Children and Young Adults with ADPKD

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PROJECT SUMMARY Autosomal dominant polycystic kidney disease (ADPKD) accounts for 10% of end stage kidney disease (ESKD) in those <65 years of age. Through a major effort of the Consortium for Radiologic studies in Polycystic Kidney Disease (CRISP) and others, the US FDA has approved the use of tolvaptan to limit kidney disease progression in adult ADPKD patients, and additional clinical trials of other novel therapies are currently underway. A key step in the development of these therapies has been the validation of height-corrected total kidney volume (htTKV) obtained from magnetic resonance imaging (MRI) as a biomarker for identifying subjects at high risk for progression, and htTKV is now used to as a key metric to assess an individual’s lifetime risk for kidney disease progression though the Mayo Imaging Classification (MIC) schema. The development of effective therapies for children and young adults with ADPKD has the potential to limit disease kidney disease progression at an earlier timepoint resulting in increased preservation of kidney function and ultimately a longer life expectancy. Unfortunately, screening asymptomatic children (<18 years) with an affected ADPKD parent is not currently recommended, so even affected young adults may not know they have the disease. Further, children with ADPKD are generally not included in clinical trials, primarily due to the absence of a validated biomarker for disease progression for ADPKD patients <15 years of age. Therefore, despite the promising developments for adult ADPKD patients, these FDA-approved treatments and multiple ongoing clinical trials are unavailable and/or not implemented for children and many young adults with ADPKD. Our preliminary data suggests that: 1) parent-offspring (ages 15-25 years) MICs are in close agreement, suggesting a potential rationale for earlier screening; and 2) a combination of clinical imaging (TKV standardized to body surface area, TKV/BSA) and rapid, quantitative MR Fingerprinting coupled with radiomics analysis can provide the means to develop a risk stratification assessment for ADPKD children 6-14 years of age. The overall objective of this multi-center proposal (University of Chicago and Cleveland Clinic / Case Western Reserve University) is to improve the clinical care for pediatric and young adult ADPKD patient by: 1) defining the association between the MIC of an ADPKD parent and their affected offspring (age 15-25 years) (Aim 1); and 2) developing an MRI-based risk classification for children <15 years of age (age 6-14 years) that can be used to support future clinical trials in this age group (Aim 2). We will recruit 80 children and young adults with ADPKD and a known affected parent. Clinical, demographic and genetic data will be obtained and subjects will undergo cross sectional (Aim 1) as well longitudinal imaging assessments (Aim 2) for a total of 3 visits over the course of 4 years. Confirmation of our preliminary findings would facilitate early identification of pediatric and young adult ADPKD patients at high risk for rapid kidney disease progression, supporting increased screening, expanded inclusion in ongoing and future clinical trials, and access to life-sustaining therapies at an earlier age.