Friday, April 4, 2025
4/4/2025
Imaging Assessments of ARPKD Kidney Disease Progression - PROJECT SUMMARY / ABSTRACT Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a potentially lethal inherited disorder that affects approximately 1/20,000 children and is genetically and clinically distinct from the more common Autosomal Dominant PKD (ADPKD). ARPKD is characterized by diffuse kidney microcysts resulting from fusiform dilatations of the collecting tubules. As these kidneys cysts accumulate, the kidneys do not show progressive enlargement, but instead accumulate more cysts and eventually become progressively more fibrotic, resulting in end-stage kidney disease (ESKD). Approximately 40-50% of ARPKD children who survive the neonatal period progress to ESKD by age 18, highlighting the significant disease burden. Importantly, there are currently no disease-specific clinically-available therapies for patients with ARPKD. Despite several potential therapies showing promise in ARPKD animal models, clinical trials are currently limited by the lack of sensitive measures for ARPKD kidney disease progression across the spectrum of disease. Conventional clinical endpoints for CKD progression (e.g., decline in glomerular filtration rate, GFR) lack the sensitivity to detect ARPKD progression in the time frame of a typical clinical trial, as the rates of GFR decline are relatively small and variable among patients, especially those with milder disease. Imaging assessments of total kidney volume, successfully utilized in ADPKD patients, are also not applicable to ARPKD as kidney size stabilizes over time despite cystic kidney disease progression. Our collaborative multi-center research team has shown in previous (preclinical) and current (clinical) NIH R01 studies that novel MR Fingerprinting (MRF, cystic burden) and non-contrast kidney Arterial Spin Labeling MRI (ASL, perfusion): (1) can accurately detect and stage ARPKD kidney disease; and (2) can measure significant kidney disease progression in ARPKD patients before conventional GFR measures. The Aims of the proposed studies are 1) to determine the capability of our multimodal MRI biomarkers to accurately and repeatably detect and stage ARPKD kidney disease across the full spectrum of disease from early-stage CKD characterized by diffuse kidney cysts (MRF) and reduced kidney perfusion (ASL) to later-stage CKD characterized by progressive kidney fibrosis (MR elastography, MRE); (2) determine the sensitivity of these MRI biomarkers to detect changes in ARPKD kidney disease progression over time in comparison to gold-standard GFR assessments; and (3) determine the feasibility of a new free- breathing MRF methodology that would allow infants and young children to be scanned without sedation. For these studies, we will recruit ARPKD patients ≥6 years of age with early, mild, and moderate CKD from across the US for 4 annual multimodal MRI scans and GFR measurements at our two collaborating sites (CC/CWRU and CHOP). Age-matched healthy controls will also be recruited for an MRI scan. If successful, the proposed studies will support use of these multimodal MRI biomarkers as outcome measures and/or high risk subject enrichment for future clinical trials for ARPKD patients.
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