Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a potentially lethal genetic disorder that affects approximately 1/20,000 children and shares common cellular pathophysiology with other cystic kidney diseases, including Autosomal Dominant PKD (ADPKD). The genetics, pathology and clinical features of ARPKD, however, are distinct from ADPKD. In ARPKD, diffuse fusiform dilatations of the collecting tubules ("microcysts") predominate rather than the macrocysts seen in ADPKD. ARPKD kidneys may be very large at presentation, but, unlike ADPKD, actually stabilize in size as normal parenchyma is replaced by cysts and progressive fibrosis develops. ARPKD morbidity and mortality is significant: 30% of children die as neonates and 40-50% of survivors progress to end-stage kidney disease (ESKD) by age 18. Importantly, there are currently no disease-specific, clinically-available therapies for ARPKD and treatment is limited to chronic kidney disease (CKD) management. Several novel therapies have shown promise in ARPKD animal models. Unfortunately, there are currently no reliable clinical measures of ARPKD progression that show changes over a several year period of a clinical trial except in the most severely affected young children, creating a roadblock for implementing clinical trials for ARPKD therapies, especially in patients with less advanced disease.
Conventional endpoints for CKD progression, e.g., 50% decline in estimated glomerular filtration rate (eGFR) or progression to ESKD have substantial limitations in assessing ARPKD progression. Studies from 2 prospective observational cohorts found that the rates of GFR decline in ARPKD patients was relatively slow but also highly variable. Magnetic Resonance Imaging (MRI) measures of total kidney volume (TKV), which have been used successfully in ADPKD trials, are generally not applicable to ARPKD, since TKV does not increase with progressive disease except in severely affected young patients. Therefore, there is a critical need for new, sensitive biomarkers to enable effective clinical trials of therapies for ARPKD. Quantitative MRI techniques, including novel Magnetic Resonance Fingerprinting (MRF), Arterial Spin Labelling (ASL) and Magnetic Resonance Elastography (MRE), have the potential to provide measurable assessments of kidney structure and function. The overall objective of this multi-site study is to establish a set of rapid, quantitative, and reproducible kidney MRI methods applicable to standard clinical MRI scanners, which could serve as potential biomarkers to risk stratify ARPKD patients for clinical trial enrollment and measure response to therapy across the kidney disease spectrum and all ages.
The Aims of this study are (1) to determine the capability of 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) to 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) to 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, the investigators 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 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.
