QSM for detection of hemorrhaging cysts and risk stratification in ADPKD

Our key objective is to develop renal quantitative susceptibility mapping (QSM) for reliable detection and quantification of hemorrhagic cysts as a prognostic biomarker of kidney function decline in autosomal dominant polycystic kidney disease (ADPKD). ADPKD is the most common hereditary kidney disease affecting over 500,000 people in the US, and characterized by formation of cysts causing compression of nephrons and progressive decline of glomerular filtration rate (GFR). The critical task in management of ADPKD is the identification of patients at higher risk of rapid kidney function decline. The only available drug to slow ADPKD progression is vasopressin V2 receptor antagonist tolvaptan. Because disease progression is highly variable and because tolvaptan has long-term adverse aquaretic and hepatotoxic effects, it is important to identify patients who are most likely to benefit from the drug. The only FDA-approved biomarker for this risk stratification is height- adjusted total kidney volume (htTKV). But htTKV is only a global measure and doesn't inform on pathogenic factors such as cyst types, distribution, fibrosis and inflammation. Patient risk stratification by renal function decline remains a critical and unanswered need. We and others have demonstrated that the hemorrhagic cystsare strongly associated with rapid progression of chronic kidney disease. Hemorrhage in ADPKD is the product of the vascular endothelial growth factor (VEGF) expression by the cystic epithelium leading to formation of highly permeable vasculature within the cyst wall. Hemorrhage and increased vessel permeability facilitate cyst volume increase. The inflammatory responses triggered by hemorrhage contribute to the pathogenesis of tubulointerstitial fibrosis. Identification and quantification of hemorrhagic activity in ADPKD provides an early window into ongoing cystogenesis and tissue remodeling before their consequences can be detected in conventional clinical imaging. At present, hemorrhagic cysts are detected as hyperintense on T1-weighted (T1w) and hypointense on T2w images in conventional MRI. However, conventional MRI intensity characteristics are unspecific and unable to differentiate between hemorrhagic and proteinaceous cyst. Breathhold MRI acquisitions cause low slice resolution and misregistration between T1w and T2w images, complicating visualization and classification of cysts. Non-contrast CT and ultrasound have low specificity for identifying hemorrhage The lack of reliable modality for the detection of hemorrhagic cysts is an unmet gap in clinical imaging. We have preliminary cross-sectional data demonstrating association between QSM and decreased eGFR in ADPKD patients, but a validation of these findings in a robustly designed longitudinal study is needed. Our central hypothesis is that detection of hemorrhage in ADPKD by QSM will allow precise identification of patients at high risk of eGFR decline benefiting most from therapeutic intervention. Our research plan has 3 specific aims: 1. Develop robust and accurate renal QSM; 2. Validate renal QSM using biochemical measurements and histology in kidney explants; 3. Validate renal QSM for eGFR decline risk stratification in ADPKD patients.