QSM for detection of hemorrhaging cysts and risk stratification in ADPKD
Project Number1R01DK139336-01A1
Former Number1R01DK139336-01
Contact PI/Project LeaderDIMOV, ALEXEY
Awardee OrganizationWEILL MEDICAL COLL OF CORNELL UNIV
Description
Abstract Text
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.
Public Health Relevance Statement
The project will 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). Successful development will result in accurate identification of patients at
greater risk of rapid disease progression and optimal targeted drug intervention (tolvaptan), improving patient's
quality of life by minimizing exposure to adverse side effects associated with the life-long treatment such as
polyuria, pollakiuria polydipsia, and drug's hepatotoxicity.
National Institute of Diabetes and Digestive and Kidney Diseases
CFDA Code
847
DUNS Number
060217502
UEI
YNT8TCJH8FQ8
Project Start Date
20-January-2025
Project End Date
30-November-2029
Budget Start Date
20-January-2025
Budget End Date
30-November-2025
Project Funding Information for 2025
Total Funding
$728,513
Direct Costs
$431,917
Indirect Costs
$296,596
Year
Funding IC
FY Total Cost by IC
2025
National Institute of Diabetes and Digestive and Kidney Diseases
$728,513
Year
Funding IC
FY Total Cost by IC
Sub Projects
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