Abstract: FR-PO155
Molecular Magnetic Resonance Imaging of Allysine to Quantify Renal Fibrogenesis
Session Information
- Molecular Mechanisms of CKD - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix
Authors
- Fuchs, Bryan C., Massachusetts General Hospital, Boston, Massachusetts, United States
- Chen, Yinching Iris, Massachusetts General Hospital, Boston, Massachusetts, United States
- Dos santos ferreira, Diego, Massachusetts General Hospital, Boston, Massachusetts, United States
- Arora, Gunisha, Massachusetts General Hospital, Boston, Massachusetts, United States
- Masia, Ricard, Massachusetts General Hospital, Boston, Massachusetts, United States
- Rosales, Ivy, Massachusetts General Hospital, Boston, Massachusetts, United States
- Colvin, Robert B., Massachusetts General Hospital, Boston, Massachusetts, United States
- Caravan, Peter, Massachusetts General Hospital, Boston, Massachusetts, United States
Background
Chronic kidney disease (CKD), most commonly caused as result of type-2 diabetes or ischemic/hypertensive nephropathy, currently affects 12% of all adults in the US. The fibrotic deposition and remodeling of extracellular matrix proteins to form cross-linked collagen fibers is a characteristic feature of CKD and eventually results in end stage renal disease. Critical to fiber formation is the enzymatic production of allysine on collagen, which facilitates fibril cross-linking through condensation reactions with neighboring allysine and lysine residues. We have developed a novel Gd-based MRI probe, GdOA, designed to target allysine for noninvasive imaging of active fibrogenesis in kidney disease.
Methods
The ability of GdOA to detect fibrogenesis was evaluated in two animal models of CKD - nephrotoxic serum nephritis (NTN) and Col4a3-/- Alport mice. For the NTN model, 129/SvEv mice were dosed at day 0 with 250 μg Sheep IgG and then with 125 μL sheep anti-rat GBM serum on day 5. Control animals received PBS injections. Animals were imaged 7 days post GBM serum injection. For the Alport model, wild type and Col4a3-/- mice were imaged at 6-10 weeks of age to assess mild and advanced stages of disease. Following MRI, kidneys were collected and assessed for hydroxyproline (HYP) content and tissue histology.
Results
The NTN model resulted in diffuse tubular injury, glomerulosclerosis, and mild fibrosis. GdOA resulted in a 6.9 fold increase in ΔR1 (probe relaxivity) in the cortex of the NTN group compared to control mice (p = 0.048). Hydroxyproline content in tissue was 1.88 fold higher for NTN animals compared to control animals (p = 0.0004) and ΔR1 showed positive correlation with increasing HYP concentrations (r = 0.625). In the Col4a3-/- mice, Gd-OA was able to detect early stages of disease and also correlated with increasing HYP concentrations.
Conclusion
The requirement of allysine for the crosslinking of ECM proteins makes it a valuable biomarker of fibrogenesis. GdOA is an oxyamine derivative of GdDOTA designed for targeted binding to allysine, with minimal off-target accumulation and rapid renal excretion. GdOA MRI demonstrated a strong correlation with the extent of disease in two animal models of CKD and therefore might provide a novel means to quantify early stages of renal fibrosis in patients.
Funding
- NIDDK Support