In vivo measurement of Renal Redox Capacity And Renal Perfusion in a Model of Chronic Kidney Disease

Presenting Author Senior Author
Name: Celine Baligand Name: Wang Jane
Email: Email:
Presenting Author’s RIG/SRG: MRI/MRS  
Presenting Author's Lab Location: Mission Bay   

Abstract Information
Imaging Modality: MR
Disease Application: Abdominal Imaging
Complete author list: Celine Baligand, David Lovett, Lalita Uttarwar, Rajeev Mahimkar, David Wilson, John Kurhanewicz, Jane Wang
Abstract highlights: Alteration of renal redox status and perfusion can be monitored non-invasively by hyperpolarized 13C dehyascorbate MR spectroscopic imaging and arterial spin labeling MRI in a transgenic murine model of chronic kidney disease.
Acute kidney injury (AKI), as can be induced by ischemia/reperfusion (I/R), predisposes patients to the development of chronic kidney disease (CKD). Transgenic mice with NTT-MMP-2 overexpression recapitulate the hallmarks of such progressive kidney disease in humans. This model shows an exaggerated response to AKI, develops progressive tubular atrophy and rarefaction of the peri-tubular capillaries, The objectives of our work are to identify markers of kidney injury using non-invasive and clinically translatable MR imaging techniques. Specifically, we aim to (1) characterize the redox status in the NNT-MMP-2 mice using in vivo HP 13C MR spectroscopy, and (2) measure renal perfusion using arterial spin labeling MRI (ASL-MRI).
Kidney redox capacity by hyperpolarized 13C dehydroascorbate (DHA) MR spectroscopy: 5-7 month-old NTT-MMP-2 (mild kidney injury on histology, n=7) and aged-matched control mice (n=4) were fasted for 8 h and pre-treated with 250 μL of 60mM of unlabeled VitC 45 min before injection of the HP 13C-DHA probe. Imaging was performed on a 3T GE-MRI scanner. 3D 13C-CSI was acquired 30s after injection of 250μL of 15mM HP 13C DHA to detect reduction to Vitamin C (VitC). Fast spin echo (FSE) T2-weighted images were acquired for anatomic localization. Spectra were analyzed in Sivic and results are reported as metabolites peak height ratios, VitC/(VitC+DHA), an index of the redox status. Kidney perfusion by ASL-MRI: Pre-saturated pulsed ASL-MRI was implemented on an Agilent 14T vertical MR system. The tagging module consisted of a slice selective saturation immediately followed by a selective inversion (positive tag, M+) or a non-selective inversion (negative tag, M-). FSE images were acquired after an evolution delay of 1.5s, and the difference (M+)-(M-) was used to calculate perfusion in mL/min/100g.
Localized C13 MRS showed the hyperpolarized DHA peak at 174 ppm and its reduced form, VitC, was detected 3.8 ppm downfield with good signal to noise. Transgenic mice showed significantly lower kidney DHA reduction to VitC as shown by the VitC/(VitC+DHA) ratio of 0.23 ± 0.04 as compared to 0.30 ± 0.03 in WT controls (p=0.002), indicating higher oxidative stress and lower redox capacity in the NNT-MMP2 kidneys. Perfusion in kidney cortex of WT mice ranged from 500 to 800 mL/min/100g, which was in good agreement with published values in mice.
HP 13C DHA imaging allowed the detection of early impairment of the redox status in the NNT-MMP2 model of CKD. This was consistent with increased oxidative stress as confirmed by fluorescence microscopy of reactive oxygen species. In addition, perfusion MRI was feasible at 14T. Work is in progress to interrogate the redox capacity and perfusion alterations following episode of AKI and during the progression of CKD. These markers have the potential to allow early diagnosis of injury and to monitor treatment response.