Evaluation of renal metabolic response to partial ureteral obstruction with hyperpolarized 13 C MRI.

Hyperpolarized 13 C magnetic resonance imaging (MRI) may be used to non-invasively image the transport and chemical conversion of 13 C-labeled compounds in vivo. In this study, we utilize hyperpolarized 13 C MRI to evaluate metabolic markers in the kidneys longitudinally in a mouse model of partial unilateral ureteral obstruction (pUUO). Partial obstruction was surgically induced in the left ureter of nine adult mice, leaving the right ureter as a control. 1 H and hyperpolarized [1-13 C]pyruvate MRI of the kidneys was performed 2 days prior to surgery (baseline) and at 3, 7 and 14 days post-surgery. Images were evaluated for changes in renal pelvis volume, pyruvate, lactate and the lactate to pyruvate ratio. After 14 days, mice were sacrificed and immunohistological staining of both kidneys for collagen fibrosis (picrosirius red) and macrophage infiltration (F4/80) was performed. Statistical analysis was performed using a linear mixed effects model. Significant kidney × time interaction effects were observed for both lactate and pyruvate, indicating that these markers changed differently between time points for the obstructed and unobstructed kidneys. Both kidneys showed an increase in the lactate to pyruvate ratio after obstruction, suggesting a shift towards glycolytic metabolism. These changes were accompanied by marked hydronephrosis, fibrosis and macrophage infiltration in the obstructed kidney, but not in the unobstructed kidney. Our results show that pUUO is associated with increased pyruvate to lactate metabolism in both kidneys, with injury and inflammation specific to the obstructed kidney. The work also demonstrates the feasibility of the use of hyperpolarized 13 C MRI to study metabolism in renal disease.

Application of flow sensitive gradients for improved measures of metabolism using hyperpolarized (13) c MRI.

PURPOSE: To develop the use of bipolar gradients to suppress partial-volume and flow-related artifacts from macrovascular, hyperpolarized spins. THEORY AND METHODS: Digital simulations were performed over a range of spatial resolutions and gradient strengths to determine the optimal bipolar gradient strength and duration to suppress flowing spins while minimizing signal loss from static tissue. In vivo experiments were performed to determine the efficacy of this technique to suppress vascular signal in the study of hyperpolarized [1-(13)C]pyruvate renal metabolism. RESULTS: Digital simulations showed that in the absence of bipolar gradients, partial-volume artifacts from the vasculature were still present, causing underestimation of the apparent reaction rate of pyruvate to lactate (kP). The addition of a bipolar gradient with b = 32 s/mm(2) sufficiently suppressed the vascular signal without a substantial decrease in signal from static tissue. In vivo results corroborate digital simulations, with similar peak lactate signal to noise ratio (SNR) but substantially different kP in the presence of bipolar gradients. CONCLUSION: The proposed approach suppresses signal from flowing spins while minimizing signal loss from static tissue, removing contaminating signal from the vasculature and increasing kinetic modeling accuracy without substantially sacrificing SNR or temporal resolution.

Magnetic resonance imaging with hyperpolarized agents: methods and applications.

In the past decade, hyperpolarized (HP) contrast agents have been under active development for MRI applications to address the twin challenges of functional and quantitative imaging. Both HP helium (3He) and xenon (129Xe) gases have reached the stage where they are under study in clinical research. HP 129Xe, in particular, is poised for larger scale clinical research to investigate asthma, chronic obstructive pulmonary disease, and fibrotic lung diseases. With advances in polarizer technology and unique capabilities for imaging of 129Xe gas exchange into lung tissue and blood, HP 129Xe MRI is attracting new attention. In parallel, HP 13C and 15N MRI methods have steadily advanced in a wide range of pre-clinical research applications for imaging metabolism in various cancers and cardiac disease. The HP [1-13C] pyruvate MRI technique, in particular, has undergone phase I trials in prostate cancer and is poised for investigational new drug trials at multiple institutions in cancer and cardiac applications. This review treats the methodology behind both HP gases and HP 13C and 15N liquid state agents. Gas and liquid phase HP agents share similar technologies for achieving non-equilibrium polarization outside the field of the MRI scanner, strategies for image data acquisition, and translational challenges in moving from pre-clinical to clinical research. To cover the wide array of methods and applications, this review is organized by numerical section into (1) a brief introduction, (2) the physical and biological properties of the most common polarized agents with a brief summary of applications and methods of polarization, (3) methods for image acquisition and reconstruction specific to improving data acquisition efficiency for HP MRI, (4) the main physical properties that enable unique measures of physiology or metabolic pathways, followed by a more detailed review of the literature describing the use of HP agents to study: (5) metabolic pathways in cancer and cardiac disease and (6) lung function in both pre-clinical and clinical research studies, concluding with (7) some future directions and challenges, and (8) an overall summary.

Potential role of the glycolytic oscillator in acute hypoxia in tumors.

Tumor acute hypoxia has a dynamic component that is also, at least partially, coherent. Using blood oxygen level dependent magnetic resonance imaging, we observed coherent oscillations in hemoglobin saturation dynamics in cell line xenograft models of head and neck squamous cell carcinoma. We posit a well-established biochemical nonlinear oscillatory mechanism called the glycolytic oscillator as a potential cause of the coherent oscillations in tumors. These data suggest that metabolic changes within individual tumor cells may affect the local tumor microenvironment including oxygen availability and therefore radiosensitivity. These individual cells can synchronize the oscillations in patches of similar intermediate glucose levels. These alterations have potentially important implications for radiation therapy and are a potential target for optimizing the cancer response to radiation.