Christoffer Laustsen

High altitude may alter oxygen availability and renal metabolism in diabetics as measured by hyperpolarized [1-13C]pyruvate magnetic resonance imaging

The kidneys account for about 10% of the whole body oxygen consumption, whereas only 0.5% of the total body mass. It is known that intrarenal hypoxia is present in several diseases associated with development of kidney disease, including diabetes, and when renal blood flow is unaffected. The importance of deranged oxygen metabolism is further supported by deterioration of kidney function in patients with diabetes living at high altitude. Thus, we argue that reduced oxygen availability alters renal energy metabolism. Here, we introduce a novel magnetic resonance imaging (MRI) approach to monitor metabolic changes associated with diabetes and oxygen availability. Streptozotocin diabetic and control rats were given reduced, normal, or increased inspired oxygen in order to alter tissue oxygenation. The effects on kidney oxygen metabolism were studied using hyperpolarized [1-(13)C]pyruvate MRI. Reduced inspired oxygen did not alter renal metabolism in the control group. Reduced oxygen availability in the diabetic kidney altered energy metabolism by increasing lactate and alanine formation by 23% and 34%, respectively, whereas the bicarbonate flux was unchanged. Thus, the increased prevalence and severity of nephropathy in patients with diabetes at high altitudes may originate from the increased sensitivity toward inspired oxygen. This increased lactate production shifts the metabolic routs toward hypoxic pathways.

Superparamagnetic iron oxide polyacrylic acid coated γ-Fe2O3 nanoparticles do not affect kidney function but cause acute effect on the cardiovascular function in healthy mice.

This study describes the distribution of intravenously injected polyacrylic acid (PAA) coated γ-Fe(2)O(3) NPs (10 mg kg(-1)) at the organ, cellular and subcellular levels in healthy BALB/cJ mice and in parallel addresses the effects of NP injection on kidney function, blood pressure and vascular contractility. Magnetic resonance imaging (MRI) and transmission electron microscopy (TEM) showed accumulation of NPs in the liver within 1h after intravenous infusion, accommodated by intracellular uptake in endothelial and Kupffer cells with subsequent intracellular uptake in renal cells, particularly the cytoplasm of the proximal tubule, in podocytes and mesangial cells. The renofunctional effects of NPs were evaluated by arterial acid-base status and measurements of glomerular filtration rate (GFR) after instrumentation with chronically indwelling catheters. Arterial pH was 7.46±0.02 and 7.41±0.02 in mice 0.5 h after injections of saline or NP, and did not change over the next 12 h. In addition, the injections of NP did not affect arterial PCO(2) or [HCO(3)(-)] either. Twenty-four and 96 h after NP injections, the GFR averaged 0.35±0.04 and 0.35±0.01 ml min(-1) g(-1), respectively, values which were statistically comparable with controls (0.29±0.02 and 0.33±0.1 ml(-1) min(-1) 25 g(-1)). Mean arterial blood pressure (MAP) decreased 12-24 h after NP injections (111.1±11.5 vs 123.0±6.1 min(-1)) associated with a decreased contractility of small mesenteric arteries revealed by myography to characterize endothelial function. In conclusion, our study demonstrates that accumulation of superparamagnetic iron oxide nanoparticles does not affect kidney function in healthy mice but temporarily decreases blood pressure.

Hyperpolarized singlet NMR on a small animal imaging system.

Nuclear spin hyperpolarization makes a significant advance toward overcoming the sensitivity limitations of in vivo magnetic resonance imaging, particularly in the case of low‐gamma nuclei. The sensitivity may be improved further by storing the hyperpolarization in slowly relaxing singlet populations of spin‐1/2 pairs. Here, we report hyperpolarized 13C spin order transferred into and retrieved from singlet spin order using a small animal magnetic resonance imaging scanner. For spins in sites with very similar chemical shifts, singlet spin order is sustained in high magnetic field without requiring strong radiofrequency irradiation. The demonstration of robust singlet‐to‐magnetization conversion, and vice versa, on a small animal scanner, is promising for future in vivo and clinical deployments. Magn Reson Med, 2012.

In vivo single-shot 13C spectroscopic imaging of hyperpolarized metabolites by spatiotemporal encoding.

Hyperpolarized metabolic imaging is a growing field that has provided a new tool for analyzing metabolism, particularly in cancer. Given the short life times of the hyperpolarized signal, fast and effective spectroscopic imaging methods compatible with dynamic metabolic characterizations are necessary. Several approaches have been customized for hyperpolarized (13)C MRI, including CSI with a center-out k-space encoding, EPSI, and spectrally selective pulses in combination with spiral EPI acquisitions. Recent studies have described the potential of single-shot alternatives based on spatiotemporal encoding (SPEN) principles, to derive chemical-shift images within a sub-second period. By contrast to EPSI, SPEN does not require oscillating acquisition gradients to deliver chemical-shift information: its signal encodes both spatial as well as chemical shift information, at no extra cost in experimental complexity. SPEN MRI sequences with slice-selection and arbitrary excitation pulses can also be devised, endowing SPEN with the potential to deliver single-shot multi-slice chemical shift images, with a temporal resolution required for hyperpolarized dynamic metabolic imaging. The present work demonstrates this with initial in vivo results obtained from SPEN-based imaging of pyruvate and its metabolic products, after injection of hyperpolarized [1-(13)C]pyruvate. Multi-slice chemical-shift images of healthy rats were obtained at 4.7T in the region of the kidney, and 4D (2D spatial, 1D spectral, 1D temporal) data sets were obtained at 7T from a murine lymphoma tumor model.

Imaging cerebral 2-ketoisocaproate metabolism with hyperpolarized 13C Magnetic Resonance Spectroscopic Imaging

The branched chain amino acid transaminase (BCAT) has an important role in nitrogen shuttling and glutamate metabolism in the brain. The purpose of this study was to describe the cerebral distribution and metabolism of hyperpolarized 2-keto[1-13C]isocaproate (KIC) in the normal rat using magnetic resonance modalities. Hyperpolarized KIC is metabolized to [1-13C]leucine (leucine) by BCAT. The results show that KIC and its metabolic product, leucine, are present at imageable quantities 20 seconds after end of KIC administration throughout the brain. Further, significantly higher metabolism was observed in hippocampal regions compared with the muscle tissue. In conclusion, the cerebral metabolism of hyperpolarized KIC is imaged and hyperpolarized KIC may be a promising substrate for evaluation of cerebral BCAT activity in conjunction with neurodegenerative disease.

Insufficient insulin administration to diabetic rats increases substrate utilization and maintains lactate production in the kidney

Good glycemic control is crucial to prevent the onset and progression of late diabetic complications, but insulin treatment often fails to achieve normalization of glycemic control to the level seen in healthy controls. In fact, recent experimental studies indicate that insufficient treatment with insulin, resulting in poor glycemic control, has an additional effect on progression of late diabetic complications, than poor glycemic control on its own. We therefore compared renal metabolic alterations during conditions of poor glycemic control with and without suboptimal insulin administration, which did not restore glycemic control, to streptozotocin (STZ)‐diabetic rats using noninvasive hyperpolarized 13C‐pyruvate magnetic resonance imaging (MRI) and blood oxygenation level–dependent (BOLD) 1H‐MRI to determine renal metabolic flux and oxygen availability, respectively. Suboptimal insulin administration increased pyruvate utilization and metabolic flux via both anaerobic and aerobic pathways in diabetic rats even though insulin did not affect kidney oxygen availability, HbA1c, or oxidative stress. These results imply direct effects of insulin in the regulation of cellular substrate utilization and metabolic fluxes during conditions of poor glycemic control. The study demonstrates that poor glycemic control in combination with suboptimal insulin administration accelerates metabolic alterations by increasing both anaerobic and aerobic metabolism resulting in increased utilization of energy substrates. The results demonstrate the importance of tight glycemic control in insulinopenic diabetes, and that insulin, when administered insufficiently, adds an additional burden on top of poor glycemic control.

Hyperpolarized Renal Magnetic Resonance Imaging: Potential and Pitfalls

The introduction of dissolution dynamic nuclear polarization (d-DNP) technology has enabled a new paradigm for renal imaging investigations. It allows standard magnetic resonance imaging complementary renal metabolic and functional fingerprints within seconds without the use of ionizing radiation. Increasing evidence supports its utility in preclinical research in which the real-time interrogation of metabolic turnover can aid the physiological and pathophysiological metabolic and functional effects in ex vivo and in vivo models. The method has already been translated to humans, although the clinical value of this technology is unknown. In this paper, I review the potential benefits and pitfalls associated with dissolution dynamic nuclear polarization in preclinical research and its translation to renal patients.

Hyperpolarized H2O MR angiography

The aim of this study was to demonstrate that dissolution‐ dynamic nuclear polarization is capable of hyperpolarizing water protons and that the signal from the hyperpolarized bolus injection can be exploited in angiographic applications.

Renal hemodynamics and oxygenation in transient renal artery occluded rats evaluated with iron-oxide particles and oxygenation-sensitive imaging.

INTRODUCTION Mild or severe renal arterial occlusion is a phenomenon occasionally observed in daily clinical practice, potentially leading to renal ischemia and a general impairment of renal function. Secondly, closing the blood flow to the kidneys can also occur during kidney transplantation procedures. However, the exact physiological effects of these conditions on renal blood perfusion as well as the renal oxygen handling are poorly understood. The objectives of this study were therefore to measure the lateral changes of renal blood perfusion in rats subjected to transient unilateral arterial occlusion (RAS), and in addition, to measure the consequences on the intrarenal oxygenation. METHODS Experimental studies were performed using sixteen adolescent rats. The left renal artery was exposed through a flank incision and acute RAS for 45 min was achieved by placing a ligature around the renal artery. MRI was performed 3 days after the surgical procedure, where a blood oxygenation sensitive sequence (BOLD MRI) was performed, followed by a perfusion-weighted imaging sequence using a single bolus of the iron-oxide nanoparticle Sinerem. The renal oxygenation of blood was indirectly measured by the BOLD-parameter R2*, and perfusion measures include relative renal blood flow, relative renal blood volume and mean transit time. Histopathologic changes through the outer stripe of the outer medulla showing typical histopathologic findings of ischemia. DISCUSSION This study demonstrated that rats with transient renal arterial stenosis (for 45 min) showed a reduction in intrarenal oxygenation and intrarenal blood flow three days after the surgical procedure. A decreased R2* was measured within the ipsilateral medulla in parallel with a decreased medullary blood flow, is probably related to a lower reabsorption load within the ipsilateral kidney. MRI may therefore be a promising tool in long-term evaluation of RAS.

High-resolution ex vivo magnetic resonance angiography: a feasibility study on biological and medical tissues

BackgroundIn biomedical sciences, ex vivo angiography is a practical mean to elucidate vascular structures three-dimensionally with simultaneous estimation of intravascular volume. The objectives of this study were to develop a magnetic resonance (MR) method for ex vivo angiography and to compare the findings with computed tomography (CT). To demonstrate the usefulness of this method, examples are provided from four different tissues and species: the human placenta, a rice field eel, a porcine heart and a turtle.ResultsThe optimal solution for ex vivo MR angiography (MRA) was a compound containing gelatine (0.05 g/mL), the CT contrast agent barium sulphate (0.43 mol/L) and the MR contrast agent gadoteric acid (2.5 mmol/L). It was possible to perform angiography on all specimens. We found that ex vivo MRA could only be performed on fresh tissue because formalin fixation makes the blood vessels permeable to the MR contrast agent.ConclusionsEx vivo MRA provides high-resolution images of fresh tissue and delineates fine structures that we were unable to visualise by CT. We found that MRA provided detailed information similar to or better than conventional CTA in its ability to visualize vessel configuration while avoiding interfering signals from adjacent bones. Interestingly, we found that vascular tissue becomes leaky when formalin-fixed, leading to increased permeability and extravascular leakage of MR contrast agent.