Thomas Stokholm Nørlinger

Renal ischemia and reperfusion assessment with three‐dimensional hyperpolarized 13C,15N2‐urea

The aim of this work was to investigate whether hyperpolarized 13C,15N2‐urea can be used as an imaging marker of renal injury in renal unilateral ischemic reperfusion injury (IRI), given that urea is correlated with the renal osmotic gradient, which describes the renal function.

Hyperpolarized 13C urea relaxation mechanism reveals renal changes in diabetic nephropathy.

Our aim was to assess a novel 13C radial fast spin echo golden ratio single shot method for interrogating early renal changes in the diabetic kidney, using hyperpolarized (HP) [13C,15N2]urea as a T2 relaxation based contrast bio‐probe.

Antioxidant treatment attenuates lactate production in diabetic nephropathy

The early progression of diabetic nephropathy is notoriously difficult to detect and quantify before the occurrence of substantial histological damage. Recently, hyperpolarized [1-13C]pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging. Ten-week-old female Wistar rats were randomly divided into three groups: healthy controls, untreated diabetic (streptozotocin treatment to induce insulinopenic diabetes), and diabetic, receiving chronic antioxidant treatment with TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) via the drinking water. Examinations were performed 2, 3, and 4 wk after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned 13C/1H-volume rat coil. The rats received intravenous hyperpolarized [1-13C]pyruvate and were imaged using a slice-selective 13C-IDEAL spiral sequence. Untreated diabetic rats showed increased renal lactate production compared with that shown by the controls. However, chronic TEMPOL treatment significantly attenuated diabetes-induced lactate production. No significant effects of diabetes or TEMPOL were observed on [13C]alanine levels, indicating an intact glucose-alanine cycle, or [13C]bicarbonate, indicating normal flux through the Krebs cycle. In conclusion, this study demonstrates that diabetes-induced pseudohypoxia, as indicated by an increased lactate-to-pyruvate ratio, is significantly attenuated by antioxidant treatment. This demonstrates a pivotal role of oxidative stress in renal metabolic alterations occurring in early diabetes.

Diabetes induced renal urea transport alterations assessed with 3D hyperpolarized 13C,15N-Urea

In the current study, we investigated hyperpolarized urea as a possible imaging biomarker of the renal function by means of the intrarenal osmolality gradient.

Early diabetic kidney maintains the corticomedullary urea and sodium gradient.

Early diabetic nephropathy is largely undetectable before substantial functional changes have occurred. In the present study, we investigated the distribution of electrolytes and urea in the early diabetic kidney in order to explore whether pathophysiological and metabolic changes appear concomitantly with a decreased sodium and urea gradient. By using hyperpolarized 13C urea it was possible to measure the essential intrarenal electrolyte gradients and the acute changes following furosemide treatment. No differences in either intrarenal urea or sodium gradients were observed in early diabetes compared to healthy controls. These results indicate that the early metabolic and hypertrophic changes occurring in the diabetic kidney prelude the later functional alterations in diabetic kidney function, thus driving the increased metabolic demand commonly occurring in the diabetic kidney.

Investigation of metabolic changes in STZ‐induced diabetic rats with hyperpolarized [1‐13C]acetate

In the metabolism of acetate several enzymes are involved, which play an important role in free fatty acid oxidation. Fatty acid metabolism is altered in diabetes patients and therefore acetate might serve as a marker for pathological changes in the fuel selection of cells, as these changes occur in diabetes patients. Acetylcarnitine is a metabolic product of acetate, which enables its transport into the mitochondria for energy production. This study investigates whether the ratio of acetylcarnitine to acetate, measured by noninvasive hyperpolarized [1‐13C]acetate magnetic resonance spectroscopy, could serve as a marker for myocardial, hepatic, and renal metabolic changes in rats with Streptozotocin (STZ)‐induced diabetes in vivo. We demonstrate that the conversion of acetate to acetylcarnitine could be detected and quantified in all three organs of interest. More interestingly, we found that the hyperpolarized acetylcarnitine to acetate ratio was independent of blood glucose levels and prolonged hyperglycemia following diabetes induction in a type‐1 diabetes model.

Imaging porcine cardiac substrate selection modulations by glucose, insulin and potassium intervention: A hyperpolarized [1-13C]pyruvate study

Cardiac metabolism has received considerable attention in terms of both diagnostics and prognostics, as well as a novel target for treatment. As human trials involving hyperpolarized magnetic resonance in the heart are imminent, we sought to evaluate the general feasibility of detection of an imposed shift in metabolic substrate utilization during metabolic modulation with glucose–insulin–potassium (GIK) infusion, and thus the limitations associated with this strategy, in a large animal model resembling human physiology. Four [1‐13C]pyruvate injections did not alter the blood pressure or ejection fraction over 180 min. Hyperpolarized [1‐13C]pyruvate conversion showed a generally high reproducibility, with intraclass correlation coefficients between the baseline measurements at 0 and 30 min as follows: lactate to pyruvate, 0.85; alanine to pyruvate, 1.00; bicarbonate to pyruvate, 0.83. This study demonstrates that hyperpolarized [1‐13C]pyruvate imaging is a feasible technique for cardiac studies and shows a generally high reproducibility in fasted large animals. GIK infusion increases the metabolic conversion of pyruvate to its metabolic derivatives lactate, alanine and bicarbonate, but with increased variability.

The chinchilla as a novel animal model of pregnancy

Several parameters are important when choosing the most appropriate animal to model human obstetrics, including gestation period, number of fetuses per gestation and placental structure. The domesticated long-tailed chinchilla (Chinchilla lanigera) is a well-suited and appropriate animal model of pregnancy that often will carry only one offspring and has a long gestation period of 105–115 days. Furthermore, the chinchilla placenta is of the haemomonochorial labyrinthine type and is therefore comparable to the human villous haemomonochorial placenta. This proof-of-concept study demonstrated the feasibility in laboratory settings, and demonstrated the potential of the pregnant chinchilla as an animal model for obstetric research and its potential usefulness for non-invasive measurements in the placenta. We demonstrate measurements of the placental and fetal metabolism (demonstrated in vivo by hyperpolarized MRI and in vitro by qPCR analyses), placental vessels (demonstrated ex vivo by contrast-enhanced CT angiography) and overall anatomy (demonstrated in vivo by whole-body CT).

Hyperpolarized [1-13C]-acetate Renal Metabolic Clearance Rate Mapping

Abstract11C-acetate is a positron emission tomography (PET) tracer of oxidative metabolism, whereas hyperpolarized 13C-acetate can be used in magnetic resonance imaging (MRI) for investigating specific metabolic processes. The aims of this study were to examine if the kinetic formalism of 11C-acetate PET in the kidneys is comparable to that of 13C-acetate MRI, and to compare the dynamic metabolic information of hyperpolarized 13C-acetate MRI with that obtained with 11C-acetate PET. Rats were examined with dynamic hyperpolarized 13C-acetate MRI or 11C-acetate PET before and after intravenous injection of furosemide, a loop diuretic known to alter both the hemodynamics and oxygen consumption in the kidney. The metabolic clearance rates (MCR) were estimated and compared between the two modalities experimentally in vivo and in simulations. There was a clear dependency on the mean transit time and MCR for both 13C-acetate and 11C-acetate following furosemide administration, while no dependencies on the apparent renal perfusion were observed. This study demonstrated that hyperpolarized 13C-acetate MRI is feasible for measurements of the intrarenal energetic demand via the MCR, and that the quantitative measures are correlated with those measured by 11C-acetate PET, even though the temporal window is more than 30 times longer with 11C-acetate.

Current state‐of‐the‐art hyperpolarized 13C‐acetate‐to‐acetylcarnitine imaging is not indicative of the altered balance between glucose and fatty acid utilization associated with diabetes

Dear Editor, Indeed acetate trafficking matters, however, hyperpolarized 13C‐acetate‐to‐acetylcarnitine is unable to detect any significant alterations between healthy controls and type‐1 diabetic rat heart, liver, and kidney, respectively in the fed state, with the current clinical setting hyperpolarized methodology. One potential reason for this could be that hyperpolarized MR experiments are in general utilizing superphysiological substrate concentrations and are thus normally considered to perturb the normal physiological conditions. This does however not alter the main conclusion of our study, the inability to differentiate 13C‐acetate‐to‐acetylcarnitine conversion between diabetics and controls, thus limiting the use of the current 13C‐acetate methodology in diabetes patients. It is however noteworthy …