The number of glomeruli and pyruvate metabolism is not strongly coupled in the healthy rat kidney.

PURPOSE: The number of glomeruli is different in men and women, as they also present different prevalence and progression of chronic kidney disease. A recent study has demonstrated a potential difference in renal metabolism between sexes, and a potential explanation could be the differences in glomeruli number. This study investigates the potential correlation between glomerular number and pyruvate metabolism in healthy kidneys. METHODS: This study is an experimental study with rats (N = 12). We used cationized-ferritin MRI to visualize and count glomeruli and hyperpolarized [1-13 C]pyruvate to map the metabolism. Dynamic contrast-enhanced MRI was used to analyze kidney hemodynamics using gadolinium tracer. RESULTS: Data showed no or subtle correlation between the number of glomeruli and the pyruvate metabolism. Minor differences were observed in the number of glomeruli (female = 24,509 vs. male = 26 350; p = .16), renal plasma flow (female = 606.6 vs. male= 455.7 ml/min/100 g; p = .18), and volume of distribution (female = 87.44 vs. male = 76.61 ml/100 ml; p = .54) between sexes. Mean transit time was significantly prolonged in males compared with females (female = 8.868 s vs. male = 10.63 s; p = .04). CONCLUSION: No strong statistically significant correlation between the number of glomeruli and the pyruvate metabolism was found in healthy rat kidneys.

Hyperpolarized [1-13 C]pyruvate combined with the hyperinsulinaemic euglycaemic and hypoglycaemic clamp technique in skeletal muscle in a large animal model.

NEW FINDINGS: What is the central question of this study? Is it possible to combine the hyperpolarized magnetic resonance technique and the hyperinsulinaemic clamp method in order to evaluate skeletal muscle metabolism in a large animal model? What is the main finding and its importance? The logistical set-up is possible, and we found substantial increments in glucose infusion rates representing skeletal muscle glucose uptake but no differences in ratios of [1-13 C]lactate to [1-13 C]pyruvate, [1-13 C]alanine to [1-13 C]pyruvate, and 13 C-bicarbonate to [1-13 C]pyruvate, implying that the hyperpolarization technique might not be optimal for detecting effects of insulin in skeletal muscle of anaesthetized animals, which is of significance for future studies. ABSTRACT: In skeletal muscle, glucose metabolism is tightly regulated by the reciprocal relationship between insulin and adrenaline, with pyruvate being at the intersection of both pathways. Hyperpolarized magnetic resonance (hMR) is a new approach to gain insights into these pathways, and human trials involving hMR and skeletal muscle metabolism are imminent. We aimed to combine the hyperinsulinaemic clamp technique and hMR in a large animal model resembling human physiology. Fifteen anaesthetized pigs were randomized to saline (control group), hyperinsulinaemic euglycaemic clamp technique (HE group) or hyperinsulinaemic hypoglycaemic clamp technique (HH group). Skeletal muscle metabolism was evaluated by hyperpolarized [1-13 C]pyruvate injection and hMR at baseline and after intervention. The glucose infusion rate per kilogram increased by a statistically significant amount in the HE and HH groups (P < 0.001). Hyperpolarized magnetic resonance showed no statistically significant changes in metabolite ratios: [1-13 C]lactate to [1-13 C]pyruvate in the HH group versus control group (P = 0.19); and 13 C-bicarbonate to [1-13 C]pyruvate ratio in the HE group versus the control group (P = 0.12). We found evidence of profound increments in glucose infusion rates representing skeletal muscle glucose uptake, but interestingly, no signs of significant changes in aerobic and anaerobic metabolism using hMR. These results imply that hyperpolarized [1-13 C]pyruvate might not be optimally suited to detect effects of insulin in anaesthetized resting skeletal muscle, which is of significance for future studies.

Development of a human heart-sized perfusion system for metabolic imaging studies using hyperpolarized [1-13 C]pyruvate MRI.

PURPOSE: Increasing worldwide demand for cardiac transplantation has spurred new developments to increase the donor pool. Normothermic preservation of heart grafts for transplantation is an emerging strategy to improve the utilization of marginal grafts. Hyperpolarized MR using metabolic tracers such as [1-13 C]pyruvate, provide a novel means of investigating metabolic status without the use of ionizing radiation. We demonstrate the use of this methodology to examine ex vivo perfused porcine heart grafts. METHODS: Hearts from three 40-kg Danish domestic pigs were harvested and subsequently perfused in Langendorff mode under normothermic conditions, using an MR-compatible perfusion system adapted to the heart. Proton MRI and hyperpolarized [1-13 C]pyruvate were used to investigate and quantify the functional and metabolic status of the grafts. RESULTS: Hearts were perfused with whole blood for 120 min, using a dynamic contrast-enhanced perfusion experiment to verify successful myocardial perfusion. Hyperpolarized [1-13 C]pyruvate MRI was used to assess the metabolic state of the myocardium. Functional assessment was performed using CINE imaging and ventricular pressure data. High lactate and modest alanine levels were observed in the hyperpolarized experiment. The functional assessment produced reduced functional parameters. This suggests an altered functional and metabolic profile compared with corresponding in vivo values. CONCLUSION: We investigated the metabolic and functional status of machine-perfused porcine hearts. Utilizing hyperpolarized methodology to acquire detailed myocardial metabolic information-in combination with already established MR methods for cardiac investigation-provides a powerful tool to aid the progress of donor heart preservation.

Cardiac pH-Imaging With Hyperpolarized MRI.

Regardless of the importance of acid-base disturbances in cardiac disease, there are currently no methods for clinical detection of pH in the heart. Several magnetic resonance imaging techniques hold translational promise and may enable in-vivo mapping of pH. We provide a brief overview of these emerging techniques. A particular focus is on the promising advance of magnetic resonance spectroscopy and imaging with hyperpolarized 13C-subtrates as biomarkers of myocardial pH. Hyperpolarization allows quantification of key metabolic substrates and their metabolites. Hereby, pH-sensitive reactions can be probed to provide a measure of acid-base alterations. To date, the most used substrates are [1-13C]pyruvate and 13C-labeled bicarbonate; however, others have been suggested. In cardiovascular medicine, hyperpolarized magnetic resonance spectroscopy has been used to probe acid-base disturbances following pharmacological stress, ischemia and heart failure in animals. In addition to pH-estimation, the technique can quantify fluxes such as the pivotal conversion of pyruvate to lactate via lactate dehydrogenase. This capability, a good safety profile and the fact that the technique is employable in clinical scanners have led to recent translation in early clinical trials. Thus, magnetic resonance spectroscopy and imaging may provide clinical pH-imaging in the near future.

Noninvasive Assessment of Fibrosis Following Ischemia/Reperfusion Injury in Rodents Utilizing Na Magnetic Resonance Imaging.

Fibrosis is often heterogeneously distributed, and classical biopsies do not reflect this. Noninvasive methods for renal fibrosis have been developed to follow chronic kidney diseases (CKD) and to monitor anti-fibrotic therapy. In this study, we combined two approaches to assess fibrosis regression following renal ischemia-reperfusion injury (IRI): magnetic resonance imaging (MRI) and noninvasive extracellular matrix (ECM) biomarkers. MRI was used to evaluate fibrosis in bilateral IRI in rats after reperfusion at 7, 14, and 21 days. This was performed with 1HT1 and T2* mapping, dynamic contrast-enhanced (DCE)-MRI, and chemical shift imaging (CSI)-23Na. The degradation of laminin gamma-1 chain (LG1M) and type III collagen (C3M) was measured in urine and plasma. Fibrosis was analyzed in tissue using fibronectin (FN) and alpha-smooth muscle actin (α-SMA) using quantitative polymerase chain reaction qPCR and western blotting. We found increased fibrosis 7 days after reperfusion, which dropped to sham levels after 21 days. Single kidney glomerular filtration rate (skGFR), perfusion (DCE-MRI), and total 23Na kidney content correlated positively with fibrotic markers FN and α-SMA as well as noninvasive LG1M and C3M. We showed that novel MRI protocols and ECM markers could track fibrogenic development. This could give rise to a multi-parametric practice to diagnose and assess fibrosis whilst treating kidney disease without using invasive methods.

The hemodynamic and metabolic effects of spironolactone treatment in acute kidney injury assessed by hyperpolarized MRI.

Renal ischemia-reperfusion injury (IRI) is one of the most common types of acute kidney injury. Spironolactone has shown promising kidney protective effects in renal IRI in rats. We investigated the hemodynamic and metabolic effects of spironolactone (100 mg/kg) administered immediately after 40 min unilateral kidney ischemia in rats. Hyperpolarized MRI using co-polarized [1-13 C]pyruvate and [13 C,15 N2 ]urea as well as 1 H dynamic contrast-enhanced (DCE) MRI was performed 24 h after induction of ischemia. We found a significant decrease in renal blood flow (RBF) in the ischemic kidney compared with the contralateral one measured using DCE and [13 C,15 N2 ]urea. The RBF measured using [1-13 C]pyruvate and [13 C,15 N2 ]urea was significantly altered by spironolactone. The RBFs in the ischemic kidney compared with the contralateral kidney were decreased similarly as measured using both [13 C,15 N2 ]urea and [1-13 C]pyruvate in the spironolactone-treated group. Spironolactone treatment increased the perfusion-corrected pyruvate metabolism by 54% in both the ischemic and contralateral kidney. Furthermore, we showed a correlation between vascular permeability using a histological Evans blue analysis and the ratio of the volumes of distribution (VoDs), ie VoD-[13 C,15 N2 ]urea/VoD-[1-13 C]pyruvate. This suggests that [13 C,15 N2 ]urea/[1-13 C]pyruvate VoD ratio may be a novel indicator of renal vascular permeability associated with renal damage in rodents.

Graft assessment of the ex vivo perfused porcine kidney using hyperpolarized [1-13 C]pyruvate.

PURPOSE: Normothermic perfusion is an emerging strategy for donor organ preservation and therapy, incited by the high worldwide demand for organs for transplantation. Hyperpolarized MRI and MRS using [1-13 C]pyruvate and other 13 C-labeled molecules pose a novel way to acquire highly detailed information about metabolism and function in a noninvasive manner. This study investigates the use of this methodology as a means to study and monitor the state of ex vivo perfused porcine kidneys, in the context of kidney graft preservation research. METHODS: Kidneys from four 40-kg Danish domestic pigs were perfused ex vivo with whole blood under normothermic conditions, using an MR-compatible perfusion system. Kidneys were investigated using 1 H MRI as well as hyperpolarized [1-13 C]pyruvate MRI and MRS. Using the acquired anatomical, functional and metabolic data, the state of the ex vivo perfused porcine kidney could be quantified. RESULTS: Four kidneys were successfully perfused for 120 minutes and verified using a DCE perfusion experiment. Renal metabolism was examined using hyperpolarized [1-13 C]pyruvate MRI and MRS, and displayed an apparent reduction in pyruvate turnover compared with the usual case in vivo. Perfusion and blood gas parameters were in the normal ex vivo range. CONCLUSION: This study demonstrates the ability to monitor ex vivo graft metabolism and function in a large animal model, resembling human renal physiology. The ability of hyperpolarized MRI and MRS to directly compare the metabolic state of an organ in vivo and ex vivo, in combination with the simple MR implementation of normothermic perfusion, renders this methodology a powerful future tool for graft preservation research.

Hyperpolarized [1-13 C] alanine production: A novel imaging biomarker of renal fibrosis.

PURPOSE: Renal tubulointerstitial fibrosis is strongly linked to the progressive decline of renal function seen in chronic kidney disease. State-of-the-art noninvasive diagnostic modalities are currently unable to detect the earliest changes associated with the onset of fibrosis. This study was undertaken to evaluate the potential for detecting the earliest alterations in fibrogenesis using a biofluid-based method and metabolic hyperpolarized [1-13 C]pyruvate imaging. METHODS: We evaluated renal fibrosis in a combined ischemia reperfusion-induced and streptozotocin-induced diabetic nephropathy rodent model by hyperpolarized [1-13 C]pyruvate MRI and correlated the metabolic MRI parameters with biomarkers of fibrosis measured on renal tissue and plasma/urine. RESULTS: The hyperglycemic rats experienced maladaptive injury repair after the ischemic insults, as shown by the elevation in the injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Renal function was significantly impaired in the ischemic hyperglycemic kidney, as seen in the reduced perfusion and single-kidney glomerular filtration rate. A deranged energy metabolism was detected in the ischemic hyperglycemic kidney, as seen in the reduced fractional perfusion of lactate. Renal fibrosis biomarkers correlated significantly with the alanine production. CONCLUSION: Hyperpolarized carbon-13 MRI provides a promising approach to assess renal fibrosis in an animal model of fibrotic chronic kidney disease. In particular, the metabolic supply of amino acids for fibrogenesis (alanine production) correlates well with biomarkers of fibrosis. Thus, [1-13 C]pyruvate-to-[1-13 C]alanine conversion might be a candidate for noninvasive assessment of renal fibrogenesis.

Glucose metabolism in brown adipose tissue determined by deuterium metabolic imaging in rats.

BACKGROUND/OBJECTIVES: Brown adipose tissue (BAT) has gained growing interest as a potential target for treatment of obesity. Currently, the most widely used technique/method for in vivo measurements of BAT activity in humans is 18FDG PET/CT. To supplement these investigations novel radiation-free methods are warranted. Deuterium metabolic imaging (DMI) is a novel modality that combines magnetic resonance spectroscopic (MRS) imaging with deuterium-labelled glucose (2H-glucose). This allows for spatio-temporal and metabolic imaging beyond glucose uptake. We aimed to evaluate if DMI could discriminate glucose metabolism in BAT of cold-acclimatised and thermoneutral rats. SUBJECTS/METHODS: Male Sprague-Dawley rats were housed in a cold environment (9 °C, n = 10) or at thermoneutrality (30 °C, n = 11) for 1 week. For imaging rats were anaesthetized, received a 2H-glucose (1 M, 1.95 g/kg) bolus and DMI was acquired at baseline followed by 20 min time intervals up to 2 h. Furthermore, Dixon MRI was performed for anatomical determination of the interscapular BAT (iBAT) depot along with dynamic contrast enhanced (DCE) MRI to evaluate perfusion. RESULTS: 2H-glucose signal was higher in cold-acclimatised rats compared with thermoneutral rats (p ≤ 0.001) indicating an overall increase in glucose uptake and metabolism. This was in line with a lower fat/water threshold, higher perfusion and increased UCP1 mRNA expression in iBAT (ninefold increment) of cold-acclimatised rats compared with thermoneutral rats. CONCLUSIONS: We find that DMI can discriminate cold-acclimatised and thermoneutral BAT in rats. This is the first study to evaluate BAT activity by DMI, which may open up for the use of the non-radioactive DMI method for BAT measurements in humans.

Detection of acute kidney injury with hyperpolarized [13 C, 15 N]Urea and multiexponential relaxation modeling.

PURPOSE: To assess the utility of Laplacian fitting to describe the differences in hyperpolarized [13 C, 15 N]urea T2 relaxation in ischemic and healthy rodent kidneys. METHODS: Six rats with unilateral renal ischemia were investigated. [13 C, 15 N]Urea T2 mapping was undertaken with a radial fast spin echo method, with subsequent postprocessing performed with regularized Laplacian fitting. RESULTS: Simulations showed that Laplacian fitting was stable down to a signal-to-noise ratio of 20. In vivo results showed a significant increase in the mono- and decrease in biexponential pools in ischemia reperfusion injury kidneys, in comparison to healthy (14 ± 10% versus 4 ± 2%, 85 ± 10% versus 95 ± 3%; P < .05). CONCLUSION: We demonstrate, for the first time, the differences in multiexponential behavior of [13 C, 15 N]urea between the healthy and ischemic rodent kidney. The distribution of relaxation pools were found to be both visually and numerically significantly different. The ability to improve the information level in hyperpolarized MR, by using the relaxation contrast mechanisms is an appealing option, that can easily be adopted in large animals and even in clinical studies in the near future.

Assessment of mouse liver [1-13C]pyruvate metabolism by dynamic hyperpolarized MRS.

Hyperpolarized [1-13C]pyruvate magnetic resonance (MR) spectroscopy has the unique ability to detect real-time metabolic changes in vivo owing to its high sensitivity compared with thermal MR and high specificity compared with other metabolic imaging methods. The aim of this study was to explore the potential of hyperpolarized MR spectroscopy for quantification of liver pyruvate metabolism during a hyperinsulinemic-isoglycemic clamp in mice. Hyperpolarized [1-13C]pyruvate was used for in vivo MR spectroscopy of liver pyruvate metabolism in mice. Mice were divided into two groups: (i) non-stimulated 5-h fasted mice and (ii) hyperinsulinemic-isoglycemic clamped mice. During clamp conditions, insulin and donor blood were administered at a constant rate, whereas glucose was infused to maintain isoglycemia. When steady state was reached, insulin-stimulated mice were rapidly infused with hyperpolarized [1-13C]pyruvate for real-time tracking of the dynamic distribution of metabolic derivatives from pyruvate, such as [1-13C]lactate, [1-13C]alanine and [13C]bicarbonate. Isotopomer analysis of plasma glucose confirmed 13C-incorporation from [1-13C]pyruvate into glucose was increased in fasted mice compared with insulin-stimulated mice, demonstrating an increased gluconeogenesis in fasted mice. The AUC ratios for [1-13C]alanine/[1-13C]pyruvate (38.2%), [1-13C]lactate/[1-13C]pyruvate (41.8%) and [13C]bicarbonate/[1-13C]pyruvate (169%) all increased significantly during insulin stimulation. Hyperpolarized [1-13C]pyruvate can be used for in vivo MR spectroscopy of liver pyruvate metabolism during hyperinsulinemic-isoglycemic clamp conditions. Under these conditions, insulin decreased gluconeogenesis and increased [1-13C]alanine, [1-13C]lactate and [13C]bicarbonate after a [1-13C]pyruvate bolus. This application of in vivo spectroscopy has the potential to identify impairments in specific metabolic pathways in the liver associated with obesity, insulin resistance and nonalcoholic fatty liver disease.

Ex Vivo Human Placenta Perfusion, Metabolic and Functional Imaging for Obstetric Research-A Feasibility Study.

Placenta metabolism is closely linked to pregnancy outcome, and few modalities are currently available for studying the human placenta. Here, we aimed to investigate a novel ex vivo human placenta perfusion system for metabolic imaging using hyperpolarized [1-13C]pyruvate. The metabolic effects of 3 different human placentas were investigated using functional and metabolic magnetic resonance imaging. The placenta glucose metabolism and hemodynamics were characterized with hyperpolarized [1-13C]pyruvate magnetic resonance imaging and by dynamic contrast-enhanced (DCE) imaging. Hyperpolarized [1-13C]pyruvate showed a decrease in the 13C-lactate/13C-pyruvate ratio from the highest to the lowest metabolic active placenta. The metabolic profile was complemented by a more homogenous distributed hemodynamic response, with a longer mean transit time and higher blood volume. This study shows different placenta metabolic and hemodynamic features associated with the placenta functional status using hyperpolarized magnetic resonance ex vivo. This study supports further studies using ex vivo metabolic imaging of the placenta alterations associated with pregnancy complications.

Glucagon infusion alters the hyperpolarized 13 C-urea renal hemodynamic signature.

Renal urea handling is central to the urine concentrating mechanism, and as such the ability to image urea transport in the kidney is an important potential imaging biomarker for renal functional assessment. Glucagon levels associated with changes in dietary protein intake have been shown to influence renal urea handling; however, the exact mechanism has still to be fully understood. Here we investigate renal function and osmolite distribution using [13 C,15 N] urea dynamics and 23 Na distribution before and 60 min after glucagon infusion in six female rats. Glucagon infusion increased the renal [13 C,15 N] urea mean transit time by 14%, while no change was seen in the sodium distribution, glomerular filtration rate or oxygen consumption. This change is related to the well-known effect of increased urea excretion associated with glucagon infusion, independent of renal functional effects. This study demonstrates for the first time that hyperpolarized 13 C-urea enables monitoring of renal urinary excretion effects in vivo.

Renal Energy Metabolism Following Acute Dichloroacetate and 2,4-Dinitrophenol Administration: Assessing the Cumulative Action with Hyperpolarized [1-13C]Pyruvate MRI.

Numerous patient groups receive >1 medication and as such represent a potential point of improvement in today's healthcare setup, as the combined or cumulative effects are difficult to monitor in an individual patient. Here we show the ability to monitor the pharmacological effect of 2 classes of medications sequentially, namely, 2,4-dinitrophenol, a mitochondrial uncoupler, and dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, both targeting the oxygen-dependent energy metabolism. We show that although the 2 drugs target 2 different metabolic pathways connected ultimately to oxygen metabolism, we could distinguish the 2 in vivo by using hyperpolarized [1-13C]pyruvate magnetic resonance imaging. A statistically significantly different pyruvate dehydrogenase flux was observed by reversing the treatment order of 2,4-dinitrophenol and dichloroacetate. The significance of this study is the demonstration of the ability to monitor the metabolic cumulative effects of 2 distinct therapeutics on an in vivo organ level using hyperpolarized magnetic resonance imaging.

Publisher Correction: Hyperpolarized [1-13C]-acetate Renal Metabolic Clearance Rate Mapping.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Effects of anesthesia on renal function and metabolism in rats assessed by hyperpolarized MRI.

PURPOSE: Anesthesia is necessary for most animal studies requiring invasive procedures. It is well documented that various types of anesthesia modulate a wide variety of important metabolic and functional processes in the body, and as such, represent a potential limitation in the study design. In the present study, we aimed to investigate the renal functional and metabolic consequences of 3 typical rodent anesthetics used in preclinical MRI: sevoflurane, inaction, and a mixture of fentanyl, fluanisone, and midazolam (FFM). METHODS: The renal effects of 3 different classes of anesthetics (inactin, servoflurane, and FFM) were investigated using functional and metabolic MRI. The renal glucose metabolism and hemodynamics was characterized with hyperpolarized [1-13 C]pyruvate MRI and by DCE imaging. RESULTS: Rats receiving sevoflurane or FFM had blood glucose levels that were 1.3-fold to 1.4-fold higher than rats receiving inactin. A 2.9-fold and 4.8-fold increased 13 C-lactate/13 C-pyruvate ratio was found in the FFM mixture anesthetized group compared with the sevoflurane and the inactin anesthetized groups. The FFM anesthesia resulted in a 50% lower renal plasma flow compared with the sevoflurane and the inactin anesthetized groups. CONCLUSION: This study demonstrates different renal metabolic and hemodynamic changes under 3 different anesthetics, using hyperpolarized MR in rats. Inactin and sevoflurane were found to affect the renal hemodynamic and metabolic status to a lesser degree than FFM. Sevoflurane anesthesia is particularly easy to induce and maintain during the whole anesthesia procedure, and as such, represents a good alternative to inaction, although it alters the blood glucose level.

Hyperpolarized 13 C,15 N2 -urea T2 relaxation changes in acute kidney injury.

PURPOSE: To investigate the correlation between renal ischemia and 13 C-urea T2 relaxation rate in an acute kidney injury (AKI) rat model. METHODS: Six rats subjected to unilateral renal ischemia were investigated. Creatinine clearance, urine output, plasma creatinine as well as blood-urea nitrogen (BUN) values were acquired before and after the procedure. 1 H T2* mapping was acquired using blood oxygenation level dependent (BOLD) MRI and hyperpolarized 13 C-urea T2 mapping was acquired using a 2D golden-angle radial approach. Kidney perfusion was estimated using noncontrast flow alternating inversion recovery arterial spin labeling. RESULTS: All rats showed clinical signs of AKI with increased plasma creatinine and increased BUN. Whole kidney 13 C-urea T2 significantly decreased 26% (P = 0.001) 24 h after reperfusion. A significantly different (3.7 times steeper; P = 0.008) osmolality gradient was observed in the contralateral kidney (P = 0.008; R2 = 0.86) compared with the postischemic kidney (P = 0.0004, R2 =0.97). Whole kidney T2* signal (P = 0.14) and T2* gradient (P = 0.26) was similar between the two kidneys. Oxygen availability dependency on 13 C-urea T2 was investigated by means of the correlation between the BOLD and T2 signals; a statistically significant difference (P = 0.03) was found in the contralateral kidney (P = 0.0001; R2 = 0.95), but not in the postischemic kidney (P = 0.31; R2 = 0.25). CONCLUSION: We demonstrate that hyperpolarized [13 C,15 N2 ]urea T2 relaxation correlates with renal oxygen tension ( T2*) in the healthy contralateral kidney, but not in the postischemic kidney. The whole kidney T2 relaxation difference between the postischemic and contralateral kidney may originate from altered blood volume in the postischemic kidney. Magn Reson Med 80:696-702, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

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

11C-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.

Hyperpolarized 13C Magnetic Resonance Imaging Can Detect Metabolic Changes Characteristic of Penumbra in Ischemic Stroke.

Magnetic resonance imaging (MRI) is increasingly the method of choice for rapid stroke assessment in patients and for guiding patient selection in clinical trials. The underlying metabolic status during stroke and following treatment is recognized as an important prognostic factor; thus, new methods are required to monitor local biochemistry following cerebral infarction, rapidly and in vivo. Hyperpolarized MRI with the tracer [1-13C]pyruvate enables rapid detection of localized [1-13C]lactate production, which has recently been shown in patients, supporting its translation to assess clinical stroke. Here we show the ability of hyperpolarized 13C MRI to detect the metabolic alterations characteristic of endothelin-1-induced ischemic stroke in rodents. In the region of penumbra, determined via T2-weighted 1H MRI, both [1-13C]pyruvate delivery and [1-13C]pyruvate cellular uptake independently increased. Furthermore, we observed a 33% increase in absolute [1-13C]lactate signal in the penumbra, and we determined that half of this increase was due to increased intracellular [1-13C]pyruvate supply and half was mediated by enhanced lactate dehydrogenase-mediated [1-13C]lactate production. Future work to characterize the kinetics of delivery, uptake, and enzymatic conversions of hyperpolarized tracers following ischemic stroke could position hyperpolarized 13C MRI as an ideal technology for rapid assessment of the penumbra during the critical time window following ischemic stroke in patients.