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.

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 [1,4-C]fumarate imaging detects microvascular complications and hypoxia mediated cell death in diabetic nephropathy.

Today, there is a general lack of prognostic biomarkers for development of renal disease and in particular diabetic nephropathy. Increased glycolytic activity, lactate accumulation and altered mitochondrial oxygen utilization are hallmarks of diabetic kidney disease. Fumarate hydratase activity has been linked to mitochondrial dysfunction as well as activation of the hypoxia inducible factor, induction of apoptosis and necrosis.

Metabolic reprogramming associated with progression of renal ischemia reperfusion injury assessed with hyperpolarized [1-C]pyruvate.

Acute kidney injury is a major clinical challenge affecting as many as 1 percent of all hospitalized patients. Currently it is not possible to accurately stratify and predict the outcome of the individual patient. Increasing evidence supports metabolic reprogramming as a potential target for new biomarkers.

Hyperpolarized [1- 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- C]pyruvate imaging.

Sex Differences in Kidney Function and Metabolism Assessed Using Hyperpolarized [1-C]Pyruvate Interleaved Spectroscopy and Nonspecific Imaging.

Metabolic sex differences have recently been shown to be particularly important in tailoring treatment strategies. Sex has a major effect on fat turnover rates and plasma lipid delivery in the body. Differences in kidney structure and transporters between male and female animals have been found.

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

Purpose: To assess the utility of Laplacian fitting to describe the differences in hyperpolarized [ C, N]urea T relaxation in ischemic and healthy rodent kidneys.

Methods: Six rats with unilateral renal ischemia were investigated. [ C, N]Urea T mapping was undertaken with a radial fast spin echo method, with subsequent postprocessing performed with regularized Laplacian fitting.

Magnetic resonance hyperpolarization imaging detects early myocardial dysfunction in a porcine model of right ventricular heart failure.

Aims: Early detection of heart failure is important for timely treatment. During the development of heart failure, adaptive intracellular metabolic processes that evolve prior to macro-anatomic remodelling, could provide an early signal of impending failure. We hypothesized that metabolic imaging with hyperpolarized magnetic resonance would detect the early development of heart failure before conventional echocardiography could reveal cardiac dysfunction.

High Intrarenal Lactate Production Inhibits the Renal Pseudohypoxic Response to Acutely Induced Hypoxia in Diabetes.

Intrarenal hypoxia develops within a few days after the onset of insulinopenic diabetes in an experimental animal model (ie, a model of type-1 diabetes). Although diabetes-induced hypoxia results in increased renal lactate formation, mitochondrial function is well maintained, a condition commonly referred to as pseudohypoxia. However, the metabolic effects of significantly elevated lactate levels remain unclear.

Metabolic consequences of lactate dehydrogenase inhibition by oxamate in hyperglycemic proximal tubular cells.

Diabetic kidney disease (DKD) is associated with altered metabolic patterns, leading to increased lactate production even in the presence of sufficient oxygen supply. Studies have shown hyperglycemia to be an important factor in determining development of DKD. Here we explore the metabolic consequences of lactate dehydrogenase (LDH) inhibition exerted by the LDH inhibitor, oxamate, in the isolated rat renal proximal tubular cells (NRK-52E) under hyperglycemic conditions.

A non-invasive biomarker of type III collagen degradation reflects ischaemia reperfusion injury in rats.

Background: Maintenance of kidney function in kidney allografts remains a challenge, as the allograft often progressively develops fibrosis after kidney transplantation. Fibrosis is caused by the accumulation of extracellular matrix proteins like type I and III collagen (COL I and III) that replace the functional tissue. We assessed the concentrations of a neo-epitope fragment of COL III generated by matrix metalloproteinase-9 cleavage (C3M) in two rat models resembling the ischaemic injury taking place following kidney transplantation.

Glucagon infusion alters the hyperpolarized 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 [ C, N] urea dynamics and Na distribution before and 60 min after glucagon infusion in six female rats.

Hyperpolarized [1- C]pyruvate MRI can image the metabolic shift in cardiac metabolism between the fasted and fed state in a porcine model.

Purpose: Owing to its noninvasive nature, hyperpolarized MRI may improve delineation of myocardial metabolic derangement in heart disease. However, consistency may depend on the changeable nature of cardiac metabolism in relation to whole-body metabolic state. This study investigates the impact of feeding status on cardiac hyperpolarized MRI in a large animal model resembling human physiology.

Renal Energy Metabolism Following Acute Dichloroacetate and 2,4-Dinitrophenol Administration: Assessing the Cumulative Action with Hyperpolarized [1-C]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-C]pyruvate magnetic resonance imaging.

C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI.

Hyperpolarised MRI with Dynamic Nuclear Polarisation overcomes the fundamental thermodynamic limitations of conventional magnetic resonance, and is translating to human studies with several early-phase clinical trials in progress including early reports that demonstrate the utility of the technique to observe lactate production in human brain cancer patients. Owing to the fundamental coupling of metabolism and tissue function, metabolic neuroimaging with hyperpolarised [1-C]pyruvate has the potential to be revolutionary in numerous neurological disorders (e.g.

Can Hyperpolarized C-Urea be Used to Assess Glomerular Filtration Rate? A Retrospective Study.

This study investigated a simple method for calculating the single-kidney glomerular filtration rate (GFR) using dynamic hyperpolarized C-urea magnetic resonance (MR) renography. A retrospective data analysis was applied to renal hyperpolarized C-urea MR data acquired from control rats, prediabetic nephropathy rats, and rats in which 1 kidney was subjected to ischemia-reperfusion. Renal blood flow was determined by the model-free bolus differentiation method, GFR was determined using the Baumann-Rudin model method.

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).

Hyperpolarized C, N -urea T relaxation changes in acute kidney injury.

Purpose: To investigate the correlation between renal ischemia and C-urea T 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.

Unilateral nephrectomy diminishes ischemic acute kidney injury through enhanced perfusion and reduced pro-inflammatory and pro-fibrotic responses.

While unilateral nephrectomy (UNx) is suggested to protect against ischemia-reperfusion injury (IRI) in the remaining kidney, the mechanisms underlying this protection remain to be elucidated. In this study, functional MRI was employed in a renal IRI rat model to reveal global and regional changes in renal filtration, perfusion, oxygenation and sodium handling, and microarray and pathway analyses were conducted to identify protective molecular mechanisms. Wistar rats were randomized to either UNx or sham UNx immediately prior to 37 minutes of unilateral renal artery clamping or sham operation under sevoflurane anesthesia.

Hyperpolarized [1,4-C]Fumarate Enables Magnetic Resonance-Based Imaging of Myocardial Necrosis.

Objectives: The aim of this study was to determine if hyperpolarized [1,4-C]malate imaging could measure cardiomyocyte necrosis after myocardial infarction (MI).

Background: MI is defined by an acute burst of cellular necrosis and the subsequent cascade of structural and functional adaptations. Quantifying necrosis in the clinic after MI remains challenging.

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 () 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.

Hyperbaric oxygen therapy reduces renal lactate production.

Intrarenal hypoxia is an acknowledged factor contributing to the development of diabetic nephropathy. Hyperbaric oxygen (HBO) therapy is a well-known adjuvant treatment for several medical conditions, such as decompression sickness, infections, and wound healing. The underlying metabolic response of HBO is largely unknown.

Imaging porcine cardiac substrate selection modulations by glucose, insulin and potassium intervention: A hyperpolarized [1- C]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- C]pyruvate injections did not alter the blood pressure or ejection fraction over 180 min.

Fumarase activity: an in vivo and in vitro biomarker for acute kidney injury.

Renal ischemia/reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), and at present, there is a lack of reliable biomarkers that can diagnose AKI and measure early progression because the commonly used methods cannot evaluate single-kidney IRI. Hyperpolarized [1,4-C]fumarate conversion to [1,4-C]malate by fumarase has been proposed as a measure of necrosis in rat tumor models and in chemically induced AKI rats. Here we show that the degradation of cell membranes in connection with necrosis leads to elevated fumarase activity in plasma and urine and secondly that hyperpolarized [1,4-C]malate production 24 h after reperfusion correlates with renal necrosis in a 40-min unilateral ischemic rat model.

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-C]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.