Noninvasive evaluation of renal pH homeostasis after ischemia reperfusion injury by CEST‐MRI

Acute kidney injury (AKI) in mice caused by sustained ischemia followed by reperfusion is associated with acute tubular necrosis and renal dysfunctional blood flow. Although the principal role of the kidney is the maintenance of acid–base balance, current imaging approaches are unable to assess this important parameter, and clinical biomarkers are not robust enough in evaluating the severity of kidney damage. Therefore, novel noninvasive imaging approaches are needed to assess the acid–base homeostasis in vivo. This study investigates the usefulness of MRI‐chemical exchange saturation transfer (CEST) pH imaging (through iopamidol injection) in characterizing moderate and severe AKI in mice following unilateral ischemia reperfusion injury. Moderate (20 min) and severe (40 min) ischemia were induced in Balb/C mice, which were imaged at several time points thereafter (Days 0, 1, 2, 7). A significant increase of renal pH values was observed as early as one day after the ischemia reperfusion damage for both moderate and severe ischemia. MRI‐CEST pH imaging distinguished the evolution of moderate from severe AKI. A recovery of normal renal pH values was observed for moderate AKI, whereas a persisting renal pH increase was observed for severe AKI on Day 7. Renal filtration fraction was significantly lower for clamped kidneys (0.54–0.57) in comparison to contralateral kidneys (0.84–0.86) following impairment of glomerular filtration. The severe AKI group showed a reduced filtration fraction even after 7 days (0.38 for the clamped kidneys). Notably, renal pH values were significantly correlated with the histopathological score. In conclusion, MRI‐CEST pH mapping is a valid tool for the noninvasive evaluation of both acid–base balance and renal filtration in patients with ischemia reperfusion injury.     

CEST MRI of sepsis‐induced acute kidney injury

Sepsis‐induced acute kidney injury (SAKI) is a major complication of kidney disease associated with increased mortality and faster progression. Therefore, the development of imaging biomarkers to detect septic AKI is of great clinical interest. In this study, we aimed to characterize the endogenous chemical exchange saturation transfer (CEST) MRI contrast in the lipopolysaccharide (LPS)‐induced SAKI mouse model and to investigate the use of CEST MRI for detecting such injury. We used a SAKI mouse model that was generated by i.p. injection of 10 mg/kg LPS. The resulting kidney injury was confirmed by the elevation of serum creatinine and histology. MRI assessments were performed 24 h after LPS injection, including CEST MRI at different B₁ strengths (1, 1.8 and 3 μT), T₁ mapping, T₂ mapping and conventional magnetization transfer contrast (MTC) MRI. The CEST MRI results were analyzed using Z‐spectra, in which the normalized water signal saturation (S_sat/S₀) is measured as a function of saturation frequency. Substantial decreases in CEST contrast were observed at both 3.5 and ? 3.5 ppm frequency offset from water at all B₁ powers, with the most significant difference obtained at a B₁ of 1.8 μT. The average S_sat/S₀ differences between injured and normal kidneys were 0.07 (0.55 ± 0.04 versus 0.62 ± 0.04, P = 0.0028) and 0.07 (0.50 ± 0.04 versus 0.57 ± 0.03, P = 0.0008) for 3.5 and ? 3.5 ppm, respectively. In contrast, the T₁ and T₂ relaxation times and MTC contrast in the injured kidneys did not show a significant change compared with the normal control. Our results showed that CEST MRI is more sensitive to the pathological changes in injured kidneys than the changes in T₁, T₂ and MTC effect, indicating its potential clinical utility for molecular imaging of renal diseases.     

Quantitative description of radiofrequency (RF) power‐based ratiometric chemical exchange saturation transfer (CEST) pH imaging

Chemical exchange saturation transfer (CEST) MRI holds great promise for the imaging of pH. However, routine CEST measurement varies not only with the pH‐dependent chemical exchange rate, but also with CEST agent concentration, providing pH‐weighted information. Conventional ratiometric CEST imaging normalizes the confounding concentration factor by analyzing the relative CEST effect from different exchangeable groups, requiring CEST agents with multiple chemically distinguishable labile proton sites. Recently, a radiofrequency (RF) power‐based ratiometric CEST MRI approach has been developed for concentration‐independent pH MRI using CEST agents with a single exchangeable group. To facilitate quantification and optimization of the new ratiometric analysis, we quantified the RF power‐based ratiometric CEST ratio (rCESTR) and derived its signal‐to‐noise and contrast‐to‐noise ratios. Using creatine as a representative CEST agent containing a single exchangeable site, our study demonstrated that optimized RF power‐based ratiometric analysis provides good pH sensitivity. We showed that rCESTR follows a base‐catalyzed exchange relationship with pH independent of creatine concentration. The pH accuracy of RF power‐based ratiometric MRI was within 0.15–0.20 pH units. Furthermore, the absolute exchange rate can be obtained from the proposed ratiometric analysis. To summarize, RF power‐based ratiometric CEST analysis provides concentration‐independent pH‐sensitive imaging and complements conventional multiple labile proton group‐based ratiometric CEST analysis. Copyright © 2015 John Wiley & Sons, Ltd.     

MRI of renal oxygenation and function after normothermic ischemia-reperfusion injury

The in vivo assessment of renal damage after ischemia-reperfusion injury, such as in sepsis, hypovolemic shock or after transplantation, is a major challenge. This injury often results in temporary or permanent nonfunction. In order to improve the clinical outcome of the kidneys, novel therapies are currently being developed that limit renal ischemia-reperfusion injury. However, to fully address their therapeutic potential, noninvasive imaging methods are required which allow the in vivo visualization of different renal compartments and the evaluation of kidney function. In this study, MRI was applied to study kidney oxygenation and function in a murine model of renal ischemia-reperfusion injury at 7 T. During ischemia, there was a strongly decreased oxygenation, as measured using blood oxygen level-dependent MRI, compared with the contralateral control, which persisted after reperfusion. Moreover, it was possible to visualize differences in oxygenation between the different functional regions of the injured kidney. Dynamic contrast-enhanced MRI revealed a significantly reduced renal function, comprising perfusion and filtration, at 24 h after reperfusion. In conclusion, MRI is suitable for the noninvasive evaluation of renal oxygenation and function. Blood oxygen level-dependent or dynamic contrast-enhanced MRI may allow the early detection of renal pathology in patients with ischemia-reperfusion injury, such as in sepsis, hypovolemic shock or after transplantation, and consequently may lead to an earlier intervention or change of therapy to minimize kidney damage.     

A comprehensive non‐invasive framework for automated evaluation of acute renal transplant rejection using DCE‐MRI

The objective was to develop a novel and automated comprehensive framework for the non‐invasive identification and classification of kidney non‐rejection and acute rejection transplants using 2D dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI). The proposed approach consists of four steps. First, kidney objects are segmented from the surrounding structures with a geometric deformable model. Second, a non‐rigid registration approach is employed to account for any local kidney deformation. In the third step, the cortex of the kidney is extracted in order to determine dynamic agent delivery, since it is the cortex that is primarily affected by the perfusion deficits that underlie the pathophysiology of acute rejection. Finally, we use an analytical function‐based model to fit the dynamic contrast agent kinetic curves in order to determine possible rejection candidates. Five features that map the data from the original data space to the feature space are chosen with a k‐nearest‐neighbor (KNN) classifier to distinguish between acute rejection and non‐rejection transplants. Our study includes 50 transplant patients divided into two groups: 27 patients with stable kidney function and the remainder with impaired kidney function. All of the patients underwent DCE‐MRI, while the patients in the impaired group also underwent ultrasound‐guided fine needle biopsy. We extracted the kidney objects and the renal cortex from DCE‐MRI for accurate medical evaluation with an accuracy of 0.97 ± 0.02 and 0.90 ± 0.03, respectively, using the Dice similarity metric. In a cohort of 50 participants, our framework classified all cases correctly (100%) as rejection or non‐rejection transplant candidates, which is comparable to the gold standard of biopsy but without the associated deleterious side‐effects. Both the 95% confidence interval (CI) statistic and the receiver operating characteristic (ROC) analysis document the ability to separate rejection and non‐rejection groups. The average plateau (AP) signal magnitude and the gamma‐variate model functional parameter α have the best individual discriminating characteristics. Copyright © 2013 John Wiley & Sons, Ltd.     

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 [1‐¹³C]pyruvate and [¹³C,¹⁵N₂]urea as well as ¹H 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 [¹³C,¹⁵N₂]urea. The RBF measured using [1‐¹³C]pyruvate and [¹³C,¹⁵N₂]urea was significantly altered by spironolactone. The RBFs in the ischemic kidney compared with the contralateral kidney were decreased similarly as measured using both [¹³C,¹⁵N₂]urea and [1‐¹³C]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‐[¹³C,¹⁵N₂]urea/VoD‐[1‐¹³C]pyruvate. This suggests that [¹³C,¹⁵N₂]urea/[1‐¹³C]pyruvate VoD ratio may be a novel indicator of renal vascular permeability associated with renal damage in rodents.     

Gaussian mixture model‐based classification of dynamic contrast enhanced MRI data for identifying diverse tumor microenvironments: preliminary results

Tumor hypoxia develops heterogeneously, affects radiation sensitivity and the development of metastases. Prognostic information derived from the in vivo characterization of the spatial distribution of hypoxic areas in solid tumors can be of value for radiation therapy planning and for monitoring the early treatment response. Tumor hypoxia is caused by an imbalance between the supply and consumption of oxygen. The tumor oxygen supply is inherently linked to its vasculature and perfusion which can be evaluated by dynamic contrast enhanced (DCE‐) MRI using the contrast agent Gd‐DTPA. Thus, we hypothesize that DCE‐MRI data may provide surrogate information regarding tumor hypoxia. In this study, DCE‐MRI data from a rat prostate tumor model were analysed with a Gaussian mixture model (GMM)‐based classification to identify perfused, hypoxic and necrotic areas for a total of ten tumor slices from six rats, of which one slice was used as training data for GMM classifications. The results of pattern recognition analyzes were validated by comparison to corresponding Ak_ep maps defining the perfused area (0.84 ± 0.09 overlap), hematoxylin and eosin (H&E)‐stained tissue sections defining necrosis (0.64 ± 0.15 overlap) and pimonidazole‐stained sections defining hypoxia (0.72 ± 0.17 overlap), respectively. Our preliminary data indicate the feasibility of a GMM‐based classification to identify tumor hypoxia, necrosis and perfusion/permeability from non‐invasively acquired, in vivo DCE‐MRI data alone, possibly obviating the need for invasive procedures, such as biopsies, or exposure to radioactivity, such as positron emission tomography (PET) exams. Copyright © 2013 John Wiley & Sons, Ltd.     

On the interference from agar in chemical exchange saturation transfer MRI parameter optimization in model solutions

Chemical exchange saturation transfer (CEST) MRI is currently set to become part of clinical routine as it enables indirect detection of low concentrated molecules and proteins. Recently, intermediate to fast exchanging functional groups of glucose and its derivatives, glutamate and dextran, have gained attention as promising CEST contrast agents. To increase the specificity of CEST MRI for certain functional groups, the presaturation module is commonly optimized. At an early stage, this is performed in well‐defined model solutions, in which, for instance, the relaxation times are adjusted to mimic in vivo conditions. This often involves agar, assuming the substance would not yield significant CEST effects by itself, which the current study proves to be an invalid assumption. Model solutions at different pH values and concentrations of agar were investigated at different temperatures at a 9.4 T human whole body MR scanner. High power presaturation of around 4 μT, optimal for investigating intermediate to fast exchanging groups, was applied. Postprocessing included spatiotemporal corrections for B₀ and spatial corrections for B₁⁺. CEST effects of up to 3 % of the bulk water signal were observed. From pH, concentration and temperature dependency, it was concluded that the observed behavior reflects a CEST effect of agar. It was also shown how to remove this undesirable contribution from CEST MRI data. It was concluded that if agar is involved in the CEST MRI parameter optimization process, its contribution to the observed effects has to be taken into account. CEST agent concentration must be sufficiently high to be able to neglect the contribution of agar, or a control sample at matched pH is necessary for correction. Experiments on pure agarose showed reduced CEST effects compared with agar but did not provide a neutral baseline either.     

Dynamic contrast-enhanced CEST MRI using a low molecular weight dextran

Natural and synthetic sugars have great potential for developing highly biocompatible and translatable chemical exchange saturation transfer (CEST) MRI contrast agents. In this study, we aimed to develop the smallest clinically available form of dextran, Dex1 (molecular weight, MW ~ 1 kDa), as a new CEST agent. We first characterized the CEST properties of Dex1 in vitro at 11.7 T and showed that the Dex1 had a detectable CEST signal at ~1.2 ppm, attributed to hydroxyl protons. In vivo CEST MRI studies were then carried out on C57BL6 mice bearing orthotopic GL261 brain tumors (n = 5) using a Bruker BioSpec 11.7 T MRI scanner. Both steady-state full Z-spectral images and single offset (1.2 ppm) dynamic dextran-enhanced (DDE) images were acquired before and after the intravenous injection of Dex1 (2 g/kg). The steady-state Z-spectral analysis showed a significantly higher CEST contrast enhancement in the tumor than in contralateral brain (∆MTR_asym^{1.2 ppm} = 0.010 ± 0.006 versus 0.002 ± 0.008, P = 0.0069) at 20 min after the injection of Dex1. Pharmacokinetic analyses of DDE were performed using the area under the curve (AUC) in the first 10 min after Dex1 injection, revealing a significantly higher uptake of Dex1 in the tumor than in brain tissue for tumor-bearing mice (AUC[0-10 min] = 21.9 ± 4.2 versus 5.3 ± 6.4%·min, P = 0.0294). In contrast, no Dex1 uptake was foundling in the brains of non-tumor-bearing mice (AUC[0-10 min] = −1.59 ± 2.43%·min). Importantly, the CEST MRI findings were consistent with the measurements obtained using DCE MRI and fluorescence microscopy, demonstrating the potential of Dex1 as a highly translatable CEST MRI contrast agent for assessing tumor hemodynamics.     

Relationship between diffusion parameters derived from intravoxel incoherent motion MRI and perfusion measured by dynamic contrast‐enhanced MRI of soft tissue tumors

Our aim was to evaluate the link between diffusion parameters measured by intravoxel incoherent motion (IVIM) diffusion‐weighted imaging (DWI) and the perfusion metrics obtained with dynamic contrast‐enhanced (DCE) MRI in soft tissue tumors (STTs). Twenty‐eight patients affected by histopathologically confirmed STT were included in a prospective study. All patients underwent both DCE MRI and IVIM DWI. The perfusion fraction f, diffusion coefficient D and perfusion‐related diffusion coefficient D* were estimated using a bi‐exponential function to fit the DWI data. DCE MRI was acquired with a temporal resolution of 3–5 s. Maps of the initial area under the gadolinium concentration curve (IAUGC), time to peak (TTP) and maximum slope of increase (MSI) were derived using commercial software. The relationships between the DCE MRI and IVIM DWI measurements were assessed by Spearman's test. To exclude false positive results under multiple testing, the false discovery rate (FDR) procedure was applied. The Mann–Whitney test was used to evaluate the differences between all variables in patients with non‐myxoid and myxoid STT. No significant relationship was found between IVIM parameters and any DCE MRI parameters. Higher f and D*f values were found in non‐myxoid tumors compared with myxoid tumors (p = 0.004 and p = 0.003, respectively). MSI was significantly higher in non‐myxoid tumors than in myxoid tumors (p = 0.029). From the visual assessments of single clinical cases, both f and D*f maps were in satisfactory agreement with DCE maps in the extreme cases of an avascular mass and a highly vascularized mass, whereas, for tumors with slight vascularity or with a highly heterogeneous perfusion pattern, this association was not straightforward. Although IVIM DWI was demonstrated to be feasible in STT, our data did not support evident relationships between perfusion‐related IVIM parameters and perfusion measured by DCE MRI. Copyright © 2015 John Wiley & Sons, Ltd.     

Assessments of tumor metabolism with CEST MRI

Chemical exchange saturation transfer (CEST) is a relatively new contrast mechanism for MRI. CEST MRI exploits a specific MR frequency (chemical shift) of a molecule while generating an image with good spatial resolution using standard MRI techniques, combining the specificity of MRS with the spatial resolution of MRI. Many CEST MRI acquisition methods have been developed to improve analyses of tumor metabolism. GluCEST, CrCEST, and LATEST can map glutamate, creatine, and lactate, which are important metabolites involved in tumor metabolism. GlucoCEST MRI tracks the pharmacokinetics of glucose transport and cell internalization within tumors. CatalyCEST MRI detects enzyme catalysis that changes a substrate CEST agent. AcidoCEST MRI measures extracellular pH of the tumor microenvironment by exploiting a ratio of two pH‐dependent CEST signals. This review describes each technique, the technical issues involved with CEST MRI and each specific technique, and the merits and challenges associated with applying each CEST MRI technique to study tumor metabolism.     

Simulation,phantom validation,and clinical evaluation of fast pH‐weighted molecular imaging using amine chemical exchange saturation transfer echo planar imaging (CEST‐EPI) in glioma at 3 T

Acidity within the extracellular milieu is a hallmark of cancer. There is a current need for fast, high spatial resolution pH imaging techniques for clinical evaluation of cancers, including gliomas. Chemical exchange saturation transfer (CEST) MRI targeting fast‐exchanging amine protons can be used to obtain high‐resolution pH‐weighted images, but conventional CEST acquisition strategies are slow. There is also a need for more accurate MR simulations to better understand the effects of amine CEST pulse sequence parameters on pH‐weighted image contrast. In the current study we present a simulation of amine CEST contrast specific for a newly developed CEST echoplanar imaging (EPI) pulse sequence. The accuracy of the simulations was validated by comparing the exchange rates and Z‐spectrum under a variety of conditions using physical phantoms of glutamine with different pH values. The effects of saturation pulse shapes, pulse durations, pulse train lengths, repetition times, and relaxation rates of bulk water and exchangeable amine protons on the CEST signal were explored for normal‐appearing white matter (NAWM), glioma, and cerebrospinal fluid. Last, 18 patients with WHO II‐IV gliomas were evaluated. Results showed that the Z‐spectrum was highly dependent on saturation pulse shape, repetition time, saturation amplitude, magnetic field strength, and T₂ within bulk water; however, the Z‐spectrum was only minimally influenced by saturation pulse duration and the specific relaxation rates of amine protons. Results suggest that a Gaussian saturation pulse train consisting of 3 × 100 ms pulses using the minimum allowable repetition time is optimal for achieving over 90% available contrast across all tissues. Results also demonstrate that high saturation pulse amplitude and scanner field strength (>3 T) are necessary for adequate endogenous pH‐weighted amine CEST contrast. pH‐weighted amine CEST contrast increased with increasing tumor grade, with glioblastoma showing significantly higher contrast compared with WHO II or III gliomas.     

Blood–spinal cord barrier permeability in experimental spinal cord injury: dynamic contrast‐enhanced MRI

After a primary traumatic injury, spinal cord tissue undergoes a series of pathobiological changes, including compromised blood–spinal cord barrier (BSCB) integrity. These vascular changes occur over both time and space. In an experimental model of spinal cord injury (SCI), longitudinal dynamic contrast‐enhanced MRI (DCE‐MRI) studies were performed up to 56 days after SCI to quantify spatial and temporal changes in the BSCB permeability in tissue that did not show any visible enhancement on the post‐contrast MRI (non‐enhancing tissue). DCE‐MRI data were analyzed using a two‐compartment pharmacokinetic model. These studies demonstrate gradual restoration of BSCB with post‐SCI time. However, on the basis of DCE‐MRI, and confirmed by immunohistochemistry, the BSCB remained compromised even at 56 days after SCI. In addition, open‐field locomotion was evaluated using the 21‐point Basso–Beattie–Bresnahan scale. A significant correlation between decreased BSCB permeability and improved locomotor recovery was observed. Copyright © 2008 John Wiley & Sons, Ltd.     

Imaging chemical exchange saturation transfer (CEST) effects following tumor‐selective acidification using lonidamine

Increased lactate production through glycolysis in aerobic conditions is a hallmark of cancer. Some anticancer drugs have been designed to exploit elevated glycolysis in cancer cells. For example, lonidamine (LND) inhibits lactate transport, leading to intracellular acidification in cancer cells. Chemical exchange saturation transfer (CEST) is a novel MRI contrast mechanism that is dependent on intracellular pH. Amine and amide concentration‐independent detection (AACID) and apparent amide proton transfer (APT*) represent two recently developed CEST contrast parameters that are sensitive to pH. The goal of this study was to compare the sensitivity of AACID and APT* for the detection of tumor‐selective acidification after LND injection. Using a 9.4‐T MRI scanner, CEST data were acquired in mice approximately 14 days after the implantation of 10⁵ U87 human glioblastoma multiforme (GBM) cells in the brain, before and after the administration of LND (dose, 50 or 100 mg/kg). Significant dose‐dependent LND‐induced changes in the measured CEST parameters were detected in brain regions spatially correlated with implanted tumors. Importantly, no changes were observed in T₁‐ and T₂‐weighted images acquired before and after LND treatment. The AACID and APT* contrast measured before and after LND injection exhibited similar pH sensitivity. Interestingly, LND‐induced contrast maps showed increased heterogeneity compared with pre‐injection CEST maps. These results demonstrate that CEST contrast changes after the administration of LND could help to localize brain cancer and monitor tumor response to chemotherapy within 1 h of treatment. The LND CEST experiment uses an anticancer drug to induce a metabolic change detectable by endogenous MRI contrast, and therefore represents a unique cancer detection paradigm which differs from other current molecular imaging techniques that require the injection of an imaging contrast agent or tracer. Copyright © 2015 John Wiley & Sons, Ltd.     

Detecting in vivo urokinase plasminogen activator activity with a catalyCEST MRI contrast agent

Urokinase plasminogen activator (uPA) promotes tumor invasion and metastasis. The monitoring of uPA activity using molecular imaging may have prognostic value and be predictive for response to anti‐cancer therapies. However, the detection of in vivo enzyme activity with molecular imaging remains a challenge. To address this problem, we designed a nonmetallic contrast agent, GR‐4Am‐SA, that can be detected with chemical exchange saturation transfer (CEST) MRI. This agent has a peptide that is cleaved by uPA, which causes a CEST signal at 5.0 ppm to decrease, and also has a salicylic acid moiety that can produce a CEST signal at 9.5 ppm, which is largely unresponsive to enzyme activity. The two CEST signals were used to determine a reaction coordinate, representing the extent of enzyme‐catalyzed cleavage of the GR‐4Am‐SA agent during an experimental study. Initial biochemical studies showed that GR‐4Am‐SA could detect uPA activity in reducing conditions. Subsequently, we used our catalyCEST MRI protocol with the agent to detect the uPA catalysis of GR‐4Am‐SA in a flank xenograft model of Capan‐2 pancreatic cancer. The results showed an average reaction coordinate of 80% ± 8%, which was strongly dependent on the CEST signal at 5.0 ppm. The relative independence of the reaction coordinate on the CEST signal at 9.5 ppm showed that the detection of enzyme activity was largely independent of the concentration of GR‐4Am‐SA within the tumor tissue. These results demonstrated the advantages of a single CEST agent with biomarker‐responsive and unresponsive signals for reliably assessing enzyme activity during in vivo cancer studies.     

Monitoring dynamic alterations in calcium homeostasis by T1‐mapping manganese‐enhanced MRI (MEMRI) in the early stage of small intestinal ischemia–reperfusion injury

Manganese‐enhanced MRI studies have proven to be useful in monitoring physiological activities associated with calcium ions (Ca²⁺) due to the paramagnetic property of the manganese ion (Mn²⁺), which makes it an excellent probe of Ca²⁺. In this study, we developed a method in which a Mn²⁺‐enhanced T₁‐map MRI could enable the monitoring of Ca²⁺ influx during the early stages of intestinal ischemia–reperfusion (I/R) injury. The Mn²⁺ infusion protocol was optimized by obtaining dose‐dependent and time‐course wash‐out curves using a Mn²⁺‐enhanced T₁‐map MRI of rabbit abdomens following an intravenous infusion of 50 mmol/l MnCl₂ (5–10 nmol/g body weight (BW)). In the rabbit model of intestinal I/R injury, T₁ values were derived from the T₁ maps in the intestinal wall region and revealed a relationship between the dose of the infused MnCl₂ and the intestinal wall relaxation time. Significant Mn²⁺ clearance was also observed over time in control animals after the infusion of Mn²⁺ at a dose of 10 nmol/g BW. This technique was also shown to be sensitive enough to monitor variations in calcium ion homeostasis in vivo after small intestinal I/R injury. The T₁ values of the intestinal I/R group were significantly lower (P < 0.05) than that of the control group at 5, 10, and 15 min after Mn²⁺ infusion. Our data suggest that MnCl₂ has the potential to be an MRI contrast agent that can be effectively used to monitor changes in intracellular Ca²⁺ homeostasis during the early stages of intestinal I/R injury. Copyright © 2015 John Wiley & Sons, Ltd.     

The role of the immune system in kidney disease

The immune system and the kidneys are closely linked. In health the kidneys contribute to immune homeostasis, while components of the immune system mediate many acute forms of renal disease and play a central role in progression of chronic kidney disease. A dysregulated immune system can have either direct or indirect renal effects. Direct immune‐mediated kidney diseases are usually a consequence of autoantibodies directed against a constituent renal antigen, such as collagen IV in anti‐glomerular basement membrane disease. Indirect immune‐mediated renal disease often follows systemic autoimmunity with immune complex formation, but can also be due to uncontrolled activation of the complement pathways. Although the range of mechanisms of immune dysregulation leading to renal disease is broad, the pathways leading to injury are similar. Loss of immune homeostasis in renal disease results in perpetual immune cell recruitment and worsening damage to the kidney. Uncoordinated attempts at tissue repair, after immune‐mediated disease or non‐immune mediated injury, result in fibrosis of structures important for renal function, leading eventually to kidney failure. As renal disease often manifests clinically only when substantial damage has already occurred, new diagnostic methods and indeed treatments must be identified to inhibit further progression and promote appropriate tissue repair. Studying cases in which immune homeostasis is re‐established may reveal new treatment possibilities.     

Quantitative chemical exchange saturation transfer (qCEST) MRI – omega plot analysis of RF‐spillover‐corrected inverse CEST ratio asymmetry for simultaneous determination of labile proton ratio and exchange rate

Chemical exchange saturation transfer (CEST) MRI is sensitive to labile proton concentration and exchange rate, thus allowing measurement of dilute CEST agent and microenvironmental properties. However, CEST measurement depends not only on the CEST agent properties but also on the experimental conditions. Quantitative CEST (qCEST) analysis has been proposed to address the limitation of the commonly used simplistic CEST‐weighted calculation. Recent research has shown that the concomitant direct RF saturation (spillover) effect can be corrected using an inverse CEST ratio calculation. We postulated that a simplified qCEST analysis is feasible with omega plot analysis of the inverse CEST asymmetry calculation. Specifically, simulations showed that the numerically derived labile proton ratio and exchange rate were in good agreement with input values. In addition, the qCEST analysis was confirmed experimentally in a phantom with concurrent variation in CEST agent concentration and pH. Also, we demonstrated that the derived labile proton ratio increased linearly with creatine concentration (P < 0.01) while the pH‐dependent exchange rate followed a dominantly base‐catalyzed exchange relationship (P < 0.01). In summary, our study verified that a simplified qCEST analysis can simultaneously determine labile proton ratio and exchange rate in a relatively complex in vitro CEST system. Copyright © 2015 John Wiley & Sons, Ltd.     

Optimization of saturation‐recovery dynamic contrast‐enhanced MRI acquisition protocol: monte carlo simulation approach demonstrated with gadolinium MR renography

Dynamic contrast‐enhanced (DCE) MRI is widely used for the measurement of tissue perfusion and to assess organ function. MR renography, which is acquired using a DCE sequence, can measure renal perfusion, filtration and concentrating ability. Optimization of the DCE acquisition protocol is important for the minimization of the error propagation from the acquired signals to the estimated parameters, thus improving the precision of the parameters. Critical to the optimization of contrast‐enhanced T₁‐weighted protocols is the balance of the T₁‐shortening effect across the range of gadolinium (Gd) contrast concentration in the tissue of interest. In this study, we demonstrate a Monte Carlo simulation approach for the optimization of DCE MRI, in which a saturation‐recovery T₁‐weighted gradient echo sequence is simulated and the impact of injected dose (D) and time delay (TD, for saturation recovery) is tested. The results show that high D and/or high TD cause saturation of the peak arterial signals and lead to an overestimation of renal plasma flow (RPF) and glomerular filtration rate (GFR). However, the use of low TD (e.g. 100 ms) and low D leads to similar errors in RPF and GFR, because of the Rician bias in the pre‐contrast arterial signals. Our patient study including 22 human subjects compared TD values of 100 and 300 ms after the injection of 4 mL of Gd contrast for MR renography. At TD = 100 ms, we computed an RPF value of 157.2 ± 51.7 mL/min and a GFR of 33.3 ± 11.6 mL/min. These results were all significantly higher than the parameter estimates at TD = 300 ms: RPF = 143.4 ± 48.8 mL/min (p = 0.0006) and GFR = 30.2 ± 11.5 mL/min (p = 0.0015). In conclusion, appropriate optimization of the DCE MRI protocol using simulation can effectively improve the precision and, potentially, the accuracy of the measured parameters. Copyright © 2016 John Wiley & Sons, Ltd.     

Linking non‐invasive parametric MRI with invasive physiological measurements (MR‐PHYSIOL): towards a hybrid and integrated approach for investigation of acute kidney injury in rats

Acute kidney injury of various origins shares a common link in the pathophysiological chain of events: imbalance between renal medullary oxygen delivery and oxygen demand. For in vivo assessment of kidney haemodynamics and oxygenation in animals, quantitative but invasive physiological methods are established. A very limited number of studies attempted to link these invasive methods with parametric Magnetic Resonance Imaging (MRI) of the kidney. Moreover, the validity of parametric MRI (pMRI) as a surrogate marker for renal tissue perfusion and renal oxygenation has not been systematically examined yet. For this reason, we set out to combine invasive techniques and non‐invasive MRI in an integrated hybrid setup (MR‐PHYSIOL) with the ultimate goal to calibrate, monitor and interpret parametric MR and physiological parameters by means of standardized interventions. Here we present a first report on the current status of this multi‐modality approach. For this purpose, we first highlight key characteristics of renal perfusion and oxygenation. Second, concepts for in vivo characterization of renal perfusion and oxygenation are surveyed together with the capabilities of MRI for probing blood oxygenation‐dependent tissue stages. Practical concerns evoked by the use of strong magnetic fields in MRI and interferences between MRI and invasive physiological probes are discussed. Technical solutions that balance the needs of in vivo physiological measurements together with the constraints dictated by small bore MR scanners are presented. An early implementation of the integrated MR‐PHYSIOL approach is demonstrated including brief interventions of hypoxia and hyperoxia.