Luke Xie

Susceptibility tensor imaging of the kidney and its microstructural underpinnings

The purpose of this study was to determine whether susceptibility tensor imaging (STI) could overcome limitations of current techniques to detect tubules throughout the kidney.

Quantitative susceptibility mapping of kidney inflammation and fibrosis in type 1 angiotensin receptor-deficient mice

Disruption of the regulatory role of the kidneys leads to diverse renal pathologies; one major hallmark is inflammation and fibrosis. Conventional magnitude MRI has been used to study renal pathologies; however, the quantification or even detection of focal lesions caused by inflammation and fibrosis is challenging. We propose that quantitative susceptibility mapping (QSM) may be particularly sensitive for the identification of inflammation and fibrosis. In this study, we applied QSM in a mouse model deficient for angiotensin receptor type 1 (AT1). This model is known for graded pathologies, including focal interstitial fibrosis, cortical inflammation, glomerulocysts and inner medullary hypoplasia. We acquired high‐resolution MRI on kidneys from AT1‐deficient mice that were perfusion fixed with contrast agent. Two MR sequences were used (three‐dimensional spin echo and gradient echo) to produce three image contrasts: T1, T2* (magnitude) and QSM. T1 and T2* (magnitude) images were acquired to segment major renal structures and to provide landmarks for the focal lesions of inflammation and fibrosis in the three‐dimensional space. The volumes of major renal structures were measured to determine the relationship of the volumes to the degree of renal abnormalities and magnetic susceptibility values. Focal lesions were segmented from QSM images and were found to be closely associated with the major vessels. Susceptibilities were relatively more paramagnetic in wild‐type mice: 1.46 ± 0.36 in the cortex, 2.14 ± 0.94 in the outer medulla and 2.10 ± 2.80 in the inner medulla (10–2 ppm). Susceptibilities were more diamagnetic in knockout mice: –7.68 ± 4.22 in the cortex, –11.46 ± 2.13 in the outer medulla and –7.57 ± 5.58 in the inner medulla (10–2 ppm). This result was consistent with the increase in diamagnetic content, e.g. proteins and lipids, associated with inflammation and fibrosis. Focal lesions were validated with conventional histology. QSM was very sensitive in detecting pathology caused by small focal inflammation and fibrosis. QSM offers a new MR contrast mechanism to study this common disease marker in the kidney. Copyright

Rapid multi-orientation quantitative susceptibility mapping.

Three-dimensional gradient echo (GRE) is the main workhorse sequence used for susceptibility weighted imaging (SWI), quantitative susceptibility mapping (QSM), and susceptibility tensor imaging (STI). Achieving optimal phase signal-to-noise ratio requires late echo times, thus necessitating a long repetition time (TR). Combined with the large encoding burden of whole-brain coverage with high resolution, this leads to increased scan time. Further, the dipole kernel relating the tissue phase to the underlying susceptibility distribution undersamples the frequency content of the susceptibility map. Scans at multiple head orientations along with calculation of susceptibility through multi-orientation sampling (COSMOS) are one way to effectively mitigate this issue. Additionally, STI requires a minimum of 6 head orientations to solve for the independent tensor elements in each voxel. The requirements of high-resolution imaging with long TR at multiple orientations substantially lengthen the acquisition of COSMOS and STI. The goal of this work is to dramatically speed up susceptibility mapping at multiple head orientations. We demonstrate highly efficient acquisition using 3D-GRE with Wave-CAIPI and dramatically reduce the acquisition time of these protocols. Using R=15-fold acceleration with Wave-CAIPI permits acquisition per head orientation in 90s at 1.1mm isotropic resolution, and 5:35min at 0.5mm isotropic resolution. Since Wave-CAIPI fully harnesses the 3D spatial encoding capability of receive arrays, the maximum g-factor noise amplification remains below 1.30 at 3T and 1.12 at 7T. This allows a 30-min exam for STI with 12 orientations, thus paving the way to its clinical application.

Imaging whole-brain cytoarchitecture of mouse with MRI-based quantitative susceptibility mapping.

The proper microstructural arrangement of complex neural structures is essential for establishing the functional circuitry of the brain. We present an MRI method to resolve tissue microstructure and infer brain cytoarchitecture by mapping the magnetic susceptibility in the brain at high resolution. This is possible because of the heterogeneous magnetic susceptibility created by varying concentrations of lipids, proteins and irons from the cell membrane to cytoplasm. We demonstrate magnetic susceptibility maps at a nominal resolution of 10-μm isotropic, approaching the average cell size of a mouse brain. The maps reveal many detailed structures including the retina cell layers, olfactory sensory neurons, barrel cortex, cortical layers, axonal fibers in white and gray matter. Olfactory glomerulus density is calculated and structural connectivity is traced in the optic nerve, striatal neurons, and brainstem nerves. The method is robust and can be readily applied on MRI scanners at or above 7T.

Magnetic Resonance Histology of Age-related Nephropathy in the Sprague Dawley Rat

Magnetic resonance histology (MRH) has become a valuable tool in evaluating drug-induced toxicity in preclinical models. However, its application in renal injury has been limited. This study tested the hypothesis that MRH could detect image-based biomarkers of chronic disease, inflammation, or age-related degeneration in the kidney, laying the foundation for more extensive use in evaluating drug toxicity. We examined the entire intact kidney in a spontaneous model of chronic progressive nephropathy. Kidneys from male Sprague Dawley rats were imaged at 8 weeks (n = 4) and 52 weeks (n =4) on a 9.4 T system dedicated to MR microscopy. Several potential contrast mechanisms were explored to optimize the scanning protocols. Full coverage of the entire kidney was achieved with isotropic spatial resolution at 31 microns (voxel volume = 30 pL) using a gradient recalled echo sequence. Isotropic spatial resolution of 15 microns (voxel volume < 4 pL) was achieved in a biopsy core specimen. Qualitative age-related structural changes, such as renal cortical microvasculature, tubular dilation, interstitial fibrosis, and glomerular architecture, were apparent. The nondestructive 3D images allowed measurement of quantitative differences of kidney volume, pelvis volume, main vessel volume, glomerular size, as well as thickness of the cortex, outer medulla, and inner medulla.

Temperature-activated ion channels in neural crest cells confer maternal fever–associated birth defects

Fever during the first trimester may induce birth defects by activating TRPV ion channels in neural crest cells. Fevers, TRPV channels, and birth defects Cardiac and craniofacial birth defects are common, but many cannot be attributed to specific mutations. An environmental trigger associated with these birth defects is fever during the first trimester. Using chick or zebrafish embryos, Hutson et al. found that hyperthermia activated temperature-sensitive TRPV1 and TRPV4 ion channels in neural crest cells, which give rise to the tissues affected by the birth defects. The authors developed a noninvasive method of transiently activating TRPV1 or TRPV4 in neural crest cells in chick embryos to mimic fever-induced stimulation of these channels. TRPV1 or TRPV4 activation resulted in cardiac and craniofacial birth defects similar to those induced by fever. These results suggest that preventing TRPV1 and TRPV4 activation during first trimester febrile episodes may reduce the incidence of common forms of birth defects. Birth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are precursor populations essential to the development of both at-risk tissues. We report that two heat-activated transient receptor potential (TRP) ion channels, TRPV1 and TRPV4, were present in neural crest cells during critical windows of heart and face development. TRPV1 antagonists protected against the development of hyperthermia-induced defects in chick embryos. Treatment with chemical agonists of TRPV1 or TRPV4 replicated hyperthermia-induced birth defects in chick and zebrafish embryos. To test whether transient TRPV channel permeability in neural crest cells was sufficient to induce these defects, we engineered iron-binding modifications to TRPV1 and TRPV4 that enabled remote and noninvasive activation of these channels in specific cellular locations and at specific developmental times in chick embryos with radio-frequency electromagnetic fields. Transient stimulation of radio frequency–controlled TRP channels in neural crest cells replicated fever-associated defects in developing chick embryos. Our data provide a previously undescribed mechanism for congenital defects, whereby hyperthermia activates ion channels that negatively affect fetal development.

MRI tools for assessment of microstructure and nephron function of the kidney.

MRI can provide excellent detail of renal structure and function. Recently, novel MR contrast mechanisms and imaging tools have been developed to evaluate microscopic kidney structures including the tubules and glomeruli. Quantitative MRI can assess local tubular function and is able to determine the concentrating mechanism of the kidney noninvasively in real time. Measuring single nephron function is now a near possibility. In parallel to advancing imaging techniques for kidney microstructure is a need to carefully understand the relationship between the local source of MRI contrast and the underlying physiological change. The development of these imaging markers can impact the accurate diagnosis and treatment of kidney disease. This study reviews the novel tools to examine kidney microstructure and local function and demonstrates the application of these methods in renal pathophysiology.

Four‐dimensional MRI of renal function in the developing mouse

The major roles of filtration, metabolism and high blood flow make the kidney highly vulnerable to drug‐induced toxicity and other renal injuries. A method to follow kidney function is essential for the early screening of toxicity and malformations. In this study, we acquired high spatiotemporal resolution (four dimensional) datasets of normal mice to follow changes in kidney structure and function during development. The data were acquired with dynamic contrast‐enhanced MRI (via keyhole imaging) and a cryogenic surface coil, allowing us to obtain a full three‐dimensional image (isotropic resolution, 125 microns) every 7.7 s over a 50‐min scan. This time course permitted the demonstration of both contrast enhancement and clearance. Functional changes were measured over a 17‐week course (at 3, 5, 7, 9, 13 and 17 weeks). The time dimension of the MRI dataset was processed to produce unique image contrasts to segment the four regions of the kidney: cortex (CO), outer stripe (OS) of the outer medulla (OM), inner stripe (IS) of the OM and inner medulla (IM). Local volumes, time‐to‐peak (TTP) values and decay constants (DC) were measured in each renal region. These metrics increased significantly with age, with the exception of DC values in the IS and OS. These data will serve as a foundation for studies of normal renal physiology and future studies of renal diseases that require early detection and intervention. Copyright

Magnetic susceptibility anisotropy outside the central nervous system.

Magnetic‐susceptibility‐based MRI has made important contributions to the characterization of tissue microstructure, chemical composition, and organ function. This has motivated a number of studies to explore the link between microstructure and susceptibility in organs and tissues throughout the body, including the kidney, heart, and connective tissue. These organs and tissues have anisotropic magnetic susceptibility properties and cellular organizations that are distinct from the lipid organization of myelin in the brain. For instance, anisotropy is traced to the epithelial lipid orientation in the kidney, the myofilament proteins in the heart, and the collagen fibrils in the knee cartilage. The magnetic susceptibility properties of these and other tissues are quantified using specific MRI tools: susceptibility tensor imaging (STI), quantitative susceptibility mapping (QSM), and individual QSM measurements with respect to tubular and filament directions determined from diffusion tensor imaging. These techniques provide complementary and supplementary information to that produced by traditional MRI methods. In the kidney, STI can track tubules in all layers including the cortex, outer medulla, and inner medulla. In the heart, STI detected myofibers throughout the myocardium. QSM in the knee revealed three unique layers in articular cartilage by exploiting the anisotropic susceptibility features of collagen. While QSM and STI are promising tools to study tissue susceptibility, certain technical challenges must be overcome in order to realize routine clinical use. This paper reviews essential experimental findings of susceptibility anisotropy in the body, the underlying mechanisms, and the associated MRI methodologies. Copyright

4D MRI of polycystic kidneys from rapamycin‐treated Glis3‐deficient mice

Polycystic kidney disease (PKD) is a life‐threatening disease that leads to a grotesque enlargement of the kidney and significant loss of function. Several imaging studies with MRI have demonstrated that cyst size in polycystic kidneys can determine disease severity and progression. In the present study, we found that, although kidney volume and cyst volume decreased with drug treatment, renal function did not improve with treatment. Here, we applied dynamic contrast‐enhanced MRI to study PKD in a Glis3 (GLI‐similar 3)‐deficient mouse model. Cysts from this model have a wide range of sizes and develop at an early age. To capture this crucial stage and assess cysts in detail, we imaged during early development (3–17 weeks) and applied high spatiotemporal resolution MRI (125 × 125 × 125 cubic microns every 7.7 s). A drug treatment with rapamycin (also known as sirolimus) was applied to determine whether disease progression could be halted. The effect and synergy (interaction) of aging and treatment were evaluated using an analysis of variance (ANOVA). Structural measurements, including kidney volume, cyst volume and cyst‐to‐kidney volume ratio, changed significantly with age. Drug treatment significantly decreased these metrics. Functional measurements of time‐to‐peak (TTP) mean and TTP variance were determined. TTP mean did not change with age, whereas TTP variance increased with age. Treatment with rapamycin generally did not affect these functional metrics. Synergistic effects of treatment and age were not found for any measurements. Together, the size and volume ratio of cysts decreased with drug treatment, whereas renal function remained the same. The quantification of renal structure and function with MRI can comprehensively assess the pathophysiology of PKD and response to treatment. Copyright