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TOMOGRAPHY, June 2016, Volume 2, Issue 2: 125-137
DOI: 10.18383/j.tom.2016.00127

Imaging Renal Urea Handling in Rats at Millimeter Resolution Using Hyperpolarized Magnetic Resonance Relaxometry

Galen D. Reed1,2, Cornelius von Morze1, Alan S. Verkman3, Bertram L. Koelsch1,2, Myriam M. Chaumeil1, Michael Lustig2,4, Sabrina M. Ronen1,2, Robert A. Bok1, Jeff M. Sands5, Peder E. Z. Larson1,2, Zhen J. Wang1, Jan Henrik Ardenkjær Larsen6,7, John Kurhanewicz1,2, and Daniel B. Vigneron1,2

1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California; 2Graduate Group in Bioengineering, University of California San Francisco, San Francisco, California, and University of California Berkeley, Berkeley, California; 3Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California; 4Department of Electrical Engineering and Computer Sciences, University of California Berkeley, Berkeley, California; 5Department of Medicine, Renal Division, Emory University, Atlanta, Georgia; and 6GE Healthcare, Brøndby, Denmark; and 7Department of Electrical Engineering, Technical University of Denmark, Kongens Lyngby, Denmark

Abstract

In this study, in vivo T2 heterogeneity of hyperpolarized [13C,15N2]urea in rat kidney has been investigated. Selective quenching of the vascular hyperpolarized 13C signal with a macromolecular relaxation agent revealed that a long T2 component of the [13C,15N2]urea signal originated from the renal extravascular space, thus allowing the vascular and renal filtrate contrast agent pools of the [13C,15N2]urea to be distinguished via multiexponential analysis. The T2 response to induced diuresis and antidiuresis was determined using 2 imaging agents—hyperpolarized [13C,15N2]urea and hyperpolarized bis-1,1-(hydroxymethyl)-1-13Ccyclopropane- 2H8 (control agent). During antidiuresis, large T2 increases in the inner medulla and papilla were observed using the former agent only. Therefore, [13C,15N2]urea relaxometry is sensitive to the following 2 steps of the renal urea handling process: glomerular filtration process and inner medullary urea transporter- A1- and urea transporter-A3-mediated urea concentrating process. To aid multiexponential data analysis, simple motion correction and subspace denoising algorithms are presented. Furthermore, a T2-edited, ultralong echo time sequence was developed for sub-2 mm3 resolution 3-dimensional encoding of urea by exploiting relaxation differences in the vascular and filtrate pools.

Supplemental Media

  • Video 1

    Periodic respiratory motion caused a 1-2 mm offset which was largely resolved along the superior/inferior (SI) axis of the animal. To correct for this observed shift, a simple search algorithm was developed in which each image was aligned with its previous time point. Given that the motion was primarily 1D, a brute-force search was implemented which translated each image in 1 mm increments over ±1 cm from the initial location along the SI axis (for a total of 20 sampling points). At each position, the normalized mutual information (MI) was calculated between the floating image and the previous time point thus generating an MI versus translation curve as shown in Fig 1. The shift which maximized this curve was then applied. An example of the motion-corrected images can be seen here. This video relates to the published article by Galen D. Reed, et al., Imaging Renal Urea Handling in Rats at Millimeter Resolution using Hyperpolarized Magnetic Resonance Relaxometry, Tomography v2(2), 2016 (www.tomography.org).

  • Video 2

    The dynamic [Carbon-13, Nitrogen-15] urea images acquired under T2 decay conditions initially showed greatly reduced signal at early echo times when accompanied by the BSA-GdDTPA chaser. At later echo times, however, the images converge and look nearly identical. This effect is most easily visualized in the supplemental video here: by the 7th time point (corresponding to a 6.8 s echo time) only urea within the kidneys is visible in both images, and the signal’s spatial variation is nearly identical in the images with and without the BSA-GdDTPA chaser. The similarity persisted in all experiments until the end of imaging acquisition. At this echo time, both images show urea signal throughout the cortex and medulla, and a dark-rim is present at the outer stripe of the outer medulla. The later echo images were acquired up to 25 seconds after the infusion of the BSA-GdDTPA chaser and provide strong evidence that the slowly decaying [Carbon-13, Nitrogen-15] urea signal component emanated from regions inaccessible to the BSA-GdDTPA. This video relates to the published article by Galen D. Reed, et al., Imaging Renal Urea Handling in Rats at Millimeter Resolution using Hyperpolarized Magnetic Resonance Relaxometry, Tomography v2(2), 2016 (www.tomography.org).

  • Video 3

    During antidiuresis, a larger fraction of the urea is collected in the inner medulla and papilla consistent UT-A1 and UT-A3 transporter activity. When the acquisition delay allowed for inner-medullary urea accumulation, large T2 increases were observed due to a strong inward T2 gradient. The supplementary video here shows the dynamic 13C urea at multiple echo times. During antidiuresis, not only is a greater inner medullary accumulation of the Carbon-13 urea observed, but the signal persists to very late echo times. This video relates to the published article by Galen D. Reed, et al., Imaging Renal Urea Handling in Rats at Millimeter Resolution using Hyperpolarized Magnetic Resonance Relaxometry, Tomography v2(2), 2016.

  • Video 4

    In the dynamic HMCP images shown in this supplementary video, the late echo times of the diuresis and antidiuresis rats look similar. This video relates to the published article by Galen D. Reed, et al., Imaging Renal Urea Handling in Rats at Millimeter Resolution using Hyperpolarized Magnetic Resonance Relaxometry, Tomography v2(2), 2016 (www.tomography.org).

  • Video 5

    3D [Carbon-13, Nitrogen-15] urea images acquired at 1.2 mm isotropic resolution (1.73 mm3 pixel volume). The full FOV in all 3 dimensions can be seen in this supplementary video. The efficacy of the blood pool suppression is evidenced by the low background signal as well as the dark interlobular arteries (magenta arrows on the image panels) and is concordant with the 3 to 5 fold suppression expected from simulation. The outer stripe of the outer medulla (OSOM) enhanced later than the cortex and inner stripe of the outer medulla (ISOM, see the 20 second and 25 second time points). Once inner medullary accumulation occurred, the inner medulla (IM) and papilla were bright due to the sequence weighting. This video relates to the published article by Galen D. Reed, et al., Imaging Renal Urea Handling in Rats at Millimeter Resolution using Hyperpolarized Magnetic Resonance Relaxometry, Tomography v2(2), 2016 (www.tomography.org).

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