0701
Functional Renal Imaging using Urea CEST-MRI1Department of Bioengineering, University of California, Berkeley, Berkeley, CA, United States, 2Berkeley Preclinical Imaging Core, University of California, Berkeley, Berkeley, CA, United States
Synopsis
Current diagnosis of renal disease and injury relies on blood urea nitrogen and serum creatinine measurements, which provide generic information about kidney function but do not provide spatial specificity during kidney failure. Urea has previously been used as a vehicle for hyperpolarized MR imaging of renal function, and as a contrast agent of CEST MRI. Here, we examine whether injection of urea can provide CEST contrast for quantitation of renal integrity via probing the spatially varying urea concentrating capacity of a kidney.
Introduction
Renal diseases such as acute kidney injury (AKI) and chronic kidney disease (CKD) are currently diagnosed based on the measurement of blood urea nitrogen (BUN) and serum creatinine. While these measurements give estimations of renal function, they do not provide any spatial information as to which specific part(s) of each or either kidney demonstrate compromised urea clearance. Previous studies have used urea as an agent for dynamic hyperpolarized carbon imaging of renal clearance1. In parallel, the amine hydrogens within urea generate chemical exchange saturation contrast (CEST) at 1ppm offset from water, and have previously been exploited as an endogenous CEST agent for imaging of kidney urea concentrations2. In this study, we sought to examine whether intraperitoneal infusion of low dose urea can be used as a CEST-MRI contrast agent for measurement of regional urea concentrating capacity in the mouse kidney.Methods
Six C57BL/6 mice were anesthetized with 1.5 – 3% isoflurane gas and were imaged using a 7T MR scanner (PharmaScan, Bruker, Ettlingen, Germany) and a 40 mm transceiver volume coil (Bruker). T2-weighted images were acquired using a RARE sequence (TR/TE = 2500 / 52 ms, NA = 2, RARE factor = 8, matrix = 256 × 256), after which a gradient echo sequence (TR/TE = 6.4 / 3.1 ms, 2 segments, matrix = 192 × 192, FOV = 35 mm × 35 mm, slice thickness = 2 mm, NA = 1) with saturation preparation (1 Gaussian pulse, B1 = 0.25 μT, pulse duration = 100 ms) at 21 offsets from -1 to 1 ppm was used to acquire a spectrum necessary for water saturation shift reference (WASSR) correction via calculation of B0 maps3. Afterwards, a complete CEST-encoded z-spectrum was acquired (70 Gaussian pulses, B1 = 0.6 μT, pulse duration = 50 ms, duty cycle = 50%, total sat time = 7 sec) to generate images ranging from -6 to 6 ppm with 0.2 ppm step size. After acquiring the first z-spectra, either 150 μL of 2M urea (n = 3) or saline (n = 3) was administered intraperitoneally over 5 minutes. Post-injection z-spectra images were also acquired using the same sequence and parameters as that were used for pre-injection z-spectra (both WASSR and CEST). T2-weighted images were used to segment the kidneys into three regions: cortex, outer medulla (OM), and inner medulla (IM). The acquired z-spectra from each region were fit using the sum of 4 Lorentzian functions representing water, urea, NOE effect, and magnetization transfer (MT)4. Changes in urea CEST contrast between scans were calculated as the change in MTRasym at 1ppm derived from Lorentzian fitting of spectra.Results
Representative T2-weighted anatomical images that distinguish the cortex and outer and inner medullae are shown in Figure 1. Corresponding reference and urea CEST-weighted images (+1ppm) reveal additional saturation after administration of urea (Figure 1). Representative Lorentzian-fit z-spectra in a mouse that received IP injection of urea (Figure 2) reveal no urea-CEST contrast in the cortex or outer medulla prior to urea injection, and only moderate contrast in the inner medulla. Following urea injection, deflections at 1ppm in all regions reveal increases of urea contrast that are largest in the inner medulla (Figure 2). In contrast, saline injection did not generate any change in urea contrast in z-spectra from all parts of the kidney (Figure 3). NOE and MT effects were constant before and after the administration of either urea or saline. The change in MTRasym at 1ppm before and after urea administration was used to probe urea concentrating dynamics in the kidney (Figure 4). The magnitude of increased MTRasym at 1ppm followed a regional pattern in mice that received urea injection, with the concentration gradient increasing from the cortex to the inner medulla. Mice that received saline did not demonstrate any increases in MTRasym.Discussion
Urea concentration of filtrate in the renal tubule increases as it moves from the cortex to inner medulla5. To examine whether urea CEST MRI can capture this difference, high resolution anatomical images were used to segment kidneys so that CEST contrast can be analyzed within distinct kidney regions. The dose of urea infused was chosen from renal physiology studies that investigated the urea concentrating ability of mouse kidneys6. As expected, higher CEST contrast was observed in the inner medulla, even before infusing urea. This observation agrees with previous hyperpolarized MRI and CEST studies that showed higher accumulation of either urea or exogenous contrast agent in inner medulla, respectively1,7.Conclusion
CEST MRI can be performed to observe urea redistribution and concentration in the kidney.Acknowledgements
This study was supported by NIH 1R01HL28592.References
1. Von Morze C et al., Monitoring urea transport in rat kidney in vivo using hyperpolarized 13C magnetic resonance imaging. Am J Physiol Renal Physiol. 2012;302(12):F1658-F1662.
2. Vinogradov E et al., Endogenous Urea CEST (urCEST) for MRI monitoring of kidney function. Proc Intl Soc Mag Reson Med. 23(2015) 3375.
3. Kim M et al., Water saturation shift referencing (WASSR) for chemical exchange saturation transfer (CEST) experiments. Magn Reson Med. 2009;61(6):1441-1450.
4. Zaiss M, Schmitt B, Bachert P. Quantitative separation of CEST effect from magnetization transfer and spillover effects by Lorentzian-line-fit analysis of z-spectra. J Magn Reson. 2011;211(2):149-155.
5. Bankir L et al., Direct and indirect cost of urea excretion. Kidney Int. 1996;49:1598-1607.
6. Bankir L, Chen K, Yang B. Lack of UT-B in vasa recta and red blood cells prevents urea-induced improvement of urinary concentrating ability. Am J Physiol Renal Physiol. 2004;286:F144-F151.
7. Longo DL et al., Iopamidol as a responsive MRI-chemical exchange saturation transfer contrast agent for pH mapping of kidneys: In vivo studies in mice at 7T. Magn Reson Med. 2011;65(1):202-211.
Figures
