Magnetic Resonance Diffusion Tensor and q-space imaging in an Animal Model of Chronic Kidney Disease.
Sourajit Mitra Mustafi1, Paul R. Territo1, Brian P. McCarthy1, Amanda A. Riley1, Jiang Lei1, Chen Lin1, Qiuting Wen1, Bruce A Molitoris2, Gary D. Hutchins1, and Yu-Chien Wu1

1Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States, 2Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States

Synopsis

In this study, we used multi-shell diffusion-weighted imaging in an animal model of Chronic Kidney Disease (CKD). We focus on the functional changes in the kidney using diffusion tensor imaging (DTI) and q-space imaging (QSI). Four Wistar rats received surgical procedure to induce ischemic fibrosis in their left kidney. The multi-shell diffusion-weighted imaging was performed on the acute stage, day 2 after the surgery. In the acute stage, the renal medulla showed significant decrease in overall diffusivity measured by DTI and increase in tissue restriction measured by q-space imaging.

Purpose

Chronic Kidney Disease (CKD) is characterized by progressive renal fibrosis that leads to end-stage renal failure and the need for dialysis or kidney transplantation1. There is a compelling need for the development of biomarkers to monitor CKD progression and help guide the evaluation of experimental treatment strategies. We hypothesize that characteristics of water diffusion and flow will serve as a biomarker for renal fibrotic burden. The objective of this study is to develop and evaluate the utility of magnetic resonance imaging based diffusion tensor2 and non-parametric q-space imaging techniques3 as biomarkers of renal fibrosis in an animal model of CKD.

Method

Preparation of the animal CKD model: An ischemia/reperfusion model was used to create hypoxia induced renal fibrosis in Wistar rats (N=4). In each animal the renal artery in one kidney was clamped for 50 minutes to induce ischemia and hypoxia (IHK), followed by restoration of blood flow. The contralateral kidney served as a control reference (CON). MRI imaging: MRI was performed 2 days following surgery. During each imaging session, rats were sedated and placed in a head-first prone position. All animal handling followed institutional Animal Care and Use Committee (IACUC) guidelines. The MRI diffusion pulse sequence was a single-shot spin-echo echo-planar imaging (SS-SE-EPI) sequence with multiple diffusion-weighting b-values (i.e. 3 shells with b-values of 150, 300 and 450 s/mm2) and multiple diffusion-weighting directions at each shell (i.e., 10, 19 and 30, respectively). Diffusion directions in each shell and in the projected sphere with all directions (i.e., total 59) were optimized for uniform diffusion sampling in the spherical space4. The repetition time (TR) is 2200 ms and echo time (TE) is 73.6 ms. A total of four signal averages was performed. The imaging parameters were field-of-view (FOV) = 128 x 64 mm, matrix size = 128 x 64, isotropic voxel size of 1 mm3, and 20 oblique coronal slices. Image Processing: DTI derived parameters including axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), and fractional anisotropy (FA) were computed5. A non-parametric q-space approach was used to compute the probability density function (PDF), a marker of very slow water diffusion (P0)3. ROIs: In the b0 image, anatomically defined layers of kidney are clearly identified. Two distinct ROIs were placed on medulla and cortex (Figure 1). Statistics: Student’s paired two tailed t-test were performed on individual ROI’s and multiple comparison Bonferroni corrections were implemented, two-tail p value < 0.01 was considered significant.

Results

All DTI indices (AD, RD, MD, and FA) showed statistically significant reductions in the medulla of the IHK kidneys (Figure 2A and B). The tissue restriction index, P0, increased in the medulla of the IHK kidneys (p < 0.01). No significant changes in DTI parameters or tissue restriction index were observed in the renal cortex of the IHK kidneys (Figures 2C and D).

Discussion and Conclusion

The observed reduction in mean diffusivity measured with DTI and increased P0 (population of very slowly diffusing water molecules) in renal medulla are consistent with the formation of fibrotic regions within the tissue. It is thought that DTI axial diffusivity is an indicator of intra-tubular flow in the renal medulla6-9 and radial diffusivity is an indicator of water reabsorption rate6. The changes in AD and RD observed in this study suggest that intra-tubular flow and water reabsorption rate decreased in the IHK kidney. The dramatic decrease in FA suggests the impact of intra-tubular flow is much higher than the impact of water reabsorption rate in our renal hypoxia induced fibrosis model. In addition, the medulla appear more sensitive ischemia induced hypoxia than renal cortices.

Acknowledgements

The work is supported by IUPUI-RITDP pilot grant.

References

1. Tonella M, Riella M. Chronic Kidney Disease and the Aging Population. Nephrol Dial Transplant 2014;29(2):221-224.

2. Wang WJ, Pui MH, Guo Y, Wang LQ, Wang HJ and Liu M. 3T magnetic resonance diffusion tensor imaging in chronic kidney disease. Abdom Imaging. 2014 Aug; 39(4): 770-775.

3. Wu YC, Alexander AL. Hybrid diffusion imaging. Neuroimage. 2007;36(3):617-29.

4. Caruyer E, Lenglet C, Saprio G, and Deriche R. Design of multishell sampling schemes with uniform coverage in diffusion MRI. Magnetic Resonance in Medicine 2013;69:(6)1534-1540.

5. Basser PJ, LeBihan MJ. Estimation of the effective self-diffusion tensor from the NMR spin echo Magn Reson B 1994;103(3):247-54.

6. Sigmund EE, Vivier PH, Sui D, et al. Intravoxel incoherent motion and diffusion-tensor imaging in renal tissue under hydration and furosemide flow challenges. Radiology. 2012;263(3):758-69.

7. Liu, Z. et al. Chronic kidney disease: pathological and functional assessment with diffusion tensor imaging at 3T MR. European radiology 2015;25, 652-660.

8. Hueper K, Hartung D, Gutberlet M, Gueler F, Sann H, Husen B, Wacker F, Reiche D. Magnetic resonance diffusion tensor imaging for evaluation of histopathological changes in a rat model of diabetic nephropathy. Invest Radiol. 2012;47(7):430-7.

Figures

Figure 1: b0 (with ROIs), DTI and P0 maps for CON and IHK kidney after two days of surgical intervention. The scale of AD, RD and MD are from 0 to 3, 1.5 and 3*10-3mm2/s respectively. FA and P0 are scaled from 0 to 0.4 and 0.3 to 0.8 respectively.

Figure 2: DTI and q-space parameters for various ROIs are compared between CON (blue bars) and IHK (grey bars) kidney. The orange bars denotes standard deviations. The statistically significant parameters (p < 0.01) are shown by connecting lines. The units for diffusivity are 1*10-3mm2/s.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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