Assessment of renal fibrosis in murine diabetic nephropathy using quantitative magnetization transfer MRI
Feng Wang
Vanderbilt University Institute of Imaging Science, Nashville, Tennessee
Department of Radiology and Radiological Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
Feng Wang and Daisuke Katagiri contributed equally to this work.
Search for more papers by this authorDaisuke Katagiri
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Feng Wang and Daisuke Katagiri contributed equally to this work.
Search for more papers by this authorKe Li
Vanderbilt University Institute of Imaging Science, Nashville, Tennessee
Search for more papers by this authorKeiko Takahashi
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorSuwan Wang
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorShinya Nagasaka
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
Search for more papers by this authorHua Li
Vanderbilt University Institute of Imaging Science, Nashville, Tennessee
Department of Radiology and Radiological Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorC. Chad Quarles
Vanderbilt University Institute of Imaging Science, Nashville, Tennessee
Department of Radiology and Radiological Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorMing-Zhi Zhang
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorAkira Shimizu
Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
Search for more papers by this authorJohn C. Gore
Vanderbilt University Institute of Imaging Science, Nashville, Tennessee
Department of Radiology and Radiological Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorRaymond C. Harris
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorCorresponding Author
Takamune Takahashi
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Correspondence Takamune Takahashi, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, S-3223 MCN, 1161 21st Avenue S., Nashville, TN, 37232. Email: [email protected]Search for more papers by this authorFeng Wang
Vanderbilt University Institute of Imaging Science, Nashville, Tennessee
Department of Radiology and Radiological Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
Feng Wang and Daisuke Katagiri contributed equally to this work.
Search for more papers by this authorDaisuke Katagiri
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Feng Wang and Daisuke Katagiri contributed equally to this work.
Search for more papers by this authorKe Li
Vanderbilt University Institute of Imaging Science, Nashville, Tennessee
Search for more papers by this authorKeiko Takahashi
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorSuwan Wang
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorShinya Nagasaka
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
Search for more papers by this authorHua Li
Vanderbilt University Institute of Imaging Science, Nashville, Tennessee
Department of Radiology and Radiological Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorC. Chad Quarles
Vanderbilt University Institute of Imaging Science, Nashville, Tennessee
Department of Radiology and Radiological Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorMing-Zhi Zhang
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorAkira Shimizu
Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
Search for more papers by this authorJohn C. Gore
Vanderbilt University Institute of Imaging Science, Nashville, Tennessee
Department of Radiology and Radiological Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorRaymond C. Harris
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Search for more papers by this authorCorresponding Author
Takamune Takahashi
Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
Correspondence Takamune Takahashi, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, S-3223 MCN, 1161 21st Avenue S., Nashville, TN, 37232. Email: [email protected]Search for more papers by this authorFunding information: This work was supported by National Institutes of Health grants DK79341, DK114809, DK97332, DK76169 (pilot project), and DK20593 (pilot program), and by Uehara Memorial Foundation, Kanae Foundation, and Nippon Medical School Grant-in-Aid for Overseas Training Program
Abstract
Purpose
Renal fibrosis is a hallmark of progressive renal disease; however, current clinical tests are insufficient for assessing renal fibrosis. Here we evaluated the utility of quantitative magnetization transfer MRI in detecting renal fibrosis in a murine model of progressive diabetic nephropathy (DN).
Methods
The db/db eNOS-/- mice, a well-recognized model of progressive DN, and normal wild-type mice were imaged at 7T. The quantitative magnetization transfer data were collected in coronal plane using a 2D magnetization transfer prepared spoiled gradient echo sequence with a Gaussian-shaped presaturation pulse. Parameters were derived using a two-pool fitting model. A normal range of cortical pool size ratio (PSR) was defined as Mean±2SD of wild-type kidneys (N = 20). The cortical regions whose PSR values exceeded this threshold (threshold PSR) were assessed. The correlations between the PSR-based and histological (collagen IV or picrosirius red stain) fibrosis measurements were evaluated.
Results
Compared with wild-type mice, moderate increases in mean PSR values and scattered clusters of high PSR region were observed in cortex of DN mouse kidneys. Abnormally high PSR regions (% area) that were detected by the threshold PSR were significantly increased in renal cortexes of DN mice. These regions progressively increased on aging and highly correlated with histological fibrosis measures, while the mean PSR values correlated much less.
Conclusion
Renal fibrosis in DN can be assessed by the quantitative magnetization transfer MRI and threshold analysis. This technique may be used as a novel imaging biomarker for DN and other renal diseases.
Supporting Information
Additional supporting information can be found in the online version of this article.
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| mrm27231-sup-0001-suppinfo.docx18 MB |
FIGURE S1. Representative ΔB0, B1, MTR, and T1 maps. FIGURE S2. The accuracy and precision of PSR derived from 5-parameter modeling approach based on the number of RF offsets and noisy simulated data with different SNRs. FIGURE S3. Renal regions in diabetic mouse, identified by in vivo T2-weighted, T1-weighted, and magnetization transfer contrast imaging. FIGURE S4. Comparison of MTR maps and MTR cortical distributions of WT and DN kidneys. FIGURE S5. Representative regional PSR distributions in normal (WT) mouse kidney. FIGURE S6. Comparison of cortical fibrosis in WT and DN mouse kidneys using anti-collagen IV and picrosirius red stain. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Retnakaran R, Cull CA, Thorne KI, et al. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes. 2006; 55: 1832-1839.
- 2Brosius FC, Saran R. Do we now have a prognostic biomarker for progressive diabetic nephropathy? J Am Soc Nephrol. 2012; 23: 376-377.
- 3Michaely HJ, Sourbron S, Dietrich O, et al. Functional renal MR imaging: an overview. Abdom Imaging. 2007; 32: 758-771.
- 4Takahashi T, Wang F, Quarles CC. Current MRI techniques for the assessment of renal disease. Curr Opin Nephrol Hypertens. 2015; 24: 217-223.
- 5Niendorf T, Pohlmann A, Arakelyan K, et al. How bold is blood oxygenation level-dependent (BOLD) magnetic resonance imaging of the kidney? Opportunities, challenges and future directions. Acta Physiol (Oxf). 2015; 213: 19-38.
- 6Wang F, Jiang R, Takahashi K, et al. Longitudinal assessment of mouse renal injury using high-resolution anatomic and magnetization transfer MR imaging. Magn Reson Imaging. 2014; 32: 1125-1132.
- 7Togao O, Doi S, Kuro-o M, et al. Assessment of renal fibrosis with diffusion-weighted MR imaging: study with murine model of unilateral ureteral obstruction. Radiology. 2010; 255: 772-780.
- 8Wang F, Kopylov D, Zu Z, et al. Mapping murine diabetic kidney disease using chemical exchange saturation transfer MRI. Magn Reson Med. 2016; 76: 1685-1695.
- 9Inoue T, Kozawa E, Okada H, et al. Noninvasive evaluation of kidney hypoxia and fibrosis using magnetic resonance imaging. J Am Soc Nephrol. 2011; 22: 1429-1434.
- 10Zhao J, Wang ZJ, Liu M, et al. Assessment of renal fibrosis in chronic kidney disease using diffusion-weighted MRI. Clin Radiol. 2014; 9: 1117-1122.
- 11Feng Q, Ma Z, Wu J, Fang W. DTI for the assessment of disease stage in patients with glomerulonephritis - correlation with renal histology. Eur Radiol. 2015; 25: 92-98.
- 12Korsmo MJ, Ebrahimi B, Eirin A, et al. Magnetic resonance elastography noninvasively detects in vivo renal medullary fibrosis secondary to swine renal artery stenosis. Invest Radiol. 2013; 48: 61-68.
- 13Friedli I, Crowe LA, Berchtold L, et al. New magnetic resonance imaging index for renal fibrosis assessment: a comparison between diffusion-weighted imaging and T1 mapping with histological validation. Sci Rep. 2016; 6: 30088.
- 14Boor P, Perkuhn M, Weibrecht M, et al. Diffusion-weighted MRI does not reflect kidney fibrosis in a rat model of fibrosis. J Magn Reson Imaging. 2015; 42: 990-998.
- 15Toya R, Naganawa S, Kawai H, Ikeda M. Correlation between estimated glomerular filtration rate (eGFR) and apparent diffusion coefficient (ADC) values of the kidneys. Magn Reson Med Sci. 2010; 9: 59-64.
- 16Wolff SD, Eng J, Balaban RS. Magnetization transfer contrast: method for improving contrast in gradient-recalled-echo images. Radiology. 1991; 179: 133-137.
- 17Wolff SD, Chesnick S, Frank JA, Lim KO, Balaban RS. Magnetization transfer contrast: MR imaging of the knee. Radiology. 1991; 179: 623-638.
- 18Wolff SD, Balaban RS. Magnetization transfer contrast (MTC) and tissue water proton relaxation in vivo. Magn Reson Med. 1989; 10: 135-144.
- 19Odrobina EE, Lam TY, Pun T, Midha R, Stanisz GJ. MR properties of excised neural tissue following experimentally induced demyelination. NMR Biomed. 2005; 18: 277-284.
- 20Catalaa I, Grossman RI, Kolson DL, et al. Multiple sclerosis: magnetization transfer histogram analysis of segmented normal-appearing white matter. Radiology. 2000; 216: 351-355.
- 21McDaniel JD, Ulmer JL, Prost RW, et al. Magnetization transfer imaging of skeletal muscle in autosomal recessive limb girdle muscular dystrophy. J Comput Assist Tomogr. 1999; 23: 609-614.
- 22Wang F, Qi HX, Zu Z, et al. Multiparametric MRI reveals dynamic changes in molecular signatures of injured spinal cord in monkeys. Magn Reson Med. 2015; 74: 1125-1137.
- 23Aisen AM, Doi K, Swanson SD. Detection of liver fibrosis with magnetic cross-relaxation. Magn Reson Med. 1994; 31: 551-556.
- 24Quesson B, Bouzier AK, Thiaudiere E, et al. Magnetization transfer fast imaging of implanted glioma in the rat brain at 4.7 T: interpretation using a binary spin-bath model. J Magn Reson Imaging. 1997; 7: 1076-1083.
- 25Kline TL, Irazabal MV, Ebrahimi B, et al. Utilizing magnetization transfer imaging to investigate tissue remodeling in a murine model of autosomal dominant polycystic kidney disease. Magn Reson Med. 2016; 75: 1466-1473.
- 26Jiang K, Ferguson CM, Woollard JR, Zhu X, Lerman LO. Magnetization transfer magnetic resonance imaging noninvasively detects renal fibrosis in swine atherosclerotic renal artery stenosis at 3.0 T. Invest Radiol. 2017; 52: 686-692.
- 27Jiang K, Ferguson CM, Ebrahimi B, et al. Noninvasive assessment of renal fibrosis with magnetization transfer mr imaging: validation and evaluation in murine renal artery stenosis. Radiology. 2017; 283: 77-86.
- 28Ramani A, Dalton C, Miller DH, Tofts PS, Barker GJ. Precise estimate of fundamental in-vivo MT parameters in human brain in clinically feasible times. Magn Reson Imaging. 2002; 20: 721-731.
- 29McGowan JC, Schnall MD, Leigh JS. Magnetization-transfer imaging with pulsed off-resonance saturation - variation in contrast with saturation duty cycle. J Magn Reson Imaging. 1994; 4: 79-82.
- 30Eng J, Ceckler TL, Balaban RS. Quantitative 1H magnetization transfer imaging in vivo. Magn Reson Med. 1991; 17: 304-314.
- 31Henkelman RM, Huang X, Xiang QS, et al. Quantitative interpretation of magnetization transfer. Magn Reson Med. 1993; 29: 759-766.
- 32Sled JG, Pike GB. Quantitative interpretation of magnetization transfer in spoiled gradient echo MRI sequences. J Magn Reson. 2000; 145: 24-36.
- 33Gochberg DF, Gore JC. Quantitative imaging of magnetization transfer using an inversion recovery sequence. Magn Reson Med. 2003; 49: 501-505.
- 34Wang F, Li K, Mishra A, et al. Longitudinal assessment of spinal cord injuries in nonhuman primates with quantitative magnetization transfer. Magn Reson Med. 2016; 75: 1685-1696.
- 35Wang F, Takahashi K, Li H, et al. Assessment of unilateral ureter obstruction with multi-parametric MRI. Magn Reson Med. 2018; 79: 2216-2227.
- 36Prabhakar SS. Pathogenic role of nitric oxide alterations in diabetic nephropathy. Curr Diab Rep. 2005; 5: 449-454.
- 37Takahashi T, Harris RC. Role of endothelial nitric oxide synthase in diabetic nephropathy: lessons from diabetic eNOS knockout mice. J Diabetes Res. 2014; 2014: 590541.
- 38Zhao HJ, Wang S, Cheng H, et al. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol. 2006; 17: 2664-2669.
- 39Brosius FC III, Alpers CE, Bottinger EP, et al. Mouse models of diabetic nephropathy. J Am Soc Nephrol. 2009; 20: 2503-2512.
- 40Cercignani M, Barker GJ. A comparison between equations describing in vivo MT: the effects of noise and sequence parameters. J Magn Reson. 2008; 191: 171-183.
- 41Hara S, Umeyama K, Yokoo T, Nagashima H, Nagata M. Diffuse glomerular nodular lesions in diabetic pigs carrying a dominant-negative mutant hepatocyte nuclear factor 1-alpha, an inheritant diabetic gene in humans. PLoS One. 2014; 9: e92219.
- 42Katagiri D, Hamasaki Y, Doi K, et al. Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition. Kidney Int. 2016; 89: 374-385.
- 43Pluim JP, Maintz JB, Viergever MA. Mutual-information-based registration of medical images: a survey. IEEE Trans Med Imaging. 2003; 22: 986-1004.
- 44Smith SA, Edden RA, Farrell JA, Barker PB, Van Zijl PC. Measurement of T1 and T2 in the cervical spinal cord at 3 tesla. Magn Reson Med. 2008; 60: 213-219.
- 45Wang F, Jiang RT, Tantawy MN, et al. Repeatability and sensitivity of high resolution blood volume mapping in mouse kidney disease. J Magn Reson Imaging. 2014; 39: 866-871.
- 46Clarke CJ, Berg TJ, Birch J, et al. The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis. Curr Biol. 2016; 26: 755-765.
- 47Breyer MD, Böttinger E, Brosius FC, et al. Diabetic nephropathy: of mice and men. Adv Chronic Kidney Dis. 2005; 12: 128-145.
- 48Farris AB, Colvin RB. Renal interstitial fibrosis: mechanisms and evaluation. Curr Opin Nephrol Hypertens. 2012; 21: 289-300.
- 49Kaneto H, Morrissey J, McCracken R, Reyes A, Klahr S. Enalapril reduces collagen type IV synthesis and expansion of the interstitium in the obstructed rat kidney. Kidney Int. 1994; 45: 1637-1647.
- 50Mohan S, Reddick RL, Musi N, et al. Diabetic eNOS knockout mice develop distinct macro- and microvascular complications. Lab Invest. 2008; 88: 515-528.
- 51Zhang MZ, Wang S, Yang S, et al. Role of blood pressure and the renin-angiotensin system in development of diabetic nephropathy (DN) in eNOS-/- db/db mice. Am J Physiol Renal Physiol. 2012; 302: F433-F438.
- 52Meyrier A. Nephrosclerosis: update on a centenarian. Nephrol Dial Transplant. 2015; 30: 1833-1841.
- 53Chevalier RL. Obstructive nephropathy: towards biomarker discovery and gene therapy. Nat Clin Pract Nephrol. 2006; 2: 157-168.
