Abstract
Magnetic resonance imaging (MRI) is a well-established modality for assessing renal morphology and function, as well as changes that occur during disease. However, the significant metabolic changes associated with renal disease are more challenging to assess with MRI. Hyperpolarized carbon-13 MRI is an emerging technique which provides an opportunity to probe metabolic alterations at high sensitivity by providing an increase in the signal-to-noise ratio of 20,000-fold or more. This review will highlight the current status of hyperpolarised 13C-MRI and its translation into the clinic and how it compares to metabolic measurements provided by competing technologies such as positron emission tomography (PET).
Similar content being viewed by others
References
Haase VH (2013) Mechanisms of hypoxia responses in renal tissue. J Am Soc Nephrol 24(4):537–541
Fiorentino M, Grandaliano G, Gesualdo L, Castellano G (2018) Acute Kidney Injury to Chronic Kidney Disease Transition. Contrib Nephrol 193:45–54
Ow CPC, Ngo JP, Ullah MM, Hilliard LM, Evans RG (2018) Renal hypoxia in kidney disease: cause or consequence? Acta Physiol 222(4):e12999
Singh P, Ricksten SE, Bragadottir G, Redfors B, Nordquist L (2013) Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease. Clin Exp Pharmacol Physiol 40(2):138–147
O'Connor PM (2006) Renal oxygen delivery: matching delivery to metabolic demand. Clin Exp Pharmac Physiol 33(10):961–967
Lawrence GM, Jepson MA, Trayer IP, Walker DG (1986) The compartmentation of glycolytic and gluconeogenic enzymes in rat kidney and liver and its significance to renal and hepatic metabolism. Histochem J 18(1):45–53
Burch HB, Narins RG, Chu C, Fagioli S, Choi S, McCarthy W et al (1978) Distribution along the rat nephron of three enzymes of gluconeogenesis in acidosis and starvation. Am J Physiol 235(3):F246–F253
Schmidt U, Marosvari I, Dubach UC (1975) Renal metabolism of glucose: anatomical sites of hexokinase activity in the rat nephron. FEBS Lett 53(1):26–28
Tai YC, Laforest R (2005) Instrumentation aspects of animal PET. Annu Rev Biomed Eng 7:255–285
Qiao H, Bai J, Chen Y, Tian J (2007) Kidney modelling for FDG excretion with PET. Int J Biomed Imaging 2007:63234
Shreve P, Chiao PC, Humes HD, Schwaiger M, Gross MD (1995) Carbon-11-acetate PET imaging in renal disease. J Nucl Med 36(9):1595–1601
Juillard L, Lemoine S, Janier MF, Barthez PY, Bonnefoi F, Laville M (2007) Validation of renal oxidative metabolism measurement by positron-emission tomography. Hypertension 50(1):242–247
Splan A, Borofka M, Casper K, Fischer N, Gunderson T, Rule A et al (2018) 11C-choline PET for evaluation of renal tubular function. J Nucl Med 59:2147
Juillard L, Janier MF, Fouque D, Lionnet M, Le Bars D, Cinotti L et al (2000) Renal blood flow measurement by positron emission tomography using 15O-labeled water. Kidney Int 57(6):2511–2518
Rider OJ, Tyler DJ (2013) Clinical implications of cardiac hyperpolarized magnetic resonance imaging. J Cardiovasc Magn Reson 15:93
Kurhanewicz J, Vigneron DB, Brindle K, Chekmenev EY, Comment A, Cunningham CH et al (2011) Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research. Neoplasia (New York) 13(2):81–97
Laustsen C (2016) Hyperpolarized renal magnetic resonance imaging: potential and pitfalls. Front Physiol 7:72
Kurhanewicz J, Vigneron DB, Ardenkjaer-Larsen JH, Bankson JA, Brindle K, Cunningham CH et al (2018) Hyperpolarized (13)C MRI: path to clinical translation in oncology. Neoplasia (New York) 21(1):1–16
Ardenkjaer-Larsen JH, Bowen S, Petersen JR, Rybalko O, Vinding MS, Ullisch M et al (2019) Cryogen-free dissolution dynamic nuclear polarization polarizer operating at 3.35 T, 6.70 T, and 10.1 T. Magn Reson Med 81(3):2184–2194
Ardenkjaer-Larsen JH, Fridlund B, Gram A, Hansson G, Hansson L, Lerche MH et al (2003) Increase in signal-to-noise ratio of %3e 10,000 times in liquid-state NMR. Proc Natl Acad Sci USA 100(18):10158–10163
Ardenkjaer-Larsen JH, Leach AM, Clarke N, Urbahn J, Anderson D, Skloss TW (2011) Dynamic nuclear polarization polarizer for sterile use intent. NMR Biomed 24(8):927–932
Golman K, Axelsson O, Jóhannesson H, Månsson S, Olofsson C, Petersson JS (2001) Parahydrogen-induced polarization in imaging: subsecond 13C angiography. Magn Reson Med 46(1):1–5
Johansson E, Olsson LE, Månsson S, Petersson JS, Golman K, Ståhlberg F et al (2004) Perfusion assessment with bolus differentiation: a technique applicable to hyperpolarized tracers. Magn Res Med 52(5):1043–1051
Leupold J, Månsson S, Petersson JS, Hennig J, Wieben O (2009) Fast multiecho balanced SSFP metabolite mapping of 1H and hyperpolarized 13C compounds. MAGMA 4:251–256
Golman K, Petersson JS (2006) Metabolic imaging and other applications of hyperpolarized 13C1. Acad Radiol 13(8):932–942
Niles DJ, Gordon JW, Huang G, Reese S, Adamson EB, Djamali A et al (2018) Evaluation of renal metabolic response to partial ureteral obstruction with hyperpolarized (13) C MRI. NMR Biomed 31(1):e3846
Laustsen C, Lipso K, Ostergaard JA, Norregaard R, Flyvbjerg A, Pedersen M et al (2014) Insufficient insulin administration to diabetic rats increases substrate utilization and maintains lactate production in the kidney. Physiol Rep 2(12):e12233
Bertelsen LB, Nielsen PM, Qi H, Norlinger TS, Zhang X, Stodkilde-Jorgensen H et al (2017) Diabetes induced renal urea transport alterations assessed with 3D hyperpolarized 13 C,15 N-Urea. Magn Reson Med 77(4):1650–1655
Laustsen C, Hansen ES, Kjaergaard U, Bertelsen LB, Ringgaard S, Stødkilde-Jørgensen H (2015) Acute porcine renal metabolic effect of endogastric soft drink administration assessed with hyperpolarized [1-13c]pyruvate. Magn Reson Med 74(2):558–563
Qi H, Mariager CO, Lindhardt J, Nielsen PM, Stødkilde-Jørgensen H, Laustsen C (2018) Effects of anesthesia on renal function and metabolism in rats assessed by hyperpolarized MRI. Magn Reson Med 80(5):2073–2080
Qi H, Nielsen PM, Schroeder M, Bertelsen LB, Palm F, Laustsen C (2018) Acute renal metabolic effect of metformin assessed with hyperpolarised MRI in rats. Diabetologia 61(2):445–454
Qi H, Nørlinger TS, Nielsen PM, Bertelsen LB, Mikkelsen E, Xu Y et al (2016) Early diabetic kidney maintains the corticomedullary urea and sodium gradient. Physiol Rep 4(5):e12714
Reed GD, von Morze C, Bok R, Koelsch BL, Van Criekinge M, Smith KJ et al (2014) High resolution 13C MRI with hyperpolarized urea: in vivo T2 mapping and 15N labeling effects. IEEE Trans Medl Imag 33(2):362–371
Reed GD, von Morze C, Verkman AS, Koelsch BL, Chaumeil MM, Lustig M et al (2016) Imaging renal urea handling in rats at millimeter resolution using hyperpolarized magnetic resonance relaxometry. Tomography 2(2):125–135
von Morze C, Bok RA, Sands JM, Kurhanewicz J, Vigneron DB (2012) Monitoring urea transport in rat kidney in vivo using hyperpolarized 13C magnetic resonance imaging. Am J Physiol Renal Physiol 302(12):F1658–F1662
Nielsen PM, Laustsen C, Bertelsen LB, Qi H, Mikkelsen E, Kristensen ML et al (2017) In situ lactate dehydrogenase activity: a novel renal cortical imaging biomarker of tubular injury? Am J Physiol Renal Physiol 312(3):F465–F473
von Morze C, Chang G-Y, Larson PEZ, Shang H, Allu PKR, Bok RA et al (2017) Detection of localized changes in the metabolism of hyperpolarized gluconeogenic precursors 13C-lactate and 13C-pyruvate in kidney and liver. Magn Reson Med 77(4):1429–1437
Hu S, Yoshihara HAI, Bok R, Zhou J, Zhu M, Kurhanewicz J et al (2012) Use of hyperpolarized [1-13C]pyruvate and [2-13C]pyruvate to probe the effects of the anticancer agent dichloroacetate on mitochondrial metabolism in vivo in the normal rat. Magn Reson Imaging 30(10):1367–1372
Laustsen C, Østergaard JA, Lauritzen MH, Nørregaard R, Bowen S, Søgaard LV et al (2013) Assessment of early diabetic renal changes with hyperpolarized [1-13C]pyruvate. Diabetes Metab Res Rev 29(2):125–129
Laustsen C, Stokholm Norlinger T, Christoffer Hansen D, Qi H, Mose Nielsen P, Bonde Bertelsen L et al (2016) Hyperpolarized C urea relaxation mechanism reveals renal changes in diabetic nephropathy. Magn Reson Med 75(2):515–518
Laustsen C, Lycke S, Palm F, Ostergaard JA, Bibby BM, Norregaard R et al (2014) High altitude may alter oxygen availability and renal metabolism in diabetics as measured by hyperpolarized [1-13C]pyruvate magnetic resonance imaging. Kidney Int 86(1):67–74
Norlinger TS, Nielsen PM, Qi H, Mikkelsen E, Hansen K, Schmidt NH et al (2017) Hyperbaric oxygen therapy reduces renal lactate production. Physiol Rep 5(6):e13217
Laustsen C, Nielsen PM, Norlinger TS, Qi H, Pedersen UK, Bertelsen LB et al (2017) Antioxidant treatment attenuates lactate production in diabetic nephropathy. Am J Physiol Renal Physiol 312(1):F192–F199
Morze CV, Allu PKR, Chang GY, Marco-Rius I, Milshteyn E, Wang ZJ et al (2018) Non-invasive detection of divergent metabolic signals in insulin deficiency vs. insulin resistance in vivo. Sci Rep 8(1):e2088
Lewis AJ, Miller JJ, McCallum C, Rider OJ, Neubauer S, Heather LC et al (2016) Assessment of metformin-induced changes in cardiac and hepatic redox state using hyperpolarized[1-13C]pyruvate. Diabetes 65(12):3544–3551
Park JM, Wu M, Datta K, Liu SC, Castillo A, Lough H et al (2017) Hyperpolarized Sodium [1-(13)C]-Glycerate as a probe for assessing glycolysis in vivo. J Am Chem Soc 139(19):6629–6634
Park JM, Khemtong C, Liu SC, Hurd RE, Spielman DM (2017) In vivo assessment of intracellular redox state in rat liver using hyperpolarized [1-(13) C]alanine. Magn Reson Med 77(5):1741–1748
Keshari KR, Wilson DM, Sai V, Bok R, Jen KY, Larson P et al (2015) Noninvasive in vivo imaging of diabetes-induced renal oxidative stress and response to therapy using hyperpolarized 13C dehydroascorbate magnetic resonance. Diabetes 64(2):344–352
Marco-Rius I, von Morze C, Sriram R, Cao P, Chang GY, Milshteyn E et al (2017) Monitoring acute metabolic changes in the liver and kidneys induced by fructose and glucose using hyperpolarized [2-(13) C]dihydroxyacetone. Magn Reson Med 77(1):65–73
Linehan WM, Srinivasan R, Schmidt LS (2010) The genetic basis of kidney cancer: a metabolic disease. Nature Rev Urol 7(5):277–285
Sciacovelli M, Frezza C (2016) Oncometabolites: Unconventional triggers of oncogenic signalling cascades. Free Rad Biol Med 100:175–181
Dong Y, Eskandari R, Ray C, Granlund KL, Santos-Cunha LD, Miloushev VZ et al (2019) Hyperpolarized MRI visualizes warburg effects and predicts treatment response to mTOR inhibitors in patient-derived ccRCC xenograft models. Can Res 79(1):242–250
Sriram R, Gordon J, Baligand C, Ahamed F, Delos Santos J, Qin H et al (2018) Non-invasive assessment of lactate production and compartmentalization in renal cell carcinomas using hyperpolarized (13)C pyruvate MRI. Cancers 10(9):e313
Tran M, Latifoltojar A, Neves JB, Papoutsaki M-V, Gong F, Comment A et al (2019) First-in-human in vivo non-invasive assessment of intra-tumoral metabolic heterogeneity in renal cell carcinoma. BJR Case Rep 5(3):20190003
Baligand C, Qin H, True-Yasaki A, Gordon JW, von Morze C, Santos JD et al (2017) Hyperpolarized (13) C magnetic resonance evaluation of renal ischemia reperfusion injury in a murine model. NMR Biomed 30(10):e3765
Clatworthy MR, Kettunen MI, Hu D-E, Mathews RJ, Witney TH, Kennedy BWC et al (2012) Magnetic resonance imaging with hyperpolarized [1,4–13C2]fumarate allows detection of early renal acute tubular necrosis. Proc Natl Acad Sci 109(33):13374–13379
Nielsen PM, Eldirdiri A, Bertelsen LB, Jørgensen HS, Ardenkjaer-Larsen JH, Laustsen C (2017) Fumarase activity: an in vivo and in vitro biomarker for acute kidney injury. Sci Rep 7:40812
Koellisch U, Laustsen C, Norlinger TS, Ostergaard JA, Flyvbjerg A, Gringeri CV et al (2015) Investigation of metabolic changes in STZ-induced diabetic rats with hyperpolarized [1–13C]acetate. Physiol Rep 3(8):e12474
Mikkelsen EFR, Mariager CO, Nørlinger T, Qi H, Schulte RF, Jakobsen S et al (2017) Hyperpolarized [1-(13)C]-acetate renal metabolic Clearance rate mapping. Scientif Rep 7(1):16002
von Morze C, Ohliger MA, Marco-Rius I, Wilson DM, Flavell RR, Pearce D et al (2018) Direct assessment of renal mitochondrial redox state using hyperpolarized (13) C-acetoacetate. Magn Reson Med 79(4):1862–1869
Nielsen PM, Szocska Hansen ES, Norlinger TS, Norregaard R, Bonde Bertelsen L, Stodkilde Jorgensen H et al (2016) Renal ischemia and reperfusion assessment with three-dimensional hyperpolarized 13C, 15N2-urea. Magn Reson Med 76(5):1524–1530
Hansen ES, Stewart NJ, Wild JM, Stødkilde-Jørgensen H, Laustsen C (2016) Hyperpolarized (13) C, (15) N2 -urea MRI for assessment of the urea gradient in the porcine kidney. Magn Reson Med 76(6):1895–1899
Qi H, Mariager CO, Nielsen PM, Schroeder M, Lindhardt J, Norregaard R et al (2019) Glucagon infusion alters the hyperpolarized 13C-urea renal hemodynamic signature. NMR Biomed 32(1):e4028
Laustsen C, Stokholm Norlinger T, Christoffer Hansen D, Qi H, Mose Nielsen P, Bonde Bertelsen L et al (2016) Hyperpolarized 13C urea relaxation mechanism reveals renal changes in diabetic nephropathy. Magn Reson Med 75(2):515–518
Mariager CO, Nielsen PM, Qi H, Ringgaard S, Laustsen C (2018) Hyperpolarized 13C,15N2 -urea T2 relaxation changes in acute kidney injury. Magn Reson Med 80(2):696–702
Ostergaard Mariager C, Nielsen PM, Qi H, Schroeder M, Bertelsen LB, Laustsen C (2017) Can hyperpolarized 13C-urea be used to assess glomerular filtration rate? A retrospective study. Tomography 3(3):146–152
Zöllner FG, Zimmer F, Klotz S, Hoeger S, Schad LR (2014) Renal perfusion in acute kidney injury with DCE-MRI: Deconvolution analysis versus two-compartment filtration model. Magn Reson Imaging 32(6):781–785
Zimmer F, Zöllner FG, Hoeger S, Klotz S, Tsagogiorgas C, Krämer BK et al (2013) Quantitative renal perfusion measurements in a rat model of acute kidney injury at 3T: testing inter- and intramethodical significance of ASL and DCE-MRI. PLoS ONE ONE 8(1):e53849
Eikefjord E, Andersen E, Hodneland E, Zöllner F, Lundervold A, Svarstad E et al (2015) Use of 3D DCE-MRI for the estimation of renal perfusion and glomerular filtration rate: an intrasubject comparison of FLASH and KWIC with a comprehensive framework for evaluation. Am J Roentgenol 204(3):W273–W281
Wigh Lipso K, Hansen ESS, Tougaard RS, Laustsen C, Ardenkjaer-Larsen JH (2017) Renal MR angiography and perfusion in the pig using hyperpolarized water. Magn Reson Med 78(3):1131–1135
Schrijvers BF, De Vriese AS, Flyvbjerg A (2004) From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. Endocr Rev 25(6):971–1010
Oates PJ (2010) Aldose reductase inhibitors and diabetic kidney disease. Curr Opin Investig Drugs 11(4):402–417
Grist JT, McLean MA, Riemer F, Schulte RF, Deen SS, Zaccagna F et al (2019) Quantifying normal human brain metabolism using hyperpolarized [1–13C]pyruvate and magnetic resonance imaging. NeuroImage 189:171–179
Miloushev VZ, Granlund KL, Boltyanskiy R, Lyashchenko SK, DeAngelis LM, Mellinghoff IK et al (2018) Metabolic imaging of the human brain with hyperpolarized (13)C pyruvate demonstrates (13)C lactate production in brain tumor patients. Can Res 78(14):3755–3760
Aggarwal R, Vigneron DB, Kurhanewicz J (2017) Hyperpolarized 1-[(13)C]-pyruvate magnetic resonance imaging detects an early metabolic response to androgen ablation therapy in prostate cancer. Eur Urol 72(6):1028–1029
Cunningham CH, Lau JY, Chen AP, Geraghty BJ, Perks WJ, Roifman I et al (2016) Hyperpolarized 13C metabolic MRI of the human heart: initial experience. Circ Res 119(11):1177–1182
Nelson SJ, Kurhanewicz J, Vigneron DB, Larson PEZ, Harzstark AL, Ferrone M, et al (2013) Metabolic imaging of patients with prostate cancer using hyperpolarized [1–13C]Pyruvate. Sci Translat Med 5(198):198ra08.
Hato T, Friedman AN, Mang H, Plotkin Z, Dube S, Hutchins GD et al (2016) Novel application of complementary imaging techniques to examine in vivo glucose metabolism in the kidney. Am J Physiol Renal Physiol 310(8):F717–F725
Milshteyn E, von Morze C, Reed GD, Shang H, Shin PJ, Larson PEZ et al (2018) Using a local low rank plus sparse reconstruction to accelerate dynamic hyperpolarized (13)C imaging using the bSSFP sequence. J Magn Reson 290:46–59
Durst M, Chiavazza E, Haase A, Aime S, Schwaiger M, Schulte RF (2016) alpha-trideuteromethyl[15N]glutamine: A long-lived hyperpolarized perfusion marker. Magn Reson Med 76(6):1900–1904
Mariager CØ, Lindhardt J, Nielsen PM, Schulte RF, Ringgaard S, Laustsen C (2019) fractional perfusion: a simple semi-parametric measure for hyperpolarized 13C MR. IEEE Trans Radiat Plasma Med Sci 3(4):523–527
Lau JY, Chen AP, Gu YP, Cunningham CH (2016) Voxel-by-voxel correlations of perfusion, substrate, and metabolite signals in dynamic hyperpolarized (13) C imaging. NMR Biomed 29(8):1038–1047
Funding
This study was funded by Aarhus University Research Foundation and Karen Elise Jensen Foundation.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
CL, SU, MP, BJ, JDJ, and FG declare no conflict of interest.
Ethical approval
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Pedersen, M., Ursprung, S., Jensen, J.D. et al. Hyperpolarised 13C-MRI metabolic and functional imaging: an emerging renal MR diagnostic modality. Magn Reson Mater Phy 33, 23–32 (2020). https://doi.org/10.1007/s10334-019-00801-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10334-019-00801-y