Skip to main content
NCBI home page
Medline Book to support NIHPA logoLink to Medline Book to support NIHPA
. 2021;2216:455–471. doi: 10.1007/978-1-0716-0978-1_27

Renal pH Mapping Using Chemical Exchange Saturation Transfer (CEST) MRI: Experimental Protocol.

Kowsalya Devi Pavuluri, Lorena Consolino, Dario Livio Longo, Pietro Irrera, Phillip Zhe Sun, Michael T McMahon
PMCID: PMC9703269  PMID: 33476017

Abstract

Chemical exchange saturation transfer (CEST) is recognized as one of the premier methods for measuring pH with this environmental variable expected to be an excellent biomarker for kidney diseases. Here we describe step-by-step CEST MRI experimental protocols for producing pH and perfusion maps for monitoring kidney pH homeostasis in rodents after administering iopamidol as contrast agent. Several CEST techniques, acquisition protocols and ratiometric approaches are described. The impact of length of acquisition time on the quality of the maps is detailed. These methods may be useful for investigating progression in kidney disease in vivo for rodent models.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This experimental protocol is complemented by two separate chapters describing the basic concepts and data analysis.

Full text of this article can be found in Bookshelf.

References

  1. Hamm LL, Nakhoul N, Hering-Smith KS (2015) Acid-base homeostasis. Clin J Am Soc Nephrol 10(12):2232–2242 doi: 10.2215/CJN.07400715. [DOI] [PMC free article] [PubMed]
  2. Soleimani M, Rastegar A (2016) Pathophysiology of renal tubular acidosis: core curriculum 2016. Am J Kidney Dis 68(3):488–498. https://doi.org/10.1053/j.ajkd.2016.03.422 doi: 10.1053/j.ajkd.2016.03.422. [DOI] [PubMed]
  3. Gil-Peña H, Mejía N, Santos F (2014) Renal tubular acidosis. J Pediatr 164(4):691–698. https://doi.org/10.1016/j.jpeds.2013.10.085 doi: 10.1016/j.jpeds.2013.10.085. [DOI] [PubMed]
  4. Gillies RJ, Raghunand N, Garcia-Martin ML, Gatenby RA (2004) pH imaging. IEEE Eng Med Biol Mag 23(5):57–64 doi: 10.1109/memb.2004.1360409. [DOI] [PubMed]
  5. Raghunand N, Howison C, Sherry AD, Zhang S, Gillies RJ (2003) Renal and systemic pH imaging by contrast-enhanced MRI. Magn Reson Med 49(2):249–257 doi: 10.1002/mrm.10347. [DOI] [PubMed]
  6. Longo DL, Busato A, Lanzardo S, Antico F, Aime S (2013) Imaging the pH evolution of an acute kidney injury model by means of iopamidol, a MRI-CEST pH-responsive contrast agent. Magn Reson Med 70(3):859–864 doi: 10.1002/mrm.24513. [DOI] [PubMed]
  7. Longo DL, Cutrin JC, Michelotti F, Irrera P, Aime S (2017) Noninvasive evaluation of renal pH homeostasis after ischemia reperfusion injury by CEST-MRI. NMR Biomed 30(7). https://doi.org/10.1002/nbm.372 doi: 10.1002/nbm.372. [DOI] [PubMed]
  8. Hashim AI, Zhang XM, Wojtkowiak JW, Martinez GV, Gillies RJ (2011) Imaging pH and metastasis. NMR Biomed 24(6):582–591. https://doi.org/10.1002/nbm.1644 doi: 10.1002/nbm.1644. [DOI] [PMC free article] [PubMed]
  9. Ashby BS (1966) pH studies in human malignant tumours. Lancet 288(7458):312–315 doi: 10.1016/s0140-6736(66)92598-0. [DOI] [PubMed]
  10. Prescott DM, Charles HC, Poulson JM, Page RL, Thrall DE, Vujaskovic Z, Dewhirst MW (2000) The relationship between intracellular and extracellular pH in spontaneous canine tumors. Clin Cancer Res 6(6):2501–2505 [PubMed]
  11. Wike-Hooley JL, van den Berg AP, van der Zee J, Reinhold HS (1985) Human tumour pH and its variation. Eur J Cancer Clin Oncol 21(7):785789–787791 doi: 10.1016/0277-5379(85)90216-0. [DOI] [PubMed]
  12. Li C, Xia J, Wei X, Yan H, Si Z, Ju S (2010) pH-activated near-infrared fluorescence nanoprobe imaging tumors by sensing the acidic microenvironment. Adv Funct Mater 20(14):2222–2230
  13. Hassan M, Riley J, Chernomordik V, Smith P, Pursley R, Lee SB, Capala J, Amir HG (2007) Fluorescence lifetime imaging system for in vivo studies. Mol Imaging 6(4):7290.2007.00019 [PMC free article] [PubMed]
  14. García-Martín M-L, Hérigault G, Rémy C, Farion R, Ballesteros P, Coles JA, Cerdán S, Ziegler A (2001) Mapping extracellular pH in rat brain gliomas in vivo by H magnetic resonance spectroscopic imaging: comparison with maps of metabolites. Cancer Res 61(17):6524–6531 [PubMed]
  15. Gillies R, Liu Z, Bhujwalla Z (1994) 31P-MRS measurements of extracellular pH of tumors using 3-aminopropylphosphonate. Am J Phys Cell Phys 267(1):C195–C203 doi: 10.1152/ajpcell.1994.267.1.C195. [DOI] [PubMed]
  16. Gillies RJ, Morse DL (2005) In vivo magnetic resonance spectroscopy in cancer. Annu Rev Biomed Eng 7:287–326 doi: 10.1146/annurev.bioeng.7.060804.100411. [DOI] [PubMed]
  17. Vermathen P, Capizzano AA, Maudsley AA (2000) Administration and 1H MRS detection of histidine in human brain: application to in vivo pH measurement. Magn Reson Med 43(5):665–675 doi: 10.1002/(sici)1522-2594(200005)43:5<665::aid-mrm8>3.0.co;2-3. [DOI] [PubMed]
  18. Bhujwalla ZM, McCoy C, Glickson J, Gillies R, Stubbs M (1998) Estimations of intra-and extracellular volume and pH by 31P magnetic resonance spectroscopy: effect of therapy on RIF-1 tumours. Br J Cancer 78(5):606 doi: 10.1038/bjc.1998.548. [DOI] [PMC free article] [PubMed]
  19. Aoki Y, Akagi K, Tanaka Y, Kawai J, Takahashi M (1996) Measurement of intratumor pH by pH indicator used in 19F-magnetic resonance spectroscopy: measurement of extracellular pH decrease caused by hyperthermia combined with hydralazine. Investig Radiol 31(11):680–689 doi: 10.1097/00004424-199611000-00002. [DOI] [PubMed]
  20. Zhou R, Bansal N, Leeper DB, Glickson JD (2000) Intracellular acidification of human melanoma xenografts by the respiratory inhibitor m-iodobenzylguanidine plus hyperglycemia: a 31P magnetic resonance spectroscopy study. Cancer Res 60(13):3532–3536 [PubMed]
  21. Ojugo AS, McSheehy PM, McIntyre DJ, McCoy C, Stubbs M, Leach MO, Judson IR, Griffiths JR (1999) Measurement of the extracellular pH of solid tumours in mice by magnetic resonance spectroscopy: a comparison of exogenous 19F and 31P probes. NMR Biomed 12(8):495–504 doi: 10.1002/(sici)1099-1492(199912)12:8<495::aid-nbm594>3.0.co;2-k. [DOI] [PubMed]
  22. Gallagher FA, Kettunen MI, Day SE, Hu D-E, Ardenkjær-Larsen JH, Jensen PR, Karlsson M, Golman K, Lerche MH, Brindle KM (2008) Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 453(7197):940–943 doi: 10.1038/nature07017. [DOI] [PubMed]
  23. Garcia-Martin ML, Martinez GV, Raghunand N, Sherry AD, Zhang S, Gillies RJ (2006) High resolution pHe imaging of rat glioma using pH-dependent relaxivity. Magn Reson Med 55(2):309–315 doi: 10.1002/mrm.20773. [DOI] [PubMed]
  24. McMahon MT, Gilad AA, Bulte JWM, van Zijl PCM (2017) Chemical exchange saturation transfer imaging: advances and applications, 1st edn. Pan Stanford Publishing, Singapore
  25. Longo D, Aime S (2017) Iodinated contrast media as pH-responsive CEST agents. In: McMahon MT, Gilad AA, JBM B, PCM VZ (eds) Chemical exchange saturation transfer imaging. Vol. Advances and applications. Pan Stanford Publishing, Singapore, pp 447–466. https://doi.org/10.1201/9781315364421-20 doi: 10.1201/9781315364421-20. [DOI]
  26. Pavuluri K, McMahon MT (2017) pH imaging using chemical exchange saturation transfer (CEST) MRI. Isr J Chem 57(9):862–879. https://doi.org/10.1002/ijch.201700075 doi: 10.1002/ijch.201700075. [DOI]
  27. Longo DL, Dastrù W, Digilio G, Keupp J, Langereis S, Lanzardo S, Prestigio S, Steinbach O, Terreno E, Uggeri F (2011) Iopamidol as a responsive MRI-chemical exchange saturation transfer contrast agent for pH mapping of kidneys: In vivo studies in mice at 7 T. Magn Reson Med 65(1):202–211 doi: 10.1002/mrm.22608. [DOI] [PubMed]
  28. Longo DL, Sun PZ, Consolino L, Michelotti FC, Uggeri F, Aime S (2014) A general MRI-CEST ratiometric approach for pH imaging: demonstration of in vivo pH mapping with iobitridol. J Am Chem Soc 136(41):14333–14336 doi: 10.1021/ja5059313. [DOI] [PMC free article] [PubMed]
  29. Wu RH, Longo DL, Aime S, Sun PZ (2015) Quantitative description of radiofrequency (RF) power-based ratiometric chemical exchange saturation transfer (CEST) pH imaging. NMR Biomed 28(5):555–565. https://doi.org/10.1002/nbm.3284 doi: 10.1002/nbm.3284. [DOI] [PMC free article] [PubMed]
  30. Yang X, Song X, Ray Banerjee S, Li Y, Byun Y, Liu G, Bhujwalla ZM, Pomper MG, McMahon MT (2016) Developing imidazoles as CEST MRI pH sensors. Contrast Media Mol Imaging 11(4):304–312 doi: 10.1002/cmmi.1693. [DOI] [PMC free article] [PubMed]
  31. McMahon MT, Gilad AA, Zhou J, Sun PZ, Bulte JW, van Zijl P (2006) Quantifying exchange rates in chemical exchange saturation transfer agents using the saturation time and saturation power dependencies of the magnetization transfer effect on the magnetic resonance imaging signal (QUEST and QUESP): pH calibration for poly-L-lysine and a starburst dendrimer. Magn Reson Med 55(4):836–847 doi: 10.1002/mrm.20818. [DOI] [PMC free article] [PubMed]
  32. Anemone A, Consolino L, Arena F, Capozza M, Longo DL (2019) Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH. Cancer Metastasis Rev. https://doi.org/10.1007/s10555-019-09782-9 doi: 10.1007/s10555-019-09782-9. [DOI] [PMC free article] [PubMed]
  33. Grenier N, Cornelis F, Le Bras Y, Rigou G, Boutault JR, Bouzgarrou M (2013) Perfusion imaging in renal diseases. Diagn Interv Imaging 94(12):1313–1322. https://doi.org/10.1016/j.diii.2013.08.018 doi: 10.1016/j.diii.2013.08.018. [DOI] [PubMed]
  34. Anemone A, Consolino L, Longo DL (2017) MRI-CEST assessment of tumour perfusion using X-ray iodinated agents: comparison with a conventional Gd-based agent. Eur Radiol 27(5):2170–2179. https://doi.org/10.1007/s00330-016-4552-7 doi: 10.1007/s00330-016-4552-7. [DOI] [PubMed]
  35. Sheth VR, Li Y, Chen LQ, Howison CM, Flask CA, Pagel MD (2012) Measuring in vivo tumor pHe with CEST-FISP MRI. Magn Reson Med 67(3):760–768. https://doi.org/10.1002/mrm.23038 doi: 10.1002/mrm.23038. [DOI] [PMC free article] [PubMed]
  36. Sun PZ, Cheung JS, Wang E, Benner T, Sorensen AG (2011) Fast multislice pH-weighted chemical exchange saturation transfer (CEST) MRI with unevenly segmented RF irradiation. Magn Reson Med 65(2):588–594. https://doi.org/10.1002/mrm.22628 doi: 10.1002/mrm.22628. [DOI] [PMC free article] [PubMed]
  37. Pavuluri K, Manoli I, Pass A, Li Y, Vernon HJ, Venditti CP, McMahon MT (2019) Noninvasive monitoring of chronic kidney disease using pH and perfusion imaging. Sci Adv. https://doi.org/10.1126/sciadv.aaw8357 doi: 10.1126/sciadv.aaw8357. [DOI] [PMC free article] [PubMed]
  38. Kim M, Gillen J, Landman BA, Zhou J, van Zijl PC (2009) Water saturation shift referencing (WASSR) for chemical exchange saturation transfer (CEST) experiments. Magn Reson Med 61(6):1441–1450. https://doi.org/10.1002/mrm.21873 doi: 10.1002/mrm.21873. [DOI] [PMC free article] [PubMed]
  39. Sun PZ, Longo DL, Hu W, Xiao G, Wu R (2014) Quantification of iopamidol multi-site chemical exchange properties for ratiometric chemical exchange saturation transfer (CEST) imaging of pH. Phys Med Biol 59(16):4493 doi: 10.1088/0031-9155/59/16/4493. [DOI] [PMC free article] [PubMed]

RESOURCES