Abstract:

The harmless potential of gadolinium-based contrast agent (GBCA) used in MRI studies was remarkable until when gadolinium was detected in the brain, bones, and skin. This study aimed to evaluate the effect of four GBCAs on the liver, heart, and kidney of Wistar rats. Twenty-five (25) male Wistar rats weighing 165-239 g were divided into 4 experimental and control groups after obtaining ethical approval from the Institutional Review Board (IRB) of the Nigerian Institute of Medical Research (NIMR). Specimens in the experimental groups received 2.5 mls / day of one GBCA and the control same normal saline through the lateral tail for 5 days consecutively / week. The Livers, Hearts and Kidneys were harvested 4 weeks following last injection. Pathohistology showed all kidney tissues exposed to Gadopentetate, 80 % to Gadodiamide, and 40 % to Dotarem and Cyclolux were inflamed. Sixty percent Gadodiamide and Doterem to the liver tissue, 50 % and 20 % to Gadopentetate and Cyclolux also inflamed. Samples exposed to Gadopentetate and Dotarem had 50 and 40 % of their heart tissue inflamed. Only those to Gadodiamide and Cyclolux were not affected. Injuries like necrosis, degeneration, and hypertrophy were also noted in all the tissues. All GBCAs were statistically significant in all tissue studied. Gadolinium-based contrast agents had a weak negative correlation with inflamed and degenerated tissues, also a weak positive correlation with hypertrophied tissue, but a moderate positive correlation with necrosis tissues of the kidney, liver, and heart.

References:

[1] Nikken, J. J., Krestin, G. P., 2007, MRI of the kidney-state of the art. European Radiology, 17(11), 2780–2793. https://doi.org/10.1007/s00330-007-0701-3.

[2] Mannelli, L., Kim, S., Hajdu, C. H., Babb, J. S., Taouli, B., 2013, Serial diffusion-weighted MRI in patients with hepatocellular carcinoma: Prediction and assessment of response to transarterial chemoembolization. Preliminary experience. European Journal of Radiology, 82(4), 577–582. https://doi.org/10.1016/j.ejrad.2012.11.026.

[3] Guglielmo, F. F., Mitchell, D. G., Gupta, S., 2014, Gadolinium contrast agent selection and optimal use for body MR imaging. Radiologic Clinics of North America, 52(4), 637–656. https://doi.org/10.1016/j.rcl.2014.02.004.

[4] Wáng, Y. X., Schroeder, J., Siegmund, H., Idée, J. M., Fretellier, N., Jestin-Mayer, G., Factor, C., Deng, M., Kang, W., Morcos, S. K., 2015, Total gadolinium tissue deposition and skin structural findings following the administration of structurally different gadolinium chelates in healthy and ovariectomized female rats. Quantitative Imaging in Medicine and Surgery,5(4),534–545. https://doi.org/10.3978/j.issn.2223.4292.2015.05.03.

[5] Nazarian, S., Hansford, R., Rahsepar, A. A., Weltin, V., McVeigh, D., Gucuk Ipek, E., Kwan, A., Berger, R. D., Calkins, H., Lardo, A. C., Kraut, M. A., Kamel, I. R., Zimmerman, S. L., Halperin, H. R., 2017, Safety of Magnetic Resonance Imaging in Patients with Cardiac Devices. The New England Journal of Medicine, 377(26), 2555–2564. https://doi.org/10.1056/NEJMoa1604267.

[6] Das, C. J., Mahalingam, S., Debnath, J., Dhawan, S., 2010, MRI contrast media: what clinicians need to know. The National Medical Journal of India, 23(5), 292–296.

[7] Pullicino, R., Das, K., 2017, Is it Safe to use gadolinium –based contrast Agents in MRI. Journal of the Royal College of Physicians of Edinburgh, 47(3),243-245.

[8] Rogosnitzky, M., Branch, S., 2016, Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms. Biometals 29,365–376 https://doi.org/10.1007/s10534-016-9931-7.

[9] Nacif, M. S., Arai, A. E., Lima, J. A., Bluemke, D. A., 2012, Gadolinium-enhanced cardiovascular magnetic resonance: administered dose in relationship to United States Food and Drug Administration (FDA) guidelines. Journal of cardiovascular magnetic resonance: official journal of the Society for Cardiovascular Magnetic Resonance, 14(1), 18. https://doi.org/10.1186/1532-429X-14-18.

[10] Gale, E. M., Caravan, P., 2018, Gadolinium-Free Contrast Agents for Magnetic Resonance Imaging of the Central Nervous System. ACS Chemical Neuroscience, 9(3), 395–397. https://doi.org/10.1021/acschemneuro.8b00044.

[11] Schieda, N., Blaichman, J. I., Costa, A. F., Glikstein, R., Hurrell, C., James, M., Jabehdar Maralani, P., Shabana, W., Tang, A., Tsampalieros, A., van der Pol, C. B., Hiremath, S., 2018, Gadolinium-Based Contrast Agents in Kidney Disease: A Comprehensive Review and Clinical Practice Guideline Issued by the Canadian Association of Radiologists. Canadian Journal of Kidney Health and Disease, 5, 2054358118778573. https://doi.org/10.1177/2054358118778573.

[12] Bae, K. T., Tao, C., Zhu, F., Bost, J. E., Chapman, A. B., Grantham, J. J., Torres, V. E., Guay-Woodford, L. M., Meyers, C. M., Bennett, W. M., Consortium for Radiologic Imaging Studies Polycystic Kidney Disease., 2009, MRI-based kidney volume measurements in ADPKD: reliability and effect of gadolinium enhancement. Clinical Journal of the American Society of Nephrology,4(4),719–725. https://doi.org/10.2215/CJN.03750708.

[13] Kanda, T., Fukusato, T., Matsuda, M., Toyoda, K., Oba, H., Kotoku, J., Haruyama, T., Kitajima, K., Furui, S., 2015, Gadolinium-based Contrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy. Radiology, 276(1), 228–232. https://doi.org/10.1148/radiol.2015142690.

[14] Bussi, S., Maisano, F., Tedoldi, F., Kirchin, M.A., 2019, Gadolinium retention and clearance after administration of macrocyclic magnetic resonance contrast agents to rats. Pediatric Radiology.,49(8),1110-1111. DOI: 10.1007/s00247-019-04439-9.

[15] Hao, D., Ai, T., Goerner, F., Hu, X., Runge, V. M., Tweedle, M., 2012, MRI contrast agents: basic chemistry and safety. Journal of Magnetic Resonance Imaging: JMRI, 36(5), 1060–1071. https://doi.org/10.1002/jmri.23725.

[16] Maurer, M., Heine, O., Wolf, M., Durmus, T., Wagner, M., Hamm, B., 2012, Tolerability and diagnostic value of gadoteric acid in the general population and in patients with risk factors: results in more than 84,000 patients. European Journal of Radiology, 81, 885–890.

[17] Abujudeh, H. H., Kosaraju, V. K., Kaewlai, R., 2010, Acute adverse reactions to gadopentetate dimeglumine and gadobenate dimeglumine: experience with 32,659 injections. AJR. American Journal of Roentgenology,194(2),430–434. https://doi.org/10.2214/AJR.09.3099.

[18] Neeley, C., Moritz, M., Brown, J.J., Zhou, Y., 2016, Acute side effects of three commonly used gadolinium contrast agents in the Nehra, A. K., McDonald, R. J., Bluhm, A. M., Gunderson, T. M., Murray, D. L., Jannetto, P. J., Kallmes, D. F., Eckel, L. J., & McDonald, J. S. (2018). Accumulation of Gadolinium in Human Cerebrospinal Fluid after Gadobutrol-enhanced MR Imaging: A Prospective Observational Cohort Study. Radiology, 288(2), 416–423. https://doi.org/10.1148/radiol.2018171105.

[19] The Royal College of Radiologists. Clinical radiology UK workforce census 2019 report. London: The Royal College of Radiologists, 2020.

[20] Shirani, F., Teimoori, A., Rashno, M., Latifi, S. M., Karandish, M., 2017, Using rats as a research model to investigate the effect of human adenovirus 36 on weight gain. ARYA Atherosclerosis, 13(4), 167–171.

[21] Sengupta, P., 2012, A Scientific Review of Age Determination for a Laboratory Rat: How old is it in comparison with Human age? Biomedical International, 2,81–9.

[22] Sengupta, P., 2013, The Laboratory Rat: Relating Its Age with Humans. International Journal of Preventive Medicine, 4(6), 624–630.

[23] [23]. Davidson, M. K., Lindsey, J. R., Davis, J. K., 1987, Requirements and selection of an animal model. Israel Journal of Medical Sciences, 23(6),551–555.

[24] Lohrke, J., Frisk, A. L., Frenzel, T., Schöckel, L., Rosenbruch, M., Jost, G., Lenhard, D. C., Sieber, M. A., Nischwitz, V., Küppers, A., Pietsch, H.,2017, Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents. Investigative Radiology, 52(6), 324–333. https://doi.org/10.1097/RLI.0000000000000344.

[25] Parasuraman, S., 2011, Toxicological screening. Journal of Pharmacology and Pharmacotherapy, 2(2),74-79. doi: 10.4103/0976-500X.81895.

[26] Nehra, A. K., McDonald, R. J., Bluhm, A. M., Gunderson, T. M., Murray, D. L., Jannetto, P. J., Kallmes, D. F., Eckel, L. J., McDonald, J. S., 2018, Accumulation of Gadolinium in Human Cerebrospinal Fluid after Gadobutrol-enhanced MR Imaging: A Prospective Observational Cohort Study.Radiology,288(2),416–423. https://doi.org/10.1148/radiol.2018171105.

[27] McDonald, R. J., McDonald, J. S., Kallmes, D. F., Jentoft, M. E., Paolini, M. A., Murray, D. L., Williamson, E. E., Eckel, L. J., 2017a, Gadolinium Deposition in Human Brain Tissues after Contrast-enhanced MR Imaging in Adult Patients without Intracranial Abnormalities. Radiology, 285(2), 546–554. https://doi.org/10.1148/radiol.2017161595.

[28] Khairinisa, M. A., Takatsuru, Y., Amano, I., Erdene, K., Nakajima, T., Kameo, S., Koyama, H., Tsushima, Y., Koibuchi, N., 2018, The Effect of Perinatal Gadolinium-Based Contrast Agents on Adult Mice Behavior. Investigative Radiology, 53(2), 110–118.

[29] Guo, B.J, Yang, Z.L., and Zhang, L.J., 2018, Gadolinium Deposition in Brain: Current Scientific Evidence and Future Perspectives. Frontier Molecular Neuroscience, 11:335. doi: 10.3389/fnmol.2018.00335.

[30] Aime, S., Caravan, P., 2009, Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. Journal of Magnetic Resonance Imaging, 30(6),1259–1267. https://doi.org/10.1002/jmri.21969.

[31] Dekkers, I. A., Roos, R., van der Molen, A. J., 2018, Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency. European Radiology,28(4),1579–1584. https://doi.org/10.1007/s00330-017-5065-8.

[32] Baerlocher, M. O., Asch, M., Myers, A., 2010, The use of contrast media. CMAJ: Canadian Medical Association Journal,182(7), 697. https://doi.org/10.1503/cmaj.090118.

[33] Andreucci, M., Solomon, R., Tasanarong, A., 2014, Side effects of radiographic contrast media: pathogenesis, risk factors, and prevention. BioMedical Research International, 2014, 741018. https://doi.org/10.1155/2014/741018.

[34] Nakajima, T., Lamid-Ochir, O., 2020, Current Clinical Issues: Deposition of Gadolinium Chelates. Rare Earth Elements and their Minerals. DOI: http://dx.doi.org/10.5772/intechopen.91260.

[35] Akgun, H., Gonlusen, G., Cartwright, J., Jr, Suki, W. N., Truong, L. D., 2006, Are gadolinium-based contrast media nephrotoxic? A renal biopsy study. Archives of Pathology & Laboratory Medicine, 130(9),1354–1357. https://doi.org/10.5858/2006-130-1354-AGCMNA.

[36] Thomsen, H.S., 2006, Nephrogenic systemic fibrosis: A serious late adverse reaction to gadodiamide. European Radiology,16(12),2619–2621. https://doi.org/10.1007/s00330-006-0495-8.

[37] Lin, S. P., & Brown, J. J. (2007). MR contrast agents: physical and pharmacologic basics. Journal of Magnetic Resonance Imaging: JMRI,25(5),884–899. https://doi.org/10.1002/jmri.20955.

[38] Elmholdt, T.R., Pedersen, M., Jorgensen, B., Sondergaar, K., Jensen, J.D., Ramsing, M., Olesen, A.B., 2011, Nephrogenic systemic fibrosis is found only among gadolinium-exposed patients with renal insufficiency: a case-control study from Denmark. British Journal of Dermatology, 165,828–836.

[39] Chen, R., Ling, D., Zhao, L., Wang, S., Liu, Y., Bai, R., Baik, S., Zhao, Y., Chen, C., Hyeon, T., 2015, Parallel Comparative Studies on Mouse Toxicity of Oxide Nanoparticle- and Gadolinium-Based T1 MRI Contrast Agents. ACS Nano, 9(12), 12425–12435. https://doi.org/10.1021/acsnano.5b05783.

[40] Murata, N., Gonzalez-Cuyar, L.F., Murata, K., Fligner, C., Dills, R., Hippe, D., Maravilla, K.R., 2016, Macrocyclic and other nongroup 1 gadolinium contrast agents deposit low levels of gadolinium in brain and bone tissue: preliminary results from 9 patients with normal renal function. Investigative Radiology. doi:10.1097/rli.0000000000000252.

[41] McDonald, R. J., McDonald, J. S., Dai, D., Schroeder, D., Jentoft, M. E., Murray, D. L., Kadirvel, R., Eckel, L. J., Kallmes, D. F., 2017b, Comparison of Gadolinium Concentrations within Multiple Rat Organs after Intravenous Administration of Linear versus Macrocyclic Gadolinium Chelates. Radiology, 285(2), 536–545. https://doi.org/10.1148/radiol.2017161594.

[42] Sanyal, S., Marckmann, P., Scherer, S., Abraham, J. L., 2011, Multiorgan gadolinium (Gd) deposition and fibrosis in a patient with nephrogenic systemic fibrosis--an autopsy-based review. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant
Association - European Renal Association, 26(11),3616–3626. https://doi.org/10.1093/ndt/gfr085.

[43] Gibby, W.A., Gibby, K.A., Gibby, W.A., 2004, Comparison of Gd DTPA-BMA (Omniscan) versus Gd HP-DO3A (ProHance) retention in human bone tissue by inductively coupled plasma atomic emission 2 eespectroscopy. Investigative Radiology, 39,138–142.

[44] Morcos, S.K., 2009, Chelates and Stability. In: Thomsen HS., ebb JA, (eds). Contrast Media. Medical Radiology (Diagnostic Imaging) [Springer, Berlin, Heidelberg]. https://doi.org/10.1007/978-3-540-72784-2_20.

[45] Robert, P., Lehericy, S., Grand, S., Violas, X., Fretellier, N., Idée, J. M., Ballet, S., Corot, C., 2015, T1-Weighted Hypersignal in the Deep Cerebellar Nuclei After Repeated Administrations of Gadolinium-Based Contrast Agents in Healthy Rats: Difference Between Linear and Macrocyclic Agents. Investigative Radiology, 50(8),473–480. https://doi.org/10.1097/RLI.0000000000000181.

[46] Major, J.L., Meade, T.J., 2009, Bio responsive, cell-penetrating, and multimeric MR contrast agents. Acc Chemical Research, 42,893–903.