An important new study was published online March 5, 2015 in Radiology. Dr. Robert McDonald and his colleagues at Mayo Clinic in Rochester, Minnesota, found high levels of gadolinium in four regions of the brain of 13 deceased patients who had 4 or more contrast-enhanced MRIs with Omniscan. None of the patients had severe renal disease. Except for one patient with an eGFR of 54, the other 12 had an eGFR between 74 and 122. The authors concluded that “intravenous GBCA exposure is associated with neuronal tissue deposition in the setting of relatively normal renal function”.
The study, Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging, sought to confirm the findings of Errante et al (2014) and Kanda et al (2103) which reported progressive increases in T1-weighted signal intensity in parts of the brain after repeated administration of a Gadolinium-based Contrast Agent (GBCA). This study examined tissue samples taken from the posterior fossa (dentate nucleus and pons) and basal ganglia (globus pallidus and thalamus) of 23 deceased patients – 13 of whom had 4 or more MRIs with Omniscan (gadodiamide), the other 10 had at least one unenhanced MRI and were the control group. By using control patients, the study “findings suggest that the signal intensity changes observed with MR imaging are specific to gadolinium deposition”.
All patients exposed to multiple doses of the GBCA had elevated levels of gadolinium in tissue samples from each brain region. The study reported a strong correlation between cumulative GBCA dose and tissue gadolinium concentration. The authors noted that, “some of the highest tissue concentrations of gadolinium were present among patients with normal renal function”.
Because the study excluded cases in which neoplasm and/or radiation therapy involved the basal ganglia or posterior fossa, McDonald and colleagues said their “results are highly suggestive that this accumulation is occurring in nondiseased neuronal tissues”. It is not known whether the gadolinium detected in the various tissues is the GBCA complex or the free gadolinium ion.
Another important study finding suggests “that gadolinium from administered GBCA is able to cross an otherwise intact blood-brain barrier and that compromise of this barrier is not necessary for tissue deposition”. In my opinion, that is a significant finding, since the product labeling for all Gadolinium-based Contrast Agents note the GBCAs “do not cross an intact blood-brain barrier”.
The study raises some important questions. It notes that “it remains unclear whether this deposition effect is limited to gadodiamide, to linear chelated GBCAs in general, or whether it manifests in both linear and the more thermodynamically stable macrocyclic gadolinium chelates”. They note that although their findings are limited to a single linear ionic GBCA (Omniscan), “established data on the chemical and biophysical properties of GBCAs suggest that this deposition is likely to occur with multiple agents and that the extent of this deposition likely correlates with the thermodynamic stability of these chelates”.
The authors concluded by saying that their findings “suggest that intravenous administration of a GBCA is associated with dose-dependent deposition in neuronal tissues that is unrelated to renal function, age, or interval between exposure and death”. They said the findings “strongly argue for future research to assess the in vivo stability and safety of GBCAs”.
Interestingly, a 2010 study by Xia et al, found insoluble deposits containing gadolinium associated with phosphorous and calcium in 7 brain tumor biopsies from 5 patients. The Gd-containing deposits were present in brain tumors following contrast-enhanced MR scans in patients without severe renal disease – the patients had eGFRs above 53.
Based on the findings of these studies, I believe that something must be done now to determine the stability and safety of all commercially available Gadolinium-Based Contrast Agents. It had been thought that patients with normal renal function do not retain gadolinium, but recent published studies call that into serious question.
McDonald, R. J., McDonald, J. S., Kallmes, D. F., Jentoft, M. E., Murray, D. L., Thielen, K. R., Williamson, E. E., et al. (2015). Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging. Radiology, 150025. doi:10.1148/radiol.15150025. Retrieved from http://dx.doi.org/10.1148/radiol.15150025
Errante, Y., Cirimele, V., Mallio, C. A., Di Lazzaro, V., Zobel, B. B., & Quattrocchi, C. C. (2014). Progressive Increase of T1 Signal Intensity of the Dentate Nucleus on Unenhanced Magnetic Resonance Images Is Associated With Cumulative Doses of Intravenously Administered Gadodiamide in Patients With Normal Renal Function, Suggesting Dechelation. Investigative Radiology, 49(10), 685–690. doi:10.1097/RLI.0000000000000072. Retrieved from http://journals.lww.com/investigativeradiology/Fulltext/2014/10000/Progressive_Increase_of_T1_Signal_Intensity_of_the.8.aspx
Kanda, T., Ishii, K., Kawaguchi, H., Kitajima, K., & Takenaka, D. (2013). High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with Increasing Cumulative Dose of a Gadolinium-based Contrast Material. Radiology, 131669. doi:10.1148/radiol.13131669. Retrieved from http://pubs.rsna.org/doi/abs/10.1148/radiol.13131669
Xia, D., Davis, R. L., Crawford, J. A., & Abraham, J. L. (2010). Gadolinium released from MR contrast agents is deposited in brain tumors: in situ demonstration using scanning electron microscopy with energy dispersive X-ray spectroscopy. Acta Radiologica , 51 (10 ), 1126–1136. doi:10.3109/02841851.2010.515614. Retrieved from http://acr.sagepub.com/content/51/10/1126.abstract