The detection of NSF in patients with impaired renal function and the deposition of GBCA in the brain of patients with normal renal function has led to a dramatic change in the administration of these agents in Europe.
Gadolinium-based contrast agents have been administered in more than 300 million patients worldwide and are considered safe in all patients with normal renal function. Until 2006 all agents were also considered safe in patients with reduced renal function in contrast to the iodine-based contrast media for X-ray and CT-scanning. Some radiologists even used gadolinium-based contrast agents for conventional X-ray (angiography) and CT-scanning. In 2006 a link between the least stable agents (Omniscan, OptiMark and Magnevist) and the development of nephrogenic systemic fibrosis (NSF) was identified in patients with reduced renal function or on dialysis [1,2]. The following year the European Society of Uroradiology (ESUR) released its guidelines for the use of gadolinium based contrast media [3]. The main message was to avoid the least stable agents in patients with severely reduced renal function. The European Medicines Agency restricted the use of the least stable agents in 2007. Subsequently European radiologists switched slowly from using linear to using macrocyclic agents. Today around 75 % of the used agents are macrocyclic in Europe. E.G. in Denmark the least stable agents are no longer authorized. Thanks to the restrictions/guidelines no new case of NSF has been reported since 2009. We have seen a few cases afterwards but they all had the contrast agent before 2009. According to the contrast media guidelines of ESUR [3] Gadolinum-based contrast agents are divided in three groups: those with the highest risk of Nephrogenic Systemic Fibrosis (NSF), including Omniscan, Magnevist and Optimark, and those with intermediate (Multihance, Ablavar, Primovist or Eovist) and lowest risk of NSF (Dotarem, Gadovist and Prohance). The lowest risk group included only macrocyclic Gadolium-based contrast agents. For the group with the highest risk for NSF eGFR measurement and clinical assessment is mandatory, whereas for the intermediate and lowest risk group of NSF eGFR measurement is not mandatory but a questionnaire for determination of further risk factors should be used. The contrast agents with the highest risk are contraindicated in patients with Chronic Kidney Disease (CKD) 4 and 5 (< 30 ml/min) including those on dialysis, acute renal insufficiency, pregnant women and neonates. They should be used with caution in patients with CKD 3 (30-60 ml/min) and children less than 1 year old. There should be at least 7 days of interval between two injections. Furthermore, lactating woman will have to stop breastfeeding for 24 hours and discard the milk. In addition, these agents should never be given in higher doses than 0.1mmol/kg per examination in any patient. These agents should also be stored separately from intermediate and low risk agents to avoid use in error of a high risk agent in a patient with poor renal function. Concerning the risk classification of intermediate and lowest risk agents there is no practical consequence in recommendation for both groups and therefore these groups were taken together. These agents should be used with caution in patients with CKD 4 and 5 and there should be at least 7 days between two injections. For lactating woman discarding the milk is not considered necessary, but the patients can discuss the issue with the doctor.
In 2014 hyperintensities in the dentate nucleus and globus pallidus on T1-weighted MR images in patients with normal renal function undergoing several contrast-enhanced MRIs with linear contrast agents have been observed and published for the first time; shortly thereafter it could be shown in an autopsy study that these hyperintensities on T1-weighed images corresponded to gadolinium deposition [4,5]. It has also been shown already many years ago that gadolinium is deposited in the bone even to a much higher extent compared to the brain [6,7]. In the meantime many retrospective studies have been published showing these T1 hyperintensities after administration of linear agents (Omniscan, Magnevist, Multihance, Primovist), but not after repetitive administration of a macrocyclic agent [8-11].
In view of the many recent publications showing hyperintensities in T1-weighted sequences in the globus pallidus, thalamus and the dentate nucleus, but also in the grey matter of the entire brain [12] of patients with normal renal function receiving repetitive and high doses of Gadolinium-based contrast agents these guidelines will probably need to be rediscussed. Up to date most of these publications showed these signal changes after repetitive administration of linear contrast agents, but larger scale studies have to be performed to prove the safe use of macrocyclic agents without substantial deposition of gadolinium in the brain. In contrast to NSF, where significant reactions (fibrosis) could be observed, we still have to see which consequences the Gd accumulation has. Up to date no neurological symptoms or pathoanatomic changes in the brain of patients with Gd accumulations have been identified. The same applies to the accumulation in the bone. Therefore, we should always use an agent that leaves the smallest amount of gadolinium in the body, currently these are the macrocyclic agents. On March 10 this year the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recommend pulling four linear contrast agents (gadobenic acid, gadodiamide, gadopentetic acid and gadoversamide) from the market by leaving only two linear agents (gadoxetic acid, a linear agent used at a low dose for liver imaging and a formulation of gadopentetic acid for intraarticular use). This is a precautionary approach leaving only the more stable macrocyclic agents on the market.
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2. Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, Thomsen HS (2006) Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. Journal of the American Society of Nephrology 17 (9):2359-2362
3. ESUR Contrast Media Safety Committee (2014) ESUR Guidelines on Contrast Media 9.0. ESUR Office Vienna.
4. 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 270 (3):834-841
5. McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Murray DL, Thielen KR, Williamson EE, Eckel LJ (2015) Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 275 (3):772-782
6. White GW, Gibby WA, Tweedle MF (2006) Comparison of Gd (DTPA-BMA)(Omniscan) versus Gd (HP-DO3A)(ProHance) relative to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy. Investigative radiology 41 (3):272-278
7. Murata N, Gonzalez-Cuyar LF, Murata K, Fligner C, Dills R, Hippe D, Maravilla KR (2016) Macrocyclic and other non–group 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 51 (7):447-453
8. Kanda T, Osawa M, Oba H, Toyoda K, Kotoku Ji, Haruyama T, Takeshita K, Furui S (2015) High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 275 (3):803-809
9. Weberling LD, Kieslich PJ, Kickingereder P, Wick W, Bendszus M, Schlemmer H-P, Radbruch A (2015) Increased signal intensity in the dentate nucleus on unenhanced T1-weighted images after gadobenate dimeglumine administration. Investigative radiology 50 (11):743-748
10. Radbruch A, Haase R, Kickingereder P, Baumer P, Bickelhaupt S, Paech D, Wick W, Schlemmer HP, Seitz A, Bendszus M (2017) Pediatric Brain: No Increased Signal Intensity in the Dentate Nucleus on Unenhanced T1-weighted MR Images after Consecutive Exposure to a Macrocyclic Gadolinium-based Contrast Agent. Radiology:162980. doi:10.1148/radiol.2017162980
11. Kahn J, Posch H, Steffen IG, Geisel D, Bauknecht C, Liebig T, Denecke T (2017) Is There Long-term Signal Intensity Increase in the Central Nervous System on T1-weighted Images after MR Imaging with the Hepatospecific Contrast Agent Gadoxetic Acid? A Cross-sectional Study in 91 Patients. Radiology:162535
12. Kuno H, Jara H, Buch K, Qureshi MM, Chapman MN, Sakai O (2016) Global and Regional Brain Assessment with Quantitative MR Imaging in Patients with Prior Exposure to Linear Gadolinium-based Contrast Agents. Radiology:160674