Introduction to Safe Use of Gadolinium-Based Contrast Agents

Gadolinium-based contrast agents (GBCAs) are routinely used in patients undergoing magnetic resonance imaging (MRI) to enhance image contrast and thereby improving detection and characterization of lesions. These agents exploit the highly paramagnetic nature of gadolinium (Gd), which alters the local magnetic properties shortening both T₁ and T₂ of tissue leading to increased signal intensity on T₁-weighted images (and reduced signal intensity on T₂-weighted images) (Elster). Since their introduction in 1988, GBCAs have been administered worldwide, with an estimate of 550 million doses being delivered (Balzer, 2017; McDonald, 2018; Endrikat, 2018). At present, roughly 30 to 45% of the MRI scans use GBCAs, with an estimated use of 40 million doses per year (Endrikat personal communication).

I Gadolinium Physicochemistry

Gadolinium and relaxivity

Gadolinium (Gd; Z = 64 and MW = 157,25 g/mol) is a rare earth metal from the Lanthanide family of elements in the periodic system. It has seven unpaired electrons in its 4f orbitals, has a high magnetic moment, and a very long electron spin relaxation time (Caravan, 1999; Lin, 2007; Hao, 2012).

The efficiency of T1-weighted contrast agents in aqueous solutions is determined by its relaxivity (r₁ = 1 / T₁). The relaxivity is determined by relaxation effects of water molecules interacting directly with the paramagnetic ion (inner sphere) and interactions with closely diffusing water molecules without interacting with the M-L complex (outer sphere).

For clinical GBCA 60% of relaxivity comes from inner sphere effects and 40% from outer sphere effects. Chelated gadolinium complexes are monohydrated (Gd(H₂O)³⁺), as in their spherical configuration there is only enough space around the gadolinium for one (inner sphere) water molecule that exchanges rapidly with other nearby water molecules (outer sphere) (De Leon-Rodriguez, 2015).

Gadolinium chelation and stability constants

In biological systems, unchelated Gd³⁺ ions are toxic because the ion has an ionic radius (107,8 pm) close to the ionic radius of Ca²⁺ (114 pm) and can bind to Ca²⁺ ion channels and Ca²⁺-dependent proteins such as metalloenzymes or messenger proteins like calmodulin or calexitin.

To suppress this potential toxicity, the Gd³⁺ ions must be tightly bound to an organic ligand to form a metal-ligand (ML) complex or chelate. The ligand will reduce toxicity, change the tissue distribution, and influence relaxivity. In the current European situation, such ligands are macrocyclic (DOTA, BT-DO3A or HP-DO3A) or linear (BOPTA or EOB-DTPA) (Table 1).

Normally, equilibrium exists for the reaction between metal M and ligand L.

The reaction can be written as: (M) + (L) (ML)

The stability of the Gadolinium-ligand complex can be described by a number of constants.

The logarithm of the thermodynamic stability constant K_therm describes the affinity of Gd for the ligand, and is normally measured at pH = 14. Higher values imply a higher stability.

K_therm = (ML) / (M) · (L).

For biological systems more appropriate is the logarithm of the apparent or conditional thermodynamic stability constant K_cond, which considers the total concentration of the free ligand, including all its protonation states. It characterizes the affinity of Gadolinium for ligand in aqueous media under physiologic conditions (pH = 7,4). In all GBCA the conditional stability is substantially lower than the thermodynamic stability. K_cond = (ML) / (M) · {(L) + (HL) + (H₂L) + ………..}

The kinetic stability describes the kinetic rate of the dissociation of the Gadolinium-Ligand complex. It is closely related to the thermodynamic stability and is most commonly described as the half-life of the dissociation of the Gd-Ligand complex or by the observed dissociation constant k_obs. To be measurable, such kinetic analyses are done under acidic conditions at pH =1 (Port, 2008). Dissociation rate = k_obs (ML).

Some commercial solutions of contrast media contain variable amounts of free ligands or calcium complexes to ensure chelation of any free Gd³⁺ or other metal traces from the vial during its shelf life. This amount is often used as indirect indicator of the instability of the compound.

The thermodynamic stability constants are a measure of how much uncomplexed Gd³⁺ will be released in biologic tissues if the system reaches equilibrium. In vivo, such new thermodynamic equilibrium is usually not reached as most of the complex is excreted long before any uncomplexed gadolinium can be released. Therefore, the kinetic stability is in vivo much more important than the thermodynamic stability.

Transmetallation

Transmetallation is the exchange between Gd³⁺ and other metal ions M⁺ that have greater affinity for the chelate. The amount of transmetallation depends on the stability of the chelating ligand. Gadolinium ions can be removed from the Gd-ligand complex by several endogenous positively charged ions like Zn²⁺, Cu²⁺, and Ca²⁺ whereby Gd³⁺ is released, while endogenous negatively charged ions like PO₄^3- and CO₃^2- can compete with the free ligand to form insoluble toxic Gd³⁺ compounds like GdPO₄ or Gd₂(CO₃)₃ (Idee, 2006).

Transmetallation can be described by the reaction: (Gd-L) + (M⁺) Gd³⁺ + (ML)

Of the most frequently described stability constants, a high kinetic stability is regarded as the most important to minimize transmetallation. Since the stability of the macrocyclic Gd chelates is much more limited by the slow release of Gd³⁺ from the complex, the kinetic stability is more important in such ligands.

The main physicochemistry and stability data of current GBCA are summarized in Table 1.

Table 1 Physicochemical characteristics and stability constants of gadolinium-based contrast agents

Name	Ligand	Structure	Ionicity	Molecular Weight	Osmolality	Viscosity 37ºC	T1 relaxivity in blood, 1.5T^a	T2 relaxivity in blood, 1.5T^a	Renal Excretion
				(Dalton)	(mOsm/kg)	(mPa s)	(L/mmol s)	(L/mmol s)	(T½; hours)

gadopentetate	DTPA	Linear	Ionic	939.0	1960	2.9	4.3	4.4	1.6

gadodiamide	DTPA-BMA	Linear	Nonionic	537.6	789	1.4	4.6	6.9	1.3

gadobenate	BOPTA	Linear	Ionic	1058.2	1970	5.4	6.7	8.9	1.2-2

gadoxetate	EOB-DTPA	Linear	Ionic	682.0	688	1.2	7.3	9.1	1.0

gadoteridol	HP-DO3A	Macrocyclic	Nonionic	558.7	630	1.3	4.4	5.5	1.6

gadobutrol	BT-DO3A	Macrocyclic	Nonionic	604.7	1390	4.9	5.3	5.4	1.5

gadoterate	DOTA	Macrocyclic	Ionic	558.6	1350	2.0	4.2	6.7	1.6

Name	Ligand	Thermodynamic Stability	Conditional Stability	Kinetic Stability	Dissociation Constant	Excess Ligand	Stability Classification	Decision EMA 2017
		(pH 14)	(pH 7.4)	(37°C, pH 1)	Kobs		EMA
		(Log K_therm)	(Log K_cond)	(T½; hours)	(s^-1)	(mmol/l)

gadopentetate	DTPA	22.5	18.4	0.16	0.58	1	Low	Artho only

gadodiamide	DTPA-BMA	16.9	14.9	0.01	12.7	25	Low	Withdraw

gadobenate	BOPTA	22.6	18.4	NA	0.41	0	Intermediate	Liver only

gadoxetate	EOB-DTPA	23.5	18.7	NA	0.16		Intermediate	Liver only

gadoteridol	HP-DO3A	23.8	17.1	1.6	0.00026	0.5	High	Maintain

gadobutrol	BT-DO3A	21.8	14.7	7.0	0.000028	1	High	Maintain

gadoterate	DOTA	25.6	19.3	23.0	0.000008	0	High	Maintain

NA = not available

Biodistribution and Elimination

After intravenous administration the GBCA is excreted by the kidneys with an early elimination half-life of about 1.5 h in patients with normal renal function. More than 90% of the injected GBCA is cleared from the body within 12 h. This early excretion phase is similar for linear and macrocyclic GBCA.

In patients with severely reduced renal function (eGFR < 30 ml/min/1.73m²) this elimination half-life for GBCA can increase up to 18-34 h (Joffe, 2008). During that time there is a potential for transmetallation with an increased release of free Gd³⁺ ions (Aime, 2009).

Recent systematic review of pharmacokinetic analysis revealed a deep compartment of distribution with long-lasting residual excretion. This long-lasting excretion is faster for macrocyclic compared to linear GBCA, correlated to the higher thermodynamic stability and differences in transmetallation. In addition, bone residence time for macrocyclic GBCA (up to 30 days) was much shorter than for linear GBCA (up to 2,5 years) (Lancelot, 2016).

II Nephrogenic Systemic Fibrosis (NSF)

Nephrogenic Fibrosing Dermopathy and Nephrogenic Systemic Fibrosis

In 2000, a previously unknown fibrosing skin disorder, resembling scleromyxedema, was first described in haemodialysis patients. At the time it was termed Nephrogenic Fibrosing Dermopathy (NFD) (Cowper, 2000), and the histopathology and differentiating features from other fibrosing disease were described later (Cowper, 2001). Ongoing research revealed that the fibrosis was not limited to the skin and subcutis, but that it was a generalized fibrotic process, which can also involve heart and pericardium, lung and pleura, muscles, diaphragm, renal tubules and the rete testis. Therefore the name was changed to Nephrogenic Systemic Fibrosis (NSF).

In 2006 the use of gadolinium was first linked to the development of NSF in patients with end-stage renal disease who developed NSF within 2-4 weeks after gadodiamide-enhanced MRA (Grobner, 2006). Almost simultaneously, another Danish group reported on thirteen patients (eight dialysis-dependent) who developed NSF after administration of 18,5 ± 5,5 mmol gadodiamide (Marckmann, 2006). The exact aetiology of NSF is unknown. There is a constant association with severe renal insufficiency, usually CKD grade 5 or dialysis. No association with the cause of the renal insufficiency has been shown and there is no indication that dialysis can induce the disease, but many patients have a history of a failed renal transplantation.

Clinical features of NSF

NSF is an illness of all age groups (8 to 87 years) without predilection for race or sex. There can be a fulminant course in 5% of cases. All affected patients have severe chronic kidney disease (CKD), while the majority is dialysis-dependent, either haemodialysis or peritoneal dialysis. The primary cutaneous lesions consist of pink, erythematous papules that coalesce into erythematous plaques and ill-demarcated brawny plaques with a ‘peau d’orange’ surface. The skin (and subcutis) is thickened and has a hardened, woody texture. The extremities are involved most frequently, the legs more often than the arms. Involvement is usually symmetrical, with extension from the ankles to the thighs and from the wrists to the upper arms. The trunk is less frequently involved. Contractures can occur in involved joints, and may lead to severe disability (days to weeks). In the involved extremities itching and sharp pains can be present.

The disease resembles the very rare scleromyxedema. ß2-microglobulin amyloidosis can also induce fibrosis in patients with advanced CKD. Other possible differential diagnoses include scleroderma, morphea (localized scleroderma), scleroedema, eosinophilic fasciitis, calciphylaxis, porphyria cutanea, and even dermatofibrosarcoma protuberans (DFSP). In an early phase there may be overlap with cellulitis, panniculitis, or drug-reactions.

NSF is a clinical and histopathological diagnosis. Laboratory tests are non-specific or related to the underlying disease. A deep skin biopsy shows irregularly thickened collagen- and elastin bundles with clefts and increased deposition of dermal mucin. Between these bundles fibroblastic cells are deposited are positive for CD-34, CD-45RO, and procollagen I. Also, large dendritic cells are present, positive for CD-68 and Factor XIIIa. Leukocytes or lymphocytes are only present in a limited number. Diagnosis of NSF is currently based on the clinicopathologic Girardi criteria (Girardi, 2011).

There is no effective treatment for NSF, and prevention is therefore very important. Restoring renal function rapidly by renal transplantation may be the best treatment.

End of 2013, the FDA Adverse Event Reporting System included 1603 NSF cases. Cases were associated with GBCA exposure before 2010, while few (if any) cases were associated with GBCA exposure after 2010. Most cases originated from USA in patients aged 51 to 60 years. Of the cases, 88% occurred in stage 5 CKD (eGFR < 15 ml/min/1.73m²) and 10% in patients with acute renal failure. Among the risk factors, chronic liver disease is no longer a significant risk factor (Smorodinsky, 2015; Fraum, 2017).

Association of NSF with gadolinium-based contrast agents

Many retrospective case-control studies have found a significant association between GBCA administration and the risk of NSF (Edwards, 2014; Zhang, 2017; Zou, 2011). Almost all unconfounded cases (i.e. definitely associated with one GBCA) are associated with linear GBCA, especially gadodiamide, but not with macrocylic GBCA. Risk factor analyses have shown that a higher cumulative linear GBCA dose (either from using high dose injections or a greater number of MRI examinations) and previous inflammatory conditions (either thrombosis or endothelial damage from vascular or transplantation surgery) are associated with increased risk (Van der Molen, 2008; Thomsen, 2016). The initial retrospective studies investigating the association between NSF and GBCA were limited by selection bias. Another important limitation is the considerable geographic differences exist in the number of reported cases, that cannot be explained by differences in patient populations and are thus possibly exist due to differences in reporting of NSF cases or medicolegal systems (Thomsen, 2016; Endrikat, 2018). Of all countries using gadolinium based contrast agents world-wide, one of the countries with the highest NSF awareness, Denmark, reported the highest prevalence worldwide with 12 cases per million inhabitants based on cases reported between 2006 and 2012 (Elmholdt, 2013).

In the published NSF cases that described a link to linear GBCAs, patients presented with symptoms starting within 2-3 months of CM administration. However also much longer delays have been described of even up to 1 to 6 years in limited number of cases. Suggested explanations for this variability between time to linear GBCA exposure and the onset of NSF symptoms are slow mobilization of Gd over time from skin or bone stores.

Analysis of cases registered at Bayer Healthcare revealed that year of market introduction and US market share 2000 to 2007 influenced the absolute number of NSF reports for each GBCA, as well as their a priori probability to cause NSF (Endrikat, 2018).

In the most recent review of 693 patients with biopsy-confirmed NSF, it was shown that only 7 cases were associated with GBCA-exposure after 2008. This indicates that the regulatory actions and practice changes have been very effective. Factors that were associated with NSF included exposure to high-risk GBCA, haemodialysis, pro-inflammatory conditions, β-blockers, hyperphosphataemia, and epoetin. For low-risk GBCA there is no need for screening of renal function prior to contrast administration (Attari, 2019).

III Gadolinium Deposition in the Brain and Body

A. Gadolinium Deposition in the Brain

Clinical studies

In 2014, it was suggested that the retrospectively observed hyperintensity of the dentate nucleus and the globus pallidus relative to the pons (dentate nucleus to pons (DNP) ratio) on unenhanced T₁-weighted images of a population of patients with brain tumours, was related to repeated administrations of linear GBCAs (Kanda, 2014). Almost simultaneously, another group reported similar findings on unenhanced T₁-weighted brain images after multiple injections of gadodiamide in patients with multiple sclerosis and patients with brain metastases (Errante, 2014).

After these initial reports, a multitude of retrospective studies have found increased SI in the dentate nucleus and or globus pallidus for linear GBCA. No such increases were found for macrocyclic GBCA, even after large doses (Radbruch, 2015; Ramalho, 2016; Radbruch, 2017). In a recent systematic review of these studies by the ESMRMB Gadolinium Research Evaluation Committee (now ESMRMB-GREC) it was shown that there was large variety in sequence type and evaluation methodologies (Quattrocchi, 2019).

One of the biggest problems is that increased SI ratios at unenhanced T₁-weighted MRI are a poor biomarker for gadolinium deposition, as SI ratios do not have linear relationship with Gd concentration, and are highly dependent on the MRI parameters used during acquisition. Absolute signal intensity (expressed in arbitrary units) in MRI depends on many MRI parameters such as field strength, sequence type/parameters, coil sensitivity/filling factor, coil tuning/matching drift, etc. Since little is known about which forms of gadolinium are present (speciation), signal intensities, or changes thereof, will not reflect true changes in gadolinium content (McDonald, 2018; Quattrocchi, 2019).

Preclinical studies

Preclinical studies in rat brains have highlighted the importance of in vivo dechelation of Gd³⁺ ions from less stable GBCAs, regardless of the presence of a renal dysfunction and with a clear dose-effect relationship. All quantities were in the nmol per gram tissue range. They have also shown that differences exist in the amount of total gadolinium retained in the brain when comparing different GBCA compounds (Robert, 2015; Jost, 2016; Robert, 2017; Smith, 2017).

To date it is unclear what forms are responsible for the increased T₁w signal increase (gadolinium speciation). Recently, it was shown that for gadolinium in the rat brain 3 different chemical forms have to be distinguished: intact chelate, gadolinium bound to macromolecules, and insoluble gadolinium salts (Frenzel, 2017). The intact chelates were found for both linear and macrocyclic GBCA, but the other forms only for linear GBCA. As precipitated gadolinium does not induce any MRI signal when excitated, it is likely that the gadolinium bound to macromolecules is responsible for the visible T₁w hyperintensity in clinical MRI (Gianolio, 2017).

Well-conducted long-term animal studies demonstrated that for linear GBCA a large portion of gadolinium was retained in the brain, with binding of soluble gadolinium to macromolecules. For macrocyclic GBCA only traces of the intact chelated gadolinium were present with complete washout in time (Robert, 2018; Jost, 2019).

Intact GBCA does not cross the intact blood-brain barrier. It is now believed that GBCA can reach the CSF via the choroid plexus and ciliary body and can reach the brain interstitium via the glympathic system along perineural sheaths and perivascular spaces of penetrating cortical arteries. GBCA distributed into the cerebrospinal fluid cavity via the glymphatic system may remain in the eye or brain tissue for a longer duration compared to the GBCA in systemic circulation. The glympathic system may be responsible for deposition in linear GBCA as well as for GBCA clearance (Taoka, 2018; Deike-Hofmann, 2019).

B. Gadolinium Deposition in the Body

Most data mentioned below are all from preclinical studies in animals.

Gadolinium deposition in bone

Lanthanide metals (gadolinium, samarium, europium, and cerium) have long been known to deposit in bone tissue and have effects on osteoblasts and osteoclasts, but the exact mechanisms are not yet well understood (Vidaud, 2012).

Gadolinium deposits have been found in samples of bone tissues of humans at higher concentrations than in brain tissue after administration of linear and macrocyclic GBCA, whereby linear GBCA deposit 4 to 25 times more than macrocyclic GBCA (White, 2006; Darrah, 2009; Wang, 2015; Murata, 2016).

The bone residence time for macrocyclic GBCA (up to 30 days) is much shorter than for linear GBCA (up to 8 years) (Darrah, 2009; Lancelot, 2016). Bone may serve as a storage compartment from which Gd is later released in the body (Thakral, 2007). It is postulated that the long-term reservoir of gadolinium in bones might implicate that some patients with high bone turnover, such as menopausal women and patients with osteoporosis may be more vulnerable to gadolinium deposition (Darrah, 2009).

Gadolinium deposition in skin

Gadolinium depositions in skin have been demonstrated ever since the association of GBCA with nephrogenic systemic fibrosis in 2006. See also section on NSF.

In skin biopsies of NSF patients, gadolinium was found along collagen bundles but also as insoluble apatite-like deposits, suggesting dechelation (Sieber, 2009; Thakral, 2009). After linear GBCA, gadolinium deposits were found up to 40-180 times more frequently than after macrocyclic GBCA, histologic changes are more extensive, and also products of dechelation of GBCA can be found (Haylor, 2012; Wang, 2015).

Recently, gadolinium has also been found in the skin of patients with normal renal function after high cumulative GBCA doses (Roberts, 2016). With normal renal function even a case of ‘gadolinium-associated plaques’ has been described, which suggest that gadolinium deposition in the skin after linear GBCA might give clinically relevant symptoms (Gathings, 2015).

Gadolinium deposition in other organs

Thus far, very little is published about the effects of gadolinium deposition in other organs.

In a clinical study in the liver, gadolinium deposits have been associated with iron overload in the livers of paediatric stem cell transplantation patients with normal renal function, reacting well to iron dechelation therapy (Maximova, 2016).

Based on animal studies, it has been suggested that residual Gd is also present in tissues samples of kidney, liver, spleen, and testis (Tweedle, 1995; Wang, 2015; McDonald, 2017; Di Gregorio, 2018; Mercantepe, 2018; Celiker, 2018; Celiker, 2019). While deposition in the brain was only 2 to 7 μg Gd, the amounts in other organs varied 168 to 2134 μg Gd for kidney, 16 to 388 μg Gd for liver, and 18 to 354 μg Gd for spleen, all per gram of tissue. In all tissues the level was highest for the linear GBCA gadodiamide (McDonald, 2017).

Self-reported clinical symptoms

Thus far, gadolinium deposition has not been associated with clinical symptoms.

Small online gadolinium toxicity support groups in USA have claimed that their members have manifested symptoms analogous to NSF and have prolonged excretion of Gd in urine following administration of GBCA. Surveys have shown variable symptoms that occur either directly or within 6 weeks of GBCA administration. Most reported symptoms are burning sensation and bone pain in lower arms and limbs, central torso pain, headache with vision/hearing changes, and skin thickening and discoloration (Burke, 2016; Semelka, 2016).

This complex of symptoms was coined “gadolinium deposition disease (GDD)”. The critical findings are the presence of gadolinium in the body beyond 30 days, combined with at least 3 of the following features, with onset after the administration of GBCA: i) central torso pain, ii) headache and clouded mentation, iii) peripheral leg and arm pain, iv) peripheral leg and arm thickening and discoloration, and v) bone pain (Semelka, 2016).

Significant differences in gadolinium levels in bone and urine have been observed between individuals experiencing symptoms and those who are not (Lord, 2018). A large study with a control population found more new symptoms within 24 h after exposure to GBCA than after unenhanced MRI. From the GDD-like symptoms, only fatigue and mental confusion were more frequently reported after enhanced MRI, questioning the term GDD (Parillo, 2019).

IV The effect of NSF and the EMA ruling

In many European countries, the described association between NSF and exposure to linear GBCAs in 2006 has resulted in the fact that most hospitals switched early (2007 and onwards) to macrocyclic GBCA use only, in most cases gadoterate or gadobutrol. After the series of publications describing increased signal intensities in the brain nuclei on unenhanced T1-weighted imaging after multiple linear GBCA exposures and post-mortem studies revealing the presence of small amounts of gadolinium in neural tissues, the European Medicines Agency instituted an article 31 procedure which eventually led to the withdrawal of EU market authorizations of the high-risk linear GBCA gadodiamide and gadoversetamide, as well as restrictions on the use of gadopentetate (MR Arthrography only) and, gadobenate (liver imaging only) (EMA, 2017; Dekkers, 2018). Therefore, for general use in MRI only macrocyclic GBCA are available, while the linear GBCA gadoxetate and gadobenate are available for liver-specific MRI.

Gadolinium metabolism and deposition still has many knowledge gaps for which an international research agenda is important. The ACR/NIH/RSNA Meeting 2018 has made a good inventory where future research should be aimed at (McDonald, 2018).

References (and suggestions for further reading)

Aime S, Caravan P. Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. J Magn Reson Imaging 2009; 30: 1259-1267.

Attari H, Cao Y, Elmholdt TR, Zhao Y, Prince MR. A systematic review of 639 patients with biopsy-confirmed Nephrogenic Systemic Fibrosis. Radiology 2019; in press. Doi: 10.1148/radiol.2019182916.

Balzer T. Presence of gadolinium (Gd) in the brain and body. Presentation to the Medical Imaging Drugs Advisory Committee, FDA. Silver Spring, MD: U.S. Food and Drug Administration, 2017.

Bellin MF, Van Der Molen AJ. Extracellular gadolinium-based contrast media: an overview. Eur J Radiol 2008; 66: 160-167.

Burke LM, Ramalho M, Al Obaidy M, Chang E, Jay M, Semelka RC. Self-reported gadolinium toxicity: a survey of patients with chronic symptoms. Magn Reson Imaging 2016; 34: 1078-1080.

Caravan P, Ellison J, McMurry TJ, Lauffer RB. Gadolinium (III) chelates as MRI contrast agents: structure, dynamics and applications. Chem Rev 1999; 99: 2293–2352.

Çeliker FB, Tumkaya L, Mercantepe T, Beyazal M, Turan A, Beyazal Polat H, et al. Effects of gadodiamide and gadoteric Acid on rat kidneys: A comparative study. J Magn Reson Imaging 2019; 49: 382-389.

Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000; 356: 1000–1001.

Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE. Nephrogenic fibrosing dermopathy. Am J Dermatopathol 2001; 23: 383–393.

Darrah TH, Prutsman-Pfeiffer JJ, Poreda RJ, Ellen Campbell M, Hauschka PV, Hannigan RE. Incorporation of excess gadolinium into human bone from medical contrast agents. Metallomics 2009; 1: 479-488.

De Kerviler E, Maravilla K, Meder JF, Naggara O, Dubourdieu C, Jullien V, et al. Adverse reactions to gadoterate meglumine: review of over 25 years of clinical use and more than 50 million doses. Invest Radiol 2016; 51: 544-551.

De León-Rodríguez LM, Martins AF, Pinho MC, Rofsky NM, Sherry AD. Basic MR relaxation mechanisms and contrast agent design. J Magn Reson Imaging 2015; 42: 545-565.

Deike-Hofmann K, Reuter J, Haase R, Paech D, Gnirs R, Bickelhaupt S, et al. Glymphatic pathway of gadolinium-based contrast agents through the brain: overlooked and misinterpreted. Invest Radiol 2019; 54: 229-237.

Dekkers IA, Roos R and. van der Molen AJ. Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency. Eur Radiol 2018; 28: 1579–1584.

Di Gregorio E, Ferrauto G, Furlan C, Lanzardo S, Nuzzi R, Gianolio E, et al. The issue of gadolinium retained in tissues insights on the role of metal complex stability by comparing metal uptake in murine tissues upon the concomitant administration of lanthanum- and gadolinium-diethylene-triaminopenta-acetate. Invest Radiol 2018; 53: 167–172.

Edwards BJ, Laumann AE, Nardone B, Miller FH, Restaino J, Raisch DW, et al. Advancing pharmacovigilance through academic-legal collaboration: the case of gadolinium-based contrast agents and nephrogenic systemic fibrosis-a Research on Adverse Drug Events and Reports (RADAR) report. Br J Radiol 2014; 87(1042): 20140307.

Elmholdt TR, Olesen AB, Jørgensen B, Kvist S, Skov L, Thomsen HS, et al. Nephrogenic systemic fibrosis in Denmark - a nationwide investigation. PLoS One 2013; 8: e82037; erratum in PloS One 2014; 9: e100407.

Elster AD. T1 shortening by Gad. Available at: http://mriquestions.com/why-does-gd-shorten-t1.html. (a great website for MRI physics & technology).

Endrikat J, Dohanish S, Schleyer N, Schwenke S, Agarwal S, Balzer T. 10 years of nephrogenic systemic fibrosis: a comprehensive analysis of nephrogenic systemic fibrosis reports received by a pharmaceutical company from 2006 to 2016. Invest Radiol 2018; 53: 541-550.

Errante Y, Cirimele V, Mallio CA, Di Lazzaro V, Zobel BB, Quattrocchi CC. 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. Invest Radiol 2014; 49: 685-690.

European Medicines Agency. EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans (21 july 2017). Available at: https://www.ema.europa.eu/en/documents/referral/gadolinium-article-31-referral-emas-final-opinion-confirms-restrictions-use-linear-gadolinium-agents_en-0.pdf Accessed: 11 July 2019.

Fraum TJ, Ludwig DR, Bashir MR, Fowler KJ. Gadolinium-based contrast agents: A comprehensive risk assessment. J Magn Reson Imaging 2017; 46: 338-353.

Frenzel T, Lengsfeld P, Schirmer H, Hütter J, Weinmann HJ. Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37° C. Invest Radiol 2008; 43: 817-828.

Frenzel T, Apte C, Jost G, Schöckel L, Lohrke J, Pietsch H. Quantification and assessment of the chemical form of residual gadolinium in the brain after repeated administration of gadolinium-based contrast agents: comparative study in rats. Invest Radiol 2017; 52: 396-404.

Gathings RM, Reddy R, Santa Cruz D, Brodell RT. Gadolinium-associated plaques: a new, distinctive clinical entity. JAMA Dermatol 2015; 151: 316-319.

Gianolio E, Bardini P, Arena F, Rachel S, Di Gregorio E, Iani R, et al. Gadolinium retention in the rat brain: assessment of the amounts of insoluble gadolinium-containing species and intact gadolinium complexes after repeated administration of gadolinium-based contrast agents. Radiology 2017; 285: 839–849.

Girardi M, Kay J, Elston DM, Leboit PE, Abu-Alfa A, Cowper SE. Nephrogenic systemic fibrosis: clinicopathological definition and workup recommendations. J Am Acad Dermatol 2011; 65: 1095-1106.e7.

Grobner T. Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006; 21: 1104–1108 (Erratum in: Nephrol Dial Transplant 2006; 21: 1745).

Hao D, Ai T, Goerner F, Hu X, Runge VM, Tweedle M. MRI contrast agents: basic chemistry and safety. J Magn Reson Imaging 2012; 36: 1060–1071.

Idée JM, Port M, Raynal I, Schaefer M, Le Greneur S, Corot C. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam Clin Pharmacol 2006; 20: 563–576.

Idée JM, Fretellier N, Robic C, Corot C. The role of gadolinium chelates in the mechanism of nephrogenic systemic fibrosis: A critical update. Crit Rev Toxicol 2014; 44: 895-913.

Joffe P, Thomsen HS, Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol 1998; 5: 491–502.

Jost G, Lenhard DC, Sieber MA, Lohrke J, Frenzel T, Pietsch H. Signal increase on unenhanced T1-weighted images in the rat brain after repeated, extended doses of gadolinium-based contrast agents: comparison of linear and macrocyclic agents. Invest Radiol 2016; 51: 83–89.

Jost G, Frenzel T, Lohrke J, Lenhard DC, Naganawa S, Pietsch H. Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: A potential pathway of entry into the brain. Eur Radiol 2017; 27:2877–2885.

Jost G, Frenzel T, Boyken J, Lohrke J, Nischwitz V, Pietsch H. Long-term excretion of gadolinium-based contrast agents: linear versus macrocyclic agents in an experimental rat model. Radiology 2019; 290: 340-348.

Kanal E. Gadolinium based contrast agents (GBCA): Safety overview after 3 decades of clinical experience. Magn Reson Imaging 2016; 34: 1341–1345.

Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D. 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 2014; 270: 834-841.

Lancelot E. Revisiting the pharmacokinetic profiles of gadolinium-based contrast agents. Invest Radiol 2016; 51: 691-700.

Le Fur M, Caravan P. The biological fate of gadolinium-based MRI contrast agents: a call to action for bioinorganic chemists. Metallomics 2019; 11: 240-254.

Lin SP, Brown JJ. MR contrast agents: physical and pharmacologic basics. J Magn Reson Imaging 2007; 25: 884–899.

Lohrke J, Frenzel T, Endrikat J, Alves FC, Grist TM, Law M, et al. 25 years of contrast-enhanced MRI: developments, current challenges and future perspectives. Adv Ther 2016; 33: 1–28.

Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006; 17: 2359-2362.

Maximova N, Gregori M, Zennaro F, Sonzogni A, Simeone R, Zanon D. Hepatic gadolinium deposition and reversibility after contrast agent-enhanced MR imaging of pediatric hematopoietic stem cell transplant recipients. Radiology 2016; 281: 418-426.

McDonald RJ, McDonald J, Kallmes D, Jentoft ME, Murray DL, Thielen KR, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015; 275: 772-782.

McDonald RJ, McDonald JS, Dai D, Schroeder D, Jentoft ME, Murray DL, et al. Comparison of gadolinium concentrations within multiple rat organs after intravenous administration of linear versus macrocyclic gadolinium chelates. Radiology 2017; 285: 536-545.

McDonald RJ, Levine D, Weinreb J, Kanal E, Davenport MS, Ellis JH, et al. Gadolinium retention: a research roadmap from the 2018 NIH/ACR/RSNA workshop on gadolinium chelates. Radiology 2018; 289: 517-534.

Mercantepe T, Tümkaya L, Çeliker FB, Topal Suzan Z, Çinar S, Akyildiz K, et al. Effects of gadolinium-based MRI contrast agents on liver tissue. J Magn Reson Imaging 2018; 48: 1367-1374.

van der Molen AJ. Nephrogenic systemic fibrosis and the role of gadolinium contrast media. J Med Imaging Radiat Oncol 2008; 52: 339-350.

Murata N, Gonzalez-Cuyar LF, Murata K, Fligner C, Dills R, Hippe D, et al. Macrocyclic and other non–group 1 gadolinium contrast agents deposit low levels of gadolinium in brain and bone tissue. Invest Radiol 2016; 51: 447-453l

Port M, Idee JM, Medina C, Robic C, Sabatou M, Corot C. Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review. Biometals 2008; 21: 469–490l

Parillo M, Sapienza M, Arpaia F, Magnani F, Mallio CA, DʼAlessio P, et al. A structured survey on adverse events occurring within 24 hours after intravenous exposure to gadodiamide or gadoterate meglumine: a controlled prospective comparison study.Invest Radiol 2019; 54: 191-197.

Pietsch H, Lengsfeld P, Jost G, Frenzel T, Hütter J, Sieber MA. Long-term retention of gadolinium in the skin of rodents following the administration of gadolinium-based contrast agents. Eur Radiol 2009; 19: 1417-1424.

Pullicino R, Radon M, Biswas S, Bhojak M, Das K. A Review of the Current evidence on gadolinium deposition in the brain. Clin Neuroradiol 2018; 28: 159-169.

Quattrocchi CC, Ramalho J, van der Molen AJ, Rovira À, Radbruch A; GREC, European Gadolinium Retention Evaluation Consortium and the ESNR, European Society of Neuroradiology. Standardized assessment of the signal intensity increase on unenhanced T1-weighted images in the brain: the European Gadolinium Retention Evaluation Consortium (GREC) Task Force position statement. Eur Radiol 2019.

Radbruch A, Weberling LD, Kieslich PJ, et al. High-signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evaluation of the macrocyclic gadolinium-based contrast agent gadobutrol. Invest Radiol 2015; 50: 805–810.

Radbruch A, Haase R, Kieslich PJ, Weberling LD, Kickingereder P, Wick W, et al. No signal intensity increase in the dentate nucleus on unenhanced T1-weighted MR images after more than 20 serial injections of macrocyclic gadolinium-based contrast agents. Radiology 2017; 282: 699-707.

Ramalho J, Semelka RC, Al-Obaidy M, Ramalho M, Nunes RH, Castillo M. Signal intensity change on unenhanced T1-weighted images in dentate nucleus following gadobenate dimeglumine in patients with and without previous multiple administrations of gadodiamide. Eur Radiol 2016; 26: 4080–4088.

Robert P, Lehericy S, Grand S, Violas X, Fretellier N, Idée JM, Ballet S, Corot C. 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. Invest Radiol 2015; 50: 473-480.

Robert P, Violas X, Grand S, Lehericy S, Idée JM, Ballet S, Corot C. Linear gadolinium-based contrast agents are associated with brain gadolinium retention in healthy rats. Invest Radiol 2016; 51: 73-82.

Robert P, Frenzel T, Factor C, et al. Methodological aspects for preclinical evaluation of gadolinium presence in brain tissue: critical appraisal and suggestions for harmonization. A joint initiative. Invest Radiol 2018; 53: 499–517.

Robert P, Fingerhut S, Factor C, Vives V, Letien J. Sperling M, et al. One-year retention of gadoliniumin the brain: comparison of gadodiamide and gadoterate meglumine in a rodent model. Radiology 2018; 288: 424–433.

Roberts DR, Lindhorst SM, Welsh CT, Maravilla KR, Herring MN, Braun KA, et al. High levels of gadolinium deposition in the skin of a patient with normal renal function. Invest Radiol 2016; 51: 280-289.

Rogosnitzky M, Branch S. Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms. Biometals 2016; 29: 365–376.

Rohrer M, Bauer H, Mintorovitch J, Requard M, Weinmann HJ. Comparison of magnetic properties of MRI contrast media solutions at different field strengths. Invest Radiol 2005; 40: 715–724.

Semelka RC, Ramalho J, Vakharia A, Al Obaidy M, Burke LM, Jay M, et al. Gadolinium deposition disease: Initial description of a disease that has been around for a while. Magn Reson Imaging 2016; 34: 1383-1390.

Sieber MA, Lengsfeld P, Frenzel T, Golfier S, Schmitt-Willich H, Siegmund F, et al. Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions. Eur Radiol 2008; 18: 2164-2173.

Smith AP, Marino M, Roberts J, Crowder JM, Castle J, Lowery L, Morton C, Hibberd MG, Evans PM. Clearance of gadolinium from the brain with no pathologic effect after repeated administration of gadodiamide in healthy rats: an analytical and histologic study. Radiology 2017; 282: 743-751.

Taoka T, Naganawa S. Gadolinium-based contrast media, cerebrospinal fluid and the glymphatic system: possible mechanisms for the deposition of gadolinium in the brain. Magn Reson Med Sci 2018; 17: 111-119.

Thakral C, Alhariri J, Abraham JL. Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications. Contrast Media Mol Imaging 2007; 2: 199-205.

Thakral C, Abraham JL. Nephrogenic systemic fibrosis: histology and gadolinium detection. Radiol Clin North Am 2009; 47: 841-853.

Thomsen HS. Nephrogenic systemic fibrosis: A serious late adverse reaction to gadodiamide. Eur Radiol 2006; 16: 2619–2621.

Thomsen HS, Marckmann P. Extracellular GBCA: differences in prevalence of NSF. Eur J Radiol 2008; 66: 180-183.

Thomsen HS, Morcos SK, Almén T, et al. Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Medium Safety Committee guidelines. Eur Radiol 2013; 23: 307-318..

Thomsen HS. Nephrogenic systemic fibrosis: a serious adverse reaction to gadolinium – 1997-2006-2016. Part 1 Acta Radiol 2016; 57: 515-520.

Thomsen HS. Nephrogenic systemic fibrosis: a serious adverse reaction to gadolinium – 1997-2006-2016. Part 2 Acta Radiol 2016; 57: 643-648.

Tweedle MF, Wedeking P, Kumar K. Biodistribution of radiolabeled, formulated gadopentetate, gadoteridol, gadoterate, and gadodiamide in mice and rats. Invest Radiol 1995; 30: 372-380.

Vidaud C, Bourgeois D, Meyer D. Bone as target organ for metals: the case of f-elements. Chem Res Toxicol 2012; 25: 1161-1175.

Wahsner J, Gale EM, Rodríguez-Rodríguez A, Caravan P. Chemistry of MRI contrast agents: current challenges and new frontiers. Chem Rev. 2018 Oct 16. doi: 10.1021/acs.chemrev.8b00363..

Wang YX, Schroeder J, Siegmund H, Idée JM, Fretellier N, Jestin-Mayer G, et al. Total gadolinium tissue deposition and skin structural findings following the administration of structurally different gadolinium chelates in healthy and ovariectomized female rats. Quant Imaging Med Surg 2015; 5: 534-545.

White GW, Gibby WA, Tweedle MF. 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. Invest Radiol 2006; 41: 272-278.

Zhang B, Liang L, Chen W, Liang C, Zhang S.An Updated Study to Determine Association between Gadolinium-Based Contrast Agents and Nephrogenic Systemic Fibrosis. PLoS One 2015; 10: e0129720.

Zou Z, Zhang HL, Roditi GH, Leiner T, Kucharczyk W, Prince MR. Nephrogenic systemic fibrosis: review of 370 biopsy-confirmed cases. JACC Cardiovasc Imaging 2011; 4: 1206-1216.

Recent Guidelines:

American College of Radiology. ACR Manual on contrast media, v10.3. Available at: www.acr.org/Clinical-Resources/Contrast-Manual. Accessed: 11 July 2019.

European Society of Urogenital Radiology Contrast Media Safety Committee. ESUR Guidelines on contrast safety, v10. Available at: www.esur-cm.org. Accessed: 11 July 2019.

Costa AF, van der Pol CB, Maralani PJ, McInnes MDF, Shewchuk JR, Verma R, et al. Gadolinium deposition in the brain: a systematic review of existing guidelines and Policy Statement issued by the Canadian Association of Radiologists. Can Assoc Radiol J 2018; 69: 373-382.

Schieda N, Maralani PJ, Hurrell C, Tsampalieros AK, Hiremath S. Updated clinical practice guideline on use of Gadolinium-Based Contrast Agents in kidney disease issued by the Canadian Association of Radiologists. Can Assoc Radiol J 2019; in press. doi: 10.1016/j.carj.2019.04.001.