Gadolinium-based contrast agents (GBCA) 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, 2021). Since their introduction in 1988, an estimate of 700 million doses have been delivered and the current (end of 2021) estimated use is 50 million doses per year (Balzer, 2017; Endrikat, 2018, McDonald, 2018; Bayer AG estimates based on various internal and external data, 2022). Overall, 30--45% of the MRI scans have used GBCAs, with high contributions in current sales by Neuroradiology (~40%) and Cardiovascular Radiology (~20%) (Bayer AG estimates, based on various internal and external data, 2022).

1. 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; Hao, 2012; Lin, 2007).

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) (Supplemental Table S2).

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 Ktherm describes the affinity of Gd for the ligand and is normally measured at pH = 14. Higher values imply a higher stability. Ktherm = (ML) / (M) · (L).

For biological systems more appropriate is the logarithm of the apparent or conditional thermodynamic stability constant Kcond, 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. Kcond = (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 commonly described as the half-life of the dissociation of the Gd-Ligand complex or by the observed dissociation constant kobs. To be measurable, such kinetic analyses are done under acidic conditions at pH =1 (Port, 2008). Dissociation rate = kobs (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 PO43- and CO32- 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 Supplemental Table S2.

Biodistribution and Elimination (see Module 10.1 for more details)

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).

2. Gadolinium Deposition in the Brain and Body (See Module 4.2.2 for update 2022)

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 and 2017; Ramalho, 2016). 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 (Jost, 2016; Robert, 2015 and 2017; Smith, 2017).

To date it is unclear what forms are responsible for the T1w signal increase (gadolinium speciation). Recently, it was shown that for gadolinium in the rat brain 3 different chemical forms must 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 change in 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 (Jost, 2019; Robert, 2018).

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 (Deike-Hofmann, 2019; Taoka, 2018).

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 (Darrah, 2009; Murata, 2016; White, 2006; Wang, 2015).

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 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, 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 (Celiker, 2018 and 2019; Di Gregorio, 2018; McDonald, 2017; Mercantepe, 2018; Tweedle, 1995; Wang, 2015) 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, except for NSF. 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,