What Nephrologists Need to Know About Gadolinium

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Author(s)

Jeffrey G Penfield, MD

Staff Physician, Section of Nephrology, Veterans Affairs North Texas Health Care System, Dallas, Texas; Assistant Professor of Medicine, Department of Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas

Disclosures

Disclosure: Jeffrey G. Penfield, MD, has disclosed no relevant financial relationships.

Robert F Reilly, Jr, MD

Professor of Medicine; Fredric L. Coe Professor of Nephrolithiasis Research; Chief, Division of Nephrology, VA North Texas Health Care System, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Disclosures

Disclosure: Robert F. Reilly, Jr., MD, has disclosed no relevant financial relationships.

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Gadolinium

Gadolinium is a rare earth element from the lanthanide series that is used as a contrast agent in MRI because of its powerful paramagnetic properties. Its seven unpaired electrons perturb proton relaxation in water, resulting in a shortened T1 relaxation time and increased magnetic resonance signal intensity. Gadolinium in its unbound state is highly toxic. It is a potent inhibitor of calcium channels and has considerable cardiovascular and neurologic toxicity. In mice, the median lethal dose (LD₅₀; i.e. the amount required to kill 50% of the population) of GdCl₃ is just 100-200 mg/kg.^[1] Free gadolinium is deposited in liver, bone and lymph nodes and, once there, is slowly released from the body at a rate of less than 1% per day.^[2]

Gadolinium must be chelated for use in humans. Chelation improves the water solubility and reduces the toxicity of the agent. The LD₅₀ in rodents increases 100-fold with chelation.^[3]Five different gadolinium chelates are approved in the US by the FDA for use as MRI agents (shown in Table 1). In the US, approximately 26.9 million MRI scans were performed in 2006 and in 45% of these cases a gadolinium chelate was administered.^[4]To date, more than 200 million patients worldwide have been exposed to gadolinium chelates.5

The only FDA-approved indication for gadolinium chelates is use as a contrast agent in MRI at a dose of 0.1 mmol/kg.^[6] These agents are also used for magnetic resonance angiography (MRA) and as contrast agents in arteriography and venography, but these are not FDA-approved indications. Dosages for these procedures are not standardized, but in a 1999 survey the nephrotoxicity of doses as high as 0.9 mmol/kg was not considered to be important by the majority of practitioners.^[7]

The pharmacokinetic properties of most gadolinium chelates are similar. The compounds are water soluble, excreted unchanged by glomerular filtration, do not undergo biotransformation, and are distributed in extracellular fluid. Notable exceptions to these rules include gadoxetic acid (Primovist^®; Bayer Schering Pharma, Berlin, Germany), gadofosveset trisodium (Vasovist^®; Bayer Schering Pharma) and gadobenate dimeglumine (MultiHance^®; Bracco Diagnostics, Princeton, NJ). Gadoxetic acid is taken up by hepatocytes; up to 50% of the agent is excreted in feces and 50% in urine. The chelate is used for enhanced imaging of the liver.^[8] Between 80-96% of circulating gadofosveset trisodium is bound to plasma proteins, and the compound has been used as a blood pool agent.^[9] Only a small proportion of circulating gadobenate dimeglumine is protein bound; it is taken up by hepatocytes and has a fecal excretion rate of 4%.^[10] Other gadolinium chelates are not bound by proteins or eliminated in feces. Molecular weights of the compounds range from 558 to 1,058 daltons. The half-life of gadolinium chelates in patients with normal renal function is approximately 1.5 hours, and more than 90% of a dose is excreted in 24 hours (Table 1).

The differences in the effects of various gadolinium preparations are attributable to gadolinium's capacity to dissociate from chelates. The LD₅₀s in rodents for various gadolinium chelates were found to vary up to 50-fold, but all were lethally toxic when the same amount of gadolinium was released from the chelate.^[11] Gadodiamide (Omniscan^®; GE Healthcare, Chalfont St Giles, Buckinghamshire, UK) has the shortest dissociation constant—30 seconds compared with 10 minutes and with 3 hours for gadopentetate dimeglumine (Magnevist^®; Bayer HealthCare Pharmaceuticals, Montville, NJ) and gadoteridol (ProHance^®, Bracco Diagnostics), respectively. The longer dissociation constant of gadoteridol is probably a function of its cyclic structure; most other gadolinium chelates have a linear structure. Release of gadolinium from a cyclic chelate requires all four covalent bonds to be broken simultaneously. The more flexible structure of linear chelates more readily facilitates gadolinium release. This fact might account for the higher incidence of NSF associated with gadodiamide and gadopentetate dimeglumine. These two agents are the gadolinium preparations most frequently used in the US, which could account for a proportion of the increased incidence of NSF associated with these chelates. Market share alone does not, however, explain the disparity in the number of cases reported to be caused by these two agents.

The propensity of gadolinium chelates to undergo transmetalation might influence their toxicity. Transmetalation refers to the capacity of other cations in the body (e.g. zinc, copper and calcium) to displace gadolinium from its chelate.^[12] Copper has high affinity for the chelates, but is not present in the body at sufficient concentrations to displace large amounts of gadolinium. The concentration of calcium in serum is high, but the affinity of calcium for chelates is low. Zinc has moderate affinity and a sufficiently high serum concentration to displace gadolinium.^[11] In humans and experimental models, the extent of transmetalation can be evaluated in vivo as urinary zinc excretion. If gadolinium is displaced from its chelate by zinc, zinc binds the chelate and is subsequently excreted in urine. There are marked differences among the gadolinium chelates in the rates of short-term (within 3 hours) urinary zinc excretion after administration of 0.1 mmol/kg of chelate. Interestingly, these differences correspond to the kinetic stability of these agents. In a study in humans, urinary zinc excretion was highest with gadodiamide (27.4 μmol) and intermediate with gadopentetate dimeglumine (5.9 μmol), both of which are linear chelates.^[13] By contrast, in the same study, urinary zinc excretion was lowest with the cyclic chelate gadoteridol (1.2 μmol).

Similarly, in vitro studies have shown that linear chelates (i.e. gadodiamide, gadopentetate dimeglumine and gadobenate dimeglumine) are susceptible to transmetalation, but cyclic chelates (i.e. gadoteridol, gadobutrol [Gadovist^®; Bayer Schering Pharma] and gadoterate meglumine [Dotarem^®; Guerbet, Paris, France]) are resistant to this process.^[14]