Transmetallation: Which Gadolinium causes NSF, and What about Overexposure in Healthy Individuals Undergoing Multiple Scanning Procedures?

Armand Rossetti

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All FDA approved gadolinium based contrast agents (GBCAs) combine a single atom of Gadolinium rare earth metal by chelating it with organic chemicals called ligands. More simply, chelation is the process of coating a less stable metal with more stable bio-friendly-type components to render the metal less reactive. The resulting lowering of the metal’s reactivity creates a more benign substance that can circulate through the body and not present a significant safety concern.

As previously discussed, individuals with kidney disease cannot clear the less toxic, chelated form of Gadolinium from the body before it loses its ligand coating, reacts with the body, and causes major problems, such as (Nephrogenic Systemic Fibrosis (NSF).

According to investigators, there are different categories of GBCAs:

1. Linear versus macrolytic structure;
2. Ionic versus non-ionic; and
3. Non-protein binding versus protein binding.

These three categories of Gadolinium contrast agents vary significantly in their propensity to release free Gadolinium, which is linked with NSF. Both the structure that makes up the particular form of coated Gadolinium and higher thermodynamic stability, or ability for the coated from to remain for longer periods in the body, will minimize the release of dangerous free (uncoated) Gadolinium that would remain in the body because the kidneys are not functioning to capacity to eliminate it.

Linear structures seem to be more reactive and macrolytic structures are more stable. That is because Release of gadolinium from a cyclic (macrolytic) chelate requires all four covalent bonds to be broken simultaneously.

Anecdotally, at least one patient, who has experienced multiple CAT scan procedures and who has received multiple GBCA injections during diagnostic treatment has reported actual pieces of metal, most likely Gadolinium, emerging through the skin. Evidently, the patient’s normal kidney function was not enough to handle the cumulative “overdosing” with Gadolinium, and that inability to handle Gadolinium elimination appears to be similar to situations where compromised kidneys are not able to handle a usual exposure of one or two injections during CAT scan diagnostic procedures.

To get a better understanding of what the chemistry and physics is all about; let’s look at the physical side of Gadolinium. The half life of Gadolinium chelates in patients with normal kidney function is 1.5 hours and more than 90% of a dose is excreted in 24 hours. Molecular weights of available GBCAs range from 558 to 1058 daltons. Free Gadolinium is up to 50 times more toxic than chelated (coated) Gadolinium GBCA.

Perhaps the following information is most important:

“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.”

As is evident, there is a wide variation between branded GBCAs, and the choice of what type of GBCA to brand may rest upon intellectual property protection considerations among manufacturers like GE, or Bracco. Each manufacturer tends to balance designing its product to avoid patent (IP) lawsuits, and then each deals with safety and effectiveness as those parameters will allow. Welcome to the fast paced and litigious IP world of competitive device manufacturing, which is not a bad thing at all, if the manufacturers are ethical, and the FDA is watching closely.