Dotarem/Clariscan, Prohance, and Gadopiclenol(Vueway). The special case of very stable MR contrast agents for Gadolinium Deposition Disease.

Many of the cases of GDD I see presently are patients who received the most stable forms of macrocyclic agents.

Why is that?

A number of well-informed individuals, a number who also are GDD sufferers believe that it is because these agents have disassembled (first time I used this word for the agent coming apart, I like it the best) releasing Gd. The cause for the disassembly they postulate: a bad batch of contrast (like 'bad dates' in Indiana Jones. Raiders of the Lost Ark) or the agent was spoiled by too high temperature in transportation or in storage at the center, or expired and disassembled.

My opinion is that simply the molecule is still relatively small and the immune system is able to recognize the presence of Gd in the small molecule, and by various means has opened the Pandora's box of toxicities to Gd, with variable expression in different people I do leave open the possibility that in some individuals, certain immune cells, such as macrophages or natural killer cells can actually break open the macrocycle and expose the Gd to better recognition.

To re-iterate my explanation:

1. all GBCAs result in acute hypersensitivity reaction, and this reaction can occur within seconds So in that time frame, even the least stable GBCAs should be fully intact, but certainly the most stable ones. So Gd is recognized by Mast cells even in intact GBCA form.

2. I am not aware of any evidence to suggest that these agents have been somehow spoiled.

Also remember that Gd is never 'free' but the GBCA agent is disassembled and the released Gd is quickly bound (within small fractions of a second) to something else.

My opinion is that the most immunogenic forms of Gd are the fully intact GBCA itself and released Gd bound to protein goo, with the latter I believe to be the most immunogenic.

My explanantion for protein goo being the most immunogenic, is

1. my opinion it is the least stable form of Gd

2. Gd is most exposed to the external environment

3. GBCAs with the greatest protein-binding (Multihave, Eovist/Ablavar, and Ablavar) have the highest incidence of mild Acute Hypersensitivity Reactions - warmth, hives, nausea, nasal/taste sensation of metal.

So finally to get to the point of this blog. Gd with Dotarem/Clariscan and Prohance, and I suspect Vueway (I would have liked them to put more thought into this tradename - it sounds like Amway to me.. some sort of pyramid scheme) are fully intact for a very long time in the body, maybe Dotarem/CLariscan forever. They cause the same symptom complex as other GBCAs which should atleast in part be disassembled. But how then can a chelator, such as the presently optimal one iv DTPA actually remove the agent if it is not binding directly to available Gd and removing it through renal excretion?

This is where, as I have written in multiple blogs, it tugs fully intact stable macrocyclic GBCA back into the circulation, and from there to renal excretion. If we are relying on the property of tugging, then a high stability constant may be atleast, if not more, important, than the property of cation-exchange that most chelators employ. So these events are occuring:

1. DTPA tugs fully intact GBCA back into circulation.

2. Subject shows clinical improvement

3. But, as one would expect, substantially less Gd is removed with chelation than if it was a less stable macrocyclic agent (Gadavist) or a linear agent (Multihance, Magnevist, Omniscan, Eovist)

The upshot of the lesser amount of Gd removal is that the standard formulas I describe of paying attention to urine Gd amounts comparing post- to pre-chelation 24 hour urines does not apply. Where for these other agents, in the early rounds of chelation we expect to see postchelation in amounts of 20 - 30 mcg/ 24 hrs, which range then from 10 to 40 times or more greater amount of Gd removal post compared to pre, it is not unusual that with these stable macrocyclic agents, the greater amount of removal may be 5 fold, and even just 1 fold more.....The post chelation Gd amounts are therefore often in the 3 - 5 mcg/24 hr range, which is the range that with the other agents I consider it worth stopping chelation. So how then do these individuals seem to get better with chelation. My opinions are based on paying more thought to where the Gd is left behind from the GBCA administration. This also emphasizes the point that has to be paid to with all heavy metals:

1. How did it get into the body.

2. At what rate did it get into the body.

   
   

Gd uniquely of the heavy metal toxicities was administered by iv route, in the majority of cases, and by fast rate. By understanding this then it explains, when one pays attention to reports of where the Gd is deposityed on histological specimens, maybe 50-70% in the endothelium of blood cells and 30% in the extracellular matrix (ECM). Extracellular vs intracellular ois still largely unknown, I think the great majority is extracellular, but I am not certain. Studies in humans (as I recently wrote) are imperative to know this. This is likely important. My opinion is that most of the symptoms of GDD comes from Gd in the ECM and not trapped in the endothelium, whether or not intracellular or extracellular. So clinical benefit comes from:

1. removal of Gd from the ECM.

2. this requires then fast bolus injection of chelator to force the chelator also into the ECM, and not leave most of it in the vascular system. . Drip technique removes primarily Gd trapped in the endothelium, as it does not get driven into the ECM (see my earlier blogs on drip vs bolus for iodine contrast agents and GBCAs).

Fortunately with these stable agents, there is ultimately less Gd left behind, my estimate is 50% less, which helps in regards to the importance of total body Gd content.

So the end result for managing patients with GDD from stable macrocyclic agents is that I spend little effort thinking about my standard approach to urine Gd content, but instead focus primarily on symptom improvement. I look at stopping chelation when they are around 80% improved byu their subjective assessment.

One interesting deviation from this overall theory is in a few patients who receive the stable macrocyclic agents, their urine values are about the same as those in the other categories, so post chelation urine values around 20 mcg./24 hr with a 20 fold increase. How does this occur: two possibilities:

1. They received another GBCA and not the most stable

2. Their immune cells were able to break the macrocyclic ring.

So the stable GBCA agents I focus on symptom improvement to determine when to stop chelation, and am not perturbed by low urine Gd amounts. It is also important to tell sufferers this, and the explanations.

Richard Semelka, MD