Gadolinium in Urine

June 5, 2018

 

Everyone who receives a GBCA retains some Gd. Realistically the ones who retain appreciable gadolinium are individuals who have received more than 1 ( 2+, 5+ when you can see in the brain in basal ganglia on T1 weighted images) GBCA enhanced MRI with linear nonionic agents. So the numbers I use for the US are that perhaps 10 - 50 million individuals have appreciable Gd in their system. Overall this group I refer to as Gadolinium Storage Condition (GSC). The remarkable thing is that the majority are not sick - despite the fact that chemists and toxicologists have realized since at least 1950 that free Gd is highly toxic. The explanation for this is, in part, that some retained Gd remains in the intact chelate (especially agents like Dotarem) and the ability of the host biological system to bind Gd rapidly that has been released, either into inorganic salts (with phosphates, carbonates, etc) or into organic macromolecules (proteins, and I am thinking there is some problems with this method of detoxifying). Gadolinium Deposition Disease (GDD) reflects the host reaction to the presence of Gd, and my opinion is that it is essentially a combination of the cellular activity involved in acute hypersensitivity reactions (polypeptide release) and subacute/chronic cellular response (essentially NSF). This is relatively rare, maybe 0.1% as common as GSC - but because of the numbers of GBCA administrations, this does translate into the 10s of thousands of sufferers.

 

Historically, radiologists have been led to believe that after 24 hours, 5 half lives of Gd-DTPA (Magnevist) all the Gd is out of the body, and certainly by 48hrs. But we now should know that some Gd is retained, linear nonionic > linear ionic > macrocyclic. This means that everyone who has received a GBCA has continued Gd being eliminated in the urine (looking at subjects with essentially normal renal function). As you are aware, Hubbs Grimm and Sharon Williams of the gadoliniumtoxicity group have already reported on urine Gd content in patients with GDD. The critical missing data, we need to know what the time curves are for urine elimination of gadolinium in healthy individuals (essentially the GSC crowd) in order to understand what the significance is of urine Gd in patients with disease (GDD group). Since all GBCAs behave somewhat differently, these urine time curves in normals have to be determined for each of the GBCAs on the market, as one would predict that these elimination curves would differ dramatically for the different agents (Eric Lancelot of Guerbet wrote a couple of nice articles on this in animal models). From this we can see if the GDD patients differ at all from normals. So at the present time, static 24 hr urine values have to be treated with some caution. This includes that the absence of appreciable Gd in urine does not mean the patient does not have GDD, and I expect over a period of time (> 1 year) this may be true for many sufferers at baseline. However what I use 24 hr urine Gd for is to ensure that the patients does have Gd in their systems (hence a critieria for GDD), and as baseline to see what the response is to the administration of a chelator. If the urine Gd increases substantially, 10-20 fold +, then we know that the patient is responded by eliminating Gd. In patients with long standing disease the level of urine in Gd may not be detectable, and for these I think a 'provocative test' is essential. But what I use as a provocative test is essentially the first treatment with iv Ca-/Zn-DTPA and look at 24 hr urine Gd content. I do not like or advocate an EDTA challenge and lesser time collection of urine.  Since the root cause for the disease is presence of Gd, the most obvious and first treatment step is to use the best available agent to remove it. Right now, the best agent available is iv Ca-/Zn- DTPA. It essentially forms a simplified Magnevist (Gd-DTPA) in vivo from the retained Gd, which I think are sites of deposit in the most mobilizable form (I believe skin and skin substrate). Surprisingly it also seems to remove macrocyclic agents as well though.

 

So, in summary: a huge number of individuals have retained Gd in their systems, the GSC individuals, but the Gd appears nontoxic in them. A much smaller group has reacted significantly to the presence of Gd, and we have to do something about them. Everyone who has received Gd will show gradual, decaying elimination curves of Gd in the urine. It is imperative that for all agents these curves be established, so we know what to make of absolute values of 24 hr urine Gd in sufferers. Data from sufferers also has to be plotted for each of the agents individuals as well.

 

This kind of work is essential - this topic came up at the NIH/FDA meeting, but discussion and action are two very different things. The essential project: Time curves for the elimination of Gd in urine in subjects with essentially normal renal function.

 

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