A Short History of NSF and GDD
The reader should note that in this blog I will not use either old terminology or incorrectly described GBCAs to avoid perpetuating outdated or incorrect information.
In the late 1990's, Shawn Cowper, a dermatopathologist from Yale, identified a skin disease in patients with chronic renal failure that exhibited exuberant fibrosis but he was able to distinguish from other entities such as scleromyxedema, because the newly described disease exhibited CD 34+ circulating fibrocytes as a distinctive feature. This disease came to be known as Nephrogenic Systemic Fibrosis (NSF). It was not until approximately 7 years later that a dialysis unit nephrologist from Austria, Grobner, observed that a series of renal failure patients in his dialysis unit with this new disease NSF, had undergone MRI with Omniscan prior to developing the disease. In the early fall of 2006 another group of dialysis unit nephrologists, Marckman et al, described a larger series of renal failure patients in Denmark who also had undergone MRI with Omniscan and developed NSF. At our center in the USA, in the late fall of 2016, our dialysis unit nephrologists brought to my attention that 26 patients of theirs had undergone MRI (with Omniscan) and had developed NSF. This population formed the basis of our two major multi-institutional studies. I suspect this pattern of identification occurred at all other major centers.
It was a small well-defined population of physicians, dialysis unit nephrologists, who were responsible for identifying patients with NSF from GBCA-enhanced MRIs, not radiologists themselves.
Animal studies supported what became recognized in humans: that nonionic linear agents were most associated with skin disease, and instability of these agents was accepted by the majority of the scientific community as causative for skin disease/ and the multi-organ disease NSF.
Chronic toxicity from Gd in subjects with normal renal function was occurring since at least 2007 (maybe for many years earlier). Ironically, one of the major set-backs for patients being recognized as having chronic Gd toxicity, is that NSF was recognized first, and well publicized. Physicians were well informed that chronic gadolinium toxicity was responsible for NSF in patients with advanced renal failure. The incorrect assumption was chronic toxicity did not occur in patients with normal renal function. It is worth mentioning at this point that acute toxicity, acute hypersensitivity reactions, were well known with GBCAs (and many other drugs) at this time in patient with normal kidneys, but not chronic toxicity.
Patients with chronic gadolinium toxicity and normal kidneys, what we have termed Gadolinium Deposition Disease (GDD), was reported to physicians by patients, since at least 2007. Conventional medical doctors (MDs) ignored patients claims that this arose after GBCA administrations (because they had normal renal function), which is still ongoing today. The only health care providers that agreed with patients that the cause of their disease was due to Gd toxicity, was integrative medicine doctors. Many of these physicians chelated these sufferers with the only agent available to them for heavy metals, EDTA. This was occurring since at least 2010, but since integrative physicians often don't publish their work and are not often well regarded by orthodox MDs, this went unnoticed. So GDD and chelation were occurring without recognition by the mainstream.
Unlike NSF, GDD patients were not seen by only one small group of physicians. Patients with normal renal function undergoing GBCA-enhanced MRI would be seen from all sorts of physicians and referred to MRI: from breast surgeons sending patients with possible breast masses, to neurologists sending patients with head-aches, to hepatologists sending patients with liver masses. No single group of physicians would see any number of patients who would return after GBCA-enhanced MRI complaining of severe symptoms, and the rare physician would see even one.
A number of patients have reported to the FDA symptoms following GBCA-enhanced MRI, individual case reports of normal renal function patients with chronic Gd toxicity, and abstracts at meetings of individual patients have been reported. Even dermatologic finding of gadolinium associated plaques in a few patients with normal kidneys. No single group of physicians, such as the dialysis unit nephrologists, championed GDD, since no group saw any number of sufferers. As with NSF, radiologists were not the physicians to be the first to see or report on these patients. The reason for this, and I am a radiologist as well, so I speak from 30 years of clinical practice: diagnostic radiologists essentially never see patients after an imaging study, especially days or weeks after a study, and even rarely see them at the time of an imaging study. So it is obvious: if you never see a patient then you never see a complication - the mistake being that we have made the assumption that this equated with there were no complications. I made this mistake myself.
The first time I heard from a patient, and the complaint was they had intense overall body burning, was in 2009, by email. I checked with the manufacturer and other directors of MRI and no one had heard of anything like it. I also labored under the misconception that if someone had normal kidney function they could not get severe chronic gadolinium toxicity. I left it at that with her. Some years later, in 2014-2015 I heard again from her, and this time I looked at this subject with conviction, because I met her and saw her sincerity. Based on her efforts of insisting with me that the disease is real, our group published the first of our papers on the subject: Gadolinium in Humans: a Family of Disorders, which appeared in the AJR. This subject is Gail Montani, and we have come to be close working partners on this subject. At that point I heard from a senior full professor in Medicine at our center who described that she too had severe symptoms after GBCA administration. She also told me the account of our meeting, that I then remembered, that I had personally told her that there should be no complications from GBCA in studying her kidneys. GBCAs were perfectly safe in subjects with normal renal function. I was wrong though, and she is now permanently injured, now 9 years later, with GDD. She also has wanted to keep private about her disease, and this emphasized to me there was no financial incentive for her - so this was powerful confirmation that the disease was 'real'. GDD became personal for me. Both these patients are reported in our first paper on the topic in Investigational Radiology: Gadolinium Toxicity in 4 patients with Normal Renal Function.
So the above explains many of the reasons why to this day GDD is not widely accepted by the majority of physicians. This is despite these additional aspects: 1. likely now at least 300 patients have reported to the FDA about having developed the symptoms of GDD following GBCA, 2. the disease has well-defined clinical features, 3. the critical feature is that new symptoms develop within 1 month, often within minutes of receiving GBCA administration (what else could it be then?), 4. the features are extremely similar to other heavy metal toxicities, 5. there are a number of peer-reviewed papers on the subject, 6. there are well over one thousand sufferers who belong to on-line patient action groups, and 7. a number of sufferers are physicians themselves.
What is holding up widespread recognition at this moment: 1. as physicians, radiologists ethically do not like to think that they are causing harm to patients unless there is rock-solid proof, 2. financial considerations on the part of radiologists, hospitals and companies (I don't need to expand on this), 3. physician concern that patient complaints may themselves be financially motivated (I don't need to expand on this), and 4. more proof is needed.
One obvious proof is necessary from a scientific perspective: 1. if findings are correct, they have to be reproducible by other groups, and to date there is not enough of this evidence of generalizability, 2. definitive lab tests should define these subjects as separate from non-sufferers (Gadolinium Storage Condition, GSC). Regarding this second point, it does remind that how do skeptics want to test individuals who show severe reaction to substances? In general, physicians accept the diagnosis of severe anaphylactic reaction, that individuals describe as having to substances from peanuts to even GBCAs. If they report having severe anaphylaxis using clinically correct descriptions (severe respiratory distress, vascular collapse), we accept that diagnosis, without for example having to force them to eat a bowl of peanuts to prove that they get anaphylaxis. In my opinion the same is true for GDD. The diagnosis would be clear by administering another GBCA - but that would make their illness much, much worse. A surrogate for this of course is chelation.
I do believe though that there are definitive tests. For example, ex vivo peripheral blood mononuclear cell (PBMC) release of cytokines should be dramatically different between GDD and GSC patients in response to GBCAs, as well as in vivo cytokine testing.
There are practical considerations for patient sufferers regarding the lack of acknowledgement of the condition. Perhaps principal among them: if the disease is not recognized then insurance may well not cover either disability from it or treatment for it. The time is changing, GDD is on the cusp of widespread acceptance.