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Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing Dermopathy: Focus on Gadolinium-based Contrast Media

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Philadelphia, Pennsylvania / November 18, 2006

EDITORIAL OVERVIEW:

Dr. James A. Tumlin Director of Clinical Research Southeast Renal Associates Associate Professor of Medicine University of North Carolina at Charlotte Charlotte, North Carolina

PANEL

Dr. Stanley Goldfarb University of Pennsylvania Philadelphia, Pennsylvania

Dr. Patrick Murray University of Chicago Chicago, Illinois

Dr. Martine Leblanc Université de Montréal Montreal, Quebec

Dr. David Perkins Credit Valley Hospital Mississauga, Ontario

Dr. Neesh Pannu University of Alberta Edmonton, Alberta

Dr. George Gettin Wu Credit Valley Hospital Mississauga, Ontario

Dr. Steven Weisbord University of Pittsburgh Pittsburgh, Pennsylvania

Editorial Overview:

Non-invasive imaging of both structural and vascular areas of potential pathology is critical in the diagnosis of atherosclerosis, ulcers, infection and solid tumours. Magnetic resonance imaging (MRI) provides views of structures and organ systems that are superior to those of other noninvasive tests, and comparable to those of more invasive imaging; as such, the use of MRI has greatly expanded over the past decade. In particular, the volume of MRI angiographic (MRA) procedures has increased dramatically in recent years and in some countries, now rivals conventional angiography for some cardiovascular imaging studies.

Much of the expanded use of MRI and MRA can be attributed to the development of safe and effective contrast agents. In particular, paramagnetic gadolinium (GAD) has emerged as a significant improvement over conventional contrast agents, being much less likely to cause severe anaphylactic reactions than iodinated material used for CT scans.

However, a new albeit rare phenomenon has emerged as a potential safety concern which may be associated with all GAD contrast agents. To that end, experts convened to discuss what little is known about this phenomenon, alternatively referred to as nephrogenic systemic fibrosis or nephrogenic fibrosing dermopathy (NSF/NFD). First described in the medical literature in 1997, NSF/NFD is a systemic sclerosing form of dermopathy characterized by intense deposition of collagen in the skin, very close to an iatrogenic cause of scleroderma.

Physiology

Initially manifest as swelling in the hands and feet, the skin becomes progressively thickened with a “peau d’orange” appearance. According to Boyd et al. (J Am Acad Dermatol 2006;56(1):27-30), progression proceeds at a variable rate, with some patients experiencing rapid advancement of the indurated areas while others experience a much slower course. Most patients also describe the lesions to be painful or pruritic. Involvement of the trunk and buttocks may ensue, but the head and neck are rarely affected. Skin hardening is such that it limits motion in most patients. The disorder may also be manifest as raised yellow spots on the whites of the eyes. Systemic involvement of the lungs, myocardium, striated muscles and diaphragm have also been reported, and in a small proportion of patients (approximately 5%) NSF/NFD proves to be fatal.

Various pathogeneses giving rise to this complex disorder have been proposed. However, one in particular, as reported by Dr. Shawn Cowper, Assistant Professor of Dermatology and Pathology, Yale University, New Haven, Connecticut, on the official site of the NSF/NFD Registry, has identified a circulating fibrocyte normally involved in wound healing and tissue remodelling as the source of fibrosis seen in NSF/NFD. These circulating fibrocyte cells are thought to leave the circulation and differentiate in the dermis into cells that functionally and histologically resemble normal dermal fibroblasts, Dr. Cowper explained. Specific factors for the differentiation of circulating fibrocytes into fibroblast-like cells are not clear but as Dr. Cowper suggested, they are likely related to underlying kidney function. McNeill et al. (Int J Dermatol 2002;41(6):364-7) were the first to propose a potential role for transforming growth factor-beta (TGF-ß), a potent fibrogenic cytokine, as a likely candidate in the development of NSF/NFD lesions, as Dr. Cowper also pointed out. Other investigators including Baron et al. (Am J Dermatopathol 2003;25(3):204-9) and Jimenez et al. (Arthritis Rheum 2004;50(8):2660-6) subsequently have identified TGF-ß as being involved in this disorder, but as Dr. Cowper indicated, its precise role is not yet understood. It is interesting, however, that circulating fibrocytes are capable of producing TGF-ß, although they are not the only cells with this capacity.

The fact that NSF/NFD has been observed almost exclusively in dialysis patients supports the observation that the differentiation of circulating fibrocytes into fibroblastlike cells is likely related to underlying kidney function, but as Dr. Cowper pointed out, neither the duration of kidney disease nor its underlying cause appears to be related to the development of NSF/NFD. It is also important to appreciate that while circulating fibroblasts may contribute to NSF/NFD in dialysis patients, there are no data linking GAD to increases in circulating volumes of fibroblasts either.

Other risk factors that appear to be associated with the development of NSF/NFD include coagulation abnormalities, deep venous thrombosis, recent surgery (particularly vascular surgery), recent failure of a transplanted kidney and sudden onset of kidney disease with severe swelling of the extremities. Dr. Cowper also characterized it as “very common” for patients who develop NSF/NFD to have undergone a recent vascular procedure such as revision of an arteriovenous fistula or angioplasty, or to have experienced a thrombotic episode approximately two weeks before the onset of skin changes.

Taking Action

No causal link has yet been identified for the development of NSF/NFD but reports to date have discovered an association with exposure to GAD-containing MRI contrast agents. The first of these emerged from the Danish Medicines Agency who reported some 25 cases of NSF/NFD over a period of four years in patients who had undergone contrast MRI procedures with gadodiamide. Of these 25 cases, 15 were serious in nature, involving disability with or without hospitalization, while symptoms were mild in the remaining 10 patients. Symptoms arose two weeks to three months following exposure to the contrast agent and all patients had severe renal impairment with a glomerular filtration rate (GFR) of 15 cc/min (15 mL/min/1.73 m2) or less. All the cases were reported by the Danish Medicines Agency—20 patients in Denmark, five in Austria—the latter five described in a recent publication (Grobner T. Nephrol Dial Transplant 2006;21(4):1104-8).

Acting on information from Danish authorities, the U.S. Food and Drug Administration (FDA) issued an advisory to healthcare professionals in June 2006, notifying them of the NSF/NFD phenomenon and their intent to investigate the matter further. In their original advisory, the FDA emphasized that no definitive link had been established between the use of GAD agents and the development of NSF/NFD, nor did they single out any particular GAD contrast agent as being implicated in the disorder. Rather, the FDA stressed that all GADcontaining contrast agents currently available in the US were part of the investigation (GAD agents in use around the world include gadodiamide, gadoversetamide, gadopentetate dimeglumine, gadoteridol and gadobenate dimeglumine).

Importantly as well, the FDA noted that all cases of NSF/NFD reported at the time of the original advisory involved patients undergoing MRA, which requires significantly higher doses of GAD contrast compared to other types of contrast-enhanced MRI procedures (it should be noted that gadodiamide is not approved for MRA in Canada). In some reports, patients with renal disease exposed to GAD contrast agents who developed NSF were acidotic at the time but others have not identified acidosis as a contributing factor to NSF/NFD; at this time, it is not clear whether systemic acidosis is an independent risk factor for the syndrome. As of December 21, 2006, the FDA had received 90 reports of patients who had developed NSF/NFD; all had moderate to endstage renal disease (ESRD) prior to undergoing either an MRI or MRA procedure with a GAD-based contrast agent.

The FDA is concurrently urging healthcare providers and patients to report adverse event information via the MedWatch program at www.fda.gov/medwatch/ index.html. In addition, the International Center for NSD/NFD Research (ICNFDR)—a collaborating group of researchers based at Yale University—are also asking physicians to report NSF/NFD cases to them, as those reported to the FDA are not necessarily reported to the ICNFDR. The official Web site for the ICNFDR is www.pathmax.com/dermweb/. As panel members here also observed, a recent poll of the European Society of Urogenital Radiology (ESUR), which includes members from North America, also identified over 150 episodes of NSF/NFD following exposure to GAD contrast media (Thomsen HS. Eur Radiol 2006;16:1219-21). In the editorial describing the ESUR survey findings, authors reiterated that no evidence presented to date has demonstrated a single case of NSF/NFD in a patient without ESRD. They concluded, “In patients without ESRD, all GAD-based contrast agents seem to be safe.” According to the latest FDA advisory, 215 cases of NSF/NFD worldwide have now been reported to the International Center for NSF/NFD Registry. Some 75 of them have been reviewed in detail and they all had received GAD-based contrast agents for MRA or MRI. The FDA also noted in its latest advisory that NSF/NFD has been reported following administration of three of the FDA-approved GAD-based contrast agents: “The FDA believes that there is a potential for NSF/NFD to occur in patients at risk following administration of any of the approved GAD-based contrast agents.”

None of the published reports reviewed by Dr. Cowper at www.pathmax.com/dermweb/ appear to link the development of NSF/NFD to either a specific agent or to a specific dose of a given agent. That said, there is a strong suspicion that significantly higher-thanrecommended doses of these agents required for MRA studies may explain the recent emergence of this disorder. This observation is also in keeping with the clinical practice of examining peripheral vascular disease with GAD and MRA.

Defining Groups at Risk

In discussing the observational evidence linking GAD-containing contrast media and NSF/NFD, panel members agreed that there are still too little data to expand much further upon this observation. As noted by Dr. Steven Weisbord, Assistant Professor of Medicine, Pittsburgh Healthcare System, Pennsylvania, thousands, perhaps even hundreds of thousands of patients with advanced kidney disease have received GAD-enhanced imaging over the years, and still there are at most only a few hundred reported cases of NSF/NFD. Thus, its incidence must by any rational calculation be extremely low.

However, one recent study published in the March 1 issue of the Clinical Journal of the American Society of Nephrology and reported by freelance medical writer Marlene Busko on Medscape (February 7, 2007), suggests that each radiologic study carried out using a GAD contrast agent presents a 2.4% risk for NSF/NFD in ESRD patients. The same group also documented an incidence of 4.3 cases per 1000 patient-years; in their ESRD population of 87 patients who had undergone 123 radiologic studies with GAD, the risk for NSF/NFD was found to be 3.4% (three out of 87 ESRD patients) retrospectively reviewed. As investigators concluded, the 2.4% risk of developing NSF/NFD after exposure to GAD is within the range of reported risk for acute renal failure from iodinated contrast agents.

It is not clear which group of patients is most at risk for NSF/NFD. Alternative imaging studies can usually be found for patients on dialysis, as Dr. Weisbord pointed out, therefore the need to expose these patients to GAD contrast agents may be extremely limited. Should the need be pressing, he suggested dialysis patients may be repeatedly dialyzed if they absolutely must undergo a GAD-assisted imaging procedure. Indeed, Dr. Weisbord felt that it may well be the pre-dialysis patient who is most at risk for NSF/NFD and there are not, at least in his own practice, many patients requiring GAD contrast agents in this situation.

Speakers here also agreed that patients who develop NSF/NFD share a number of other disorders including advanced renal disease and the worse their renal function, the more likely they are to undergo GAD-enhanced imaging. A multivariate analysis including all likely factors is therefore imperative, and speakers agreed that it is premature to associate NSF/NFD with one compound when patients indeed possess many other common features that may escalate their risk as well. What is clear is that precautions should be taken when possible. As is now recommended by the FDA, alternative imaging methods or contrast agents other than a GADbased agent should be carefully considered for patients with moderate renal disease (GFR <60 mL/min/1.73 m2) as well as those with ESRD (GFR <15 mL/min/1.73 m2). The FDA also suggest that patients with moderate to end-stage renal disease who need to undergo MRI or MRA with a GAD-based contrast agent be promptly dialyzed to eliminate circulating GAD, as from the first to the third dialysis session, average GAD-based contrast clearance rates are 78%, 96%, and 99%, respectively. GE Healthcare, who distributes gadodiamide, also support the practice of dialyzing ESRD patients immediately after administration of the agent.

Strategies to Improve Symptoms

The only intervention that appears to ameliorate symptoms related to NSF/NFD is improvement in renal function, but a wide variety of strategies has been proposed. According to the official Web site of the ICNFDR, improving renal function seems to arrest NSF/NFD and may allow for gradual reversal of the process over time. Here are some of the approaches that have met with some success.

Oral steroids: Have shown some efficacy in doses of 1 mg/kg orally per day. Risk of hyperglycemia in patients with concomitant diabetes, and gastrointestinal ulceration in patients overall. Osteoporosis is often accelerated with prednisone.

Topical calcipotriol under occlusion: Response is largely subjective and anecdotal but some report improvement in localized disease. The combination of occluded calcipotriol and clobetasol with vascular compression stockings has been reported to be of benefit as well. Extracorporeal photopheresis (ECP): Does not improve renal function but in the three patients in whom ECP was introduced, plaques did soften after several courses. The Yale experience suggests that patients with longstanding NSF/NFD (greater than one year) may not respond to ECP.

Plasmapheresis: Three patients with either a liver or kidney transplant reportedly improved with this modality, and renal function improved in two of them.

Thalidomide: Some report subjective improvement but two patients in the Yale registry apparently developed NSF/NFD while taking thalidomide for other medical problems.

Physical therapy: Swimming in particular may help slow progression of joint contractures.

Pentoxifylline: The use of pentoxifylline 1200 mg/day apparently stabilized symptoms in two NSF/NFD patients and one with less severe disease somewhat improved.

High-dose intravenous immunoglobulin therapy: One patient showed objective improvement with one cycle but further improvement was not observed with additional cycles.

Renal transplantation: Several patients have achieved significant improvement with a return to normal kidney function, but in others, kidney transplant led to no obvious improvement of the lesions.

Intravenous sodium thiosulfate: One dialysis patient exposed to multiple doses of GAD apparently experienced dramatic improvement in pain and skin changes after the first few treatments with this agent. The hypothesis is that the benefit from sodium thiosulfate may be due to its chelating and antioxidant properties. -

Questions and Answers With:

Dr. Stanley Goldfarb

Dr. Martine Leblanc

Dr. Patrick Murray

Dr. Neesh Pannu

Dr. David Perkins

Dr. James Tumlin

Dr. Steven Weisbord

Dr. George Gettin Wu

Q. What is your overall impression about awareness of NSF/NFD among specialists and why do you think gadodiamide has most often been implicated with this disorder?

Dr. Goldfarb: In Dr. Henrik Thomsen’s e-mail communication with European members of the ESUR, what came back was that the majority [of ESUR members] was not aware of what NSF/NFD was. Secondly, the people who knew about it started doing something about it so they started taking precautions and [initiating] protocols when dealing with GAD. And thirdly, the people who knew about it and who were doing something about it happened to be gadodiamide users. This may be one possible reason why gadodiamide is being seen more often with this condition.

Dr. Tumlin: It’s my understanding that gadodiamide has been the agent most implicated in this, but then again, it is the one that is most available in places where this observation has been made.

Dr. Murray: If we are talking about a patient with an acute coronary syndrome who needs a coronary angiogram, there is a lack of alternatives for these types of patients and we just have to prophylax them as we might, with the available data. So whereas GAD was a straightforward decision for many of us before, I think what we are trying to sort out here is: is there something else to consider or are there other risks?

Dr. Wu: This is not on the radar screen for most radiologists or nephrologists here, so I think the education process has to be much more widespread. But I would say that so far, not many of us have yet been exposed to this information and I think that should come.

Dr. Tumlin: We also need to meet with our dermatology colleagues and we are going to be working with General Electric to help us develop a relationship with dermatologists to help us understand this. In particular, I would think dermatologists who work with chronic inflammatory processes would be most appropriate, as NSF/NFD gives you this scleroderma-like motif and we should be looking at it from the same sort of pathophysiological point of view.

Q. Have any of you had personal experience with NSF/NFD?

Dr. Weisbord: I haven’t personally seen this condition but did hear of a case in Pittsburgh of a patient who had failed transplantation, i.e. a patient with advanced chronic kidney disease (CKD) who responded to photopheresis as a treatment. So although I haven’t personally seen it, it is a very significant condition and there seems to be enough [observational evidence] there for a potential association with GAD which definitely warrants further study.

Dr. Tumlin: I had a case at Emory about three years ago. I saw these bizarre patches and it came back as NFD. I don’t know if the patient had had GAD at all so it was one case, it was perplexing but the patient did not do that well.

Dr. Perkins: I haven’t seen it and I’m not sure if Dr. Wu has, either.

Dr. Pannu: We have about 900 dialysis patients in our centre and we have not seen a single case of NSF/NFD, nor have we been approached by the MRI radiologists.

Q. Please offer your suggestions to better identify patients with NSF/NFD.

Dr. Weisbord: This is not a condition for which there will likely be a clinical trial, so with something like this with very low incidence rates, you may do something like a large retrospective cohort study with a large database with thousands of patients, identify patients with ESRD who received GAD for MRA and MRI and then look forward to their outcomes—namely, what was the incidence of NSF in ESRD in patients who underwent MRI or MRA. This could be done in the context of administrative data, i.e. how many had visits to dermatologists or very serious adverse events, and there would be evidence [for this] in the administrative database in terms of codes for dermatologic conditions.

Dr. Tumlin: At Emory, there is a large system where dermapathologies are done and there is a large one in North Carolina as well. So if there were a way we could identify the number of biopsies proven to be NSF/NFD, then work backwards from that and find out from individual cases what their exposure to GAD was, you could better define what all the other variables may have been [that contribute to the disorder].

Dr. Goldfarb: I think the way to pursue this is to come up with a collaboration with dermatologists and rheumatologists and devise some sort of analysis of large numbers of patients who’ve gotten the agent, then look forward after they have received the agent to see if they develop some sort of adverse event. This is probably the easiest and quickest way to try and come up with an estimate of how frequent the problem is. And I agree with what [Dr. Weisbord] said: a very sophisticated case-control study could be done on these patients that would answer the question about concurrent risk factors and interactions between risk factors. But getting data on this is absolutely crucial, as we really have no idea of the magnitude of this issue, who’s at risk, and what we should be concerned about. Even though NSF/NFD is a rare condition, we need data on it as it will have a ripple effect and affect practice everywhere.

Dr. Tumlin: Some type of animal model studies should also be considered. You could take animal models with varying degrees of acidosis and then load those animals with varying types of chelating agents that cause transmetallation where you can supplant GAD on its carrier molecule with other molecules such as zinc. That would provide insight into interpreting findings from animal model studies with retrospective data that we can’t yet get our hands on. So I think this would be a smart thing to do and it could be very helpful towards making very simple recommendations.

Dr. Pannu: I also think it’s important to figure out the pathophysiology of this condition, particularly with respect to the role of GAD; animal models would be the way to go. My concern about existing registries is that to get into the registry, somebody obviously had to recognize a patient had it, so the question is: is this high on the radar screen for radiologists or nephrologists or dermatologists at large? I would guess that it is not. It certainly hasn’t come up at any Canadian meetings that I’m aware of and I’m also not sure if there are even any reported cases in Canada. So if we could create some sort of voluntary prospective registry in patients who do need these sorts of studies and then look at them three months’ post-procedure and ascertain whether they had to see a dermatologist [after the procedure], it might help identify the scope of the problem, because I think it’s probably vastly under-reported now.

Dr. Perkins: The exact frequency of the occurrence of NSF/NFD is unknown. However, most would agree it is very rare (<1%). Hence, a formal prospective study would be very challenging and costly. Research on mechanism of disease should be a focus, particularly with reference to severe renal impairment and potential for transmetallation and GAD or ligandbased toxicity.

Q. Given the serious nature of NSF/NFD, why is the problem only recently coming to our attention?

Dr. Tumlin: Conventional structural applications of MRI involve relatively small doses of contrast media. When use of MRI evolved into vascular applications, the dose of contrast required to capture the image increased substantially.

Q. Does the risk of NSF/NFD appear limited to patients with severe renal impairment, or would you have any reservations about performing MRA with GAD contrast in patients with less severe renal impairment?

Dr. Pannu: No [reservations]. In our centre, we routinely use GAD-enhanced imaging on these patients with no reported cases of NSF/NFD. I would not change my practice on the basis of a case series without further proof of association. The risk of iodinated contrast and the indication for the test need to be weighed against the relatively minor risk of developing this complication.

Dr. Perkins: Data at this point seem to suggest that NSF/NFD is primarily limited to patients with severe renal impairment, whether on dialysis or not (use GFR<15 mL/min/1.73 m2 as a cutoff, i.e. stage V CKD). I would at this point feel comfortable using GAD-based contrast agents in patients with less severe renal impairment.

Dr. Leblanc: It appears to be restricted to late-stage CKD patients. So we have to ask: does a CKD state promote fibrosis? Likely so. I don’t think that patients with no or mild renal disease present the same risk. If that were the case, we would probably have heard about it already.

Dr. Murray: I think that first we have to decide if there is a problem, because I don’t think we know that yet because we are not seeing it, and we also have to know if it is occurring at recommended dosing, i.e. is it occurring at less than 0.3 mL/kg? If it’s never seen at that dose, then I think we can be comfortable doing what we have been doing. Sending patients for renal MRAs is a safe practice.

Q. How would you advise clinicians who are considering MRA procedures for patients?

Dr. Pannu: To be aware of the complication, to inform patients about it and to seriously weigh the risk and the benefits of such imaging studies. If there is solid indication for the test, the result of which will alter management, then MRA should be used.

Dr. Perkins: For those with a GFR <15 mL/min/1.73 m2: use non-gadodiamide, GAD-based contrast agents when MRA is needed (i.e. when an alternative safe radiologic study could not provide the same answer). Inform patients of this rare but serious association. I would also recommend close monitoring for NSF/NFD in the first two to four months’ post-MRA. Always minimize the dose used. For patients with a GFR>15 mL/min/1.73 m2, use any of the GAD-based contrast agents and always minimize the dose used. I would again recommend close monitoring for NSF/NFD in the first two to four months’ post-MRA as part of ongoing surveillance. At this point, I do not think that dialysis should be recommended post-MRA in patients not already on renal replacement therapies.

Dr. Leblanc: Do MRA only if necessary. Be aware that such a complication exists and be able to recognize it. More information should come over the next few years. On the other hand, potential nephrotoxicity of GAD agents as shown in animal models needs to be better characterized in humans, in particular, what the “safe” dose would be and whether preventive measures would be useful.

Q. Does the risk of NSF/NFD appear to pertain to all GAD contrast agents? In your opinion, how should the risk be presented or described to physicians?

Dr. Pannu: At this point, we don’t know enough about the disorder to determine if there is a class effect.

Dr. Perkins: I am only aware of confirmed reports of NSF/NFD with gadodiamide use. Hence, I believe it is too early to claim a “class effect,” although there is some thought that this might be the case. I believe that monographs of all GAD-based contrast agents should include mention of this rare but serious potential association in patients with advanced CKD. It would be important to state that causation has not been proven and that GAD-based contrast agents other than gadodiamide may also carry this serious association. I would also recommend close monitoring of patients with advanced CKD in the first two to four months’ post-MRA with other GADbased contrast agents.

Dr. Leblanc: At this point, I consider NSF/NFD as a relatively rare event following GAD administration and yes, I would say [it pertains to] all GAD agents and consider it a class effect until more data are available, since I don’t think there are enough data right now to point to one single agent only. -

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