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• W2048748411 abstract "THE PREPARATIONS FOR THE scientific and educational programs of the Joint Annual Meeting of the ISMRM and the ESMRMB typically begin one and a half to two years prior to the meeting date. During the preparation phase of the 2007 meeting in Berlin, Thomas Grobner and others described a possible relationship between gadolinium containing MRI contrast agents and a new disease—nephrogenic systemic fibrosis (NSF)—a disease previously unrecognized and unknown to radiologists and other MR users. Further reports soon surfaced. Within the span of a few months, NSF became a major challenge to MRI practitioners. We were faced with a potentially very serious adverse reaction as a complication of our daily practice, yet there was no solid evidence about its etiology, pathogenesis, or risk factors. Because of the importance of NSF to the MRI community, the Annual Meeting Program Committee decided well after the usual “no further changes date” (in January 2007) that it was necessary to provide a forum for this important topic during the upcoming Annual Meeting. The Annual Program Committee felt it was necessary to organize a session that would provide the most up-to-date information possible from experts on the topic, and to hear first-hand expert opinions on the nature of the disease, risk factors, and suggestions for modifications of clinical practice to mitigate potential complications of contrast agent usage. The Committee wanted ISMRM members to hear from experts to gain a better understanding of the pathogenesis of the disease, to explore possible legal consequences in the countries of its members, and to discuss and recommend future scientific investigations. Despite the very short time frame available to organize the NSF forum, we were delighted that we were able to recruit the world's top experts from all relevant disciplines, including pathology, radiology, and nephrology, as well as representatives of the European Union's regulatory agency—the European Medicines Agency (EMEA). The two-hour session, held on May 22, proved to be very timely and highly informative. This session was recorded in its entirety. It is available on the ISMRM web site, at http://cds.ismrm.org/protected/NSF. Introduction Georg Bongartz and Walter Kucharczyk (moderators) Systemic Fibrosis: What is it, and where does it come from? Shawn Cowper, Yale University, New Haven, CT, USA Relation to Gadolinium Exposure and on Differences among Gadolinium Chelates Henrik S. Thomsen, Copenhagen University, Copenhagen, Denmark Consequences for the MR Community—Alternative Diagnostic Pathways Peter Dawson, University College, London, England, UK NSF—The Nephrologist's Point of View and the Patient's Point of View Harm Peters, Charité–University Berlin, Germany Legal and Regulatory Issues Panos Tsintis, Xavier Kurz, and Doris Stenver (EMEA, Sector of Pharmacovigilance), London, UK—presented via teleconference Shawn Cowper has collected the largest number of NSF patients. These are listed in the NSF Registry at Yale University. Dr. Cowper's presentation provided a historical and epidemiological context on NSF, based on the 235 cases of NSF gathered in the Registry, and from recent reports made by government health officials, industry, and other publications regarding the relationship between Gd-administration and the development of NSF. He offered a view dating back to the first case in 1997, initially described as a scleromyxedema-type of cutaneous fibrosis, and a systemic fibrosing disease. He indicated that the extremely disabling cutaneous manifestations dominated the appearance of NSF, and that all patients to date had severe renal dysfunction. He described the histology of NSF as differing from similar diseases in that circulating fibrocytes cause the severe fibrosis of various tissues in NSF. Dr. Cowper said that as investigators searched for an etiology and risk factors, many concomitant diseases were suspected, vascular diseases being among these. Ironically, this often led to an MR investigation, or to a gadolinium-enhanced magnetic resonance angiography (MRA). But it was only in 2006 that the link between NSF and Gd was suspected and initially published by Thomas Grobner et al. [1] Henrik Thomsen and his group have published the largest series so far on with NSF linked to Gd-exposure. In his presentation, Dr. Thomsen reviewed the chemical properties of Gd-compounds, and the differences between them. He focused on the differences of molecular structure (linear vs. macrocyclic) and charge (nonionic vs. ionic chelates), both of which affect chelate stability. In his presentation, he clearly stated a superiority of macrocyclic and ionic agents over other compounds. In a direct comparison of brands, Thomsen noted that more than 90% of proven NSF cases are related to Gadodiamide, and some to Gadopentate. He also found literature warnings on the instability of Gadodiamide as early as 1980, based on animal studies. In man, the consequences were not recognized until 1996. Thomsen sated that there is a problem of linking the development of NSF to a specific contrast agent because many patients have received different agents. He added that his analysis of other potential risk factors, like erythropoietin (EPO), iron, angiotensin converting enzyme (ACE) inhibitors or other medications, did not prove to be statistically relevant in the development of NSF. Dr. Thomsen drew the conclusion that linear and nonionic products like Gadodiamide are much more of a risk to trigger NSF than other agents. He stated that in his own practice at Copenhagen University, he has switched from Gadodiamide to macrocyclic and ionic drugs. Since then, he has seen no further cases of NSF in his patients. Peter Dawson has a long history of involvement in many trials on contrast media safety and toxicity. In his presentation he summarized the differences between various Gd agents in terms of their thermodynamic stability and kinetic stability. He indicated that while the former is relevant in the bottle, it is the latter that is relevant in vivo. He stated that there are different ways to evaluate stability, and this can contribute to controversies among pharmacologists and vendors. He also addressed the nephrotoxicity of Gd-chelates at large, which was more or less neglected for a long time. He pointed out that due to their outstanding safety profiles, gadolinium-containing-agents have occasionally been used for some contrast-enhanced X-ray imaging studies, like computed tomography (CT) or digital subtraction angiography (DSA), in patients with renal failure to avoid the risk of contrast-induced nephropathy (CIN) from iodinated agents. This practice may have even led to some NSF cases. Dawson stated that there is strong circumstantial evidence to support the hypothesis that: free Gd 3+ released from the chelate is implicated in the development of NSF—even if it is not the only cause, and even if it is not the sole factor in a complex process involving the pre-inflammatory milieu in and around end-stage kidney disease. In his summary, he hypothesized that some agents are less stable than others (with macrocyclic agents being more stable than linear agents) and that kinetic stability is the relevant index in vivo. Severe renal failure leads to extended contrast media residence time, leading to an increased potential to undergo metabolic processes and cause reactive cell proliferation. Dawson considered a low pH a potential factor in renal disease that contributes to the toxic reaction. He stated that the relative hydrophobicity of some Gd-chelates may be a key factor in facilitating cell entry—and intracellular Gd chelates are extremely toxic. With the new knowledge of potential gadolinium toxicity in renal failure patients, caution becomes necessary. Recommendations and guidelines exist for some linear agents in patients with estimated glomerular filtration rate (eGFR) < 30 and must be followed with care: macrocyclic agents should be given and the lowest dose to achieve the required result. It is unrealistic to check renal function on all patients submitted to contrast-enhanced MRI. A history and a questionnaire concerning: abnormal renal function in the past, diabetes, hypertension, medication with nephrotoxic drugs, gout, etc. should suffice to determine whether a patient needs a measurement of renal function (eGFR by the Cockroft formula). Alternative imaging techniques should always be considered. Multislice CT is frequently the obvious alternative. However, contrast enhancement is almost always essential. In cases of renal impairment this is equally or even more problematic because of the risk of CIN. Harm Peters contributed the views of nephrology to the discussion. He argued that the new situation must be seen in a risk/benefit balance. He emphasized the relatively low incidence of NSF, even in the patients at greatest risk (chronic kidney disease stage IV–V), and compared this to the very high risk of CIN with iodinated contrast media, which itself has a markedly increased mortality rate. He proposed to carefully check the justification for MRI in renally impaired patients, to completely switch to macrocyclic Gd chelates, to reduce the dose to the minimum possible, and correct acidosis if appropriate. In patients on hemodialysis, he recommended hemodialysis as soon as possible after Gd administration, with up to three sessions over three days. Representatives from the a regulatory agency, the European Medicines Agency (EMEA) contributed to the NSF session via teleconference from London. They were unable to attend in person due to an unavoidable scheduling conflict with a meeting on regulatory affairs. Their three representatives were Panos Tsintis, Xavier Kurz, and Doris Stenver. They gave a short introduction on the role and constitution of EMEA and its related organs. Tsintis described the complex organizational structure of the European Pharmacovigilance Authority and its limited direct option to release direct regulations to all European countries. The decision to introduce contraindications to Gadodiamide and warnings to other GD-agents was based on retrospective clinical analyses, although defined trials were not available at that time (Jan 2007)—with no clear evidence for the pathogenesis of NSF. The warning was extended to moderate renal insufficiency following the report by Sadowsky in late 2006. In contrast to the U.S. Food and Drug Administration (FDA), hemodialysis was not recommended in renally impaired patients following Gd-exposure because of lack of evidence. Doris Stenver addressed the topic of whether NSF is related to all Gd-compounds or just to gadodiamide, and how views on this issue lead to warnings about whether advisories should be directed to a “drug effect” or “class of drugs effect” (class effect). For the time being, the European Authorities have decided on a class effect for linear Gd agents as is most appropriate, and have announced further investigations on Gadopentate (which was subsequently included in the contraindications list one month later). Stenver expressed concerns about the delay between the initial recognition of NSF cases, and the length of time to report these cases regulatory authorities in 2007, which led to immediate reactions by the EMEA in February 2007. Further investigations will focus on linear compounds, on the effect of hemodialysis and on the patient group with intermediate renal insufficiency. The EMEA representatives offered no explanation on the differences in regulatory advisories between the FDA and the EMEA. The NSF forum was extremely well attended, attesting to the importance of and interest in the topic. At the conclusion of the formal presentations by the invited speakers, there was an expert panel discussion with questions from the audience. This had an exceptionally large number of participants, with long queues at the audience microphones. The question and answer session far exceeded its time allocation, and had to be terminated by the moderators to avoid scheduling conflicts with the next lecture. It was very clear to all who attended that there were many more questions to be answered, yet this forum served its purpose of providing the most current information available to the MRI community. Many questions remain, and are subject to active investigation. At the present time, it is the consensus view of experts in the area that NSF only occurs in patients with renal failure, and that the vast majority of NSF cases occur in patients with end-stage chronic renal disease. Based on current data there is a clear preponderance of cases with certain Gd-containing agents, and far fewer NSF cases, if any, with other agents, particularly those with a macrocyclic molecular structure. There is some debate whether this preponderance of NSF cases with certain agents is real, or whether there is a bias, either in reporting, or because there is a bias in use of certain agents in the most complex cases, which in turn are at highest risk of developing NSF. There also seems to be a strong association of NSF occurrence with total dose of contrast agent administered. Patients who have received large or multiple doses of Gd-agents, constitute the largest group of NSF cases. With respect to treatment, no effective treatment seems to exist, although anecdotal evidence suggests that kidney transplantation has resulted in significant improvement in some patients. Awareness of NSF has grown significantly over the past year. The practice of administering Gd-contrast agents for contrast-enhanced MRI (CEMRI) has been modified virtually everywhere. Lower NSF risk Gd-agents, for example, macrocyclic agents, are now administered to patients with known renal failure, and in some practices to all patients, just in case the patient might have “silent renal failure.” Some practitioners are now routinely determining eGFR before any CEMRI, to detect those cases of silent renal failure. Other patients are completely triaged away from MRI, particularly those on dialysis. These patients may instead receive a noncontrast exam, or contrast-enhanced CT (with an iodinated contrast agent) if anuric. Despite our increased awareness of NSF, and the heightened precautions we are taking to reduce the incidence of NSF, we all remain aware that NSF is a very rare adverse effect, and that CEMRI is an extremely valuable diagnostic test in a large number of patients. Therefore, from considerations of benefit-to-risk to the patient, CEMRI remains the appropriate test to do for many indications, even in patients with the severe renal failure. It was clear from this forum that we should not stop doing CEMRI because of NSF, but we should do everything we can to reduce the risk. As the leading scientific and educational society in MRI in the world, the ISMRM intends to stay on top of this important topic on a continuous basis. The ISMRM has created a 20-member international NSF Work Group, with experts from a wide variety of disciplines, both from within the ISMRM membership, and outside consultants. The Group is actively working to create an international registry of NSF cases, to survey the ISMRM community on issues related to NSF, and to facilitate information exchange on this topic. The ISMRM is considering funding prospective research studies to further examine risk factors, to study pathogenesis and etiology, and to issue recommendations to its members and the MR imaging community at large. The results of these investigations, and ISMRM recommendations, when available, will appear on the ISMRM web page at http://www.ismrm.org, and/or in its journals." @default.
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• W2048748411 title "Nephrogenic systemic fibrosis: Summary of the special symposium" @default.
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