Advertisement
American Journal of Kidney Diseases

Nephrogenic Systemic Fibrosis and Gadolinium-Enhanced Magnetic Resonance Imaging: Does a US Food and Drug Administration Alert Influence Practice Patterns in CKD?

      Related Article, p. 458
      Nephrogenic systemic fibrosis (NSF), which was first recognized in 1997 and described in the literature in 2000,
      • Cowper S.E.
      • Robin H.S.
      • Steinberg S.M.
      • Su L.D.
      • Gupta S.
      • LeBoit P.E.
      Scleromyxedema-like cutaneous disease in renal-dialysis patients.
      is considered to be a systemic fibrotic disorder that clinically presents with nonspecific scleroderma-like skin lesions.
      • Cowper S.E.
      • Robin H.S.
      • Steinberg S.M.
      • Su L.D.
      • Gupta S.
      • LeBoit P.E.
      Scleromyxedema-like cutaneous disease in renal-dialysis patients.
      • Cowper S.E.
      • Su L.D.
      • Bhawan J.
      • Robin H.S.
      • LeBoit P.E.
      Nephrogenic fibrosing dermopathy.
      • Cowper S.E.
      Nephrogenic fibrosing dermopathy: the first 6 years.
      Collagen is deposited in tissues and the cutaneous findings of NSF include extensive thickening and hardening of the skin, hyperpigmentation, plaques, papules, and nodules.
      • Cowper S.E.
      • Robin H.S.
      • Steinberg S.M.
      • Su L.D.
      • Gupta S.
      • LeBoit P.E.
      Scleromyxedema-like cutaneous disease in renal-dialysis patients.
      • Cowper S.E.
      • Su L.D.
      • Bhawan J.
      • Robin H.S.
      • LeBoit P.E.
      Nephrogenic fibrosing dermopathy.
      • Cowper S.E.
      Nephrogenic fibrosing dermopathy: the first 6 years.
      Gadolinium-based magnetic resonance imaging (MRI) contrast agents are a family of gadolinium formulations that are used to improve the diagnostic yield of MRI scans. Overall, gadolinium-based contrast agents have been found to be extremely safe, with over 200 million administrations worldwide
      • Thomsen H.S.
      Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide.
      and, until recently, no known serious complications. In early 2006, a possible relationship between these agents and NSF was reported in patients with severely decreased glomerular filtration rate (GFR).
      • Grobner T.
      Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?.
      The delayed excretion and prolonged tissue exposure to circulating contrast agent is likely a key factor in the relationship between decreased GFR and NSF.
      • High W.A.
      • Ayers R.A.
      • Chandler J.
      • Zito G.
      • Cowper S.E.
      Gadolinium is detectable within the tissues of patients with nephrogenic systemic fibrosis.
      A series of US Food and Drug Administration (FDA) warnings were issued subsequently.
      US Food and Drug Administration
      Questions and answers on gadolinium-based contrast agents.
      US Food and Drug Administration
      Information for healthcare professionals gadolinium-based contrast agents for magnetic resonance imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, ProHance).
      US Food and Drug Administration
      FDA Requests Boxed Warning for Contrast Agents Used to Improve MRI Images.
      Since that time there has been a decrease in NSF events, with no new cases reported over the past 12-18 months, as related at a recent FDA-sponsored meeting,
      US Food and Drug Administration Center for Drug Evaluation and Research
      Transcript of Joint Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory Committees meeting.
      and with a total of around 600 tissue biopsy–confirmed NSF cases globally. It has been presumed that the reason for the decreased NSF incidence has been a greater awareness of the relationship between gadolinium-based contrast agent use and this potential complication, although there has been no confirmation of this presumption. In this issue of the American Journal of Kidney Diseases, an article by Kim et al
      • Kim K.-H.
      • Fonda J.R.
      • Lawler E.V.
      • Gagnon D.
      • Kaufman J.S.
      Change in use of gadolinium-enhanced mangetic resonance studies in kidney disease patients after US Food and Drug Administration warnings: a cross-sectional study of veterans affairs health care system data from 2005-2008.
      looks at practice trends in gadolinium-based contrast agent use over time within the US Department of Veterans Affairs (VA) Health Care System. Drawing from the VA national database, these authors show data on the utilization rate of gadolinium-based contrast agents in MRI exams performed over the past several years and conclude that there has been a proportional decrease in administration of these agents in patients with decreased estimated GFR, and an increase in serum creatinine testing over the same time period, which corresponds to the timing of the FDA advisories.
      On May 23, 2007, the FDA requested a black box warning regarding the potential risk of NSF among patents with kidney failure to be added to the product descriptions of all 5 existing FDA-approved gadolinium-based contrast agents marketed in the United States: Magnevist (gadopentetate dimeglumine), MultiHance (gadobenate dimeglumine), Omniscan (gadodiamide), OptiMARK (gadoversetamide), and Prohance (gadoteridol).
      US Food and Drug Administration
      FDA Requests Boxed Warning for Contrast Agents Used to Improve MRI Images.
      All 5 agents were treated equally in this regard despite data suggesting that certain agents possessed a seemingly greater risk than others in precipitating NSF, even accounting for differences in market share.
      Of particular note, the majority of NSF cases have been associated with one of the agents, gadodiamide.
      • Broome D.R.
      Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting.
      • Martin D.R.
      • Semelka R.C.
      • Chapman A.B.
      • et al.
      Nephrogenic systemic fibrosis versus contrast induced nephropathy: risks and benefits of contrast-enhanced MR and CT in renally impaired patients.
      This agent has perhaps the least stable formulation, and stability of the chelate has been proposed as an important factor in the development of NSF in patients unable to clear the agent through their kidneys. It has been noted that few if any of the reported NSF cases have occurred in relation to the most stable macrocyclic or higher relaxivity agents.
      • Martin D.R.
      • Semelka R.C.
      • Chapman A.B.
      • et al.
      Nephrogenic systemic fibrosis versus contrast induced nephropathy: risks and benefits of contrast-enhanced MR and CT in renally impaired patients.
      • Kanal E.
      • Broome D.R.
      • Martin D.R.
      • Thomsen H.S.
      Response to the FDA's May 23, 2007, nephrogenic systemic fibrosis update.
      Animal models in rodents given repeated high doses of different gadolinium-based contrast agents have shown that those associated with most of the reported human NSF cases have a higher relative toxicity, and that the skin lesions that develop in rodents mimic the histology seen in human NSF.
      • Pietsch H.
      • Lengsfeld P.
      • Jost G.
      • Frenzel T.
      • Hutter J.
      • Sieber M.A.
      Long-term retention of gadolinium in the skin of rodents following the administration of gadolinium-based contrast agents.
      Furthermore, the rodents given similar doses of higher-stability linear or macrocyclic agents develop milder or no evidence of NSF-like skin histology; the levels of gadodiamide deposition measured in tissues correlate similarly. The clinical reports of greatest import have derived from centers that had previously reported on NSF incidence using one agent (mostly gadodiamide) and then switched to a different protocol that used a different contrast agent in patients with severely decreased GFR, including dialysis patients.
      • Martin D.R.
      • Kalb B.
      • Salman K.
      • et al.
      Decreased incidence of NSF in patients on dialysis after changing gadolinium contrast-enhanced MRI protocols.
      • Prince M.R.
      • Zhang H.
      • Morris M.
      • et al.
      Incidence of nephrogenic systemic fibrosis at two large medical centers.
      These newer clinical reports have shown a reproducible pattern of diminished NSF incidence in patients with decreased GFR, even those on dialysis, after switching to a higher-stability and/or lower-dose gadolinium-based contrast agent; for example, reporting an NSF incidence in dialysis patients of 2.6% with gadodiamide and 0.0% with gadobenate dimeglumine.
      • Martin D.R.
      • Kalb B.
      • Salman K.
      • et al.
      Decreased incidence of NSF in patients on dialysis after changing gadolinium contrast-enhanced MRI protocols.
      In view of the noted decrease in NSF incidence, it has been presumed that this is a result of changes in practice patterns, although we have lacked any direct analysis on a large scale. The approach employed by Kim et al
      • Kim K.-H.
      • Fonda J.R.
      • Lawler E.V.
      • Gagnon D.
      • Kaufman J.S.
      Change in use of gadolinium-enhanced mangetic resonance studies in kidney disease patients after US Food and Drug Administration warnings: a cross-sectional study of veterans affairs health care system data from 2005-2008.
      focused on measuring a number of MRI study characteristics as a function of time (their data spans from 2002-2008) and then overlaying these charted and graphed findings on the dates of FDA advisories and black box warnings. Questions raised subsequently or not addressed by the article include the following: (1) Has there been a change in contrast agent use patterns, with avoidance of certain gadolinium-based contrast agents implicated in NSF? (2) Has there been a change in NSF incidence in the VA patients? (3) What has been the impact on overall imaging protocols; for instance, has there been not just a shift from contrast to noncontrasted MRI, but a concomitant shift from MRI to computed tomography (CT)? (4) Are the findings of this study generalizable to non-VA centers?
      The incidence of NSF is not provided in this report and would be challenging to measure. While the VA offers a central information database to draw from, it is not a uniform set of medical facilities; each VA center may be administering gadolinium-based contrast agents by different protocols and using MRI in different algorithms. Moreover, each VA center may be detecting NSF with differing levels of sensitivity and specificity.
      It has been predicted that with recognition of the association between gadolinium-based contrast agents and NSF, clinicians would divert patients from MRI to CT for fear of NSF. The degree to which this has occurred and the overall health impact are subsequent questions that should be raised, but are difficult to answer. It may be hypothesized that a shift to CT may yield a net negative health effect on our patients
      • Martin D.R.
      • Semelka R.C.
      • Chapman A.B.
      • et al.
      Nephrogenic systemic fibrosis versus contrast induced nephropathy: risks and benefits of contrast-enhanced MR and CT in renally impaired patients.
      ; this hypothesis is based on the potential adverse health effects of exposing patients to ionizing radiation (1 in 1,000 lifetime attributable risk from cancer death per abdominal CT), allergenic effects from iodinated contrast agents (1 in 400,000 deaths attributed to iodinated contrast agents), and contrast-induced acute kidney injury. Unlike gadolinium-based contrast agents, where NSF risk may be negligible in all but patients with CKD stage 5 (GFR ≤15 mL/min/1.73 m2) and receiving dialysis, contrast-induced acute kidney injury may be induced in patients with even moderately decreased GFR (CKD stage 3). It is logical to expect that patients at risk for harmful effects of contrast-enhanced CT have received this test in place of MRI as a direct result of concerns over NSF. It is also a potential concern that CT and MRI are not diagnostically equivalent and that, for fear of NSF, a properly indicated MRI may be replaced with a test that is less sensitive and specific for the disease for which the scan would have been ordered, yielding adverse effects from incorrect, missed, or delayed diagnosis, additional biopsies, or suboptimal therapies.
      The body of literature on NSF supports the conclusion that the risk for this condition is negligible for estimated GFR >30 mL/min/1.73 m2, regardless of contrast agent used, even taking into account the gadolinium-based contrast agents most associated with NSF. Findings summarized in one figure of the Kim et al article shows use of gadolinium-enhanced MRI has declined markedly even in patients with estimated GFR >30 mL/min/1.73 m2. A potentially alarming concern is that patients with essentially no objective risk for NSF are being diverted to alternative, possibly harmful, diagnostic pathways.
      Trends in the type of gadolinium-based contrast agents used are not reported by Kim et al. This is a further complication to the analysis in the evolution of safer gadolinium-enhanced MRI protocols designed to reduce NSF risk. There are, in addition, findings to support early dialysis, within 1 day, following gadolinium-based contrast agent administration in dialysis patients.
      • Prince M.R.
      • Zhang H.
      • Morris M.
      • et al.
      Incidence of nephrogenic systemic fibrosis at two large medical centers.
      While the FDA has not made an official change to the advisory on gadolinium-based contrast agents to consider the differential NSF risk between agents, this essential distinction is contained within the advisory statements issued by the European Medicines Agency (EMEA), the European equivalent to the FDA. While counterpoints have been made regarding the theoretical concern for NSF, even regarding agents that are more stable, the increasingly large sample size of end-stage renal disease patients exposed to safer gadolinium-based contrast agents represents the most critical data from which policies should be derived.
      • Martin D.R.
      • Kalb B.
      • Salman K.
      • et al.
      Decreased incidence of NSF in patients on dialysis after changing gadolinium contrast-enhanced MRI protocols.
      The report of Kim et al has revealed important trends in practice patterns that we have suspected, but not quantified previously. Their results are compelling, yet the health outcomes of these changes in practice patterns remain unknown. The relative weight of FDA warnings regarding changes in MRI utilization patterns, versus that from other sources, including European regulatory warnings, American College of Radiology advisories, peer-reviewed journal publications, or presentations and discussions at the variety of meetings covering both imaging and nonimaging specialties, remains to be determined. The challenge is in understanding the full impact of these changes on imaging protocols, as described by Kim et al. An immediate goal should be to reset the discussion towards understanding and optimally managing the relative differential risks for use of safer gadolinium-enhanced MRI protocols in patients who have severely decreased kidney function and to be aware of the relative risks of the alternatives.

      Acknowledgements

      Financial Disclosure: The author declares that he has no relevant financial interests.

      References

        • Cowper S.E.
        • Robin H.S.
        • Steinberg S.M.
        • Su L.D.
        • Gupta S.
        • LeBoit P.E.
        Scleromyxedema-like cutaneous disease in renal-dialysis patients.
        Lancet. 2000; 356: 1000-1001
        • Cowper S.E.
        • Su L.D.
        • Bhawan J.
        • Robin H.S.
        • LeBoit P.E.
        Nephrogenic fibrosing dermopathy.
        Am J Dermatopathol. 2001; 23: 383-393
        • Cowper S.E.
        Nephrogenic fibrosing dermopathy: the first 6 years.
        Curr Opin Rheumatol. 2003; 15: 785-790
        • Thomsen H.S.
        Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide.
        Eur Radiol. 2006; 16: 2619-2621
        • Grobner T.
        Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?.
        Nephrol Dial Transplant. 2006; 21: 1104-1108
        • High W.A.
        • Ayers R.A.
        • Chandler J.
        • Zito G.
        • Cowper S.E.
        Gadolinium is detectable within the tissues of patients with nephrogenic systemic fibrosis.
        J Am Acad Dermatol. 2007; 56: 21-26
        • US Food and Drug Administration
        Questions and answers on gadolinium-based contrast agents.
        (Accessed June 29, 2010)
        • US Food and Drug Administration
        Information for healthcare professionals gadolinium-based contrast agents for magnetic resonance imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, ProHance).
        (Update May 23, 2007) (Accessed June 29, 2010)
        • US Food and Drug Administration
        FDA Requests Boxed Warning for Contrast Agents Used to Improve MRI Images.
        (Accessed June 29, 2010)
        • US Food and Drug Administration Center for Drug Evaluation and Research
        Transcript of Joint Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory Committees meeting.
        December 8, 2009 (Accessed June 1, 2010)
        • Kim K.-H.
        • Fonda J.R.
        • Lawler E.V.
        • Gagnon D.
        • Kaufman J.S.
        Change in use of gadolinium-enhanced mangetic resonance studies in kidney disease patients after US Food and Drug Administration warnings: a cross-sectional study of veterans affairs health care system data from 2005-2008.
        Am J Kidney Dis. 2010; 56: 458-467
        • Broome D.R.
        Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting.
        Eur J Radiol. 2008; 66: 230-234
        • Martin D.R.
        • Semelka R.C.
        • Chapman A.B.
        • et al.
        Nephrogenic systemic fibrosis versus contrast induced nephropathy: risks and benefits of contrast-enhanced MR and CT in renally impaired patients.
        J Magn Reson Imaging. 2009; 30: 1350-1356
        • Kanal E.
        • Broome D.R.
        • Martin D.R.
        • Thomsen H.S.
        Response to the FDA's May 23, 2007, nephrogenic systemic fibrosis update.
        Radiology. 2008; 246: 11-14
        • Pietsch H.
        • Lengsfeld P.
        • Jost G.
        • Frenzel T.
        • Hutter J.
        • Sieber M.A.
        Long-term retention of gadolinium in the skin of rodents following the administration of gadolinium-based contrast agents.
        Eur Radiol. 2009; 19: 1417-1424
        • Martin D.R.
        • Kalb B.
        • Salman K.
        • et al.
        Decreased incidence of NSF in patients on dialysis after changing gadolinium contrast-enhanced MRI protocols.
        J Magn Reson Imaging. 2010; 31: 440-446
        • Prince M.R.
        • Zhang H.
        • Morris M.
        • et al.
        Incidence of nephrogenic systemic fibrosis at two large medical centers.
        Radiology. 2008; 248: 807-816