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Editorial |
1 From the Department of Diagnostic Radiology, (P.H.K.), Department of Internal Medicine, Section of Nephrology (A.K.A.), and Department of Dermatology and Pathology (S.E.C.), Yale School of Medicine, 333 Cedar St, PO Box 208042, New Haven, CT 06520-8042; and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (E.K.). Received September 21, 2006; revision requested November 13; revision received December 11; final version accepted December 15. Address correspondence to P.H.K. (e-mail: phillip.kuo{at}yale.edu).
Nephrogenic systemic fibrosis (NSF), described in 2000 (1), is an emerging systemic disorder characterized by widespread tissue fibrosis. Originally known as nephrogenic fibrosing dermopathy because of its dominant cutaneous findings, the nomenclature was revised in recent years to reflect an increased understanding of its systemic effects (1,2). While the precise cause of NSF remains a mystery, it is known to occur only in patients with renal disease–generally in those requiring dialysis. NSF may develop rapidly and can sometimes result in patients becoming confined to a wheelchair within a few weeks. More commonly, the skin thickening is insidious and can be confused clinically with peripheral edema. Pathophysiologically, NSF results in increased tissue deposition of collagen, commonly resulting in thickening and hardening of the skin of the extremities and often culminating in immobility and contractures of the joints. In some patients, there is clinical involvement of other tissues (lung, skeletal muscle, heart, diaphragm, esophagus, etc), although the patient may not be clinically symptomatic (3). While NSF sometimes stabilizes, it rarely spontaneously remits. No consistently effective therapy exists, although rapid correction in renal function (by medical or surgical means) generally results in a cessation of progression and often in a reversal of symptoms (4).
With renal dysfunction at the core of this condition, the possibility that renally excreted endogenous or exogenous substances may be triggering NSF has been of great interest. Since NSF appears not to have existed prior to 1997, suspicion that a recently introduced agent might be the culprit has been rampant, but investigation by several authors and by the Centers for Disease Control and Prevention has so far failed to identify a single causative medication (3). Of great interest, the author of a recent article (5) has suggested that administration of intravenous contrast material for magnetic resonance (MR) imaging (ie, gadolinium chelates) has been associated with a small cluster of patients with NSF in Austria (five of nine imaged patients). A Web-based medical advisory originating in Denmark claims that, since January 2002, approximately 400 patients with severely impaired renal function were administered gadolinium-based MR contrast material; 20 patients (5%) subsequently were diagnosed with NSF (6). Other unpublished U.S. experience (S.E.C., October 2006) suggests an approximate incidence of 3% for the development of NSF in the setting of severe renal failure and administration of intravenous contrast material for MR imaging.
An international NSF registry at Yale University (New Haven, Conn) maintains records on over 215 patients with NSF worldwide. A survey now underway has revealed that more than 95% of all NSF patients surveyed (currently approximately 100) have been exposed to a gadolinium chelate within 2–3 months prior to disease onset. The majority of the patients were being maintained with dialysis. However, a number of patients with impaired renal function have been reported to the registry, the severity of whose disease has been difficult to determine retrospectively.
To the best of our knowledge, the overwhelming majority of known NSF cases at this point (
90%) represent patients who had previously received gadodiamide (Omniscan; GE Healthcare, Princeton, NJ) (7). Nevertheless, there have been reports of NSF cases associated with other agents. As of October 26, 2006, there have been a total of 57 cases of NSF associated with prior gadolinium-based MR contrast agent administration reported to the U.S. Food and Drug Administration (FDA) MedWatch Web site (http://www.fda.gov/medwatch). Of the 57 cases of NSF reported to the FDA to date, six are definitely associated with gadopentetate dimeglumine (Magnevist; Berlex Imaging, Montville, NJ); two, with gadoversetamide (OptiMARK; Mallinckrodt, St Louis, Mo); and three, with gadodiamide plus gadoversetamide associated; for three other cases, the associated specific gadolinium-based MR contrast agent was not definitively identified. For the remainder, gadodiamide was the associated agent (George Mills, MD [FDA], personal communication, October 26, 2006). The FDA has sufficient confidence in these MedWatch reports to induce an update to their Public Health Advisory in the near future (George Mills, MD, personal communication, October 26, 2006). While the FDA fully recognizes that the reports available at this time focus on gadodiamide, the FDA nevertheless continues to be concerned that this may be a class issue rather than a specific agent issue (George Mills, MD, personal communication, October 26, 2006).
Both standard- and high-dose administrations of these agents have been recorded, and multiple administrations have been reported. In some cases, patients were exposed to additional contrast enhanced MR imaging procedures in an effort to investigate the patient's sudden and inexplicable lower extremity skin hardening (S.E.C., unpublished data, October 2006).
Although a causative relationship between gadolinium chelates and NSF has not been firmly established, the data are certainly suspicious that such a relationship may exist. This suspicion has been compounded by the recent detection of gadolinium in tissue biopsy specimens from some patients with known NSF (8,9), including some in whom the biopsy was performed as long as 11 months after the original intravenous administration of the gadolinium-based MR contrast agent (8).
If such a causative relationship exists, some questions that immediately emerge include the following: (a) How do renal failure and MR contrast agents trigger NSF? Is the effect related to the extended half-life of these agents far beyond the typical expected 70–90 minutes exhibited by those with normal renal function (10)? (b) Are other factors necessary to place a patient at risk? (c) Does the proinflammatory milieu in renal failure contribute to the fibrotic response (11)? (d) Is metabolic acidosis necessary for the disease to occur (5)? (e) Why did the initial reports appear in 1997, when gadolinium-containing contrast agents had already been used in patients with renal failure for several years? (f) Is the gadolinium, gadolinium chelate complex, or the chelator the culprit?
While at this time there are more questions than answers, the recognition of an epidemiologic association between the administration of gadolinium-based MR contrast agents and the development of NSF prompts caution in the use of these agents in the setting of renal disease. The FDA currently provides recommendations posted on their Web site and quoted below (12):
Gadolinium-containing contrast agents, especially at high doses, should be used only if clearly necessary in patients with advanced kidney failure (those currently requiring dialysis or with a Glomerular Filtration Rate (GFR) = 15 cc/min or less).It may be prudent to institute prompt dialysis in patients with advanced kidney dysfunction who receive a gadolinium contrast MRA. Although there are no data to determine the utility of dialysis to prevent or treat NSF/NFD [nephrogenic fibrosing dermopathy] in patients with decreased kidney function, average excretory rates of gadolinium are 78%, 96%, and 99% in the first to third hemodialysis sessions, respectively (Okada et al, Acta Radiologica, vol 42 p. 339, May 2001).
Although there is evidence associating the development of NSF in patients with renal failure with only some, but not all, of the FDA-approved gadolinium-based MR contrast agents to date, prudence dictates that we apply our concern to all gadolinium-based MR contrast agents in this regard until more definitive information is forthcoming. For the use of all gadolinium-based MR contrast agents in patients with stage 4 or 5 chronic kidney disease (ie, patients maintained with either hemodialysis or peritoneal dialysis) or patients with a GFR of less than 30 mL/min/1.73 m2, we follow the approach listed below. We share this solely as our approach rather than as an official recommendation of any kind.
1. In consultation with the ordering physician, we consider alternative imaging or nonimaging modalities that may provide the requested clinical diagnostic data at a lower potential risk. The benefits and risks of an MR study with the addition of contrast material should be evaluated on an individual basis for each patient.
2. We administer gadolinium-based MR contrast agents to a patient with stage 4 or 5 chronic kidney disease or with acute kidney injury and markedly impaired GFR or who undergoes dialysis, if prescribed by a state-licensed physician. We inform patients of the benefits, risks, and alternatives, based on currently available information, and prospectively record in writing the disclosure and the informed consent.
3. If administration of a gadolinium-based MR contrast agent is deemed necessary, we consider using the lowest dose needed to reliably provide the diagnostic information being clinically sought. In the absence of a specific reason to the contrary, consider a default dose of no more than half the standard dose for these patients.
4. We perform any additional nonenhanced sequences that may be helpful, and we monitor the study to evaluate for the continuing necessity of contrast agent.
5. For patients maintained with hemodialysis, we ensure hemodialysis treatment as soon as possible, ideally within 3 hours after the administration of the gadolinium-containing contrast agent. A second dialysis session within 24 hours can also be performed if it is clinically safe to do so.
6. For patients undergoing peritoneal dialysis, we ensure that patients have no periods with a dry abdomen (ie, peritoneal cavity contains no dialysate), and we perform more frequent manual exchanges or additional automated peritoneal dialysis cycles for at least 48 hours after administration. However, there are data to suggest that hemodialysis clears the gadolinium-based MR contrast agent more effectively than does peritoneal dialysis (10). Therefore, we consider hemodialysis for patients undergoing peritoneal dialysis who may still have a functional vascular access for hemodialysis, for patients thought to be at higher risk because of the dose used or prior recent exposure, and for those who have other risk factors, according to the judgment of the nephrologist.
7. Insufficient data exist to estimate the risk of developing NSF in relationship to the GFR in patients with chronic kidney disease who are not maintained with dialysis. The primary concern would be for patients with stage 4 chronic kidney disease (defined as GFR of 15–30 mL/min/1.73 m2). On the other hand, initiating hemodialysis in patients without vascular access for the sole purpose of removing gadolinium-based MR contrast material entails some risks and discomfort, including the potential need for permanent hemodialysis sooner than anticipated. As such, initiating hemodialysis for the sole purpose of removing a gadolinium chelate needs to be evaluated on an individual basis, and a risk-benefit assessment must be made regarding the need for gadolinium chelate administration versus the risks of developing NSF and/or initiating dialysis.
8. We refrain from administering gadolinium-based MR contrast agents to patients in whom there may be relatively protected spaces that the gadolinium chelates might enter but from which they may not readily be cleared. An example of such a space is the amniotic fluid, where at least some of these contrast agents can accumulate shortly after intravenous administration, as observed by one of the authors (E.K.).
9. If there is a diagnosis or clinical suspicion of NSF in the patient, we discourage exposure to any gadolinium chelates.
10. In light of the observation that the overwhelming majority of cases of NSF are associated with prior gadodiamide administration specifically, we do not administer this agent to patients with any renal disease.
At this time, the relationship between NSF and gadolinium chelates remains unclear. Further studies are now underway at the Centers for Disease Control Prevention, the FDA, and in the medical regulatory agencies of the European Union. If we encounter NSF in a patient, we proceed as follows:
1. We ascertain whether there is a history of administration of a gadolinium-based MR contrast agent in the weeks or months preceding the initial diagnosis. We record the date of administration and the dose and brand of the contrast agent administered, as well as the date of onset or diagnosis of NSF (as precisely as possible).
2. We report the event to the FDA (or appropriate non-U.S. regulatory agency) online through the MedWatch reporting program (http://www.fda.gov/medwatch/) or by phone (1-800-FDA-1088).
3. We report the case to the NSF registry at Yale University (http://www.icnfdr.org).
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FOOTNOTES |
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