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Genitourinary Imaging |
1 From the Departments of Radiology (E.A.S., R.W.G.), Dermatology (L.K.B., A.L.G.), Medicine (M.R.C., A.D.), and Biophysics (A.L.W.), University of Wisconsin, 600 Highland Ave, Madison, WI 53792-3252. Received December 15, 2006; revision requested January 3, 2007; revision received January 10; final version accepted January 11. Address correspondence to E.A.S. (e-mail: esadowski{at}uwhealth.org).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONIMPLICATION FOR PATIENT CAREReferences |
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Materials and Methods: This HIPAA-compliant study had institutional review board approval; informed consent was waived. Statistical analysis was performed for all available clinical and laboratory data in patients with biopsy-confirmed NSF. The data from the patients with NSF were compared with data from a control population of patients with renal insufficiency but who did not develop NSF.
Results: There were eight male and five female patients, aged 17–69 years, with a diagnosis of NSF. Within 6 months of diagnosis, all 13 patients had been exposed to gadodiamide and one had been exposed to gadobenate dimeglumine in addition to gadodiamide. At the time of contrast material–enhanced magnetic resonance (MR) imaging, all 13 patients had renal insufficiency (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) and were hospitalized for a proinflammatory event (major surgery, infection, or vascular event). The group with NSF had significantly decreased eGFR (P = .01), more proinflammatory events (P < .001), and more contrast-enhanced MR examinations per patient (P = .002) than did the control group.
Conclusion: A combination of factors, including altered kidney function, inflammatory burden, and exposure to gadolinium-based contrast agents may all play a role in development of NSF. Alternative imaging should be considered in patients with these factors. If use of a gadolinium-based agent is clinically indicated, the referring physician and patient should be informed of the potential risk of developing NSF.
© RSNA, 2007
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONIMPLICATION FOR PATIENT CAREReferences |
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The relationship between gadolinium-based contrast agents and NSF was suggested in January 2006, when Grobner (6) reported a case series of five patients, all of whom received a gadolinium-based contrast agent prior to the diagnosis of NSF. Since then, other reports in the dermatology and nephrology literature have been published supporting the possible link between gadolinium-based contrast agents and NSF (6,9–12). The Danish Medical Agency reported on 25 patients with NSF in Denmark and Austria earlier in 2006, with all patients receiving gadodiamide (Omniscan; GE Healthcare, Oslo, Norway) prior to the onset of NSF (13). There are also a growing number of patients with NSF being reported to the Food and Drug Administration (FDA), the American College of Radiology, the International Center for Nephrogenic Fibrosing Dermopathy Research, and the European Society of Urogenital Radiology. These organizations are collecting data on patients with NSF to calculate the relative incidence of NSF in those receiving the various clinically available gadolinium-based contrast agents.
At this time, it is not known whether a single agent or all gadolinium-based contrast agents are associated with NSF. Therefore, the FDA currently warns physicians to exercise caution when using any gadolinium-based contrast agent in patients with renal disease (13). The European Society of Urogenital Radiology recently released guidelines on the safe use of contrast media and warned physicians specifically not to use gadodiamide in patients with renal disease (15).
The purpose of this study was to retrospectively review cases of biopsy-confirmed NSF in 13 patients, to evaluate the associated risk factors, and to report the incidence of NSF at our institution.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONIMPLICATION FOR PATIENT CAREReferences |
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Patients with NSF
In the 13 patients with biopsy-confirmed NSF, we (all authors) examined all available clinical and laboratory information from the 6 months prior to the diagnosis of NSF. Data collected included age, sex, cause of kidney disease, first signs of NSF noted by the patient or documented in the chart, biopsy findings, dates of contrast-enhanced MR imaging examinations, type of agent, dose of agent, concurrent proinflammatory events (ie, major surgery, infection, vascular event or thrombosis), concurrent medications, dialysis status, and clinical outcome. For our study, we have defined a proinflammatory condition or event to encompass all processes in which the body has sustained major tissue injury, such as vascular surgery, transplantation surgery, or other major surgery; sepsis, pneumonia, osteomyelitis, or other major infection; and arterial or venous thrombosis that has caused ischemia or organ or limb damage. We use this term to encompass all states in which the body is attempting an intense healing response and major inflammatory pathways are activated. We included all contrast-enhanced MR imaging examinations performed within 6 months prior to the patient's diagnosis of NSF. The laboratory values examined included, but were not limited to, serum creatinine (sCr) levels; estimated glomerular filtration rates (eGFR); serum bicarbonate, calcium-phosphate product, magnesium, hemoglobin, and albumin levels; red blood cell morphology, antinuclear antibody titers, and C-reactive protein levels. For albumin and red blood cell morphology, we accepted results up to 2 weeks before or after the contrast-enhanced MR imaging examination. Apart from the albumin and red blood cell morphology measures, all other laboratory results used in the analysis were obtained within 24 hours of the MR imaging examination.
Control Patients
We retrospectively reviewed a clinical database for all patients who underwent contrast-enhanced MR imaging between June 2005 and July 2006. We then applied the search criteria of inpatient status, eGFR < 60 mL/min/1.73 m2 (with the Modification of Diet in Renal Disease, or MDRD, formula), and coexistence of a major proinflammatory event (major surgery, infection, or vascular event) (16). In this subset of hospitalized patients, we (all authors) reviewed all clinical and laboratory data in the same fashion as for the patients with NSF. From the initial analyses performed in patients with NSF, we (E.A.S. and A.D.) chose the criteria of renal insufficiency, inpatient status, and presence of a proinflammatory process to compare NSF patients to a group of control patients with similar renal function and underlying conditions.
Statistical Analyses
Data are presented as the mean and standard error of the mean. For individuals who had undergone multiple contrast-enhanced MR examinations, we determined the mean value (eg, mean sCr) from the separate laboratory values available at the time of each MR examination. The Mann-Whitney and Student t tests were used to compare nonparametric and parametric continuous data, respectively. The 
2 and Fisher exact tests were performed to compare parametric and nonparametric categoric data, respectively. Stepwise multiple logistic regression analyses were performed to determine independent covariates associated with the development of NSF. Variables were retained if P < .05 and were dismissed if P > .10. From the initial analyses performed in patients with NSF, the following independent variables were used: age; sex; eGFR; sCr, serum bicarbonate, and albumin levels; hemoglobin; number of proinflammatory events per patient; and number of contrast-enhanced MR imaging examinations per patient. The equation logit p(NSF) = ln[p/(1 – p)] was used, where p is the probability of presence of NSF. Analyses were performed with statistical software (MedCalc, Mariakerke, Belgium; and SigmaStat for Windows, SPSS, Chicago, Ill).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONIMPLICATION FOR PATIENT CAREReferences |
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Disease progression in our patients was variable. The mortality rate in our series was 31% (four of 13): The cause of death was acute respiratory distress syndrome in one patient, sepsis with respiratory failure in one patient, hypoxic hypercarbic respiratory failure due to esophageal rupture in one patient, and cardiac arrest due to ventricular fibrillation in one patient. Whether or not the cause of death was partly attributable to NSF was not addressed in the clinical notes or autopsy reports.
At the time of contrast-enhanced MR imaging, all 13 patients had decreased kidney function (eGFR < 60 mL/min/1.73 m2) (Table 2). Of particular note, two of our patients had only a mild decrease in renal function, with eGFR > 30 mL/min/1.73 m2. These patients were experiencing an episode of acute renal insufficiency, which can manifest with variable decreases in eGFR. We also noted that all patients with NSF had abnormal red blood cell morphology, primarily in the shape of the cells (Table 2). In 12 of 13 patients hypoalbuminemia (albumin < 3.9 g/dL [39 g/L]) was present, and in 11 patients anemia was present (hemoglobin < 12 g/dL [120 g/L]) (Table 2). For all other laboratory data, no obvious abnormal trends were observed.
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Control Patients
Our search for all patients who underwent contrast-enhanced MR imaging between June 2005 and July 2006 resulted in a database of 4236 patients, of whom 393 had eGFR < 60 mL/min/1.73 m2 and 3843 had eGFR > 60 mL/min/1.73 m2 (Fig 2). In the 393 patients with eGFR < 60 mL/min/1.73 m2, 139 were outpatients and 254 were hospitalized. In the 254 hospitalized patients with eGFR < 60 mL/min/1.73 m2, 123 had no documented proinflammatory events (see Materials and Methods), and 131 had a proinflammatory event occurring at the time of contrast-enhanced MR examination (Fig 2). Of these 131 patients, 125 did not develop NSF and six patients did between June 2005 and July 2006. This results in a 1-year incidence of 4.6%.
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Stepwise multiple logistic regression analyses demonstrated that sCr level, number of proinflammatory events per patient, and number of contrast-enhanced MR examinations per patient were independent risk factors for development of NSF (Table 3). The probability of NSF in a patient could be predicted with the following formula: logit p(NSF) = –8.706 + (0.962 · CE) + (0.470 · sCr) + (1.623 · PE), where logit p(NSF) = ln[p/(1 – p)], p is the probability of the presence of NSF, CE is the number of contrast-enhanced MR examinations, and PE is the number of proinflammatory events (surgery, infection, and arterial or venous thrombosis) (Table 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONIMPLICATION FOR PATIENT CAREReferences |
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All of the patients in our study had received gadodiamide within 6 months prior to the diagnosis of NSF. In a single patient, gadobenate dimeglumine had been administered 1 week before administration of gadodiamide, and this patient developed symptoms of NSF approximately 1 month later. Although most of our patients, as well as those reported on in the literature, had more advanced kidney disease, our case series included a small number of patients with less severe kidney disease. The variability of eGFR measurements in some of our patients was likely due to the fact there was acute kidney injury in our population. These observations indicate that even a mild decline in eGFR may be associated with NSF if other risk factors are present.
Our findings are in concordance with previous reports linking NSF with decreased kidney function, exposure to gadolinium-based contrast agents, and the presence of major tissue injury (eg, surgery, ischemic limb) (3,5,17–19). Cowper (3,5) has proposed that the underlying mechanism in the pathogenesis of NSF includes the preexistence of kidney dysfunction and concurrent tissue injury (surgery, ischemia). This inflammatory milieu may cause the release of cytokines, which recruit circulating fibrocytes from the bone marrow. These circulating fibrocytes then deposit in the skin and joints where they release more cytokines, growth hormones, and neoangiogenic factors, resulting in fibrosis (3). Our results support this potential mechanism, because all of our patients with NSF were undergoing a major inflammatory response to tissue injury at the time of contrast-enhanced MR examination just prior to the diagnosis of NSF.
We use the term proinflammatory condition or event to include a broad group of entities in which the body has sustained major tissue injury through vascular complications (thromboembolic events), surgery, or systemic infection. This rationale is based on previous reports, which showed that most patients with NSF had some form of endothelial or vascular injury (eg, surgery, thromboembolic event, vascular rejection, malignant hypertension) and that up to 90% of patients have undergone some form of surgery (eg, transplantation, fistula repair, other reconstructive vascular procedures) (3,5,8,17–19). Hypercoagulability and thrombotic episodes were also associated with NSF in as many as 12% of patients (5). We therefore grouped all these events into the category of proinflammatory conditions because they all are clinically identifiable sources of inflammation.
The authors of several recent reports have suggested an association between NSF and various metabolic disorders such as acidosis, high calcium-phosphate products, and the presence of antinuclear antibody titer, elevated C-reactive protein level, and elevated erythrocyte sedimentation rate (20–22). We did note that all patients with NSF had abnormal red blood cell morphology and the majority had hypoalbuminemia and anemia, but we were unable to demonstrate significant differences in these parameters between the control and NSF groups. It is unclear if hypoalbuminemia and abnormalities in red blood cell morphology contribute to the development of NSF, and further investigation in a larger group of patients would be necessary to answer this question. We did not find the majority of our NSF patients to be acidotic, according to their serum bicarbonate levels, nor did we find all patients to have markedly abnormal calcium-phosphate levels. Unfortunately, many of the patients in our series did not have available antinuclear antibody titers or other biomarkers of inflammation such as C-reactive protein level and erythrocyte sedimentation rate.
Most recently, two groups of researchers have used electron-dispersion spectroscopy to document the presence of gadolinium in biopsy specimens of patients with NSF (11,12). These investigators could not determine whether the gadolinium in tissue was bound to a chelate. Other heavy metals were discovered as well, including calcium, zinc, and iron. Heavy metals, including gadolinium, are toxic at low concentrations when they are free ions circulating in the body. In vivo, the gadolinium ion is bound to a particular chelate. All clinically available gadolinium-based contrast agents have been shown to be extremely stable in vivo (23). The stability of gadolinium-based agents depends on multiple parameters such as the thermodynamic stability constant, the solubility constant, the selectivity constants, and the kinetics of the molecule. Although some agents such as gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, New Jersey) and gadobenate dimeglumine have higher thermodynamic stability than does gadodiamide, the selectivity constant of gadodiamide is higher than that of gadopentetate dimeglumine. Moreover, the lethal dose gadodiamide is 14.8 mmol/kg, while the lethal dose of both gadopentetate and gadobenate dimeglumine is in the range of 6 mmol/kg and (22–27).
All of these constants have been determined from studies performed in vitro and in animals with normal renal function (22–27). The stability constants are not known in vivo, in the context of ongoing renal insufficiency, or when the body is undergoing healing after major tissue injury. Therefore, it is difficult to hypothesize if one agent is substantially more stable than another by simply using one parameter, and it is beyond the scope of this article to speculate which agent, if any, is safe for use. However, gadodiamide was used in the majority of patients with NSF reported in the literature (6,9,10,14,15). The FDA is currently investigating all gadolinium-based contrast agents as the potential cause of NSF (13).
Our study was limited by its retrospective nature, the relatively small number of patients with NSF, and the lack of complete biochemical data in all cases. Nonetheless, it is one of the largest single-center series published to date. Our study is one of the first to examine a large control group with renal insufficiency that also received gadolinium-based contrast material. This comparison may help parse the true incidence and risk factors for NSF more precisely than would a simple case series.
The European Society of Urogenital Radiology, the FDA, the American College of Radiology, and the International Center for Nephrogenic Fibrosing Dermopathy Research urge all of us to submit data on patients with NSF at our respective institutions, to help determine the relative incidence of NSF in those receiving the various clinically available gadolinium-based contrast agents. Because the relative incidence of NSF in those receiving the various clinically available gadolinium-based contrast agents has yet to be established, the FDA currently warns physicians to exercise caution when using any gadolinium-based contrast agent in patients with renal disease (13). The European Society of Urogenital Radiology recently released guidelines on the safe use of contrast media and warned physicians specifically not to use gadodiamide in patients with renal disease (15).
Recent recommendations have been made by two institutions regarding gadolinium-based contrast agents in patients with severe renal disease (eGFR < 30 mL/min/1.73 m2). Our study results have led us to include patients with milder level of renal insufficiency in the "at risk" category (eGFR < 60 mL/min/1.73 m2), particularly if the patient is hospitalized with a proinflammatory condition (28). Our approach is to avoid the administration of gadolinium-containing agents to all patients at risk. Many times, an alternative imaging examination can help answer the clinical question without the use of a gadolinium-based agent. Unenhanced MR imaging, computed tomography (CT) without or with iodinated contrast material, ultrasonography, conventional radiography, and nuclear medicine studies, alone or in concert with one another, can all provide answers to many clinical questions. If the patient is already undergoing dialysis, CT with an iodinated contrast agent may be a viable option. If the use of a gadolinium-based contrast agent is considered to be clinically indicated, the referring physician and the patient should be informed of the potential risks of developing NSF. Lower doses of the contrast agent or the use of a contrast agent that is not implicated as strongly as gadodiamide could also be considered. In patients who are already undergoing renal replacement therapy, dialysis after exposure to gadolinium will increase the clearance of the molecule. It should be noted that there are no data to demonstrate that either dialysis therapy after gadolinium or a lower dose of a gadolinium-based contrast agent reduces the incidence of NSF.
In conclusion, our data suggest that a combination of factors, including altered kidney function, intense inflammatory burden, and exposure to gadolinium-based contrast agents, may play a role in the development of NSF. Despite an apparent association between these insults and the development of NSF, the exact cause remains unknown. In patients at risk, alternative imaging examinations should be considered to avoid the administration of gadolinium-based contrast agents. If the use of a gadolinium-containing contrast agent is deemed clinically indicated, the referring physician and the patient should be informed of the potential risk of developing NSF.
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IMPLICATION FOR PATIENT CARE |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONIMPLICATION FOR PATIENT CAREReferences |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: eGFR = estimated glomerular filtration rate • FDA = Food and Drug Administration • NSF = nephrogenic systemic fibrosis • sCr = serum creatinine
Authors stated no financial relationship to disclose.
Author contributions: Guarantors of integrity of entire study, E.A.S., A.D.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, E.A.S., L.K.B., M.R.C., A.L.G., R.W.G., A.D.; clinical studies, E.A.S., L.K.B., M.R.C., A.L.W., A.D.; statistical analysis, E.A.S., A.L.W., A.L.G., R.W.G., A.D.; and manuscript editing, E.A.S., L.K.B., M.R.C., A.L.W., R.W.G., A.D.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONIMPLICATION FOR PATIENT CAREReferences |
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