The purpose of this work is to provide current information on the rapidly evolving subject of nephrogenic systemic fibrosis (NSF), to establish the radiologic approach to the management of high-risk patients for NSF, and to assess the probabilistic risk of NSF compared to contrast induced nephropathy (CIN), as encountered with iodinated contrast media used in computed tomographic (CT) imaging. NSF is a disease process of considerable concern following gadolinium-containing contrast agents (GCCA) exposure in patients with diminished renal function. To minimize the possibility of NSF development in high-risk patients, GGCAs should not be used when they are not necessary, or the GCCAs, that have not at present been associated with NSF development, should be used at the lowest possible diagnostic dose, when they are necessary. Contrast-induced nephropathy is also a great risk in this patient population following the adminstration of iodinated contrast media (CM). In patients with diminished renal function who are not on regular dialysis, the risk of CIN following the administration of iodinated CM is higher than the risk of NSF following the administration of the most stable GCCAs. Risk benefit analysis should be performed prior to the administration of all CM, and the best combination of safety and diagnostic accuracy should be sought. Concern of NSF or CIN should not prevent the use of contrast agents in magnetic resonance imaging or computed tomography when they are deemed essential.
In 1997, Cowper et al identified a scleromyxoedema-like cutaneous disease in renal dialysis patients that they described in an initial series of fifteen patients in 2000. Subsequent to the observation of this condition in other subjects, this entity became initially described as nephrogenic fibrosing dermopathy . In 2005, Daram et al reported that this disease was not solely restricted to the skin and that systemic involvement may occur, and they proposed the new description as nephrogenic systemic fibrosis (NSF). Although the skin findings are similar to systemic sclerosis, NSF spares the face and lacks the serologic markers of systemic sclerosis .
In 2006, Dr. Thomas Grobner discovered an association between NSF development and gadodiamide, which is one of gadolinium-containing contrast agents (GCCAs) employed as a standard in contrast-enhanced magnetic resonance imaging (MRI). In this landmark study, Dr. Grobner found that all of his patients with NSF had been exposed to gadodiamide prior to the development of NSF. Therefore, he proposed a triggering role for gadolinium in NSF development in patients with diminished renal function . To date, several studies have confirmed the proposed role of GCCAs in NSF development .
Following these reports, the Food and Drug Administration (FDA) of the United States of America (USA) has published a warning that the use of all GCCAs should be avoided in high-risk patients unless the diagnostic information is essential and not available with noncontrast MRI . In Europe, the European Medicine Agency (EMEA) issued a similar warning with two clear distinctions, that only the use of specific GCCAs associated with the development of NSF are contraindicated in high-risk patients and those specific GCCAs should also be cautiously used in low-risk patients, including patients with stage 3 chronic kidney disease . Both agencies have asked the manufactures to include these warnings on the product labeling of GCCAs .
GCCAs have long been considered safe and preferred over iodinated contrast media (CM) in patients with renal impairment . However, the discovery of the association of GCCAs with the development of NSF demonstrates that GCCAs should also be used with caution in all patients, particularly in patients with renal impairment . Due to the widespread use of GCCAs in MRI studies and common occurrence of renal impairment in the general population, the medical community should be familiar with NSF and the imaging management of patients at high risk for NSF.
Thus, the purpose of this review is to provide current information on the rapidly evolving subject of NSF, to establish the radiologic approach to the management of high-risk patients for NSF, and to assess the probabilistic risk of NSF compared with contrast-induced nephropathy (CIN), as encountered with iodinated CM used in computed tomographic (CT) imaging.
NSF
Definition
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Epidemiology
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Pathophysiology and Risk Factors
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Diminished Renal Function
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Table 1
Stages of Renal Diseases †
Stage Description GFR ∗ (mL/min/1.73 m 2 ) 1 Kidney damage with normal or increased GFR ≥90 2 Kidney damage with mildly decreased GFR 60–89 3 Moderately decreased GFR 30–59 4 Severely decreased GFR 15–29 5 Kidney failure <15 (or dialysis)
Chronic kidney disease is defined as either kidney damage, or GFR lower than 60 mL/min/1.73 m 2 for more than 3 months.
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Pharmacokinetics of GCCA
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Table 2
Thermodynamic Stability Constants and Dissociation Rates of Gadolinium-Containing Contrast Agents (GCCAs) †
Generic Name Chemical Abbreviation Product Name Amine Structure Charge Excretion Thermodynamic Stability Constant Dissociation Rate Gadoversetamide Gd-DTPA-BMEA OptiMark (Mallinckrodt, St Louis, MO, ABD) Linear Non-ionic Renal 16.8 >2.2 × 10 −2 Gadodiamide Gd-DTPA-BMA Omniscan (GE Healthcare, Buckinghamshire, United Kingdom) Linear Non-ionic Renal 16.8 >2 × 10 −2 Gadopentetate dimeglumine Gd-DTPA Magnevist (Bayer Schering Pharma AG, Germany) Linear Ionic Renal 22.2 1.2 × 10 −3 Gadobenate dimeglumine Gd-BOPTA MultiHance (Bracco Diagnostics, Milan, Italy) Linear Ionic Renal (%97), Biliary (3%) 22.6 – ∗ Gadoxetik asit Gd-EOB-BOPTA Primovist (Bayer Schering Pharma AG, Germany) Linear Ionic Renal (50%), Biliary (50%) 23.4 – ∗ Gadobutrol Gd-DO3A-butriol Gadovist (Bayer Schering Pharma AG, Germany) Macrocyclic Non-ionic Renal 21.0 2.8 × 10 −6 Gadoteridol Gd-HP-DO3A ProHance (Bracco Diagnostics, Milan, Italy) Macrocyclic Non-ionic Renal 23.8 6.4 × 10 −5 Gatoterate meglumine Gd-DOTA Dotarem (Guerbet, Aulnay-sous-Bois, France) Macrocyclic Ionic Renal 25.6 8.4 × 10 −7
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Co-factors
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Circulating Fibrocyte Hypothesis
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Clinical Findings
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Diagnosis
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Treatment and Prognosis
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Recommended guidelines to minimize the risk of NSF
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Probabilistic risk assessment of NSF versus CIN
CIN
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NSF versus CIN
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Conclusion
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