Faculty Peer Reviewed
In 2006 and 2007, Clinical Correlations reported on the FDA’s announcement of a link between Nephrogenic Systemic Fibrosis (NSF), a rare progressive condition identified in some patients with kidney disease, and exposure to gadolinium-based contrast agents (GBCAs). The initial lesion of NSF is classically a large “brawny” hyperpigmented nodular plaque that appears fixed to the underlying tissues when palpated. It most often develops on the lower extremities, often mimicking chronic venous stasis changes, but the fibrosis itself can extend across joints causing contractures, and most critically can involve viscera such as the heart, lungs, and skeletal muscle. It is progressive and unremitting, and associated with a threefold increased risk of all cause mortality (mostly cardiovascular events) within 2 years of diagnosis.
Since NSF’s identification as a disease entity, there has been a marked shift in radiological standards and practices, as well as rapid growth of literature regarding the disease. Recent studies suggest that NSF is not directly related to GBCAs themselves, but instead to their release of free gadolinium in-vivo and its deposition in soft tissue (Abraham, Thakral, Skov, Rossen, & Marckmann, 2008).
GBCAs are all molecules that chelate the heavy metal gadolinium, though not all in the same way. These chemicals fit in two sets of independent categories, ionic and non-ionic, and more importantly linear and cyclic. All are supposed to prevent release of free gadolinium in-vivo, however several studies have shown that under certain conditions some gadolinium does get released. This flaw appears to particularly affect the linear chelates, which can release between a hundred to a thousand fold more free gadolinium than the cyclic chelates (Frenzel, Lengsfeld, Schirmer, Hutter, & Weinmann, 2008). Through a mechanism not yet fully understood, but likely associated with either a preexisting or triggered inflammatory state, free gadolinium causes the activation of fibroblastic cells and the development of the characteristic NSF lesions (Steger-Hartmann, Raschke, Riefke, Pietsch, Sieber, & Walter, 2009). There is a direct association between total lifetime amount of gadolinium contrast and risk of developing NSF with subsequent exposures, although even single exposures have been sufficient to cause the disorder. This risk is multiplied the more severe the renal insufficiency, with the theory being that a longer time-to-clearance allows greater time for disassociation of free gadolinium and thus greater overall exposure. It bears repeating that some degree of renal insufficiency (either acute or chronic) appears to be required for NSF to develop, as effectively all well documented cases of NSF have occurred in patients with eGFRs less than 30 ml/min.
This link between free gadolinium and the development of NSF is supported by retrospective data showing that the risk of developing NSF differs between types of GBCAs (Prince, Zhang, Roditi, Leiner, & Kucharczyk, 2009). Gadodiamide (brand name Omniscan), a linear gadolinium chelate with the highest propensity to disassociate to free gadolinium in vivo, has also been noted to be associated with a tenfold higher risk of developing NSF than gadopentate dimeglumine (aka Magnevist) an ionic linear chelate slightly more resistant to disassociation (Wertman, et al., 2008). Unfortunately, lower risk does not equate to no risk, and the last two years have also seen case reports of all the GBCAs being associated with incidents of NSF (Abujudeh, et al., 2009).
Despite a better understanding of the pathophysiology of NSF, treatment options remain elusive. Many treatments have been tried for patients with NSF, including renal transplantation, corticosteroids, IVIG, plasmapheresis, hemodialysis, and heavy metal chelation, all of which have never been proven more than anecdotally successful. Given the apparent hyperproliferative nature of the disease, many of the proposed treatments utilize anti-cell proliferation medications such as imatinib (Gleevec) and rapamycin. There are some preliminary data suggesting some of these treatments may have some effect, but data are largely limited to single case reports at this time. However, though treatment efforts have been largely futile to date, prevention strategies have been much more successful. Prior to the FDA’s warning in 2006, belief in the relative safety of GBCAs led to their repeated use at higher than recommended dosages, and in patients with end stage renal disease and any level of chronic kidney disease . After the FDA black-box warning in 2007, many institutions instituted strict new guidelines for the usage of contrast in MRIs, also switching from less stable linear chelates like gadodiamide (Omniscan) and gadopentate dimeglumine (Magnevist) to more stable linear and cyclic chelates such as gadobenate dimeglumine (MultiHance) and gadotiredol (ProHance). Common among these new guidelines have been:
1) Assessment of patient renal function by calculation of estimated glomerular filtration rate (eGFR) is now required prior to the use of gadolinium contrast.
2) Gadolinium exposure is now minimized, even among those with normal renal function (markedly decreased usage of above-label doses of contrast).
3) Contrast MRI was avoided if at all possible in patients with severe CKD (GFR <30), those on renal replacement therapy, or those with acute renal failure.
These new regulations have markedly decreased the incidence of NSF, even among those at highest risk. One recent study by Altun et al. found that after implementation of GBCA usage policies two large U.S. universities saw the incidence of NSF go from ~3% of high risk patients receiving contrast (patients with end stage renal disease or acute renal failure) to zero (Altun, Martin, Wertman, Lugo-Somolinos, Fuller, & Semelka, 2009). In light of these data, even though the exact pathophysiology and treatment of NSF may still elude us, current safety protocols appear to be dramatically changing the rate of occurrence of the disease.There is hope that NSF may become a progressively rarer entity in the future despite ever increasing usage of MRI as an imaging modality.
To learn more about NSF a good resource is the International Center for Nephrogenic Systemic Fibrosis Research website: http://www.icnsfr.org/
Dr. Hsueh is a 3rd-year resident at NYU Langone Medical Center
Peer reviewed by David Goldfarb, MD, Nephrology Section Editor, Clinical Correlations
Image courtesy of Wikimedia Commons.
Abraham, J., Thakral, C., Skov, L., Rossen, K., & Marckmann, P. (2008). Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. BRITISH JOURNAL OF DERMATOLOGY , 158 (2), 273-280.
Abujudeh, H., Kaewlai, R., Kagan, A., Chibnik, L., Nazarian, R., Rosalynn, M., et al. (2009). Nephrogenic Systemic Fibrosis after Gadopentetate Dimeglumine Exposure: Case Series of 36 Patients. RADIOLOGY , 253 (1), 81-89.
Altun, E., Martin, D., Wertman, R., Lugo-Somolinos, A., Fuller, E., & Semelka, R. (2009). Nephrogenic Systemic Fibrosis: Change in Incidence Following a Switch in Gadolinium Agents and Adoption of a Gadolinium Policy-Report from Two US Universities. RADIOLOGY , 253 (3), 689-696.
Chandran, S., Petersen, J., Jacobs, C., Fiorentino, D., Doeden, K., & Lafayette, R. (2009). Imatinib in the treatment of nephrogenic systemic fibrosis. Am J Kidney Dis. , 53 (1), 129-32.
Cowper, S. (2001-2009). http://www.icnsfr.org. Retrieved June 28, 2010, from ICNSFR Website: www.icnsfr.org
Frenzel, T., Lengsfeld, P., Schirmer, H., Hutter, J., & Weinmann, H.-J. (2008). Stability of Gadolinium-Based Magnetic Resonance Imaging Contrast Agents in Human Serum at 37C. Investigative Radiology , 43 (12), 817-828.
Prince, M., Zhang, H., Roditi, G., Leiner, T., & Kucharczyk, W. (2009). Risk Factors for NSF: A Literature Review. JOURNAL OF MAGNETIC RESONANCE IMAGING , 30 (6), 1298-1308.
Steger-Hartmann, T., Raschke, M., Riefke, B., Pietsch, H., Sieber, M., & Walter, J. (2009). The involvement of pro-inflammatory cytokines in nephrogenic systemic fibrosis – A mechanistic hypothesis based on preclinical results from a rat model treated with gadodiamide. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY , 61 (6), 537-552.
Swaminathan, S., Arbiser, J., Hiatt, K., High, W., Abul-Ezz, S., Horn, T., et al. (2010). Rapid improvement of Nephrogenic Systemic Fibrosis with rapamycin therapy: possible role of phospho-70-ribosomal-S6 kinase. J Am Acad Dermatol. , 62 (2), 343-5.
Wertman, R., Altun, E., Martin, D., Mitchell, D., Leyendecker, J., O’Malley, R., et al. (2008). Risk of nephrogenic systemic fibrosis: Evaluation of gadolinium chelate contrast agents at four American universities. RADIOLOGY , 248 (3), 799-806.