Gadolinium and nephrogenic systemic fibrosis: The evidence of things not seen
Gadolinium exposure
To date, nearly all patients who have developed NSF have had known exposure to gadolinium-containing contrast agents. Gadolinium has been found in tissue of patients with NSF,6,7 yielding the postulate that gadolinium drives tissue fibrosis.
More patients with chronic kidney disease who developed NSF had been exposed to gadodiamide (Omniscan) than to other gadolinium-containing contrast agents, leading to the hypothesis that less-stable gadolinium-chelate complexes release greater amounts of free gadolinium, which then deposits in tissue and triggers fibrosis. However, it has not yet been determined that the gadolinium deposited in tissue is in the free form and not bound to chelate. Furthermore, this attractive hypothesis must be tempered by the recognition that NSF also has developed after exposure to gadopentetate dimeglumine (Magnevist), a more stable gadolinium-chelate complex than gadodiamide.8 The greater number of patients who have developed NSF after gadodiamide exposure may reflect the relative use of these contrast agents in radiology practice.
It is important to be aware that gadolinium-containing contrast agents are used in more than just magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Because gadolinium also blocks transmission of x-rays, radiologists occasionally have used gadolinium-containing contrast agents for angiography, venography, fistulography, and computed tomography in patients for whom use of iodinated contrast agents is contraindicated. Thus, a patient with chronic kidney disease may have received a gadolinium-containing contrast agent even if no magnetic resonance study had been performed.
Assessment of tissue gadolinium content may confirm prior exposure to a gadolinium-containing contrast agent if the patient does not recall having undergone an imaging study. In the one report that claims the development of NSF in two patients without prior gadolinium exposure, tissue was not assessed for gadolinium content.9
No study has yet been performed to assess the relative prevalence of NSF among patients with different stages of chronic kidney disease who have been exposed to gadolinium-containing contrast agents. Thus, it is impossible to ascertain a threshold of renal dysfunction above which the use of gadolinium-containing contrast agents might be safe.
In 90 patients with stage 5 chronic kidney disease, we found that 30% of those who previously had undergone gadolinium-enhanced imaging studies developed cutaneous changes of NSF; the relative risk of developing these skin changes after exposure to a gadolinium-containing contrast agent was 10.7 (95% confidence interval 1.5–6.9).8
Thus, it is essential that guidelines for the use of these contrast agents be formulated and implemented. Caution must be observed when administering a gadolinium-containing contrast agent to a patient with any degree of renal dysfunction. These patients must be informed of the possible risk of developing NSF, and appropriate follow-up must be conducted to assess for potential changes of NSF.
Other possible risk factors
Not all patients with chronic kidney disease who are exposed to gadolinium-containing contrast agents develop NSF: factors other than the degree of renal dysfunction must be involved in the pathogenesis of this condition.
Exposure to medications commonly taken by patients with chronic kidney disease, such as erythropoietin10 and iron supplements,11 has been suggested as a contributing factor. However, these medications are so widely used that this exposure is unlikely to explain why some patients develop NSF after receiving gadolinium-containing contrast agents and others do not.
Interestingly, lanthanum carbonate (Fosrenol) was approved by the US Food and Drug Administration in 2004 for use as a phosphate binder in patients with stage 5 chronic kidney disease. Since lanthanum and gadolinium both are rare earth metals of the lanthanide series, one might speculate that lanthanum deposition in tissue could produce similar changes or could potentiate those induced by gadolinium.
Future prospective case-control studies need to address risk factors for the development of NSF.
EFFECTIVE TREATMENT NEEDED
Because NSF imposes a markedly increased rate of death and devastating morbidity,8 efforts must be directed toward preventing its development and treating those who already are affected. So far, no treatment has been universally effective in reversing the fibrotic changes of NSF. Potentially effective therapeutic agents must be identified and studied in these patients.
Although performing hemodialysis promptly after the use of a gadolinium-containing contrast agent would appear to be a prudent clinical practice, there are no data to suggest that it is effective in preventing NSF. If free gadolinium disassociates from its chelate and deposits rapidly in tissue, it is unclear that hemodialysis could be performed soon enough to prevent this deposition. Furthermore, hemodialysis is not without associated potential risks and morbidity, especially in people with chronic kidney disease who are not already receiving hemodialysis. Thus, at present, avoiding the use of gadolinium-containing contrast agents in patients with chronic kidney disease appears to be the best preventive strategy.
A NAME CHANGE
Over the past decade, much has been learned about the clinical manifestations, course, and pathogenesis of NSF. However, the term “nephrogenic” in the name of this disease is misleading, in that this fibrosing disorder is not caused by the kidneys. Although some degree of renal dysfunction appears to be necessary for NSF to develop, the presence of gadolinium in tissue seems to drive fibrosis. Thus, it is time that “nephrogenic systemic fibrosis” be renamed more precisely as “gadolinium-associated systemic fibrosis” or “GASF.”
