Correspondence
Nephrogenic Systemic Fibrosis, Gadolinium, and Iron Mobilization
N Engl J Med 2007; 357:720-722August 16, 2007
- Article
To the Editor:
Nephrogenic systemic fibrosis is a newly described systemic disorder that occurs in patients with renal insufficiency.1,2 The functional consequences of nephrogenic systemic fibrosis are often devastating and may be fatal. Since nephrogenic systemic fibrosis develops after exposure to gadolinium-containing magnetic resonance contrast agents in some patients,3 the Food and Drug Administration recommended avoiding such agents in patients with renal insufficiency. The mechanism by which nephrogenic systemic fibrosis develops after gadolinium exposure remains unknown.
Gadolinium is administered as a chelate, since free gadolinium is toxic. Metals such as iron are capable of inducing the dissociation of gadolinium from its chelate (transmetallation). We postulated that some patients with renal insufficiency may have a heightened susceptibility to iron mobilization, which may contribute to gadolinium toxicity and nephrogenic systemic fibrosis. We present prospective data for two patients who had iron mobilization and inflammation after gadodiamide administration (Table 1Table 1
Prospective Findings before and after Gadodiamide Administration in Two Patients.). Patient 1 also had acute kidney injury and nephrogenic systemic fibrosis. We also provide additional evidence for the role of iron mobilization in nephrogenic systemic fibrosis from iron studies performed before and after gadodiamide exposure in 10 patients with biopsy-proven nephrogenic systemic fibrosis (Table 2Table 2
Retrospective Findings in 10 Patients with Nephrogenic Systemic Fibrosis.). The median time lag between gadodiamide exposure and the first available iron-study data was 13 days. In two patients, transferrin saturation remained over 100% (transferrin oversaturation) more than 1 week after gadodiamide exposure.Given a standard dose of 0.1 mmol of gadolinium per kilogram of body weight and a plasma volume of 40 ml per kilogram and assuming a strictly intravascular distribution, the theoretical maximum gadolinium concentration in plasma would be 2.5 mmol per liter. At such concentrations, gadodiamide caused minimal negative interference during in vitro measurement of serum iron levels and transferrin saturation (data not shown), suggesting that changes in these values after gadodiamide administration are unlikely to be due to its in vitro interference with these assays. Available data from liver-function tests in the patients suggest that iron mobilization is unlikely to be a result of parenchymal liver damage (Table 1). Other relevant laboratory data are summarized in Table 2. Eight of the 10 patients with biopsy-proven nephrogenic systemic fibrosis were already dependent on dialysis; the other two became dependent on dialysis 5 and 16 days after receiving gadodiamide. Four patients died after nephrogenic systemic fibrosis was diagnosed (median interval between diagnosis and death, 52 days; range, 37 to 76).
Our data suggest that gadodiamide exposure in patients with renal insufficiency may result in a substantial decrease in total iron-binding capacity and increased iron mobilization, resulting in transferrin oversaturation. On this basis, we postulate that in some patients, iron mobilization may lead to transmetallation and release of free gadolinium. Indeed, previous studies have shown the presence of gadolinium and iron in tissues affected by nephrogenic systemic fibrosis.4 Free gadolinium and catalytic iron5 may synergistically coordinate, resulting in oxidative stress, inflammation, and tissue injury. We speculate that exaggerated wound healing (in which erythropoietin may participate) occurs in response to the injury, resulting in a phenotype characteristic of nephrogenic systemic fibrosis.
5 ReferencesSundararaman Swaminathan, M.D.
Thomas D. Horn, M.D.
Donna Pellowski, M.D.
Sameh Abul-Ezz, M.D.
Joshua A. Bornhorst, Ph.D.
Sanjaya Viswamitra, M.D.
Sudhir V. Shah, M.D.
University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199
sswaminathan@uams.edu 1
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