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Commentary |
1 Department of Diagnostic Radiology, Yale University School of Medicine, New
Haven, CT
2 Present address: Department of Medicine, Section of Hematology/Oncology,
University of Arizona School of Medicine, 1515 N. Campbell Ave., PO Box
245024, Tucson, AZ.
3 Department of Radiology, Southern Arizona Veterans Administration Hospital,
Tucson, AZ.
Received May 7, 2008; accepted after revision June 27, 2008.
P. H. Kuo received an honorarium as a one-time speaker for Bracco
Diagnostics.
Keywords: circulating fibrocyte • contrast agent • gadolinium • mechanism • nephrogenic systemic fibrosis
The understanding of the pathogenesis of nephrogenic systemic fibrosis (NSF) and its link with gadolinium-containing contrast agents is still in an early stage. The studies by Wiginton et al. [1] and Golding and Provenzale [2] in the April 2008 issue of the AJR provide key insights into the mechanism of NSF. Hypotheses on the mechanism of NSF have been developed that may influence clinical decisions on the administration of gadolinium-containing contrast agents. The administration of such agents to patients with kidney disease results in decreased clearance and therefore retention of the gadolinium-containing contrast agent [3].
This retained gadolinium in lesions of NSF can be found years after administration [4, 5]. Retrospective patient studies have correlated higher total dose of gadolinium-containing contrast agents with increased incidence of NSF [6–8]. These findings have formed the basis for hypotheses proposing that the increased residence time of gadolinium-containing contrast agents in patients with kidney disease provides the opportunity for dechelation and subsequent retention of gadolinium, which in turn activate cells responsible for NSF [9, 10]. Further corollaries are that as retained gadolinium increases so too does the risk for induction of NSF, and that the retained gadolinium also maintains disease activity. This article proposes an important concept: Inorganic gadolinium in the body does not trigger NSF nor does it maintain disease activity. Published data suggest that administration of gadolinium as a chelate is necessary to cause NSF and therefore that retained inorganic gadolinium is, to coin the term, "NSF-inert."
A prevailing theory is that gadolinium is released from its chelate by competitive binding with other metals in the body through a process known as transmetallation [11]. In the body, free gadolinium released from its chelate likely forms insoluble precipitates with phosphate or hydroxide that are unlikely to further dissociate in tissues. What proof is there that the inorganic species of gadolinium is NSF-inert and that the gadolinium chelate is the NSF-active species? The study by Edward et al. [12] showed that although gadodiamide increased growth of fibroblasts, gadolinium in the form of GdCl had no effect on proliferation of fibroblasts in culture. An increase in collagen production was also seen with gadodiamide but GdCl was not tested.
Serum from patients with NSF increased collagen production by fibroblasts over that of dialysis controls. This result supports that factors in the serum could account for the systemic fibrosis but does not exclude a possible role for local tissue factors, as hypothesized by others. Sieber et al. [13] showed that gadodiamide and gadolinium–ethylenediamine tetraacetic acid caused NSF in rats. Inorganic gadolinium was not tested in this rodent model; however, extensive older studies on the toxicology of lanthanides reported no findings matching those of NSF. In addition, the study by Wiginton et al. [1] analyzed skin biopsies from patients with NSF and showed gadolinium in both unaffected and affected areas. The finding of gadolinium in the unaffected tissue supports the concept that local disease activity may not correlate with locally retained inorganic gadolinium.
Reports of increased disease activity coinciding with a decline in renal function need not be explained by decreased clearance of gadolinium mobilized from storage sites such as bone with subsequent deposition in NSF-affected tissues such as skin [14]. Most patients with kidney disease who receive a gadolinium-containing contrast agent do not develop NSF, so clearly there are other crucial factors that increase susceptibility to NSF. These still poorly defined factors may play a role not only in the initial triggering of NSF but also in the level of disease activity and severity. If so, exacerbation of NSF with a decline in renal function can be attributable to factors other than gadolinium. Removal of these factors that are present in greater abundance with kidney disease appears to be sufficient to halt NSF because the disease remits with return of normal kidney function [15]. However, the importance of the gadolinium stored in bone certainly warrants further study.
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A model of pathogenesis based on the gadolinium chelate as the NSF-active species is perhaps best thought of using the venerable real estate axiom, "location, location, location" (Fig. 2). The intravascular compartment is exposed to the highest concentration of gadolinium-containing contrast agents. Within the intravascular compartment are circulating fibrocytes and monocytes, both of which are capable of internalizing gadolinium-containing contrast agents. Circulating fibrocytes in particular likely play a central role in the pathogenesis because they are characteristic histopathologic findings in NSF [16]. In addition to collagen production, circulating fibrocytes also have properties of immune cells [17]. The monocyte–macrophage lineage may also be crucial, given their production of chemokines and other interactions with various components of the inflammatory response. The effect of gadolinium-containing contrast agents on endothelial cells may also be critical given the importance of the endothelium on trafficking of cells from the blood to the skin and other tissues affected by NSF. Indeed, the initial triggering of NSF by gadolinium-containing contrast agents and subsequent progression of disease without reexposure to the trigger bear a marked resemblance to other autoimmune diseases [18]. The inflammatory–immune system appears to show "memory" such that once NSF has developed, reexposure to the initial trigger (gadolinium-containing contrast agents) need not occur to sustain disease activity. Indeed, the circulating fibrocytes found in NSF lesions likely represent a cell population continuously recruited from the marrow because they are CD34+, and the expression of this marker declines once the cells have left the bone marrow. Therefore, these circulating fibrocytes would not be the original ones exposed to the triggering dose of gadolinium-containing contrast agent in the intravascular compartment.
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Finally, in the subcellular compartment, endosomes or lysosomes may provide an environment for release of free gadolinium, possibly through a combination of lower pH and enzymatic action. Intracellular free gadolinium would have a greater chance of activating cellular machinery than would free gadolinium in serum before it binds to phosphate and is rendered insoluble and NSF-inert. In particular, interaction with calcium pathways is possible, given the similar ionic radii of gadolinium and calcium. Excess ligand in the formulated gadolinium-containing contrast agents may also be internalized in the same vesicle as the gadolinium-containing contrast agents and therefore still be able to act as a sink for free gadolinium, even in the subcellular compartment. Therefore, this model is compatible with the observed protective effect of excess ligand seen in the rodent model [13].
This model has important clinical implications for the prevention of NSF. Less emphasis is placed on the cumulative dose of gadolinium-containing contrast agents and more is placed on the identification and management of risk factors for NSF. The study by Golding and Provenzale [2] adds further proof that infection or inflammation is one of the key risk factors that, when combined with gadolinium-containing contrast agents, can trigger NSF. The combination of the inflammatory milieu already present with kidney disease and an acute infectious or inflammatory process may provide the kindling for the proper fibrotic pathways to be ignited by gadolinium-containing contrast agents. Using the analogy of a wildfire, the NSF continues in the presence of renal disease without readministration of gadolinium-containing contrast agents just as a wildfire continues to burn long after the initial lightning strike. The time that must elapse between administrations of gadolinium-containing contrast agents in order not to increase the risk of NSF is still an important and difficult question.
This model emphasizing waxing and waning NSF susceptibility would suggest that the safe period of time could be highly variable both within a single patient and also for different patients. Therefore, research needs to focus on better characterizing and quantifying the risk factors that determine NSF susceptibility. Hopefully, for example, a quantitative serum marker for NSF susceptibility or a risk stratification score tallied from clinical factors can be developed. Hypothetically, more stable gadolinium-containing contrast agents such as the macrocyclics would not release gadolinium within the cell to activate the necessary cellular machinery for NSF [11, 19, 20]. To complicate matters further, the various agents may also be internalized within cells to different degrees [21]. Also, this model would predict that for hemodialysis to be an effective preventive measure, it must be performed as soon as possible after the administration of gadolinium-containing contrast agents.
Further cellular and animal studies with gadolinium-containing contrast agents and insoluble forms of gadolinium will undoubtedly improve the models of the pathogenesis of NSF. A better understanding of individual susceptibility to NSF is crucial for patient care, given the importance of contrast-enhanced MRI in the evaluation of so many abnormalities.
Acknowledgments
I wish to thank Geri Mancini for invaluable assistance with production of the figures.
References
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This article has been cited by other articles:
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  J. L. Abraham and M. Edward Free Gadolinium Is a Likely Trigger of Nephrogenic Systemic Fibrosis Am. J. Roentgenol., October 1, 2009; 193(4): W354 - W354. [Full Text] [PDF]
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P. H. Kuo Reply Am. J. Roentgenol., October 1, 2009; 193(4): W355 - W355. [Full Text] [PDF]
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 W. A. High Estimates of Risk, Empirical Treatment Observations, and Unexpected Laboratory Findings Reveal the Complexity of Nephrogenic Systemic Fibrosis Arch Dermatol, October 1, 2009; 145(10): 1178 - 1182. [Full Text] [PDF]
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J. M. Provenzale Nephrogenic Systemic Fibrosis: Some Considerations on the Debate Regarding Its Cause Am. J. Roentgenol., December 1, 2008; 191(6): 1867 - 1869. [Full Text] [PDF]
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