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The suitability of gadolinium complexes as magnetic resonance imaging contrast agents depends on a number of factors. A thermodynamic relationship to toxicity exists if one assumes that the chemotoxicity of the intact complex is minimal but that the toxicity of the components of the complex (free metal and uncomplexed ligands) is substantial.
The suitability of gadolinium complexes as magnetic resonance imaging contrast agents depends on a number of factors. A thermodynamic relationship to toxicity exists if one assumes that the chemotoxicity of the intact complex is minimal but that the toxicity of the components of the complex (free metal and uncomplexed ligands) is substantial.


Release of Gd(III) from the complex is responsible for the toxicity associated with gadolinium complexes; this release appears to be a consequence of Zn<sup>2+</sup>, Cu<sup>2+</sup>, and Ca<sup>2+</sup> transmetallatiou in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd(III) complexes, all become lethally toxic when they release precisely the same quantity of Gd(III). It is also supported by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn<sup>2+</sup> deficiency. Finally, this hypothesis predicts that subtle changes in formulation can further enhance the intrinsic safety of these complexes. The added Ca<sup>2+</sup> salt of the ligand must have a favorable toxicity so that the decrease in toxicity from in vivo transmetallation is not offset, or overcome, by the addition of a toxic component to the formulation.<ref>THE RELATIONSHIP BETWEEN THERMODYNAMICS AND THE TOXICITY OF GADOLINIUM COMPLEXES: Magnetic Resonance Imaging, Vol. 8 pp. 467-468, 1990, ftp://124.42.15.59/ck/2011-01/165/060/614/791/The%20relationship%20between%20thermodynamics%20and%20the%20toxicity%20of%20gadolinium%20complexes..pdf</ref>
Release of Gd(III) from the complex is responsible for the toxicity associated with gadolinium complexes; this release appears to be a consequence of Zn<sup>2+</sup>, Cu<sup>2+</sup>, and Ca<sup>2+</sup> transmetallation in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd(III) complexes, all become lethally toxic when they release precisely the same quantity of Gd(III). It is also supported by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn<sup>2+</sup> deficiency. Finally, this hypothesis predicts that subtle changes in formulation can further enhance the intrinsic safety of these complexes. The added Ca<sup>2+</sup> salt of the ligand must have a favorable toxicity so that the decrease in toxicity from in vivo transmetallation is not offset, or overcome, by the addition of a toxic component to the formulation.<ref>THE RELATIONSHIP BETWEEN THERMODYNAMICS AND THE TOXICITY OF GADOLINIUM COMPLEXES: Magnetic Resonance Imaging, Vol. 8 pp. 467-468, 1990, ftp://124.42.15.59/ck/2011-01/165/060/614/791/The%20relationship%20between%20thermodynamics%20and%20the%20toxicity%20of%20gadolinium%20complexes..pdf</ref>


==Relation to acute kidney injury==
==Relation to acute kidney injury==

Revision as of 00:35, 30 December 2012

Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy is a rare and serious syndrome that involves fibrosis of skin, joints, eyes, and internal organs. The first cases were identified in 1997 and its cause is not fully understood. However, there is much evidence to suggest that it is associated with exposure to gadolinium (with gadolinium-based MRI contrast agents being frequently used as contrast agents for magnetic resonance imaging) in patients with severe kidney failure.[1] Epidemiological studies suggest that the incidence of NSF is unrelated to gender, race, or age and it is not thought to have a genetic basis. A registry for NSF has identified about 335 cases as of 2011.[2]

Most patients with NSF have undergone hemodialysis for renal failure, some have never undergone dialysis and others have received only peritoneal dialysis. Many patients have taken immunosuppressive medications and have other diseases, such as hepatitis C. Four of the seven gadolinium contrast agents approved by the U.S. Food and Drug Administration have been principally implicated in NSF, including Omniscan, MultiHance, Magnevist, and OptiMARK.

Systemic symptoms

In NSF, patients develop large areas of hardened skin with fibrotic nodules and plaques. NSF may also cause joint contractures resulting in joint pain and limitation in range of motion. In its most severe form, NSF may cause severe systemic fibrosis affecting internal organs including the lungs, heart and liver.[3][4]

Microscopic pathology

At the microscopic level, NSF resembles scleromyxedema. Both conditions show a proliferation of dermal fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and deposits of mucin.[5] More recent case reports have described the presence of sclerotic bodies (also known as elastocollagenous balls) in skin biopsies from NSF patients. While not universally present, this finding is believed to be unique to NSF [6][7]

History

The first cases of NSF were identified in 1997,[8] but NSF was first described as an independent disease entity in 2000.[9] While skin involvement is on the foreground, the process may involve any organ and resembles diffuse scleroderma or systemic sclerosis.[10] In 2006, the link between NSF and gadolinium-containing contrast agents was made.[11][12][13] As a result, gadolinium-containing contrast is now considered contraindicated in patients with an estimated glomerular filtration rate (a measure of renal function) under 60 and especially under 30 ml/mn.[14] One retrospective study of the Veterans Affairs Electronic Medical Record found no cases of NSF among 141 patients receiving hemodialysis for chronic kidney disease who received gadoteridol (ProHance).[15]

Classification of gadolinium contrast agents as to risk

The European Medicines Agency has classified the gadolinium-containing contrast agents into three risk groups:[16]

The suitability of gadolinium complexes as magnetic resonance imaging contrast agents depends on a number of factors. A thermodynamic relationship to toxicity exists if one assumes that the chemotoxicity of the intact complex is minimal but that the toxicity of the components of the complex (free metal and uncomplexed ligands) is substantial.

Release of Gd(III) from the complex is responsible for the toxicity associated with gadolinium complexes; this release appears to be a consequence of Zn2+, Cu2+, and Ca2+ transmetallation in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd(III) complexes, all become lethally toxic when they release precisely the same quantity of Gd(III). It is also supported by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn2+ deficiency. Finally, this hypothesis predicts that subtle changes in formulation can further enhance the intrinsic safety of these complexes. The added Ca2+ salt of the ligand must have a favorable toxicity so that the decrease in toxicity from in vivo transmetallation is not offset, or overcome, by the addition of a toxic component to the formulation.[17]

Relation to acute kidney injury

NSF has also developed in patients with acute kidney injury [14], even if renal function subsequently returned to normal following GBCM administration [15]. In one series, up to 20% of NSF cases were diagnosed in patients who had been in some element of transient acute renal failure (often, but not always, superimposed upon chronic kidney disease) at the time of GBCM administration [16].[18]

It can be noted that this classification was released after another proposition would have left the safest category (ionic cyclical structure) with only one agent (Dotarem, not sold in North America). The intermediate category would have been both ionic linear structure and non-ionic cyclical structure. The third category most at risk was unchanged (linear non-ionic).[19]

References

  1. ^ Thomsen HS. (2009) Nephrogenic systemic fibrosis: history and epidemiology Radiol Clin North Am. 47(5):827-31
  2. ^ The NSF registy site.
  3. ^ Kucher C, Steere, J, Elenitsas, R, Siegel, DL, Xu, X. (2006) Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis with diaphragmatic involvement in a patient with respiratory failure. J Am Acad Dermatol 54: S31-34
  4. ^ Krous H, Breisch, E, Chadwick, AE, Pinckney, L, Malicki, DM, Benador, N. (2007) Nephrogenic systemic fibrosis with multiorgan involvement in a teenage male after lymphoma, Ewing's sarcoma, end-stage renal disease, and hemodialysis. Pediatr Dev Pathol 10: 395-402.
  5. ^ Scheinfeld, NS; Cowper, S; Kovarik, CL; Butler, DF. "Nephrogenic Systemic Fibrosis." Emedicine. [1]
  6. ^ Bhawan J, Swick BL, Koff AB, Stone MS. (2009) Sclerotic bodies in nephrogenic systemic fibrosis: a new histopathologic finding. J Cutan Pathol. 36(5):548-52.
  7. ^ , Wiedemeyer K, Kutzner, H, Abraham, JL, Thakral, C, Carlson, JA, Tran, TA, Hausser, I, Hartschuh, W. (2009) The evolution of osseous metaplasia in localized cutaneous nephrogenic systemic fibrosis: a case report. Am J Dermatopathol 31: 674-681.
  8. ^ Cowper SE (2003). "Nephrogenic fibrosing dermopathy: the first 6 years". Current Opinion in Rheumatology. 15 (6): 785–790. doi:10.1097/00002281-200311000-00017. PMID 14569211.
  9. ^ Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE (2000). "Scleromyxoedema-like cutaneous diseases in renal-dialysis patients". Lancet. 356 (9234): 1000–1. doi:10.1016/S0140-6736(00)02694-5. PMID 11041404.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Mendoza FA, Artlett CM, Sandorfi N, Latinis K, Piera-Velazquez S, Jimenez SA (2006). "DESCRIPTION OF TWELVE CASES OF NEPHROGENIC FIBROSING DERMOPATHY AND REVIEW OF THE LITERATURE". Semin. Arthritis Rheum. 35 (4): 238–49. doi:10.1016/j.semarthrit.2005.08.002. PMC 1434722. PMID 16461069.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Grobner T (2006). "Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?". Nephrol. Dial. Transplant. 21 (4): 1104–8. doi:10.1093/ndt/gfk062. PMID 16431890.
  12. ^ Marckmann P, Skov L, Rossen K; et al. (2006). "Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging". J. Am. Soc. Nephrol. 17 (9): 2359–62. doi:10.1681/ASN.2006060601. PMID 16885403. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  13. ^ Centers for Disease Control and Prevention (CDC) (2007). "Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents--St. Louis, Missouri, 2002-2006". MMWR Morb. Mortal. Wkly. Rep. 56 (7): 137–41. PMID 17318112.
  14. ^ Kanal E, Barkovich AJ, Bell C; et al. (2007). "ACR guidance document for safe MR practices: 2007". AJR. American journal of roentgenology. 188 (6): 1447–74. doi:10.2214/AJR.06.1616. PMID 17515363. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  15. ^ Reilly, Robert (2008). "Risk for Nephrogenic Systemic Fibrosis with Gadoteridol (ProHance) in Patients Who Are on Long-Term Hemodialysis". Clin J Am Soc Nephrol. 3. 3 (3): 747–751. doi:10.2215/CJN.05721207. PMC 2386692. PMID 18287249. {{cite journal}}: Unknown parameter |month= ignored (help)
  16. ^ Medicines and Healthcare products Regulatory Agency. Drug Safety Update, August 2007 pg 2-4. Link (121 KB)
  17. ^ THE RELATIONSHIP BETWEEN THERMODYNAMICS AND THE TOXICITY OF GADOLINIUM COMPLEXES: Magnetic Resonance Imaging, Vol. 8 pp. 467-468, 1990, ftp://124.42.15.59/ck/2011-01/165/060/614/791/The%20relationship%20between%20thermodynamics%20and%20the%20toxicity%20of%20gadolinium%20complexes..pdf
  18. ^ Revision performed with input from and approval of the ACR Subcommittee on MR Safety, Nephrogenic Systemic Fibrosis, http://www.acr.org/SecondaryMainMenuCategories/quality_safety/contrast_manual/NephrogenicSystemicFibrosis.aspx
  19. ^ http://www.ismrm.org/special/EMEA2.pdf
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