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Gadolinium and lanthanum: A iatrogenic transmetallation?
Available online at www.sciencedirect.com
Clinical Biochemistry 41 (2008) 1029 – 1033
Review
Gadolinium and lanthanum: A iatrogenic transmetallation? Simona Brambilla a,⁎, Serenella Valaperta a , Giorgio Graziani b , Alessandro Montanelli a a
Clinical Laboratory, IRCCS Istituto Clinico Humanitas, Rozzano, Milano, Italy Nephrology Unit, IRCCS Istituto Clinico Humanitas, Rozzano, Milano, Italy
b
Received 7 March 2008; received in revised form 9 May 2008; accepted 13 May 2008 Available online 3 June 2008
Keywords: Gadolinium; Lanthanum; Nephrogenic systemic fibrosis
Contents Lanthanum (La) . . . Gadolinium (Gd) . . . Toxicity of gadolinium Conclusions . . . . . . References . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . and lanthanum-based drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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An emerging skin disease inducing progressive severe dermal sclerosis and joint induration with severe movement restriction has been identified as Nephrogenic Systemic Fibrosis (NSF). In some patients NSF may rapidly progress and involve internal organs leading to fatal outcome. On May 2007 FDA issued a public health advisory concerning a possible link between NSF and exposure to gadolinium (an element of the lanthanides family) containing contrast agents used for Magnetic Resonance Angiography in advanced kidney failure (ESRD with GFR b 30 mL/min) or in hemodialysis treated patients [1]. The lanthanides series (Ln) includes the 15 chemical elements with atomic number between 57 and 71, all with a basic behaviour (Table 1). These elements were in older literature called rare earth, “earth” because of their resemblance with aluminium, considered an “earth” and “rare” because of their supposed rareness in nature. Nowadays it is known that these elements are relatively abundant, i.e. cerium is nearly as abundant as tin and cobalt, neodymium and lanthanum are more abundant than lead. ⁎ Corresponding author. Istituto Clinico Humanitas, Viale Manzoni 56, 20089 Rozzano, Milano, Italy. Fax: +39 282244790. E-mail address: [email protected] (S. Brambilla).
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The Ln form a separate family because the 14 electrons 4f come gradually in, and they have a quite little influence on the valence electrons, whereas the external p and d orbitals remain empty. 4f are inner orbitals that's why they don't undergo alterations after binding with ligands. This happens, on the contrary, with the complexes of transitional metals. Throughout the series, except for cerium and europium, there is quite a unique oxidation state (3+). These characteristics are due to the difficult ionisation of 4f orbitals, that are internal as already said. The increase from 57 to 71 in nucleus charge, not completely shielded by f electrons, causes a shrinking in outer electronic orbitals so that the corresponding trivalent ions radius gradually reduces from lanthanum to lutetium. As a consequence the basic behaviour of oxides, that depends on radius/cation charge ratio, regularly reduces. This phenomenon is called “lanthanoids shrinking”. Once the separation of rare earth was one of the hardest operations, nowadays on the contrary it can be performed by injecting the solution of metals, linked to a complexing agent, in long cation exchanging HPLC columns. In the metallic state the elements of this group are silvery, hard, easily oxidable in wet air and are among the most electropositive metals. Their compounds derive quite only from the trivalent state and they are very similar to those of aluminium.
0009-9120/$ - see front matter © 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2008.05.009
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S. Brambilla et al. / Clinical Biochemistry 41 (2008) 1029–1033
Lanthanum (La) Chemical element discovered in 1839 by the swedish Carl Gustaf Mosander, when he partially decomposed cerium nitrate warming it and treating the resulting salt with diluted nitric acid. From the resulting solution he isolated a new rare earth that he baptized lantana. The name comes from the greek word lanthánein, to be hidden. It is one of the most reactive rare earth metals. It directly reacts with carbon, nitrogen, boron, selenium, silicon, phosphorus, sulphur and with halogens. Late evidences indicate that this element is, in a slight percentage, absorbed by the digestive apparatus and, if injected in blood, its elimination is very slow. Recently in medicine La carbonate has been used as phosphates chelant to prevent their accumulation in patients with kidney failure. An oral dose of 2.5– 3.5 g fractioned in 2 or 3 administrations can lower phosphates levels to normal ranges in most patients chelating the dietary phosphate at intestinal level [2]. La is slightly absorbed and therefore the renal elimination is negligible, both in normal subjects and in hemodialysis treated patients. La plasmatic concentrations in hemodialysis treated patients administered with chronic therapy until 3 g/die is 0.35–0.78 ug/L and this demonstrates its absorption [3]. The slight quantity that crosses the gastrointestinal barrier enters portal circulation, is carried by proteins, enters the hepatocytes by endocytosis and, at the low endolysosomial pH, is released from the carrier protein. After lysosomial membrane fusion with the biliary canaliculus, La enters biliary tract and is excreted with bile [4]. As a consequence it is scarcely accumulated in liver, as found in 100 patients in hemodyalisis treatment for more than 4 years. The sole other tissue, in these patients, with measurable La levels in experimental models is bone, in particular in cells near the remodelment areas (osteoclasts, macrophages) [3].
linium oxide) from Mosander's yttria in 1886. Only recently the pure element has been isolated. As Gd3+ ion Gd is a Lewis acid with great affinity for bases such as H2O and OH−. Its affinity for OH− explains its toxicity: at physiological pH and in the presence of free phosphates it precipitates as hydroxide (colourless and gelatinous) and as phosphate (white and dusty). The charged complexes are then eliminated with urines and cannot cross the intact hemato-encephalic barrier. Because of these characteristics and because of its ferromagnetism, Gd is extensively used as a contrast medium for magnetic resonance when linked to a chelating compound in order to hinder its toxicity. Gd is administered in a standard intravenous dose of 0.1 mmol/kg, or more in case of angiographic imaging. It is eliminated at 99% by kidneys with a 2 h half-life in healthy patients, greatly extended to 5.6–9.2 h in patients with severe kidney failure and over 60 h in hemodialysis treated patients [5]. The free form of Gd is toxic for biological tissues. Endogenous metals such as Zn2+, Cu2+ and Fe3+ can destabilize the Gdchelating compound by transmetallation (see box in this page), with the release of Gd3+ from its ligand. Free Gd3+ ions are scarcely soluble and usually form phosphate and carbonate salts, sometimes it accumulates in tissues, as widely proven [6]. The awareness about the problem is stimulating researchers Transmetallation is a chemical reaction typical of organometallic compounds describing the exchange of ligands between two metal centers (M and M′) M-R+M′-R′↔M-R′+M′-R The two metals need not be the same. The ligands can be organic or inorganic. towards the synthesis of new Gd complexes with a fast water exchange, a high water relaxivity and a very good stability versus zinc transmetallation [7].
Gadolinium (Gd) The first observation about gadolinium dates back to 1880. In this year Jean Charles Galissard de Marignac observed spectral lines of Gd in samples of didymium and gadolinite. Paul Emile Lecoq de Boisbaudran separated gadolinia (gadoTable 1 Lanthanides: atomic number, extensive names and symbols Atomic number
Element
Symbol
57 58 59 60 61 62 63 64 65 66 67 68 69 70 71
Lanthanum Cerium Praseodymium Neodymium Promethium Samarium Europium Gadolinium Terbium Dysprosium Holmium Erbium Thulium Ytterbium Lutetium
La Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Tm Yb Lu
Toxicity of gadolinium and lanthanum-based drugs These two chemical elements have two clinical applications, both in favour of patients with severe kidney failure: Gd in a diagnostic field and La in the therapeutic one. These two applications are different in terms of aim and in terms of kind and length of administration: Gd has an intravenous administration way in a unique dose, La is administered per os in fractioned doses and for longer periods. Some curious behaviours have come out from clinical observation of treated patients, particularly on a toxicologic plane. Gd is thought to be the cause of NSF, just in patients with severe kidney failure for whom it was suggested as an alternative to iodinated media. NSF was firstly described in 2000 by Cowper [8] and hitherto the NSF registry reports about 215 cases. This pathology can be linked with the use of Gd in advanced kidney failure (ESRD) and in hemodialysis treated (HD) patients [9,10]. The dermal lesion is described as areas of induration and thickness with erythematosus violaceous plaques affecting limbs or trunk. The European Society of Urogenital Radiology
S. Brambilla et al. / Clinical Biochemistry 41 (2008) 1029–1033
(ESUR) guidelines reports the clinical stages of the disease: initially it presents with pain, pruritus, swelling erythema, usually in the legs, and later there is a thickening in skin and in subcutaneous tissues and brawny plaques appear. In the most severe forms fibrosis may involve internal organs: muscles, diaphragm, lungs, heart, liver. The resulting consequences are contractures, cachexia and death in patients with severe visceral lesions. The disease is apparently similar to systemic sclerosis, but the absence of facial lesions and the negativity of anti SCL70 and anti-centromere antibodies allow to correctly distinguish the NSF from systemic sclerosis. The histological picture of skin lesions shows collagen bundles penetrating the dermal superficial fascia. These bundles contain CD34/protocollagenexpressing fibroblasts-like CD68/factor expressing dendritic cells (Fig. 1). The pathogenesis of Gd-related NSF still remains unknown. The dermal fibrotic lesions may be the consequence of released Gd ions forming hydroxide and phosphate complexes then engulfed by the phagocytic system and activating a fibrous reaction with involvement of dendritic cells, TGF-beta synthesis, attraction of fibrocytes and precipitating the fibrotic cascade as occurs in the wound healing process. The bone marrow-derived circulating fibrocytes seem responsible for the systemic dermal sclerosis namely in uremic milieu in which many profibrogenic factors, such as erythropoietin therapy, hyperparathyroidism and metabolic acidosis, may play an important role in promoting the systemic inflammation [11,12,13]. The linkage between Gd infusion in ESRD and HD patients and NSF occurrence is still unexplained. It must be considered that in renal failure patients half-life of infused Gd is over 30 h, in comparison to an hour and a half in subjects with normal renal function, being Gd namely
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excreted in urines. Therefore in ESRD and HD patients the delayed Gd excretion may increase its toxicity. Another important point to contemplate is the stability of Gd chelates used as Gadolinium-Based magnetic resonance Contrast Agent (GBMCA). In this context Gd compounds with linear chelates are considered more unstable than macrocyclic Gd chelates [14] (Fig. 2). Moreover although the overwhelming majority of reported NSF patients received Gd infusion, a recent report of 57 cases of NSF, 43/57 were associated with gadodiamide infusion (Omniscan) but 6/57 with gadopentate dimeglumine (Magnevist) infusion, 2/57 with gadoversetamide (Optimark) and 3/57 with both gadodiamide and gadoversetamide infusion [15]. These data suggest that the occurrence of NSF in ESRD patients is not exclusively associated with gadodiamide infusion, a linear chelate. Despite a lot of reports indicating the exposure to Gd in ESRD or HD patients as a very probable trigger of NSF, the sure cause–effect relation still remains unproven. Many raising data suggest that Gd could be the exclusive trigger of the severe dermal systemic disease. The great variability of time between the Gd infusion and the onset of the disease, ranging from few months to years, suggests that also other factors should be involved in the pathogenesis of NSF. In the Collidge's retrospective study the median time from Gd infusion and the onset of disease was 76 days, but in the same report one case developed NSF without previous Gd administration [9]. Moreover the lack of a true laboratory or clinical marker indicating the start of the disease makes the early identification of the onset of NSF more difficult. On the other hand, in some cases of NSF the skin biopsy failed to demonstrate the Gd ion in dermal tissue [16]. A recent large case-control study conducted by the CDC in
Fig. 1. Images of NSF: (A) Arm skin. Thickening of the skin often with browny hyperpigmentation and, sometimes with distinct papules and subcutaneous nodules. (B and C) Dermis biopsy. Randomly arranged collagen bundles and highly increased number of spindled and plump fibroblast-like cells [modified from “The International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR)” available at www.icnfdr.org].
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Fig. 2. (A and B) examples of linear Gd compounds (gadodiamide and gadopentetate dimeglumine), (C and D) examples of macrocyclic Gd compounds (gadoterate meglumine and gadoteridol).
St Louis Missouri reports 33 cases of NSF, 19 of whom were case-matched with ESRD patients without developing the dermal disease. Furthermore many patients developing NSF were previously Gd infused without any adverse affect, indicating the lack of a sure cause–effect demonstration [17]. Furthermore there is no demonstration of the relationship between the dose of Gd infusion and the risk of developing NSF [18]. Another recent case-report describes two organ transplanted patients developing NSF without previous Gd administration. These findings suggest both the existence of other factors triggering in individual patients NSF development and that Gd alone should not be considered the sole trigger [19]. In this field, many factors related to ESRD or HD have been considered as possible causes, such as the immune system hyperactivity which promotes systemic inflammation, solid organ transplantation, steroids or immunosuppressive drugs [20]. Other concausal factors that have been considered as interactive in developing NSF were: genetic predisposition, chronic phlogistic diseases, recent cardiovascular surgery, arterial manipulation for vascular access procedures with associated endothelial lesions, hypercoagulable condition (anti-cardiolipin antibodies), thrombosis, massive bone marrow stimulation and iron mobilisation by abnormal erythropoietin administration [21,22,23]. A recent immunohistochemical study on skin biopsies in NSF patients employing antibodies anti TG-2 and Factor XIIIa transglutaminases shows an increased expression of these markers by dermal fibroblasts, histiocytes mucine and elastic fibers. The authors emphasize the possible role of Gd in activating these tranglutaminase isopeptides, usually present in endothelial and normal dendritic dermal cells. Therefore in NSF patients the Gdinduced transglutaminase activation may explain the widespread systemic inflammation and fibrosis. These results may indicate that the drugs at risk of increasing transglutaminase activity in ESRD patients, such as glucocorticoids, topic vitamin D analogues and N-acetyl cysteine, should be avoided and suggest the possible role of cysteamine or other transglutaminase inhibitors as a treatment and for prevention of NSF [24].
According to the transmetallation theory, many body fluid minerals such as zinc, copper, phosphate, calcium should have a major affinity for chelates than Gd. Consequently a Gd dechelation may easily occur with the release of Gd ions, thus explaining its toxicity, namely in renal failure patients [25,26]. Also the altered metabolic profile found in renal insufficiency can further promote transmetallation and shift the equilibrium towards the dissociation of Gd ions [27]. Nevertheless it is likewise known that patients with severe kidney failure are administered lanthanum oral therapy (as lanthanum carbonate), another rare earth, able to participate in transmetallation processes as well. Some clinical investigations show the efficacy of lanthanum carbonate that strongly binds to intestinal phosphate salts forming an insoluble salt poorly absorbed by intestinal tract [28]. Nevertheless its efficacy is related to the intestinal salt ionisation that may promote free mineral intestinal absorption. According to this hypothesis a progressive lanthanum accumulation in liver and bone of uremic and normal rats has been reported [29]. Therefore it is conceivable that in some lanthanum long-term treated uremic patients the risk of its accumulation and the possible interference with the Gdtriggering NSF cannot be excluded [30]. The lanthanum toxicity theory may explain the present diffusion of Gd-induced NSF only in countries where the use of lanthanum carbonate was introduced some years ago: such as the USA and Northern Europe. Whereas, despite the large use of Gd as contrast agent for MR in renal failure patients, no cases of NSF have until now, been reported in Italy and other Southern European countries, where lanthanum carbonate has been introduced only recently into therapy. There are also recent evidences of lanthanum “radiographic contrast medium behaviour”: this one administered to nephropatic patients per os, can give a gut opacization, in particular of colon [31]. As a matter of fact it seems reasonable that Gd and La, after an initial phase of (bone) accumulation as documented in humans for La [32] and in rats for Gd [29], during years are
S. Brambilla et al. / Clinical Biochemistry 41 (2008) 1029–1033
slowly mobilized from their storage sites. This mobilization is potentially toxic and responsible for the iatrogenic disease [27]. Conclusions The two rare earth, quite similar as far as chemistry is concerned, have been employed very differently in a medical field, about the aim, the pharmaceutical formulation and the way of administration. Notwithstanding this they show, as in an “exchanging role play”, biochemical and physiopathological behaviours “superimposible” for some aspects. This leads to seriously consider the need for the activation of a close biochemical–clinical surveillance, particularly for ESRD patients. References [1] FDA. Public Health Advisory — Gadolinium-containing Contrast Agents for Magnetic Resonance Imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance. Available at: http://www.fda. gov/cder/drug/advisory/gadolinium_agents.htm. Accessed May, 2007 [2] Freemont AJ. Lanthanum carbonate. Drugs Today 2006;42(12):759–70. [3] De Broe ME. Can the risk of gadolinium be extrapolated to lanthanum? Semin Dial 2008 Mar–Apr;21(2):142–4. [4] Yang Z, Schryvers D, Roels F, D'Haese PC, De Broe ME. Demonstration of lanthanum in liver cells by energy-dispersive X-ray spectroscopy, electron energy loss spectroscopy and high-resolution transmission electron microscopy. J Microsc 2006 Aug;223:133–9. [5] Joffe P, Thomsen HS, Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol 1998 Jul;5(7):491–502. [6] Idée JM, Port M, Raynal I, Schaefer M, Le Greneur S, Corot C. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam Clin Pharmacol 2006 Dec;20(6):563–76 Review. Erratum in: Fundam Clin Pharmacol 2007 Jun;21(3):335. [7] Henoumont C, Henrotte V, Laurent L, Vander Elst L, Muller RN. Synthesis of a new gadolinium complex with a high affinity for human serum albumin and its manifold physicochemical characterization by proton relaxation rate analysis, NMR diffusometry and electrospray mass spectrometry. J Inorg Biochem 2008;Apr;(102):721–30. [8] Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000 Sep 16;356(9234):1000–1. [9] Collidge TA, Thomson PC, Mark PB, Traynor JP, Jardine AG, Morris STW, Simpson K, Roditi GH. Gadolinium-enhanced MR imaging and Nephrogenic Systemic Fibrosis: retrospective study of renal replacement therapy cohort. Radiology 2007 Oct;245(1):168–75. [10] Deo A, Fogel M, Cowper SE. Nephrogenic systemic fibrosis: population study examining the relationship of disease development to gadolinium exposure. Clin J Am Soc Nephrol 2007 Mar;2(2):264–7. [11] Ortonne N, Lipsker D, Chantrel F, Bohem N, Grosshans E, Cribier B. Presence of CD45RO+ CD34+ cells with collagen synthesis activity in nephrogenic fibrosing dermopathy. A new pathogenic hypothesis. Br J Dermatol 2004 May;150(5):1050–2. [12] Swaminathan S, Ahmed I, Mc Carthy JT. Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med 2006 Aug 1;145(3):234–5.
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[13] Pedersen M. Safety update on the possible causal relationship between gadolinium-containing-MRI agents and Nephrogenic Systemic Fibrosis. J Magn Reson Imaging 2007 May;25(5):881–3. [14] Khurana A, Runge VM, Naranayan M, Greene JF, Nickel AE. Nephrogenic Systemic Fibrosis: a review of 6 cases temporally related to gadodiamide injection (Omniscan). Invest Radiol 2007 Feb;42(2): 139–45. [15] Kuo PH, Kanal E, Abu-Alfa AK, Cowper SE. Gadolinium-based-MR contrast agents and nephrogenic systemic fibrosis. Radiology 2007 Mar;242(3):647–9. [16] Boyd AS, Zic JA, Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2007 Jan;56(1):27–30. [17] Centres for Disease Control and Prevention (CDC). Nephrogenic fibrosis dermopathy associated with exposure to gadolinium-containing contrast agents. St Louis Missouri 2002–2006. MMWR Morb Mortal Wkly Rep 2007 Feb 23;56(7):137–41. [18] Marckmann P, Skov L, Rossen K. Nephrogenic Systemic Fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006 Sep;17(9): 2359–62. [19] Wahba IM, Simpson EL, White K. Gadolinium is not the only trigger for nephrogenic systemic fibrosis: insights from two cases and review of the recent literature. Am J Transplant 2007 Oct;7(10):2425–2432. Review. [20] Sadowski EA, Bennett LK, Chan MR. Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology 2007 Apr;243(1):148–57. [21] Weiss AS, Lucia MS, Teitelbaum I. A case of nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis. Nat Clin Pract Nephrol 2007 Feb;3(2):111–5. [22] Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 2003 Nov;15(6):785–790. Review. [23] Mendoza FA, Artlett CM, Sandorfi N, Latinis K, Piera-Velazquez S, Jimenez SA. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 2006 Feb;35 (4):238–49. [24] Parsons AC, Yosipovitch G, Sheehan DJ, Sangueza OP, Geenberg CS, Sane DC. Transglutaminases: the missing link in nephrogenic systemic fibrosis. Am J Dermopathol 2007 Oct;29(5):433–6. [25] Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic fibrosis; why radiologists should de concerned? Am J Rad 2007 Feb;188(2):586–92. [26] Bongartz G. Imaging in the time of NFD/NSF: do we have to change our routines concerning renal insufficiency? MAGMA 2007 Apr;20(2): 57–62. [27] Abraham JL, Thakral C, Skov L, Rossen K, Marckmann P. Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol 2008 Feb;158(2):273–80. [28] Cozzolino M, Brancaccio D. Hyperphosphatemia in dialysis patients: the therapeutic role of lanthanum carbonate. Int J Artif Organs 2007 Apr;30 (4):293–300. Review. [29] Slatopolsky E, Liapis H, Finch J. Progressive accumulation of lanthanum in the liver of normal and uremic rats. Kidney Int 2005 Dec;68(6):2809–13. [30] Aime S, Canavese C, Stratta P. Advisory about gadolinium calls for caution in the treatment of uremic patients with lanthanum carbonate. Kidney Int 2007 Nov;72(9):1162–3. [31] Cerny S, Kunzendorf U. Radiographic appearance of lanthanum. N Engl J Med 2006 Sep 14;355(11):1160. [32] Spasovsky GB, Sikole A, Gelev S, Masin-Spasovska J, Freemont T, Webster I, et al. Evolution of bone and plasma concentration of lanthanum in dialysis patients before, during 1 year of treatment with lanthanum carbonate and after 2 years of follow-up. Nephrol Dial Transplant 2006(21):2217–24.
Clinical Biochemistry 41 (2008) 1029 – 1033
Review
Gadolinium and lanthanum: A iatrogenic transmetallation? Simona Brambilla a,⁎, Serenella Valaperta a , Giorgio Graziani b , Alessandro Montanelli a a
Clinical Laboratory, IRCCS Istituto Clinico Humanitas, Rozzano, Milano, Italy Nephrology Unit, IRCCS Istituto Clinico Humanitas, Rozzano, Milano, Italy
b
Received 7 March 2008; received in revised form 9 May 2008; accepted 13 May 2008 Available online 3 June 2008
Keywords: Gadolinium; Lanthanum; Nephrogenic systemic fibrosis
Contents Lanthanum (La) . . . Gadolinium (Gd) . . . Toxicity of gadolinium Conclusions . . . . . . References . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . and lanthanum-based drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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An emerging skin disease inducing progressive severe dermal sclerosis and joint induration with severe movement restriction has been identified as Nephrogenic Systemic Fibrosis (NSF). In some patients NSF may rapidly progress and involve internal organs leading to fatal outcome. On May 2007 FDA issued a public health advisory concerning a possible link between NSF and exposure to gadolinium (an element of the lanthanides family) containing contrast agents used for Magnetic Resonance Angiography in advanced kidney failure (ESRD with GFR b 30 mL/min) or in hemodialysis treated patients [1]. The lanthanides series (Ln) includes the 15 chemical elements with atomic number between 57 and 71, all with a basic behaviour (Table 1). These elements were in older literature called rare earth, “earth” because of their resemblance with aluminium, considered an “earth” and “rare” because of their supposed rareness in nature. Nowadays it is known that these elements are relatively abundant, i.e. cerium is nearly as abundant as tin and cobalt, neodymium and lanthanum are more abundant than lead. ⁎ Corresponding author. Istituto Clinico Humanitas, Viale Manzoni 56, 20089 Rozzano, Milano, Italy. Fax: +39 282244790. E-mail address: [email protected] (S. Brambilla).
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The Ln form a separate family because the 14 electrons 4f come gradually in, and they have a quite little influence on the valence electrons, whereas the external p and d orbitals remain empty. 4f are inner orbitals that's why they don't undergo alterations after binding with ligands. This happens, on the contrary, with the complexes of transitional metals. Throughout the series, except for cerium and europium, there is quite a unique oxidation state (3+). These characteristics are due to the difficult ionisation of 4f orbitals, that are internal as already said. The increase from 57 to 71 in nucleus charge, not completely shielded by f electrons, causes a shrinking in outer electronic orbitals so that the corresponding trivalent ions radius gradually reduces from lanthanum to lutetium. As a consequence the basic behaviour of oxides, that depends on radius/cation charge ratio, regularly reduces. This phenomenon is called “lanthanoids shrinking”. Once the separation of rare earth was one of the hardest operations, nowadays on the contrary it can be performed by injecting the solution of metals, linked to a complexing agent, in long cation exchanging HPLC columns. In the metallic state the elements of this group are silvery, hard, easily oxidable in wet air and are among the most electropositive metals. Their compounds derive quite only from the trivalent state and they are very similar to those of aluminium.
0009-9120/$ - see front matter © 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2008.05.009
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Lanthanum (La) Chemical element discovered in 1839 by the swedish Carl Gustaf Mosander, when he partially decomposed cerium nitrate warming it and treating the resulting salt with diluted nitric acid. From the resulting solution he isolated a new rare earth that he baptized lantana. The name comes from the greek word lanthánein, to be hidden. It is one of the most reactive rare earth metals. It directly reacts with carbon, nitrogen, boron, selenium, silicon, phosphorus, sulphur and with halogens. Late evidences indicate that this element is, in a slight percentage, absorbed by the digestive apparatus and, if injected in blood, its elimination is very slow. Recently in medicine La carbonate has been used as phosphates chelant to prevent their accumulation in patients with kidney failure. An oral dose of 2.5– 3.5 g fractioned in 2 or 3 administrations can lower phosphates levels to normal ranges in most patients chelating the dietary phosphate at intestinal level [2]. La is slightly absorbed and therefore the renal elimination is negligible, both in normal subjects and in hemodialysis treated patients. La plasmatic concentrations in hemodialysis treated patients administered with chronic therapy until 3 g/die is 0.35–0.78 ug/L and this demonstrates its absorption [3]. The slight quantity that crosses the gastrointestinal barrier enters portal circulation, is carried by proteins, enters the hepatocytes by endocytosis and, at the low endolysosomial pH, is released from the carrier protein. After lysosomial membrane fusion with the biliary canaliculus, La enters biliary tract and is excreted with bile [4]. As a consequence it is scarcely accumulated in liver, as found in 100 patients in hemodyalisis treatment for more than 4 years. The sole other tissue, in these patients, with measurable La levels in experimental models is bone, in particular in cells near the remodelment areas (osteoclasts, macrophages) [3].
linium oxide) from Mosander's yttria in 1886. Only recently the pure element has been isolated. As Gd3+ ion Gd is a Lewis acid with great affinity for bases such as H2O and OH−. Its affinity for OH− explains its toxicity: at physiological pH and in the presence of free phosphates it precipitates as hydroxide (colourless and gelatinous) and as phosphate (white and dusty). The charged complexes are then eliminated with urines and cannot cross the intact hemato-encephalic barrier. Because of these characteristics and because of its ferromagnetism, Gd is extensively used as a contrast medium for magnetic resonance when linked to a chelating compound in order to hinder its toxicity. Gd is administered in a standard intravenous dose of 0.1 mmol/kg, or more in case of angiographic imaging. It is eliminated at 99% by kidneys with a 2 h half-life in healthy patients, greatly extended to 5.6–9.2 h in patients with severe kidney failure and over 60 h in hemodialysis treated patients [5]. The free form of Gd is toxic for biological tissues. Endogenous metals such as Zn2+, Cu2+ and Fe3+ can destabilize the Gdchelating compound by transmetallation (see box in this page), with the release of Gd3+ from its ligand. Free Gd3+ ions are scarcely soluble and usually form phosphate and carbonate salts, sometimes it accumulates in tissues, as widely proven [6]. The awareness about the problem is stimulating researchers Transmetallation is a chemical reaction typical of organometallic compounds describing the exchange of ligands between two metal centers (M and M′) M-R+M′-R′↔M-R′+M′-R The two metals need not be the same. The ligands can be organic or inorganic. towards the synthesis of new Gd complexes with a fast water exchange, a high water relaxivity and a very good stability versus zinc transmetallation [7].
Gadolinium (Gd) The first observation about gadolinium dates back to 1880. In this year Jean Charles Galissard de Marignac observed spectral lines of Gd in samples of didymium and gadolinite. Paul Emile Lecoq de Boisbaudran separated gadolinia (gadoTable 1 Lanthanides: atomic number, extensive names and symbols Atomic number
Element
Symbol
57 58 59 60 61 62 63 64 65 66 67 68 69 70 71
Lanthanum Cerium Praseodymium Neodymium Promethium Samarium Europium Gadolinium Terbium Dysprosium Holmium Erbium Thulium Ytterbium Lutetium
La Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Tm Yb Lu
Toxicity of gadolinium and lanthanum-based drugs These two chemical elements have two clinical applications, both in favour of patients with severe kidney failure: Gd in a diagnostic field and La in the therapeutic one. These two applications are different in terms of aim and in terms of kind and length of administration: Gd has an intravenous administration way in a unique dose, La is administered per os in fractioned doses and for longer periods. Some curious behaviours have come out from clinical observation of treated patients, particularly on a toxicologic plane. Gd is thought to be the cause of NSF, just in patients with severe kidney failure for whom it was suggested as an alternative to iodinated media. NSF was firstly described in 2000 by Cowper [8] and hitherto the NSF registry reports about 215 cases. This pathology can be linked with the use of Gd in advanced kidney failure (ESRD) and in hemodialysis treated (HD) patients [9,10]. The dermal lesion is described as areas of induration and thickness with erythematosus violaceous plaques affecting limbs or trunk. The European Society of Urogenital Radiology
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(ESUR) guidelines reports the clinical stages of the disease: initially it presents with pain, pruritus, swelling erythema, usually in the legs, and later there is a thickening in skin and in subcutaneous tissues and brawny plaques appear. In the most severe forms fibrosis may involve internal organs: muscles, diaphragm, lungs, heart, liver. The resulting consequences are contractures, cachexia and death in patients with severe visceral lesions. The disease is apparently similar to systemic sclerosis, but the absence of facial lesions and the negativity of anti SCL70 and anti-centromere antibodies allow to correctly distinguish the NSF from systemic sclerosis. The histological picture of skin lesions shows collagen bundles penetrating the dermal superficial fascia. These bundles contain CD34/protocollagenexpressing fibroblasts-like CD68/factor expressing dendritic cells (Fig. 1). The pathogenesis of Gd-related NSF still remains unknown. The dermal fibrotic lesions may be the consequence of released Gd ions forming hydroxide and phosphate complexes then engulfed by the phagocytic system and activating a fibrous reaction with involvement of dendritic cells, TGF-beta synthesis, attraction of fibrocytes and precipitating the fibrotic cascade as occurs in the wound healing process. The bone marrow-derived circulating fibrocytes seem responsible for the systemic dermal sclerosis namely in uremic milieu in which many profibrogenic factors, such as erythropoietin therapy, hyperparathyroidism and metabolic acidosis, may play an important role in promoting the systemic inflammation [11,12,13]. The linkage between Gd infusion in ESRD and HD patients and NSF occurrence is still unexplained. It must be considered that in renal failure patients half-life of infused Gd is over 30 h, in comparison to an hour and a half in subjects with normal renal function, being Gd namely
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excreted in urines. Therefore in ESRD and HD patients the delayed Gd excretion may increase its toxicity. Another important point to contemplate is the stability of Gd chelates used as Gadolinium-Based magnetic resonance Contrast Agent (GBMCA). In this context Gd compounds with linear chelates are considered more unstable than macrocyclic Gd chelates [14] (Fig. 2). Moreover although the overwhelming majority of reported NSF patients received Gd infusion, a recent report of 57 cases of NSF, 43/57 were associated with gadodiamide infusion (Omniscan) but 6/57 with gadopentate dimeglumine (Magnevist) infusion, 2/57 with gadoversetamide (Optimark) and 3/57 with both gadodiamide and gadoversetamide infusion [15]. These data suggest that the occurrence of NSF in ESRD patients is not exclusively associated with gadodiamide infusion, a linear chelate. Despite a lot of reports indicating the exposure to Gd in ESRD or HD patients as a very probable trigger of NSF, the sure cause–effect relation still remains unproven. Many raising data suggest that Gd could be the exclusive trigger of the severe dermal systemic disease. The great variability of time between the Gd infusion and the onset of the disease, ranging from few months to years, suggests that also other factors should be involved in the pathogenesis of NSF. In the Collidge's retrospective study the median time from Gd infusion and the onset of disease was 76 days, but in the same report one case developed NSF without previous Gd administration [9]. Moreover the lack of a true laboratory or clinical marker indicating the start of the disease makes the early identification of the onset of NSF more difficult. On the other hand, in some cases of NSF the skin biopsy failed to demonstrate the Gd ion in dermal tissue [16]. A recent large case-control study conducted by the CDC in
Fig. 1. Images of NSF: (A) Arm skin. Thickening of the skin often with browny hyperpigmentation and, sometimes with distinct papules and subcutaneous nodules. (B and C) Dermis biopsy. Randomly arranged collagen bundles and highly increased number of spindled and plump fibroblast-like cells [modified from “The International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR)” available at www.icnfdr.org].
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Fig. 2. (A and B) examples of linear Gd compounds (gadodiamide and gadopentetate dimeglumine), (C and D) examples of macrocyclic Gd compounds (gadoterate meglumine and gadoteridol).
St Louis Missouri reports 33 cases of NSF, 19 of whom were case-matched with ESRD patients without developing the dermal disease. Furthermore many patients developing NSF were previously Gd infused without any adverse affect, indicating the lack of a sure cause–effect demonstration [17]. Furthermore there is no demonstration of the relationship between the dose of Gd infusion and the risk of developing NSF [18]. Another recent case-report describes two organ transplanted patients developing NSF without previous Gd administration. These findings suggest both the existence of other factors triggering in individual patients NSF development and that Gd alone should not be considered the sole trigger [19]. In this field, many factors related to ESRD or HD have been considered as possible causes, such as the immune system hyperactivity which promotes systemic inflammation, solid organ transplantation, steroids or immunosuppressive drugs [20]. Other concausal factors that have been considered as interactive in developing NSF were: genetic predisposition, chronic phlogistic diseases, recent cardiovascular surgery, arterial manipulation for vascular access procedures with associated endothelial lesions, hypercoagulable condition (anti-cardiolipin antibodies), thrombosis, massive bone marrow stimulation and iron mobilisation by abnormal erythropoietin administration [21,22,23]. A recent immunohistochemical study on skin biopsies in NSF patients employing antibodies anti TG-2 and Factor XIIIa transglutaminases shows an increased expression of these markers by dermal fibroblasts, histiocytes mucine and elastic fibers. The authors emphasize the possible role of Gd in activating these tranglutaminase isopeptides, usually present in endothelial and normal dendritic dermal cells. Therefore in NSF patients the Gdinduced transglutaminase activation may explain the widespread systemic inflammation and fibrosis. These results may indicate that the drugs at risk of increasing transglutaminase activity in ESRD patients, such as glucocorticoids, topic vitamin D analogues and N-acetyl cysteine, should be avoided and suggest the possible role of cysteamine or other transglutaminase inhibitors as a treatment and for prevention of NSF [24].
According to the transmetallation theory, many body fluid minerals such as zinc, copper, phosphate, calcium should have a major affinity for chelates than Gd. Consequently a Gd dechelation may easily occur with the release of Gd ions, thus explaining its toxicity, namely in renal failure patients [25,26]. Also the altered metabolic profile found in renal insufficiency can further promote transmetallation and shift the equilibrium towards the dissociation of Gd ions [27]. Nevertheless it is likewise known that patients with severe kidney failure are administered lanthanum oral therapy (as lanthanum carbonate), another rare earth, able to participate in transmetallation processes as well. Some clinical investigations show the efficacy of lanthanum carbonate that strongly binds to intestinal phosphate salts forming an insoluble salt poorly absorbed by intestinal tract [28]. Nevertheless its efficacy is related to the intestinal salt ionisation that may promote free mineral intestinal absorption. According to this hypothesis a progressive lanthanum accumulation in liver and bone of uremic and normal rats has been reported [29]. Therefore it is conceivable that in some lanthanum long-term treated uremic patients the risk of its accumulation and the possible interference with the Gdtriggering NSF cannot be excluded [30]. The lanthanum toxicity theory may explain the present diffusion of Gd-induced NSF only in countries where the use of lanthanum carbonate was introduced some years ago: such as the USA and Northern Europe. Whereas, despite the large use of Gd as contrast agent for MR in renal failure patients, no cases of NSF have until now, been reported in Italy and other Southern European countries, where lanthanum carbonate has been introduced only recently into therapy. There are also recent evidences of lanthanum “radiographic contrast medium behaviour”: this one administered to nephropatic patients per os, can give a gut opacization, in particular of colon [31]. As a matter of fact it seems reasonable that Gd and La, after an initial phase of (bone) accumulation as documented in humans for La [32] and in rats for Gd [29], during years are
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slowly mobilized from their storage sites. This mobilization is potentially toxic and responsible for the iatrogenic disease [27]. Conclusions The two rare earth, quite similar as far as chemistry is concerned, have been employed very differently in a medical field, about the aim, the pharmaceutical formulation and the way of administration. Notwithstanding this they show, as in an “exchanging role play”, biochemical and physiopathological behaviours “superimposible” for some aspects. This leads to seriously consider the need for the activation of a close biochemical–clinical surveillance, particularly for ESRD patients. References [1] FDA. Public Health Advisory — Gadolinium-containing Contrast Agents for Magnetic Resonance Imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance. Available at: http://www.fda. gov/cder/drug/advisory/gadolinium_agents.htm. Accessed May, 2007 [2] Freemont AJ. Lanthanum carbonate. Drugs Today 2006;42(12):759–70. [3] De Broe ME. Can the risk of gadolinium be extrapolated to lanthanum? Semin Dial 2008 Mar–Apr;21(2):142–4. [4] Yang Z, Schryvers D, Roels F, D'Haese PC, De Broe ME. Demonstration of lanthanum in liver cells by energy-dispersive X-ray spectroscopy, electron energy loss spectroscopy and high-resolution transmission electron microscopy. J Microsc 2006 Aug;223:133–9. [5] Joffe P, Thomsen HS, Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol 1998 Jul;5(7):491–502. [6] Idée JM, Port M, Raynal I, Schaefer M, Le Greneur S, Corot C. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam Clin Pharmacol 2006 Dec;20(6):563–76 Review. Erratum in: Fundam Clin Pharmacol 2007 Jun;21(3):335. [7] Henoumont C, Henrotte V, Laurent L, Vander Elst L, Muller RN. Synthesis of a new gadolinium complex with a high affinity for human serum albumin and its manifold physicochemical characterization by proton relaxation rate analysis, NMR diffusometry and electrospray mass spectrometry. J Inorg Biochem 2008;Apr;(102):721–30. [8] Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000 Sep 16;356(9234):1000–1. [9] Collidge TA, Thomson PC, Mark PB, Traynor JP, Jardine AG, Morris STW, Simpson K, Roditi GH. Gadolinium-enhanced MR imaging and Nephrogenic Systemic Fibrosis: retrospective study of renal replacement therapy cohort. Radiology 2007 Oct;245(1):168–75. [10] Deo A, Fogel M, Cowper SE. Nephrogenic systemic fibrosis: population study examining the relationship of disease development to gadolinium exposure. Clin J Am Soc Nephrol 2007 Mar;2(2):264–7. [11] Ortonne N, Lipsker D, Chantrel F, Bohem N, Grosshans E, Cribier B. Presence of CD45RO+ CD34+ cells with collagen synthesis activity in nephrogenic fibrosing dermopathy. A new pathogenic hypothesis. Br J Dermatol 2004 May;150(5):1050–2. [12] Swaminathan S, Ahmed I, Mc Carthy JT. Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med 2006 Aug 1;145(3):234–5.
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[13] Pedersen M. Safety update on the possible causal relationship between gadolinium-containing-MRI agents and Nephrogenic Systemic Fibrosis. J Magn Reson Imaging 2007 May;25(5):881–3. [14] Khurana A, Runge VM, Naranayan M, Greene JF, Nickel AE. Nephrogenic Systemic Fibrosis: a review of 6 cases temporally related to gadodiamide injection (Omniscan). Invest Radiol 2007 Feb;42(2): 139–45. [15] Kuo PH, Kanal E, Abu-Alfa AK, Cowper SE. Gadolinium-based-MR contrast agents and nephrogenic systemic fibrosis. Radiology 2007 Mar;242(3):647–9. [16] Boyd AS, Zic JA, Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2007 Jan;56(1):27–30. [17] Centres for Disease Control and Prevention (CDC). Nephrogenic fibrosis dermopathy associated with exposure to gadolinium-containing contrast agents. St Louis Missouri 2002–2006. MMWR Morb Mortal Wkly Rep 2007 Feb 23;56(7):137–41. [18] Marckmann P, Skov L, Rossen K. Nephrogenic Systemic Fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006 Sep;17(9): 2359–62. [19] Wahba IM, Simpson EL, White K. Gadolinium is not the only trigger for nephrogenic systemic fibrosis: insights from two cases and review of the recent literature. Am J Transplant 2007 Oct;7(10):2425–2432. Review. [20] Sadowski EA, Bennett LK, Chan MR. Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology 2007 Apr;243(1):148–57. [21] Weiss AS, Lucia MS, Teitelbaum I. A case of nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis. Nat Clin Pract Nephrol 2007 Feb;3(2):111–5. [22] Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 2003 Nov;15(6):785–790. Review. [23] Mendoza FA, Artlett CM, Sandorfi N, Latinis K, Piera-Velazquez S, Jimenez SA. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 2006 Feb;35 (4):238–49. [24] Parsons AC, Yosipovitch G, Sheehan DJ, Sangueza OP, Geenberg CS, Sane DC. Transglutaminases: the missing link in nephrogenic systemic fibrosis. Am J Dermopathol 2007 Oct;29(5):433–6. [25] Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic fibrosis; why radiologists should de concerned? Am J Rad 2007 Feb;188(2):586–92. [26] Bongartz G. Imaging in the time of NFD/NSF: do we have to change our routines concerning renal insufficiency? MAGMA 2007 Apr;20(2): 57–62. [27] Abraham JL, Thakral C, Skov L, Rossen K, Marckmann P. Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol 2008 Feb;158(2):273–80. [28] Cozzolino M, Brancaccio D. Hyperphosphatemia in dialysis patients: the therapeutic role of lanthanum carbonate. Int J Artif Organs 2007 Apr;30 (4):293–300. Review. [29] Slatopolsky E, Liapis H, Finch J. Progressive accumulation of lanthanum in the liver of normal and uremic rats. Kidney Int 2005 Dec;68(6):2809–13. [30] Aime S, Canavese C, Stratta P. Advisory about gadolinium calls for caution in the treatment of uremic patients with lanthanum carbonate. Kidney Int 2007 Nov;72(9):1162–3. [31] Cerny S, Kunzendorf U. Radiographic appearance of lanthanum. N Engl J Med 2006 Sep 14;355(11):1160. [32] Spasovsky GB, Sikole A, Gelev S, Masin-Spasovska J, Freemont T, Webster I, et al. Evolution of bone and plasma concentration of lanthanum in dialysis patients before, during 1 year of treatment with lanthanum carbonate and after 2 years of follow-up. Nephrol Dial Transplant 2006(21):2217–24.