Gadolinium and nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF) is characterized by red skin areas or plaques that over several weeks successively develop to painful thickened skin with a ‘woody’ texture, resembling ‘peau d’orange’. Starting at the extremities, it may spread to the trunk, and may progressively inhibit flexion of adjacent joints. In skin biopsies of affected areas, thickened collagen bundles, mucin deposition, and proliferation of fibroblasts and elastic fibers are seen. Originally described as nephrogenic fibrosing dermopathy (NFD) because of its primarily cutaneous manifestation, this entity was then named NSF because of systemic involvement of other organs like lungs, myocardium, or striated muscles. The pathogenesis of the disease is not yet known, but our observations suggest a close association between development of NSF and exposure to gadolinium-containing contrast agents, thereafter confirmed by other authors. Recently, gadolinium was demonstrated to be detectable in skin tissue samples of affected patients. In this short review, the development of NSF and its sequential association with the exposure to gadolinium-containing contrast agents is presented. The mechanisms likely to cause NFD/NSF are discussed. Nephrogenic systemic fibrosis (NSF) is characterized by red skin areas or plaques that over several weeks successively develop to painful thickened skin with a ‘woody’ texture, resembling ‘peau d’orange’. Starting at the extremities, it may spread to the trunk, and may progressively inhibit flexion of adjacent joints. In skin biopsies of affected areas, thickened collagen bundles, mucin deposition, and proliferation of fibroblasts and elastic fibers are seen. Originally described as nephrogenic fibrosing dermopathy (NFD) because of its primarily cutaneous manifestation, this entity was then named NSF because of systemic involvement of other organs like lungs, myocardium, or striated muscles. The pathogenesis of the disease is not yet known, but our observations suggest a close association between development of NSF and exposure to gadolinium-containing contrast agents, thereafter confirmed by other authors. Recently, gadolinium was demonstrated to be detectable in skin tissue samples of affected patients. In this short review, the development of NSF and its sequential association with the exposure to gadolinium-containing contrast agents is presented. The mechanisms likely to cause NFD/NSF are discussed. Nephrogenic systemic fibrosis (NSF),1.Leboit P.E. What nephrogenic fibrosing dermopathy might be.Arch Dermatol. 2003; 139: 928-930Crossref PubMed Scopus (98) Google Scholar, 2.Ting W.W. Stone M.S. Madison K.C. Kurtz K. Nephrogenic fibrosing dermopathy with systemic involvement.Arch Dermatol. 2003; 139: 903-906Crossref PubMed Scopus (255) Google Scholar, 3.Daram S.R. Cortese C.M. Bastani B. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: Report of a new case with literature review.Am J Kidney Dis. 2005; 46: 754-759Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar named nephrogenic fibrosing dermopathy (NFD) at first in 2001,4.Cowper S.E. Su L. Robin H. et al.Nephrogenic fibrosing dermopathy.Am J Dermatopathol. 2001; 23: 383-393Crossref PubMed Scopus (416) Google Scholar is an acquired disease, yet considered idiopathic. NSF is observed in patients with renal insufficiency, most but not all of whom have undergone dialysis for renal failure.4.Cowper S.E. Su L. Robin H. et al.Nephrogenic fibrosing dermopathy.Am J Dermatopathol. 2001; 23: 383-393Crossref PubMed Scopus (416) Google Scholar,5.Swartz R.D. Crofford L.J. Phan S.H. et al.Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure.Am J Med. 2003; 114: 563-572Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar Since its recognition in 1997 and first description in literature in 2000,6.Cowper S.E. Robin H.S. Steinberg H.M. et al.Scleromyxedema-like cutaneous disease in renal-dialysis patients.Lancet. 2000; 356: 1000-1001Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar more than 215 cases have been reported worldwide. Among others, an association of NSF with coagulation abnormalities, recent vascular surgery or intervention4.Cowper S.E. Su L. Robin H. et al.Nephrogenic fibrosing dermopathy.Am J Dermatopathol. 2001; 23: 383-393Crossref PubMed Scopus (416) Google Scholar (e.g. fistula operation and angioplasty), administration of erythropoietin7.Swaminathan S. Ahmad I. McCarthy J.T. et al.Nephrogenic fibrosing dermopathy and high dose erythropoetin therapy.Ann Intern Med. 2006; 145: 234-235Crossref PubMed Scopus (123) Google Scholar or angiotensin converting enzyme inhibitors,8.Fazeli A. Lio P.A. Liu V. Nephrogenic fibrosing dermopathy: are ACE inhibitors the missing link?.Arch Dermatol. 2004; 140 (letter): 1401Crossref PubMed Google Scholar and presence of antiphospholipid antibodies9.Mackay-Wiggan J.M. Cohen D.J. Hardy M.A. et al.Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease).Am Acad Dermatol. 2003; 48: 55-60Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar has been discussed by several authors so far, but the pathogenesis of this entity is still not clearly identified. Clinically, NSF is characterized by initial swelling of distal parts of the extremities with subsequent thickening, indurations, and hardening of the skin in the following weeks. Distinct nodules can also be seen (Figures 1 and 2). The (distal) extremities are the most common area of involvement, followed by the trunk. The face is almost never involved.4.Cowper S.E. Su L. Robin H. et al.Nephrogenic fibrosing dermopathy.Am J Dermatopathol. 2001; 23: 383-393Crossref PubMed Scopus (416) Google Scholar The disease may be progressive and lead to skin stiffness and serious physical disability. Skin biopsy is required to confirm the diagnosis of NSF and to differentiate from other fibrosing skin disorders. There are specific histopathologic features, namely thickened dermis (Figure 3) with bundles of collagen and surrounding clefts, mucin deposition (Figure 4), and a proliferation of fibroblasts and elastic fibers. Signs of inflammation are absent, which makes this disorder a distinct entity.10.Cowper S.E. Nephrogenic fibrosing dermopathy: the first six years.Curr Opin Rheumatol. 2003; 15: 785-790Crossref PubMed Scopus (238) Google ScholarFigure 2Clinical picture early in the course of nephrogenic systemic fibrosis. Right leg of a patient with NSF lasting 4 weeks only: after diffuse swelling of the skin, erythematous papules and nodules became apparent.View Large Image Figure ViewerDownload (PPT)Figure 3Skin biopsy of the right leg of an affected patient. The dermis is thickened and demonstrates swollen collagen bundles with surrounding clefts and spindle cell proliferation. Interstitial mucin deposition is frequently present (hematoxylin and eosin stain).View Large Image Figure ViewerDownload (PPT)Figure 4Fibrosis (Magnified Figure 3). Fibrocytes (yellow arrow) and swollen collagen bundles (green arrow) with surrounding clefts are shown. Interstitial mucin (red arrows) is increased, inflammatory cells are absent. The light blue arrow indicates degenerated collagen fibers (hematoxylin and eosin stain).View Large Image Figure ViewerDownload (PPT) Recently, we reported on the observation of a series of five patients, who had received gadolinium-containing contrast agents for magnetic resonance imaging (MRI) examinations and subsequently developed NSF within 2–4 weeks.11.Grobner T. Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?.Nephrol Dial Transplant. 2006; 21 (Erratum in Nephrol Dial Transplant 2006; 21: 1745): 1104-1108Crossref PubMed Scopus (1402) Google Scholar Our findings were substantiated by a Danish group shortly thereafter, who presented data on 13 patients with NSF following gadodiamide administration.12.Marckmann P. Skov L. Rossen K. et al.Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging.J Am Soc Nephrol. 2006; 17: 2359-2362Crossref PubMed Scopus (1055) Google Scholar These authors calculated an odds ratio of 32.5 to acquire NSF when exposed to gadodiamide. These findings have prompted the United States Food and Drug Administration (FDA) to issue a public health advisory regarding gadolinium-containing contrast agents and a possible link to development of NSF.13.2006http://www.fda.gov/cder/drug/advisory/gadoliniumagents.htmGoogle Scholar Most recently, official authorities (European Medicines Agency (EMEA), Pharmacovigilance Working Party (PhVWP), and the Committee on Medicinal Products for human Use – (CHMP)) as well as the manufacturers of Gadodiamide (Omniscan®, Amersham Health, Oslo, Norway and Carrigtohill, County Cork, Ireland) have considered administration of gadodiamide to be contraindicated in patients with a glomerular filtration rate (GFR) less than 30 ml/min/1.73 m2 as well as in liver transplant recipients. This mini review summarizes the current view of the possible link between exposure to gadolinium-containing contrast media and development of NSF. Gadolinium (Gd), with atomic number 64, belongs to the lanthanide series. The trivalent gadolinium ion (Gd3+) is very close to the divalent calcium ion as reflected by size, bonding, coordination, and donor atom preference.14.Evans C. Biochemistry of the Lanthanides. Plenum Press, New York1990Crossref Google Scholar Gadolinium has unusual superconductive and ferromagnetic properties, is used in microwave applications, and Gd compounds are used to make phosphors in color TV sets. Non-complexed gadolinium is unsuitable for clinical use, as it may precipitate and is retained for long periods in the body. Insolubility and toxicity of Gd is largely eliminated by forming either macrocyclic or linear chelates, for example Gd-DTPA (diethylene triaminepentaacetic acid).15.Weinmann H.J. Brasch R.C. Press W.R. Wesbey G.E. Characteristics of gadolinium–DTPA complex: a potential NMR contrast agent.Am J Roentgenol. 1984; 142: 619-624Crossref PubMed Scopus (1101) Google Scholar The biochemical effects induced by gadolinium salts, for example GdCl3 (gadolinium chloride), may occur through interference with intracellular calcium-dependent processes and calcium entry into cells. Gadolinium presumably displaces calcium ions from cation-binding sites on cellular membranes and binds to and activates the extracellular calcium-sensing receptor, which is present on various tissues like fibroblasts, kidney, parathyroid glands, hepatocytes, and pancreas. GdCl3 can form mineral emboli in the circulation, which are deposited in the capillary bed of organs and are taken up by phagocytosis.16.Barnhardt J.L.K.N. Bakan D.A. Berk R.N. Biodistribution of GdCl3 and Gd–DTPA and their influence on proton magnetic relaxation in rat tissues.Magn Reson Imaging. 1987; 5: 221-231Abstract Full Text PDF PubMed Scopus (68) Google Scholar Electron-dense deposits found in various organs have been shown to contain gadolinium and may consist of a complex of gadolinium and phosphate.17.Lazar G. The reticuloendothelial-blocking effect of rare earth metals in rats.J Reticuloendothel Soc. 1973; 13: 231-237PubMed Google Scholar Free Gd ion also blocks macrophage function and may cause cell death, which is likely to occur as a result of initial phagocytosis of gadolinium particles.17.Lazar G. The reticuloendothelial-blocking effect of rare earth metals in rats.J Reticuloendothel Soc. 1973; 13: 231-237PubMed Google Scholar This process is likely to be mediated by pinocytosis-based internalization. It has been proposed that lanthanide ions may leak into cells through pores induced by lanthanide ions bound to the membrane.18.Cheng Y. Huijing Y. Huakuan L. et al.The events relating to lanthanide ions enhanced permeability of human erythrocyte membrane: binding, conformational change, phase transition and ion transport.Chem-Biol Interact. 1999; 121: 267-289Crossref PubMed Scopus (36) Google Scholar The sequence of events during Gd permeation through the cell membrane into erythrocytes starts with Gd binding to membrane phospholipid, followed by a transfer to membrane proteins and ends with a phase transition in the lipid bilayer and aggregation of membrane proteins that results in the perforation of the membrane.18.Cheng Y. Huijing Y. Huakuan L. et al.The events relating to lanthanide ions enhanced permeability of human erythrocyte membrane: binding, conformational change, phase transition and ion transport.Chem-Biol Interact. 1999; 121: 267-289Crossref PubMed Scopus (36) Google Scholar Gadolinium-containing contrast agents are widely used and have been thought to be safe, even in patients with impaired renal function. The frequency of minor side effects is low. Some pharmacologic characteristics of several Gd-containing contrast agents that are FDA-approved are given in Table 1.19.Prince M.R. Erel H.E. Lent R.W. et al.Gadodiamide administration causes spurious hypocalcemia.Radiology. 2003; 227: 639-646Crossref PubMed Scopus (79) Google Scholar,20.Uggeri F. Aime S. Anelli P.L. et al.Novel contrast agents for magnetic resonance imaging. Synthesis and characterisation of the ligand BOPTA and its Ln(III) complexes.Inorg Chem. 1995; 34: 633-642Crossref Scopus (177) Google Scholar Although Gd-containing contrast agents are rapidly cleared with a half-life of 1.3 h in healthy volunteers, according to pharmacokinetic studies, the half-life is markedly prolonged up to 30–120 h in chronic renal failure. In hemodialysis and peritoneal dialysis patients, half-life is prolonged to 2.6 and 52.7 h, respectively.21.Joffe P. Thomsen H.S. Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis.Acad Radiol. 1998; 5: 491-502Abstract Full Text PDF PubMed Scopus (283) Google Scholar A study on the safety of Gd-containing contrast agents in 70 hemodialysis patients with measurement of Gd excretory rates via hemodialysis in 11 patients revealed an average rate of 78.2, 95.6, 98.7, and 99.5% in the first to fourth standard hemodialysis session (i.e. 4 h sessions every other day, three/week), respectively.22.Okada S. Katagiri K. Kumazaki T. Yokoyama H. Safety of gadolinium contrast agent in hemodialysis patients.Acta Radiol. 2001; 42: 339-341Crossref PubMed Scopus (100) Google ScholarTable 1Characteristics of some gadolinium-containing contrast agents (FDA-approved)Generic nameAbbreviationTrademarkOsmolality (mOsmol/kg/l)Excess chelate content (mg/ml) (according to package inserts)Stability constant19.Prince M.R. Erel H.E. Lent R.W. et al.Gadodiamide administration causes spurious hypocalcemia.Radiology. 2003; 227: 639-646Crossref PubMed Scopus (79) Google Scholar,20.Uggeri F. Aime S. Anelli P.L. et al.Novel contrast agents for magnetic resonance imaging. Synthesis and characterisation of the ligand BOPTA and its Ln(III) complexes.Inorg Chem. 1995; 34: 633-642Crossref Scopus (177) Google ScholarElimination routeGadobenate-dimeglumineGd-BOPTAMultiHance®19700.001018.4Biliary/renalGadodiamideGd-DTPA-BMAOmniscan®78012.001014.9RenalGadopentate-dimeglumineGd-DTPAMagnevist®19400.401018.1RenalGadoteridolGd-HP-DO3AProHance®6300.231017.1RenalGadoversetamideGd-DTPA-BMEAOptimark®111028.401015.0Renal Open table in a new tab Possible side effects occur owing to dissociation of the gadolinium–ligand complex into metal ion and ligand. This process is facilitated by endogenous metals like iron, zinc, and copper, by calcium, and by endogenous acids.23.Mann J.S. Stability of gadolinium complexes in vitro and in vivo.J Comput Assist Tomogr. 1993; 17: S19-S23Crossref PubMed Scopus (47) Google Scholar In renal failure, there is common evidence of both metabolic acidosis and absence of adequate clearance of Gd-containing contrast agent.24.Vorobiov M. Basok A. Tovbin D. et al.Iron-mobilizing properties of the gadolinium–DTPA complex: clinical and experimental observations.Nephrol Dial Transplant. 2003; 18: 884-887Crossref PubMed Scopus (37) Google Scholar Free Gd solubility is poor, thereby favoring formation of precipitates of salts with anions like phosphate, carbonate, or hydroxyl. These salts may be deposited in tissues like muscle, skin, liver, bone, and other organs.24.Vorobiov M. Basok A. Tovbin D. et al.Iron-mobilizing properties of the gadolinium–DTPA complex: clinical and experimental observations.Nephrol Dial Transplant. 2003; 18: 884-887Crossref PubMed Scopus (37) Google Scholar The majority of patients reported with NSF after contrast MRI studies were administered gadodiamide.11.Grobner T. Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?.Nephrol Dial Transplant. 2006; 21 (Erratum in Nephrol Dial Transplant 2006; 21: 1745): 1104-1108Crossref PubMed Scopus (1402) Google Scholar,12.Marckmann P. Skov L. Rossen K. et al.Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging.J Am Soc Nephrol. 2006; 17: 2359-2362Crossref PubMed Scopus (1055) Google Scholar This may be attributed, to some extent, to the fact that gadodiamide is among the most widely used Gd-containing contrast agents, especially in Europe. The molecular structure of chelate-binding Gd in the case of gadodiamide is linear. It is a non-tissue-specific and non-ionic low osmolar (780 mOsm/kg) agent. As it is less stable, gadodiamide differs from most other non-tissue-specific extracellular MRI contrast agents by having an excess of chelate (Table 1). The high amounts of chelate are added to overcome the problem of salt formation and precipitation as outlined above, which may take place with agents susceptible to transmetallation, that is release of free Gd ion from the chelate and subsequent binding to endogenous ions.25.Behra-Miellet J. Gressier B. Brunet C. et al.Free gadolinium and gadodiamide, a gadolinium chelate used in magnetic resonance imaging: evaluation of their in vitro effects on human neutrophil viability.Methods Find Exp Clin Pharmacol. 1996; 18: 437-442PubMed Google Scholar Gadodiamide is almost exclusively excreted renally and therefore has a markedly prolonged half-life in patients with renal failure.26.Thomsen H.S. Contrast Media. Safety Issues and ESUR Guidelines. Springer, Berlin, Heidelberg, New York2006Crossref Google Scholar After the description of NSF as a new entity, many speculated on factors that might trigger or even cause the development of this new disease.4.Cowper S.E. Su L. Robin H. et al.Nephrogenic fibrosing dermopathy.Am J Dermatopathol. 2001; 23: 383-393Crossref PubMed Scopus (416) Google Scholar, 7.Swaminathan S. Ahmad I. McCarthy J.T. et al.Nephrogenic fibrosing dermopathy and high dose erythropoetin therapy.Ann Intern Med. 2006; 145: 234-235Crossref PubMed Scopus (123) Google Scholar, 8.Fazeli A. Lio P.A. Liu V. Nephrogenic fibrosing dermopathy: are ACE inhibitors the missing link?.Arch Dermatol. 2004; 140 (letter): 1401Crossref PubMed Google Scholar, 9.Mackay-Wiggan J.M. Cohen D.J. Hardy M.A. et al.Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease).Am Acad Dermatol. 2003; 48: 55-60Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar In January 2006 (electronic publication ahead of print), Grobner11.Grobner T. Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?.Nephrol Dial Transplant. 2006; 21 (Erratum in Nephrol Dial Transplant 2006; 21: 1745): 1104-1108Crossref PubMed Scopus (1402) Google Scholar was the first to propose that gadolinium-containing contrast media might trigger the development of NSF. Five patients with end-stage renal disease and hemodialysis were presented, all of whom had developed NFD/NSF within 2–4 weeks after MRI with gadodiamide. Besides administration of Gd-containing contrast media, the only other finding that all five patients had in common was the presence of metabolic acidosis at the time of MRI, while four other patients who had undergone MRI and were not affected by NSF were not acidotic at the time of examination. The average volume of gadodiamide used for MRI in our patients was 35 ml (17.5 mmol). No other exposure or common event could be identified. A few months later, our findings were substantiated by Marckmann et al.,12.Marckmann P. Skov L. Rossen K. et al.Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging.J Am Soc Nephrol. 2006; 17: 2359-2362Crossref PubMed Scopus (1055) Google Scholar who published a case series of 13 patients with end-stage renal disease and chronic hemodialysis who had all been exposed to gadodiamide before the development of NSF. The median time from gadodiamide exposure to the first clinical signs of NSF noted was 25 days (range 2–75 days). The average contrast volume was 38 ml (19 mmol). An association with coexistent acidosis was not seen. Development of NSF without prior gadolinium administration was not observed by these authors and no further cases of NSF were noted since the use of gadodiamide was stopped in their unit. The most recent report from the Loma Linda University Medical Center in California on 12 patients with NSF also concluded on a strong association between development of NSF and gadodiamide administration, not only in dialysis patients (n=8) but also in patients with hepatorenal syndrome (n=4).27.Broome D.R. Girguis M.S. Baron P.W. et al.Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned.Am J Radiol. 2007; 188: 1-7Google Scholar Evenepoel et al.28.Evenepoel P. Zeegers M. Segaert S. et al.Nephrogenic fibrosing dermopathy: a novel, disabling disorder in patients with renal failure.Nephrol Dial Transplant. 2004; 49: 469-473Crossref Scopus (74) Google Scholar also reported two cases of severe NSF in 2004. The unique and common factor for all three European reports11.Grobner T. Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?.Nephrol Dial Transplant. 2006; 21 (Erratum in Nephrol Dial Transplant 2006; 21: 1745): 1104-1108Crossref PubMed Scopus (1402) Google Scholar, 12.Marckmann P. Skov L. Rossen K. et al.Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging.J Am Soc Nephrol. 2006; 17: 2359-2362Crossref PubMed Scopus (1055) Google Scholar, 28.Evenepoel P. Zeegers M. Segaert S. et al.Nephrogenic fibrosing dermopathy: a novel, disabling disorder in patients with renal failure.Nephrol Dial Transplant. 2004; 49: 469-473Crossref Scopus (74) Google Scholar was that all patients had received gadodiamide. In the United States, too, the majority of NSF patients have received gadodiamide,27.Broome D.R. Girguis M.S. Baron P.W. et al.Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned.Am J Radiol. 2007; 188: 1-7Google Scholar with only a few patients who have had other Gd-containing contrast agents (gadopentate or gadoversetamide). Another common feature of most of the affected patients was the high dose of Gd-containing contrast agent used in the patients reported, as most had magnetic resonance angiograms where two- to threefold doses of Gd-containing contrast agent were needed (0.2–0.3 mmol/kg body weight instead of 0.1 mmol/kg with conventional MRI), a feature of possible relevance in patients with impaired renal clearance. To date, it is uncertain whether other Gd-based contrast media are involved in some of the affected patients, but this is a matter of current evaluation.26.Thomsen H.S. Contrast Media. Safety Issues and ESUR Guidelines. Springer, Berlin, Heidelberg, New York2006Crossref Google Scholar The 2006 public health advisory of the FDA on gadolinium use does not discriminate between different Gd preparations at all, but recommends a careful consideration of risks and benefits of MRI with Gd-containing contrast agents and advises to choose alternative imaging methods whenever possible.13.2006http://www.fda.gov/cder/drug/advisory/gadoliniumagents.htmGoogle Scholar Recently, two independent study groups described gadolinium to be detectable in skin and soft tissue specimens of patients who had been administered Gd-containing contrast agents and had NSF using the technique of scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS).29.Boyd A.S. Zic J.A. Abraham J.L. Gadolinium deposition in nephrogenic fibrosing dermopathy.J Am Acad Dermatol. 2007; 56: 27-30Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar,30.High W.A. Ayers R.A. Chandler J. et al.Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis.J Am Acad Dermatol. 2007; 56: 21-26Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar Boyd et al.29.Boyd A.S. Zic J.A. Abraham J.L. Gadolinium deposition in nephrogenic fibrosing dermopathy.J Am Acad Dermatol. 2007; 56: 27-30Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar described SEM/EDS analyses in four patients with NSF in whom linear Gd deposition was demonstrable in dermal vessel walls and along the basal lamina of eccrine sweat gland in areas with concomitant calcium–phosphate deposition. High et al.30.High W.A. Ayers R.A. Chandler J. et al.Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis.J Am Acad Dermatol. 2007; 56: 21-26Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar examined a single histologic section each of specimens derived from seven NSF patients with prior exposure to Gd. They demonstrated detectable Gd in four patients and in all positive controls. No Gd was detected in a random dermatopathology case specimen (without NSF) serving as a negative control. In three of the four Gd-containing specimens, the metal was confined to areas of fibrosis. All Gd particles were less than 1 μm in diameter and were located intracellular, possibly within lysosomes. Additionally, they identified large deposits of iron in all specimens and of other metals like copper, zinc, nickel, tin, vanadium, and aluminum in some of them. The authors speculate that the iron accumulation might possibly result from contamination by the microtome blade itself, but may also be due to iron administration to dialysis patients eventually in large boluses. Deposition of iron in the tissue as shown30.High W.A. Ayers R.A. Chandler J. et al.Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis.J Am Acad Dermatol. 2007; 56: 21-26Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar might be favored by an iron-liberating effect of Gd-chelate with elevation of free serum iron, especially in iron-overloaded patients after Gd-containing contrast media examination.24.Vorobiov M. Basok A. Tovbin D. et al.Iron-mobilizing properties of the gadolinium–DTPA complex: clinical and experimental observations.Nephrol Dial Transplant. 2003; 18: 884-887Crossref PubMed Scopus (37) Google Scholar Free iron is highly toxic and, besides other effects, leads to metabolic acidosis and might be an additional cofactor to trigger fibrosis. Although speculative to date, an interesting hypothesis can be suggested on the role of circulating fibrocytes in the context of the two studies on Gd deposition in NSF-affected skin specimens.29.Boyd A.S. Zic J.A. Abraham J.L. Gadolinium deposition in nephrogenic fibrosing dermopathy.J Am Acad Dermatol. 2007; 56: 27-30Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar,30.High W.A. Ayers R.A. Chandler J. et al.Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis.J Am Acad Dermatol. 2007; 56: 21-26Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar These recently characterized blood-borne cells, circulating fibrocytes31.Quan T.E. Cowper S. Wu S.P. et al.Circulating fibrocytes: collagen secreting cells of the peripheral blood.Int J Biochem Cell Biol. 2004; 36: 598-606Crossref PubMed Scopus (476) Google Scholar positive for CD34 and procollagen and involved in wound healing, may invade the dermis and differentiate to dermal cells, resembling functionally and histologically normal fibroblasts, thereby inducing the fibrosing process. Boyd et al.29.Boyd A.S. Zic J.A. Abraham J.L. Gadolinium deposition in nephrogenic fibrosing dermopathy.J Am Acad Dermatol. 2007; 56: 27-30Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar describe abundant CD34-positive cells in their specimens, and High et al.30.High W.A. Ayers R.A. Chandler J. et al.Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis.J Am Acad Dermatol. 2007; 56: 21-26Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar discuss that after transmetallation of Gd–chelate complexes, free Gd (and other metals like iron) may be a target for these circulation fibrocytes. Therefore, cutaneous Gd deposition may serve as a nidus for the fibrosing process that leads to the development of NSF.29.Boyd A.S. Zic J.A. Abraham J.L. Gadolinium deposition in nephrogenic fibrosing dermopathy.J Am Acad Dermatol. 2007; 56: 27-30Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar The recent finding of detectable Gd particles in skin specimens of NSF patients is highly supportive of a strong epidemiologic association between exposure to Gd-containing contrast agents and development of NSF as observed clinically. The Gd ion with its calcium-mimicking effects and the carrier molecule are likely to be involved in the mechanisms that lead to NSF. Acidosis, although not a conditio sine qua non, may be a state additionally favoring a transmetallation process with liberation of free, toxic Gd ion. The observed iron deposition in affected tissue could be another cofactor for the development of fibrosis. Although interesting new hypotheses on the cause of NSF are arising, the pathomechanism of this disease is still unknown. Other factors, for example the calcium–phosphorus–parathyroid hormone metabolism, endothelial dysfunction, and others, have to be studied. Besides, most but not all patients reported with NSF were exposed to Gd-containing contrast agents.