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Quantification of gadolinium in fresh skin and serum samples from patients with nephrogenic systemic fibrosis

Published:November 01, 2010DOI:https://doi.org/10.1016/j.jaad.2009.12.044

      Background

      Nephrogenic systemic fibrosis (NSF) is a rare, potentially fatal fibrosing disorder associated with renal insufficiency and gadolinium (Gd)-based contrast exposure. The cause remains unknown. To date, all efforts to investigate skin Gd concentrations in patients with NSF have been performed on paraffin-embedded samples, and Gd deposition has not been correlated with disease activity by a statistically significant analysis.

      Objective

      We sought to: (1) quantify Gd concentration in fresh tissue skin biopsy specimens; (2) quantify and compare synchronous Gd concentration of affected skin and unaffected skin in patients with NSF (n = 13) with a control group (n = 13); and (3) quantify serum Gd.

      Methods

      We used inductively coupled plasma mass spectrometry.

      Results

      In patients with NSF, the mean ratio of paired Gd concentrations of affected skin to unaffected skin was 23.1, ranging from 1.2 to 88.9. Mean serum Gd concentrations in patients with NSF were 4.8 ng/mL, which is more than 10 times the level in control patients. A statistically significant correlation existed between serum and affected skin Gd concentrations (r2 = .74, P < .0001).

      Limitations

      Because of the feasibility of this study, the main limitation was the small sample size (n = 13 affected and 13 control).

      Conclusions

      Determination of Gd concentrations in fresh skin samples and serum using inductively coupled plasma mass spectrometry demonstrates significant differences in the amounts of Gd in involved versus nonlesional skin of patients with NSF. This supports the role of differential free Gd deposition from Gd-based contrast in the pathogenesis of NSF.

      Key words

      Abbreviations used:

      AS (affected skin), GBCA (gadolinium-based contrast agent), Gd (gadolinium), ICP-MS (inductively coupled plasma mass spectrometry), NSF (nephrogenic systemic fibrosis), US (unaffected skin)
      • Inductively coupled plasma mass spectrometry can be used to measure gadolinium (Gd) concentrations in fresh skin and serum specimens.
      • There is a statistically significant difference in Gd concentrations of affected skin compared with unaffected skin of patients with nephrogenic systemic fibrosis; additionally, Gd concentration in unaffected skin is significantly greater than in healthy control skin samples.
      • The dynamics of Gd flux among body compartments in patients with nephrogenic systemic fibrosis supports the role of differential free Gd deposition from Gd-based contrast agents in the pathogenesis of nephrogenic systemic fibrosis.
      Nephrogenic systemic fibrosis (NSF) was first described in 2000 as a scleromyxedema-like dermopathy affecting 15 patients on hemodialysis.
      • Cowper S.E.
      • Robin H.S.
      • Steinberg S.M.
      • Su L.D.
      • Gupta S.
      • LeBoit P.E.
      Scleromyxedema-like cutaneous diseases in renal-dialysis patients.
      Clinical symptoms of this disease include progressive thickening, discoloration, and induration of the skin that can lead to contracture of the extremities in severe cases.
      • Moschella S.L.
      • Kay J.
      • Mackool B.T.
      • Liu V.
      Case records of the Massachusetts General Hospital: weekly clinicopathological exercises; case 35-2004. A 68-year-old man with end-stage renal disease and thickening of the skin.
      Histopathologic identification of CD34+ and procollagen I positive fibrocytes, along with cutaneous mucin and collagen deposition without circulating monoclonal IgG paraprotein, are also characteristics of the disease.
      • Cowper S.E.
      • Robin H.S.
      • Steinberg S.M.
      • Su L.D.
      • Gupta S.
      • LeBoit P.E.
      Scleromyxedema-like cutaneous diseases in renal-dialysis patients.
      • Galan A.
      • Cowper S.E.
      • Bucala R.
      Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy).
      The systemic involvement of the disease was first realized in 2003 and it is now known that NSF can affect other organs including the heart, lungs, and striated muscle.
      • Galan A.
      • Cowper S.E.
      • Bucala R.
      Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy).
      • Ting W.W.
      • Stone M.S.
      • Madison K.C.
      • Kurtz K.
      Nephrogenic fibrosing dermopathy with systemic involvement.
      • Kay J.
      • Bazari H.
      • Avery L.L.
      • Koreishi A.F.
      Case records of the Massachusetts General Hospital; case 6-2008. A 46-year-old woman with renal failure and stiffness of the joints and skin.
      The clinical course can be both rapidly progressive and fatal.
      • Kay J.
      • Bazari H.
      • Avery L.L.
      • Koreishi A.F.
      Case records of the Massachusetts General Hospital; case 6-2008. A 46-year-old woman with renal failure and stiffness of the joints and skin.
      Although several different attempted therapies have been administered, some leading to moderate disease regression, there is no known intervention that is uniformly effective.
      • Kay J.
      • High W.A.
      Imatinib mesylate treatment of nephrogenic systemic fibrosis.
      As of March 2010, more than 335 cases of NSF have been identified according to the Yale NSF Registry.

      Cowper SE. Nephrogenic fibrosing dermopathy [ICNSFR Website]. 2001-2009. Available at: http://www.icnsfr.org. Accessed March 14, 2010.

      However, the cause and underlying disease mechanism remain unknown.

      Cowper SE. Nephrogenic fibrosing dermopathy [ICNSFR Website]. 2001-2009. Available at: http://www.icnsfr.org. Accessed March 14, 2010.

      • Marckmann P.
      Nephrogenic systemic fibrosis: epidemiology update.
      There are many proposed contributing factors and associated conditions including renal insufficiency (estimated glomerular filtration rate < 30 mL/min/1.73 mm2), pharmaceutical erythropoietin use, hypocalcemia, acidosis, gadolinium (Gd)-based contrast agent (GBCA) exposure, low serum albumin concentrations, and high serum ferritin concentrations.
      • Wiginton C.D.
      • Kelly B.
      • Oto A.
      • Jesse M.
      • Aristimuno P.
      • Ernst R.
      • et al.
      Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue.
      • Swaminathan S.
      • Ahmed I.
      • McCarthy J.T.
      • Albright R.C.
      • Pittelkow M.R.
      • Caplice N.M.
      • et al.
      Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy.
      Strong evidence, however, has pointed to GBCA exposure in patients with renal insufficiency as being the most significant contributory factor.
      • Bhave G.
      • Lewis J.B.
      • Chang S.S.
      Association of gadolinium based magnetic resonance imaging contrast agents and nephrogenic systemic fibrosis.
      In light of the association between GBCA exposure and disease pathogenesis, attempts to both identify and quantify Gd concentrations in skin biopsy specimens of patients with NSF have been made. The first attempt to qualitatively identify Gd in tissue using scanning electron microscopy with energy dispersive x-ray spectroscopy found detectable concentrations of Gd in 4 of 7 patients with NSF.
      • High W.A.
      • Ayers R.A.
      • Chandler J.
      • Zito G.
      • Cowper S.E.
      Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis.
      The same group subsequently used inductively coupled plasma mass spectrometry (ICP-MS) to quantify the Gd concentrations in the paraffin-embedded skin biopsy specimens that contained Gd.
      • High W.A.
      • Ayers R.A.
      • Cowper S.E.
      Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis.
      Another group from Denmark used scanning electron microscopy with energy dispersive x-ray spectroscopy to quantify Gd in tissue by counting the number of Gd particles per field area and found detectible concentrations in all of 20 patients with NSF.
      • Abraham J.L.
      • 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.
      Furthermore, Gd was not detectable in the skin of patients with normal renal function after exposure to GBCAs using quantitative scanning electron microscopy with energy dispersive x-ray spectroscopy.
      • Boyd A.S.
      • Sanyal S.
      • Abraham J.L.
      Gadolinium is not deposited in the skin of patients with normal renal function after exposure to gadolinium-based contrast agents.
      To date, quantification of Gd in skin has been performed only on paraffin-embedded samples.
      • Wiginton C.D.
      • Kelly B.
      • Oto A.
      • Jesse M.
      • Aristimuno P.
      • Ernst R.
      • et al.
      Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue.
      • High W.A.
      • Ayers R.A.
      • Chandler J.
      • Zito G.
      • Cowper S.E.
      Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis.
      • High W.A.
      • Ayers R.A.
      • Cowper S.E.
      Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis.
      • Abraham J.L.
      • 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.
      • Boyd A.S.
      • Sanyal S.
      • Abraham J.L.
      Gadolinium is not deposited in the skin of patients with normal renal function after exposure to gadolinium-based contrast agents.
      • Boyd A.S.
      • Zic J.A.
      • Abraham J.L.
      Gadolinium deposition in nephrogenic fibrosing dermopathy.
      • Khurana A.
      • Greene Jr., J.F.
      • High W.A.
      Quantification of gadolinium in nephrogenic systemic fibrosis: re-examination of a reported cohort with analysis of clinical factors.
      • Thakral C.
      • Abraham J.L.
      Automated scanning electron microscopy and x-ray microanalysis for in situ quantification of gadolinium deposits in skin.
      • Thakral C.
      • Alhariri J.
      • Abraham J.L.
      Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications.
      • Swaminathan S.
      • High W.A.
      • Ranville J.
      • Horn T.D.
      • Hiatt K.
      • Thomas M.
      • et al.
      Cardiac and vascular metal deposition with high mortality in nephrogenic systemic fibrosis.
      In this report, we use ICP-MS to quantify Gd concentrations in fresh tissue biopsy specimens from 13 patients with histologically diagnosed NSF. We compare Gd concentrations in both affected skin (AS) and unaffected skin (US) in patients with NSF, and in a patient control group with no NSF, and we correlate these findings to blood serum results from 12 of our 13 patients with NSF.

      Methods

       Gd tissue analysis

      Approval to test for and measure Gd concentrations in patient tissue and blood samples after obtaining informed consent was granted by our institutional review board. The 4-mm punch biopsy specimens including epidermis, dermis, and small amounts of fat-subcutaneous tissue were obtained from AS and US on 13 patients with earlier biopsy documentation of NSF. US was defined as clear absence of clinical and physical skin involvement by detailed clinical examination and palpation of the cutaneous tissues. In addition, biopsy specimens were obtained from 13 patients with estimated glomerular filtration rates greater than 30 mL/min/1.73 mm2 and no known NSF to serve as negative controls. The biopsy specimens were placed in saline and transported to our metals laboratory for Gd quantification. Wet weights of the fresh tissue were recorded as were dry weights after samples were desiccated in a 90°C oven for at least 4 hours. Patient samples and quality control specimens were digested in acid-washed Teflon (DuPont, Wilmington, DE) tubes in 0.5 mL of trace metal grade nitric acid (Fisher Scientific, Hampton, NH) at 80°C for 10 minutes. In all, 0.5 mL of trace metal grade hydrogen peroxide was added and the heating step repeated. After full digestion, specimens were cooled to room temperature and 1 mL of type 1 water was added to bring the solution to 2 mL total volume.
      Quality control materials with certified and informational values of Gd were purchased from the European Commission Joint Research Center (Geel, Belgium) and the National Institute of Standards and Technology (Gaithersburg, MD). These materials were prepared in an identical fashion to the patient samples and were used to confirm the accuracy of the analytical method.
      Aqueous acidic calibrating standards were purchased in 25% nitric acid (Inorganic Ventures, Lakewood, NJ). Calibrators, reagent blanks, and samples were diluted 1:25 with a diluent containing 1% nitric acid and terbium internal standard into Sarstedt 13 × 75 mm polystyrene tubes (Sarstedt, Newton, NC) and mixed thoroughly.
      Gd was quantified in the digested samples using an ICP-MS equipped with a dynamic reaction cell (Perkin-Elmer SCIEX ELAN DRC II, PerkinElmer, Shelton, CT) operated in standard (vented cell) mode.

       Gd serum analysis

      Blood samples were drawn from 12 of the 13 patients with a diagnosis of NSF. Samples were quantitatively analyzed for Gd using a modification of the aforementioned method by matrix-matching the calibration curve using Gd-free plasma obtained from our components laboratory. Serum Gd concentration in unexposed healthy adult human beings is less than 0.2 ng/mL, with the lowest reportable concentration of the method being 0.1 ng/mL.

       Statistics

      Statistical analysis was performed with software (JMP, Version 7.0.1, SAS Institute Inc, Cary, NC). Continuous variables are expressed as mean ± SD. Correlation between serum Gd concentrations and AS biopsy specimen Gd concentrations was calculated using univariant linear regression analysis and Pearson correlation coefficient. The Wilcoxon signed rank test was used to compare means. A P value less than .05 was considered statistically significant.

      Results

      We quantified Gd concentrations in multiple skin biopsy specimens from 13 patients with histologically confirmed NSF, a history of renal failure, and earlier exposure to GBCA. From each patient, at least one biopsy specimen was taken from AS and one from US. Serum concentrations of Gd were also quantified in 12 of the 13 patients (Table I). The AS biopsy specimens had a mean Gd concentration of 71.4 μg/g dry weight ± 89.4 (range 6.3-348.7 μg/g dry weight). The US biopsy specimens had a mean Gd concentration of 10.2 μg/g dry weight ± 19.9 (range 0.6-68.2 μg/g dry weight). In all patients with NSF, AS had a statistically significant higher Gd concentration than US (P = .04). The mean ratio of paired Gd concentrations of AS to US was 23.1, ranging from 1.2 to 88.9.
      Table IGadolinium levels in affected and unaffected skin and in serum from 13 patients with nephrogenic systemic fibrosis
      ASUSAS/USSerum Gd (ng/mL)
      PatientGd (μg/g)SiteGd (μg/g)Site
      177 M73.6R medial calf1.5Abdomen49.12
      263 F6.3L calf0.6Abdomen10.52
      355 F186.1R thigh28.2Abdomen6.62.9
      70.2R forearm2.5
      460 F13.1L forearm2.4Abdomen5.52.5
      543 M55.0L forearm1.7Abdomen32.41.7
      647 F16.2R calf2.4Abdomen6.80.6
      765 F18.5L lateral calf4.0Abdomen4.61.6
      842 F55.7R lateral calf
      Patient 8 refused US biopsy.
      Patient 8 refused US biopsy.
      NA4.1
      940 F8.1L hand0.6Abdomen13.5
      Patient 9 refused blood draw.
      1069 M13.6R thigh11.1Abdomen1.24.4
      1141 M348.7L calf68.2Abdomen5.138.9
      1270 F52.0R calf1.3Abdomen40.01.2
      74.0L thigh56.9
      1346 F80.0L thigh0.9Abdomen88.91.3
      Mean ± SD71.4 ± 89.410.2 ± 19.923.1 ± 26.64.8 ± 9.9
      AS, Affected skin; F, female; Gd, gadolinium; L, left; M, male; NA, not applicable; R, right; US, unaffected skin.
      Skin Gd levels are reported in μg/g of dry sample weight. For patients 3 and 12 two biopsy specimens from AS were taken from different sites in same day.
      Patient 8 refused US biopsy.
      Patient 9 refused blood draw.
      The mean serum Gd concentration in patients with NSF was 4.8 ng/mL ± 9.9 (range 0.6-38.9 ng/mL). This is greater than the Gd concentration of less than 0.2 ng/mL found in healthy human control subjects determined by our institution and in the literature.
      • Saussereau E.
      • Lacroix C.
      • Cattaneo A.
      • Mahieu L.
      • Goulle J.P.
      Hair and fingernail gadolinium ICP-MS contents in an overdose case associated with nephrogenic systemic fibrosis.
      There was a statistically significant correlation between serum and AS Gd concentrations (r2 = .74, P < .0001). Eleven of the 13 control patients had skin Gd concentration below detectable range (<0.1 μg/g dry weight); two of the 13 had a threshold concentration of 0.1 μg/g dry weight (Table II). Interestingly, mean Gd concentrations in US of patients with NSF (10.2 μg/g dry weight) was significantly greater than mean Gd concentrations in the skin of healthy control subjects (P < .0001).
      Table IIGadolinium levels in skin of control patients
      Weight (mg)Gd concentration (μg/g dry weight)
      PatientWetDry
      171 M165.19553.6930.1
      282 F94.20230.0600.1
      383 F46.53115.026<0.1
      483 F187.47655.432<0.1
      555 M38.78614.228<0.1
      689 F56.51912.218<0.1
      783 F34.69911.133<0.1
      8
      Patient-identifying information was removed from these samples.
      78.68715.343<0.1
      9
      Patient-identifying information was removed from these samples.
      54.61920.556<0.1
      10
      Patient-identifying information was removed from these samples.
      58.85713.753<0.1
      11
      Patient-identifying information was removed from these samples.
      87.77326.210<0.1
      12
      Patient-identifying information was removed from these samples.
      57.61534.859<0.1
      13
      Patient-identifying information was removed from these samples.
      58.40015.159<0.1
      F, Female; Gd, gadolinium; M, male.
      Specimens were obtained from excess skin from clinically indicated biopsies.
      Patient-identifying information was removed from these samples.

      Discussion

      In 2006 Grobner
      • Grobner T.
      Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?.
      proposed that GBCA may be a trigger for NSF development in patients with renal failure who underwent magnetic resonance angiography. Since then, numerous chart review studies have demonstrated a very strong connection between NSF and GBCA exposure. As of February 2008, 190 of the 195 biopsy-proven NSF cases reported in the medical literature were associated with GBCA.
      • Broome D.R.
      Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting.
      The exact mechanism of how Gd exposure triggers NSF has yet to be elucidated. However, a proposed mechanism is that free Gd is released from the chelated form found in GBCA via a process known as transmetallation.
      • Swaminathan S.
      • Horn T.D.
      • Pellowski D.
      • Abul-Ezz S.
      • Bornhorst J.A.
      • Viswamitra S.
      • et al.
      Nephrogenic systemic fibrosis, gadolinium, and iron mobilization.
      Because most GBCAs are renally excreted, patients with low glomerular filtration rate retain GBCA longer systemically, potentially increasing the chance for transmetallation to occur.
      • Bhave G.
      • Lewis J.B.
      • Chang S.S.
      Association of gadolinium based magnetic resonance imaging contrast agents and nephrogenic systemic fibrosis.
      • 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.
      Transmetallation allows the release of free Gd, which is toxic, with subsequent deposition of the ion in various tissues. The consequent pathogenesis is believed to involve migration of CD34+ and procollagen I positive fibrocytes from the circulation into tissue where sufficient concentrations of Gd reside. The fibrocytes become activated in a transforming growth factor beta (TGF-β)-dependent manner, leading to deposition of mucin, elastin, and collagen bundles.
      • Cowper S.E.
      • Bucala R.
      • Leboit P.E.
      Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis–setting the record straight.
      Our results validate the notion of differential Gd deposition in affected tissue by showing higher concentrations of Gd in AS versus US from the same patients. Previous studies have suggested a differential Gd deposition in AS versus US,
      • High W.A.
      • Ayers R.A.
      • Cowper S.E.
      Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis.
      but our work presents a comprehensive analysis that demonstrates a statistically significant difference.
      This study successfully demonstrates quantification of Gd concentration in fresh tissue samples and serum using ICP-MS. We found that skin biopsy specimens from anatomic regions with active NSF pathology uniformly had higher concentrations of Gd than biopsy specimens from regions spared involvement by NSF in the same patient. Furthermore, all patients had elevated serum Gd concentrations compared with non-NSF control subjects. Patients with higher serum Gd tended to have higher skin Gd concentration, and there was statistical significance in the correlation between these variables. Higher serum Gd concentration could simply indicate a shorter time between GBCA exposure and serum concentration measurement. However, further investigation would be necessary to prove this relationship. Interestingly, we further demonstrate a statistically significant increase in the Gd levels of US in patients with NSF compared with skin samples of control patients. This indicates that elevated Gd concentration is not necessarily sufficient to induce NSF pathogenesis, and there may be a threshold level of Gd or other cofactors required for development of disease.
      Most recently, High et al
      • High W.A.
      • Ranville J.F.
      • Brown M.
      • Punshon T.
      • Lanzirotti A.
      • Jackson B.P.
      Gadolinium deposition in nephrogenic systemic fibrosis: an examination of tissue using synchrotron x-ray fluorescence spectroscopy.
      used a valuable national technology resource, synchrotron x-ray fluorescence spectroscopy, to map Gd deposition in affected tissue from two patients with NSF. They observed a gradient of Gd deposition in the tissue that correlated with fibrosis and cellularity. Thus, even within diseased cutaneous tissues, activity or severity of NSF correlates with concentration of Gd.
      To our knowledge, our study is the first to analyze fresh skin tissue samples and quantitate Gd concentrations in patients with NSF. Previous studies have used paraffin-embedded samples. Advantages of using fresh tissue include the option of direct sample analysis and a shortened sample processing time. Whether Gd analysis in fresh tissue is more accurate than paraffin-embedded tissue is unknown. Previous work comparing the concentrations of toxic metal in fresh tissue versus paraffin-embedded tissue showed that formalin fixing essentially has little effect on tissue concentration for copper, iron, calcium, magnesium, zinc, cadmium, or mercury. However, concentrations of aluminum and manganese did change over time with storage in formalin.
      • Bush V.J.
      • Moyer T.P.
      • Batts K.P.
      • Parisi J.E.
      Essential and toxic element concentrations in fresh and formalin-fixed human autopsy tissues.
      These studies have not been performed for Gd so it is not known if tissue concentrations change over time for formalin fixed paraffin-embedded tissue.
      Table I demonstrates two patients, each with two biopsy specimens of AS (patients 3 and 12). Same-day biopsy specimens of AS from two different regions were obtained in these patients; the Gd concentration demonstrated appreciable difference correlating with observed clinical differences.
      Whereas Boyd et al
      • Boyd A.S.
      • Sanyal S.
      • Abraham J.L.
      Gadolinium is not deposited in the skin of patients with normal renal function after exposure to gadolinium-based contrast agents.
      reported no detectible Gd deposits in the skin of patients with normal renal function who were exposed to GBCA, two of our control subjects did have detectible concentrations at 0.1 μg/g dry weight. Both of these patients had previous GBCA exposure, one 8 months and the other 16 months before biopsy. Gd is known to be detectable in bone tissue from patients with normal renal function 4 days after exposure to GBCA.
      • White G.W.
      • Gibby W.A.
      • Tweedle M.F.
      Comparison of Gd(DTPA-BMA) (Omniscan) versus Gd(HP-DO3A) (ProHance) relative to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy.
      Our ICP-MS method was sufficiently sensitive to detect Gd deposition in the skin of healthy individuals months after GBCA exposure. The significance of the detectable levels in these two patients is unclear. A prospective study of Gd deposition kinetics in the skin of healthy individuals with normal renal function after exposure to GBCA will be required to address this issue.
      Limitations of our study include a relatively small sample size of affected individuals (n = 13), which is inherent to the feasibility of this investigation.

      Conclusion

      ICP-MS is a highly sensitive method to detect Gd in fresh skin biopsy specimens and blood serum. This technology has been used to measure Gd concentrations in other tissue as well, including fingernails, hair, heart, and blood vessels in patients with NSF.
      • Swaminathan S.
      • High W.A.
      • Ranville J.
      • Horn T.D.
      • Hiatt K.
      • Thomas M.
      • et al.
      Cardiac and vascular metal deposition with high mortality in nephrogenic systemic fibrosis.
      • Saussereau E.
      • Lacroix C.
      • Cattaneo A.
      • Mahieu L.
      • Goulle J.P.
      Hair and fingernail gadolinium ICP-MS contents in an overdose case associated with nephrogenic systemic fibrosis.
      The findings herein demonstrate statistically significant greater concentrations of Gd in situ in regions of the skin with NSF pathology compared with regions without NSF pathology for the same patient. Clinically observed differential involvement by NSF is quantitatively supported and directly related to concentrations in blood serum Gd.

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