Skip to main content

Advertisement

SpringerLink
Log in

Nephrogenic systemic fibrosis: An epidemic of gadolinium toxicity

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Nephrogenic systemic fibrosis is a devastating systemic fibrosing disorder that afflicts patients with renal dysfunction. Growing evidence supports the hypothesis that gadolinium-containing contrast agents (GCCAs) trigger the development of nephrogenic systemic fibrosis. Hence, this condition is most appropriately called gadolinium-associated systemic fibrosis (GASF). In this report, we review the history of GASF, its association with prior GCCA exposure, its clinicopathologic features, the relevant pharmacology of GCCAs, the likely role of GCCAs in its pathogenesis, and potential treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Cowper SE, Robin HS, Steinberg SM, et al.: Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000, 356:1000–1001.

    Article  PubMed  CAS  Google Scholar 

  2. Cowper SE, Su LD, Bhawan J, et al.: Nephrogenic fibrosing dermopathy. Am J Dermatopathol 2001, 23:383–393.

    Article  PubMed  CAS  Google Scholar 

  3. Ting WW, Stone MS, Madison KC, Kurtz K: Nephrogenic fibrosing dermopathy with systemic involvement. Arch Dermatol 2003, 139:903–906.

    Article  PubMed  Google Scholar 

  4. Thomsen HS: Nephrogenic systemic fibrosis: A serious late adverse reaction to gadodiamide. Eur Radiol 2006, 16:2619–2621.

    Article  PubMed  Google Scholar 

  5. Cowper SE, Bucala R, Leboit PE: Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis—setting the record straight. Semin Arthritis Rheum 2006, 35:208–210.

    Article  PubMed  Google Scholar 

  6. Grobner T: Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006, 21:1104–1108.

    Article  PubMed  CAS  Google Scholar 

  7. 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, 17:2359–2362.

    Article  PubMed  Google Scholar 

  8. Kay J: Gadolinium and nephrogenic systemic fibrosis: the evidence of things not seen. Cleve Clin J Med 2008, 75:112, 114, 117.

    PubMed  Google Scholar 

  9. Auron A, Shao L, Warady BA: Nephrogenic fibrosing dermopathy in children. Pediatr Nephrol 2006, 21:1307–1311.

    Article  PubMed  Google Scholar 

  10. Swartz RD, Crofford LJ, Phan SH, et al.: Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure. Am J Med 2003, 114:563–572.

    Article  PubMed  Google Scholar 

  11. Kalb RE, Helm TN, Sperry H, et al.: Gadolinium-induced nephrogenic systemic fibrosis in a patient with an acute and transient kidney injury. Br J Dermatol 2008, 158:607–610.

    Article  PubMed  CAS  Google Scholar 

  12. Mendoza FA, Artlett CM, Sandorfi N, et al.: Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 2006, 35:238–249.

    Article  PubMed  Google Scholar 

  13. Broome DR, Girguis MS, Baron PW, et al.: Gadodiamide-Associated Nephrogenic Systemic Fibrosis: Why Radiologists Should Be Concerned. Am J Roentgenol 2007, 188:586–592.

    Article  Google Scholar 

  14. Todd DJ, Kagan A, Chibnik LB, Kay J: Cutaneous changes of nephrogenic systemic fibrosis: predictor of early mortality and association with gadolinium exposure. Arthritis Rheum 2007, 56:3433–3441.

    Article  PubMed  Google Scholar 

  15. Rydahl C, Thomsen HS, Marckmann P: High prevalence of nephrogenic systemic fibrosis in chronic renal failure patients exposed to gadodiamide, a gadolinium-containing magnetic resonance contrast agent. Invest Radiol 2008, 43:141–144.

    PubMed  CAS  Google Scholar 

  16. Centers for Disease Control and Prevention (CDC): Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents—St. Louis, Missouri, 2002–2006. MMWR Morb Mortal Wkly Rep 2007, 56:137–141.

    Google Scholar 

  17. Baron PW, Cantos K, Hillebrand DJ, et al.: Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis. Am J Dermatopathol 2003, 25:204–209.

    Article  PubMed  Google Scholar 

  18. Maloo M, Abt P, Kashyap R, et al.: Nephrogenic systemic fibrosis among liver transplant recipients: a single institution experience and topic update. Am J Transplant 2006, 6:2212–2217.

    Article  PubMed  CAS  Google Scholar 

  19. Swaminathan S, Ahmed I, McCarthy JT, et al.: Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med 2006, 145:234–235.

    PubMed  Google Scholar 

  20. Marckmann P, Skov L, Rossen K, et al.: Case-control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant 2007, 22:3174–3178.

    Article  PubMed  CAS  Google Scholar 

  21. Dharnidharka VR, Wesson SK, Fennell RS: Gadolinium and nephrogenic fibrosing dermopathy in pediatric patients. Pediatr Nephrol 2007, 22:1395.

    Article  PubMed  Google Scholar 

  22. Fazeli A, Lio PA, Liu V: Nephrogenic fibrosing dermopathy: are ACE inhibitors the missing link? Arch Dermatol 2004, 140:1401.

    Article  PubMed  Google Scholar 

  23. Swaminathan S, Horn TD, Pellowski D, et al.: Nephrogenic systemic fibrosis, gadolinium, and iron mobilization. N Engl J Med 2007, 357:720–722.

    Article  PubMed  CAS  Google Scholar 

  24. Moschella SL, Kay J, Mackool BT, 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. N Engl J Med 2004, 351:2219–2227.

    Article  PubMed  CAS  Google Scholar 

  25. Kay J, Kagan A, Chibnik LB, et al.: Nephrogenic fibrosing dermopathy develops following gadopentetate dimeglumine exposure [abstract]. Arthritis Rheum 2007, 56(Suppl):S546–S547.

    Google Scholar 

  26. Streams BN, Liu V, Liegeois N, Moschella SM: Clinical and pathologic features of nephrogenic fibrosing dermopathy: a report of two cases. J Am Acad Dermatol 2003, 48:42–47.

    Article  PubMed  Google Scholar 

  27. Daram SR, Cortese CM, Bastani B: Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: report of a new case with literature review. Am J Kidney Dis 2005, 46:754–759.

    Article  PubMed  Google Scholar 

  28. Jimenez SA, Artlett CM, Sandorfi N, et al.: Dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy): study of inflammatory cells and transforming growth factor beta1 expression in affected skin. Arthritis Rheum 2004, 50:2660–2666.

    Article  PubMed  CAS  Google Scholar 

  29. Gibson SE, Farver CF, Prayson RA: Multiorgan involvement in nephrogenic fibrosing dermopathy: an autopsy case and review of the literature. Arch Pathol Lab Med 2006, 130:209–212.

    PubMed  Google Scholar 

  30. Kucher C, Steere J, Elenitsas R, et al.: Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis with diaphragmatic involvement in a patient with respiratory failure. J Am Acad Dermatol 2006, 54(2 Suppl):S31–34.

    Article  PubMed  Google Scholar 

  31. Saenz A, Mandal R, Kradin R, Hedley-Whyte ET: Nephrogenic fibrosing dermopathy with involvement of the dura mater. Virchows Arch 2006, 449:389–391.

    Article  PubMed  Google Scholar 

  32. Kay J, Bazari H, Avery LL, Koreishi AF: Case records of the Massachusetts General Hospital. Case 6-2008. A 46-yearold woman with renal failure and stiffness of the joints and skin. N Engl J Med 2008, 358:827–838.

    Article  PubMed  CAS  Google Scholar 

  33. Edsall LC, English 3rd JC, Patterson JW: Calciphylaxis and metastatic calcification associated with nephrogenic fibrosing dermopathy. J Cutan Pathol 2004, 31:247–253.

    Article  PubMed  Google Scholar 

  34. Bucala R: Circulating fibrocytes: cellular basis for NSF. J Am Coll Radiol 2008, 5:36–39.

    Article  PubMed  Google Scholar 

  35. Centers for Disease Control and Prevention (CDC): Eosinophilia-myalgia syndrome and L-tryptophan-containing products-New Mexico, Minnesota, Oregon, and New York, 1989. MMWR Morb Mortal Wkly Rep 1989, 38:785–788.

    Google Scholar 

  36. Martinez-Tello FJ, Navas-Palacios JJ, Ricoy JR, et al.: Pathology of a new toxic syndrome caused by ingestion of adulterated oil in Spain. Virchows Archiv 1982, 397:261–285.

    Article  CAS  Google Scholar 

  37. Evenepoel P, Zeegers M, Segaert S, et al.: Nephrogenic fibrosing dermopathy: a novel, disabling disorder in patients with renal failure. Nephrol Dial Transplant 2004, 19:469–473.

    Article  PubMed  Google Scholar 

  38. Kucher C, Xiaowei X, Pasha T, Elenitsas R: Histopathologic comparison of nephrogenic fibrosing dermopathy and scleromyxedema. J Cutan Pathol 2005, 32:484–490.

    Article  PubMed  Google Scholar 

  39. Dixon AJ, Dixon MP, Askew DA, Wilkinson D: Prospective study of wound infections in dermatologic surgery in the absence of prophylactic antibiotics. Dermatol Surg 2006, 32:819–826; discussion 826–817.

    Article  PubMed  CAS  Google Scholar 

  40. Bloom H, Heeke B, Leon A, et al.: Renal insufficiency and the risk of infection from pacemaker or defibrillator surgery. Pacing Clin Electrophysiol 2006, 29:142–145.

    Article  PubMed  Google Scholar 

  41. Bogoch ER, Gross DK: Surgery of the hand in patients with systemic sclerosis: outcomes and considerations. J Rheumatol 2005, 32:642–648.

    PubMed  Google Scholar 

  42. Ahmed I, Goldstein B: Diabetes mellitus. Clin Dermatol 2006, 24:237–246.

    Article  PubMed  Google Scholar 

  43. Alguire PC, Mathes BM: Skin biopsy techniques for the internist. J Gen Intern Med 1998, 13:46–54.

    Article  PubMed  CAS  Google Scholar 

  44. Collidge TA, Thomson PC, Mark PB, et al.: Gadolinium-enhanced MR imaging and nephrogenic systemic fibrosis: retrospective study of a renal replacement therapy cohort. Radiology 2007, 245:168–175.

    Article  PubMed  Google Scholar 

  45. Othersen JB, Maize JC Jr, Woolson RF, Budisavljevic MN: Nephrogenic systemic fibrosis after exposure to gadolinium in patients with renal failure. Nephrol Dial Transplant 2007, 22:3179–3185.

    Article  PubMed  CAS  Google Scholar 

  46. Deo A, Fogel M, Cowper SE: Nephrogenic systemic fibrosis: a population study examining the relationship of disease development to gadolinium exposure. Clin J Am Acad Nephrol 2007, 1:264–267.

    Article  Google Scholar 

  47. 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. Method Find Exp Clin Pharmacol 1996, 18:437–442.

    CAS  Google Scholar 

  48. Husztik E, Lazar G, Parducz A: Electron microscopic study of Kupffer-cell phagocytosis blockade induced by gadolinium chloride. Br J Exp Pathol 1980, 61:624–630.

    PubMed  CAS  Google Scholar 

  49. Itoh N, Kawakita M: Characterization of Gd3+ and Tb3+ binding sites on Ca2+,Mg2+-adenosine triphosphatase of sarcoplasmic reticulum. J Biochem 1984, 95:661–669.

    PubMed  CAS  Google Scholar 

  50. Spencer AJ, Wilson SA, Batchelor J, et al.: Gadolinium chloride toxicity in the rat. Toxicol Pathol 1997, 25:245–255.

    Article  PubMed  CAS  Google Scholar 

  51. Biagi BA, Enyeart JJ: Gadolinium blocks low-and high-threshold calcium currents in pituitary cells. Am J Physiol 1990, 259:C515–520.

    PubMed  CAS  Google Scholar 

  52. Lansman JB: Blockade of current through single calcium channels by trivalent lanthanide cations. Effect of ionic radius on the rates of ion entry and exit. J Gen Physiol 1990, 95:679–696.

    Article  PubMed  CAS  Google Scholar 

  53. Boyd AS, Zic JA, Abraham JL: Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2007, 56:27–30.

    Article  PubMed  Google Scholar 

  54. Vorobiov M, Basok A, Tovbin D, et al.: Iron-mobilizing properties of the gadolinium-DTPA complex: clinical and experimental observations. Nephrol Dial Transplant 2003, 18:884–887.

    Article  PubMed  CAS  Google Scholar 

  55. Idee JM, Port M, Raynal I, et al.: Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam Clin Pharmacol 2006, 20:563–576.

    Article  PubMed  CAS  Google Scholar 

  56. Mann JS: Stability of gadolinium complexes in vitro and in vivo. J Comput Assist Tomogr 1993, 17(Suppl 1):S19–23.

    PubMed  Google Scholar 

  57. VanWagoner M, O’Toole M, Worah D, et al.: A phase I clinical trial with gadodiamide injection, a nonionic magnetic resonance imaging enhancement agent. Invest Radiol 1991, 26:980–986.

    Article  PubMed  CAS  Google Scholar 

  58. 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, 5:491–502.

    Article  PubMed  CAS  Google Scholar 

  59. Johnson DB, Lerner CA, Prince MR, et al.: Gadolinium-enhanced magnetic resonance angiography of renal transplants. Magn Reson Imaging 1997, 15:13–20.

    Article  PubMed  CAS  Google Scholar 

  60. Arsenault TM, King BF, Marsh JW Jr, et al.: Systemic gadolinium toxicity in patients with renal insufficiency and renal failure: retrospective analysis of an initial experience. Mayo Clin Proc 1996, 71:1150–1154.

    PubMed  CAS  Google Scholar 

  61. Sam AD, Morasch MD, Collins J, et al.: Safety of gadolinium contrast angiography in patients with chronic renal insufficiency. J Vasc Surg 2003, 38:313–318.

    Article  PubMed  Google Scholar 

  62. US Food and Drug Administration: Public Health Advisory. Gadolinium-containing contrast agents for magnetic resonance imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance. Available at www.fda.gov/cder/drug/advisory/gadolinium_agents.htm. Accessed March 14, 2008.

  63. Abraham JL, Thakral C, Skov L, et al.: Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol 2008, 158:273–280.

    Article  PubMed  CAS  Google Scholar 

  64. Grobner T: Author reply. Nephrol Dial Transplant 2006, 21:3604–3605.

    Article  Google Scholar 

  65. Kuo PH, Kanal E, Abu-Alfa AK, Cowper SE: Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis. Radiology 2007, 242:647–649.

    Article  PubMed  Google Scholar 

  66. Sadowski EA, Bennett LK, Chan MR, et al.: Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology 2007, 243:148–157.

    Article  PubMed  Google Scholar 

  67. High WA, Ayers RA, Chandler J, et al.: Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007, 56:21–26.

    Article  PubMed  Google Scholar 

  68. High WA, Ayers RA, Cowper SE: Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007, 56:710–712.

    Article  PubMed  Google Scholar 

  69. White GW, Gibby WA, Tweedle MF: 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. Invest Radiol 2006, 41:272–278.

    Article  PubMed  Google Scholar 

  70. Saussereau E, Lacroix C, Cattaneo A, et al.: Hair and fingernail gadolinium ICP-MS contents in an overdose case associated with nephrogenic systemic fibrosis. Forensic Sci Int 2008, 176:54–57.

    Article  PubMed  CAS  Google Scholar 

  71. 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, 7:2425–2432.

    Article  PubMed  CAS  Google Scholar 

  72. Thakral C, Alhariri J, Abraham JL: Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications. Contrast Media Mol Imaging 2007, 2:199–205.

    Article  PubMed  CAS  Google Scholar 

  73. Harpur ES, Worah D, Hals PA, et al.: Preclinical safety assessment and pharmacokinetics of gadodiamide injection, a new magnetic resonance imaging contrast agent. Invest Radiol 1993, 28(Suppl 1):S28–43.

    PubMed  CAS  Google Scholar 

  74. Levine JM, Taylor RA, Elman LB, et al.: Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy). Muscle Nerve 2004, 30:569–577.

    Article  PubMed  Google Scholar 

  75. Pieringer H, Schmekal B, Janko O, Biesenbach G: Treatment with corticosteroids does not seem to benefit nephrogenic systemic fibrosis. Nephrol Dial Transplant 2007, 22:3094.

    Article  PubMed  Google Scholar 

  76. Chung HJ, Chung KY: Nephrogenic fibrosing dermopathy: response to high-dose intravenous immunoglobulin. Br J Dermatol 2004, 150:596–597.

    Article  PubMed  Google Scholar 

  77. Hubbard V, Davenport A, Jarmulowicz M, Rustin M: Scleromyxoedema-like changes in four renal dialysis patients. Br J Dermatol 2003, 148:563–568.

    Article  PubMed  CAS  Google Scholar 

  78. Gilliet M, Cozzio A, Burg G, Nestle FO: Successful treatment of three cases of nephrogenic fibrosing dermopathy with extracorporeal photopheresis. Br J Dermatol 2005, 152:531–536.

    Article  PubMed  CAS  Google Scholar 

  79. Richmond H, Zwerner J, Kim Y, Fiorentino D: Nephrogenic systemic fibrosis: relationship to gadolinium and response to photopheresis. Arch Dermatol 2007, 143:1025–1030.

    Article  PubMed  Google Scholar 

  80. Yerram P, Saab G, Karuparthi PR, et al.: Nephrogenic systemic fibrosis: a mysterious disease in patients with renal failure—role of gadolinium-based contrast media in causation and the beneficial effect of intravenous sodium thiosulfate. Clin J Am Acad Nephrol 2007, 1:258–263.

    Article  CAS  Google Scholar 

  81. Druker BJ, Tamura S, Buchdunger E, et al.: Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996, 2:561–566.

    Article  PubMed  CAS  Google Scholar 

  82. Daniels CE, Wilkes MC, Edens M, et al.: Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J Clin Invest 2004, 114:1308–1316.

    PubMed  CAS  Google Scholar 

  83. Wang S, Wilkes MC, Leof EB, Hirschberg R: Imatinib mesylate blocks a non-Smad TGF-beta pathway and reduces renal fibrogenesis in vivo. Faseb J 2005, 19:1–11.

    Article  PubMed  CAS  Google Scholar 

  84. Distler JH, Jungel A, Huber LC, et al.: Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum 2007, 56:311–322.

    Article  PubMed  CAS  Google Scholar 

  85. Kay J, High WA: Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum 2008 (in press).

  86. Duff G: Gadolinium-containing MRI contrast agents and nephrogenic systemic fibrosis (NSF). Available at http://www.ismrm.org/special/EMEA1.pdf. Accessed March 14, 2008.

  87. US Food and Drug Administration: Information for Health Care Professionals: Gadolinium-based contrast agents for magnetic resonance imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, ProHance). Available at http://www.fda.gov/cder/drug/InfoSheets/HCP/gcca_200705HCP.pdf. Accessed March 14, 2008.

  88. Bayer HealthCare Pharmaceuticals: Magnevist safety information: Nephrogenic systemic fibrosis or nephrogenic fibrosing dermopathy (NSF/NFD). Available at http://www.berleximaging.com/html/magnevist/nsf_nfd.html. Accessed March 14, 2008.

  89. Flaten H: Omniscan. Available at http://www.omniscan-news.com/letter.shtml. Accessed March 14, 2008.

  90. Lauenstein TC, Salman K, Morreira R, et al.: Nephrogenic systemic fibrosis: center case review. J Magn Reson Imaging 2007, 26:1198–1203.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Yawkey 2-174, 55 Fruit Street, Boston, MA, 02114, USA

    Jonathan Kay

Authors
  1. Derrick J. Todd
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonathan Kay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan Kay.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Todd, D.J., Kay, J. Nephrogenic systemic fibrosis: An epidemic of gadolinium toxicity. Curr Rheumatol Rep 10, 195–204 (2008). https://doi.org/10.1007/s11926-008-0033-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-008-0033-6

Keywords

Search

Navigation