Advertisement

Nephrogenic Systemic Fibrosis: A Review of History, Pathophysiology, and Current Guidelines

  • Julian M. HazeltonEmail author
  • Michael K. Chiu
  • Hani H. Abujudeh
Quality and Safety (H Abujudeh, Section Editor)
  • 5 Downloads
Part of the following topical collections:
  1. Quality and Safety

Abstract

Purpose of Review

Nephrogenic systemic fibrosis (NSF) is a rare systemic disease with a high mortality. The purpose of this review is to provide clinicians with guidance regarding safe administration of GBCAs to patients with renal disease.

Summary

Development of NSF has been linked to the administration of gadolinium-based contrast agents (GBCAs) in patients with renal disease. Due to the wide variety of available GBCAs and recommendations regarding safe administration of these agents, it can be difficult for clinicians to choose the best GBCA for this patient population.

Recent Findings

Although the current ACR guidelines have virtually eliminated the risk of NSF, future research may lead to the development of alternative contrast agents for patients at risk of NSF who require contrast-enhanced MRIs.

Keywords

Gadolinium Nephrogenic systemic fibrosis MRI contrast guidelines Gadolinium safety End-stage renal disease 

Notes

Acknowledgements

The authors would like to thank Dr. Harlan Harvey for reviewing their manuscript.

Compliance with Ethical Guidelines

Conflict of interest

Julian M. Hazelton and Michael K. Chiu each declare no potential conflicts of interest. Hani H. Abujudeh is a section editor for Current Radiology Reports.

Human and Animal Rights

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Recently published papers of particular interest have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Hammer FD, et al. Gadolinium dimeglumine: an alternative contrast agent for digital subtraction angiography. Eur Radiol. 1999;9(1):128–36.PubMedGoogle Scholar
  2. 2.
    Spinosa DJ, et al. Gadolinium-based contrast agents in angiography and interventional radiology. AJR Am J Roentgenol. 1999;173(5):1403–9.PubMedGoogle Scholar
  3. 3.
    Cowper SE, et al. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet. 2000;356(9234):1000–1.PubMedGoogle Scholar
  4. 4.
    McNeill AM, Barr RJ. Scleromyxedema-like fibromucinosis in a patient undergoing hemodialysis. Int J Dermatol. 2002;41(6):364–7.PubMedGoogle Scholar
  5. 5.
    Ting WW, et al. Nephrogenic fibrosing dermopathy with systemic involvement. Arch Dermatol. 2003;139(7):903–6.PubMedGoogle Scholar
  6. 6.
    Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol. 2003;15(6):785–90.PubMedGoogle Scholar
  7. 7.
    Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104–8.PubMedGoogle Scholar
  8. 8.
    Marckmann P, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol. 2006;17(9):2359–62.PubMedGoogle Scholar
  9. 9.
    Abujudeh, H. Nephrogenic systemic fibrosis, renal disease, and gadolinium based MR contrast agents: where we stand today. Presented at the ARRS, Thursday, May 10, 2007.Google Scholar
  10. 10.
    Swaminathan S, et al. Cardiac and vascular metal deposition with high mortality in nephrogenic systemic fibrosis. Kidney Int. 2008;73(12):1413–8.PubMedGoogle Scholar
  11. 11.
    Tweedle MF. Physicochemical properties of gadoteridol and other magnetic resonance contrast agents. Invest Radiol. 1992;27(Suppl 1):S2–6.PubMedGoogle Scholar
  12. 12.
    Lorusso V, et al. Magnetic resonance contrast agents: from the bench to the patient. Curr Pharm Des. 2005;11(31):4079–98.PubMedGoogle Scholar
  13. 13.
    Idee JM, et al. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam Clin Pharmacol. 2006;20(6):563–76.PubMedGoogle Scholar
  14. 14.
    Boyd AS, Zic JA, Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol. 2007;56(1):27–30.PubMedGoogle Scholar
  15. 15.
    High WA, et al. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol. 2007;56(1):21–6.PubMedGoogle Scholar
  16. 16.
    FDA. Gadolinium-based contrast agents (GBCAs) and the NSF risk: regulatory. https://www.fda.gov/Drugs/default.htm (2011).
  17. 17.
    Abujudeh HH, et al. Retrospective assessment of prevalence of nephrogenic systemic fibrosis (NSF) after implementation of a new guideline for the use of gadobenate dimeglumine as a sole contrast agent for magnetic resonance examination in renally impaired patients. J Magn Reson Imaging. 2009;30(6):1335–40.PubMedGoogle Scholar
  18. 18.
    •• ACR. ACR manual on contrast 2018. ACR committee on drugs and contrast, 2018. This manual outlines the current ACR recommendations for safe utilization of GBCAs. Google Scholar
  19. 19.
    • Endrikat J, et al. 10 years of nephrogenic systemic fibrosis: a comprehensive analysis of nephrogenic systemic fibrosis reports received by a pharmaceutical company from 2006 to 2016. Invest Radiol. 2018;53(9):541–50. This article outlines the importance of scrutinizing all reported cases of NSF to accurately correlate the risk of NSF associated with a given GBCA. Google Scholar
  20. 20.
    Thomsen HS, Marckmann P, Logager VB. Update on nephrogenic systemic fibrosis. Magn Reson Imaging Clin N Am. 2008;16(4):551–60, vii.Google Scholar
  21. 21.
    Grebe SO, et al. Chronic inflammation and accelerated atherosclerosis as important cofactors in nephrogenic systemic fibrosis following intravenous gadolinium exposure. Clin Exp Nephrol. 2008;12(5):403–6.PubMedGoogle Scholar
  22. 22.
    Mendoza FA, et al. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum. 2006;35(4):238–49.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Sadowski EA, et al. Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology. 2007;243(1):148–57.PubMedGoogle Scholar
  24. 24.
    • Thomson LK, et al. Diagnosing nephrogenic systemic fibrosis in the post-FDA restriction era. J Magn Reson Imaging. 2015;41(5):1268–71. This article outlines the importance of accurate record keeping and experienced clinicians when diagnosing NSF. Google Scholar
  25. 25.
    Abujudeh HH, et al. Nephrogenic systemic fibrosis after gadopentetate dimeglumine exposure: case series of 36 patients. Radiology. 2009;253(1):81–9.PubMedGoogle Scholar
  26. 26.
    Broome DR, et al. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. AJR Am J Roentgenol. 2007;188(2):586–92.PubMedGoogle Scholar
  27. 27.
    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(2):141–4.PubMedGoogle Scholar
  28. 28.
    Cassis TB, et al. Nephrogenic fibrosing dermopathy in a patient with acute renal failure never requiring dialysis. Int J Dermatol. 2006;45(1):56–9.PubMedGoogle Scholar
  29. 29.
    Centers for Disease, Control and Prevention. Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents—St. Louis, Missouri, 2002-2006. MMWR Morb Mortal Wkly Rep. 2007;56(7):137–41.Google Scholar
  30. 30.
    •• Soulez G, et al. Prospective cohort study of nephrogenic systemic fibrosis in patients with stage 3-5 chronic kidney disease undergoing MRI with injected gadobenate dimeglumine or gadoteridol. AJR Am J Roentgenol. 2015;205(3):469–78. This article outlines the safety of two group II GBCA and their lack of association with any NSF cases. Google Scholar
  31. 31.
    Wertman R, et al. Risk of nephrogenic systemic fibrosis: evaluation of gadolinium chelate contrast agents at four American universities. Radiology. 2008;248(3):799–806.PubMedGoogle Scholar
  32. 32.
    Kaewlai R, et al. Nephrogenic systemic fibrosis. Am J Roentgenol. 1976;199(1):W17–23.Google Scholar
  33. 33.
    •• Nicola R, et al. Contrast media extravasation of computed tomography and magnetic resonance imaging: management guidelines for the radiologist. Curr Probl Diagn Radiol. 2016;(3):161–64. This article outlines the guidelines that should be used to prevent NSF. Google Scholar
  34. 34.
    Baranyai Z, et al. Dissociation kinetics of open-chain and macrocyclic gadolinium(III)-aminopolycarboxylate complexes related to magnetic resonance imaging: catalytic effect of endogenous ligands. Chemistry. 2012;18(51):16426–35.PubMedGoogle Scholar
  35. 35.
    Kimura J, et al. Human comparative study of zinc and copper excretion via urine after administration of magnetic resonance imaging contrast agents. Radiat Med. 2005;23(5):322–6.PubMedGoogle Scholar
  36. 36.
    Swaminathan S, et al. Nephrogenic systemic fibrosis, gadolinium, and iron mobilization. N Engl J Med. 2007;357(7):720–2.PubMedGoogle Scholar
  37. 37.
    Cowper SE, Bucala R, Leboit PE. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis—setting the record straight. Semin Arthritis Rheum. 2006;35(4):208–10.PubMedGoogle Scholar
  38. 38.
    • Birka M, et al. Diagnosis of nephrogenic systemic fibrosis by means of elemental bioimaging and speciation analysis. Anal Chem. 2015;87(6):3321–28. This article reinforces the pathological mechanism by which GBCA cause NSF vis deposition in the skin. Google Scholar
  39. 39.
    Del Galdo F, et al. NFkappaB activation and stimulation of chemokine production in normal human macrophages by the gadolinium-based magnetic resonance contrast agent Omniscan: possible role in the pathogenesis of nephrogenic systemic fibrosis. Ann Rheum Dis. 2010;69(11):2024–33.PubMedGoogle Scholar
  40. 40.
    Wermuth PJ, Jimenez SA. Gadolinium compounds signaling through TLR4 and TLR7 in normal human macrophages: establishment of a proinflammatory phenotype and implications for the pathogenesis of nephrogenic systemic fibrosis. J Immunol. 2012;189(1):318–27.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Wagner B, Drel V, Gorin Y. Pathophysiology of gadolinium-associated systemic fibrosis. Am J Physiol Renal Physiol. 2016;311(1):F1–11.PubMedPubMedCentralGoogle Scholar
  42. 42.
    • Schmidt-Lauber C, et al. Gadolinium-based compounds induce NLRP3-dependent IL-1beta production and peritoneal inflammation. Ann Rheum Dis. 2015;74(11):2062–69. This article proposes a pathological mechanism by which GBCA cause NSF. Google Scholar
  43. 43.
    Prince MR, et al. Incidence of nephrogenic systemic fibrosis at two large medical centers. Radiology. 2008;248(3):807–16.PubMedGoogle Scholar
  44. 44.
    Girardi M, et al. Nephrogenic systemic fibrosis: clinicopathological definition and workup recommendations. J Am Acad Dermatol. 2011;65(6):1095–106.PubMedGoogle Scholar
  45. 45.
    Moschella SL, et al. 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(21):2219–27.PubMedGoogle Scholar
  46. 46.
    Perez-Rodriguez J, et al. Nephrogenic systemic fibrosis: incidence, associations, and effect of risk factor assessment—report of 33 cases. Radiology. 2009;250(2):371–7.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Todd DJ, et al. Cutaneous changes of nephrogenic systemic fibrosis: predictor of early mortality and association with gadolinium exposure. Arthritis Rheum. 2007;56(10):3433–41.PubMedGoogle Scholar
  48. 48.
    Jimenez SA, 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(8):2660–6.PubMedGoogle Scholar
  49. 49.
    Barker-Griffith A, Goldberg J, Abraham JL. Ocular pathologic features and gadolinium deposition in nephrogenic systemic fibrosis. Arch Ophthalmol. 2011;129(5):661–3.PubMedGoogle Scholar
  50. 50.
    Collidge TA, et al. Gadolinium-enhanced MR imaging and nephrogenic systemic fibrosis: retrospective study of a renal replacement therapy cohort. Radiology. 2007;245(1):168–75.PubMedGoogle Scholar
  51. 51.
    Kanal E, et al. ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol. 2007;188(6):1447–74.PubMedGoogle Scholar
  52. 52.
    Centers for Disease Control. Eosinophilia-myalgia syndrome and l-tryptophan-containing products—New Mexico, Minnesota, Oregon, and New York, 1989. MMWR Morb Mortal Wkly Rep. 1989;38(46):785–8.Google Scholar
  53. 53.
    Martinez-Tello FJ, et al. Pathology of a new toxic syndrome caused by ingestion of adulterated oil in Spain. Virchows Arch A. 1982;397(3):261–85.Google Scholar
  54. 54.
    Kadiyala D, Roer DA, Perazella MA. Nephrogenic systemic fibrosis associated with gadoversetamide exposure: treatment with sodium thiosulfate. Am J Kidney Dis. 2009;53(1):133–7.PubMedGoogle Scholar
  55. 55.
    Yerram P, 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 Soc Nephrol. 2007;2(2):258–63.PubMedGoogle Scholar
  56. 56.
    Wahba IM, et al. The case for ultraviolet light therapy in nephrogenic fibrosing dermopathy—report of two cases and review of the literature. Nephrol Dial Transplant. 2007;22(2):631–6.PubMedGoogle Scholar
  57. 57.
    Richmond H, et al. Nephrogenic systemic fibrosis: relationship to gadolinium and response to photopheresis. Arch Dermatol. 2007;143(8):1025–30.PubMedGoogle Scholar
  58. 58.
    Todd DJ, Kay J. Gadolinium-induced fibrosis. Annu Rev Med. 2016;67:273–91. This article outlines possible antifibrotic treatment attempts for NSF. Google Scholar
  59. 59.
    Gilliet M, et al. Successful treatment of three cases of nephrogenic fibrosing dermopathy with extracorporeal photopheresis. Br J Dermatol. 2005;152(3):531–6.PubMedGoogle Scholar
  60. 60.
    Lauchli S, et al. Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis. Dermatology. 2004;208(3):278–80.PubMedGoogle Scholar
  61. 61.
    Mathur K, et al. Extracorporeal photopheresis improves nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: three case reports and review of literature. J Clin Apher. 2008;23(4):144–50.PubMedGoogle Scholar
  62. 62.
    Cuffy MC, et al. Renal transplantation for nephrogenic systemic fibrosis: a case report and review of the literature. Nephrol Dial Transplant. 2011;26(3):1099–101.PubMedGoogle Scholar
  63. 63.
    Panesar M, Banerjee S, Barone GW. Clinical improvement of nephrogenic systemic fibrosis after kidney transplantation. Clin Transplant. 2008;22(6):803–8.PubMedGoogle Scholar
  64. 64.
    Panesar M, Yacoub R. What is the role of renal transplantation in a patient with nephrogenic systemic fibrosis? Semin Dial. 2011;24(4):373–4.PubMedGoogle Scholar
  65. 65.
    FDA. FDA drug safety communication: new warnings for using gadolinium-based contrast agents in patients with kidney dysfunction. Silver Spring: FDA; 2010.Google Scholar
  66. 66.
    Choyke PL, et al. Determination of serum creatinine prior to iodinated contrast media: is it necessary in all patients? Techn Urol. 1998;4:65–9.Google Scholar
  67. 67.
    • Too CW, et al. Screening for impaired renal function in outpatients before iodinated contrast injection: comparing the Choyke questionnaire with a rapid point-of-care-test. Eur J Radiol. 2015;84:1227–31. This article outlines the high sensitivity of the Choyke questionnaire, a short questionnaire used to screen for patients with renal disease. Google Scholar
  68. 68.
    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(3):272–8.PubMedGoogle Scholar
  69. 69.
    Kay J, et al. 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. N Engl J Med. 2008;358(8):827–38.PubMedGoogle Scholar
  70. 70.
    • Semelka RC, et al. Gadolinium in humans: a family of disorders. AJR Am J Roentgenol. 2016;207(2):229–33. This article describes and proposes naming the histopathologically confirmed presence of GBCA within brain tissue. Google Scholar
  71. 71.
    • Semelka RC. Gadolinium deposition disease: Initial description of a disease that has been around for a while. Magn Reson Imaging. 2016;34(10):1383–90. This article outlines the clinical manifestions of gadolinium toxicity in patients with normal renal function. Google Scholar
  72. 72.
    • Bussi S, et al. Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats. J Magn Reson Imaging. 2018;47(3):746–52. This article demonstrates the varying ability of the human body to excrete GBCA and which GBCAs are most likely to accumulate within human tissue. Google Scholar
  73. 73.
    • Boehm-Sturm P, et al. Low-molecular-weight iron chelates may be an alternative to gadolinium-based contrast agents for T1-weighted contrast-enhanced MR imaging. Radiology. 2018;286(2):537–46. This article outlines the possible use of alternative non-gadolinium based contrast agents for MRI. Google Scholar
  74. 74.
    Morgan DE, et al. Assessment of adverse reaction rates during gadoteridol-enhanced MR imaging in 28,078 patients. Radiology. 2011;259(1):109–16.PubMedGoogle Scholar
  75. 75.
    • Forgacs A, et al. Mono-, bi-, and trinuclear bis-hydrated Mn(2 +) complexes as potential MRI contrast agents. Inorg Chem. 2015;54(19):9576–87. This article outlines the possibility of using manganese-based contrast agents for MRI. Google Scholar
  76. 76.
    • Nguyen HV, et al. Nitroxide-based macromolecular contrast agents with unprecedented transverse relaxivity and stability for magnetic resonance imaging of tumors. ACS Cent Sci. 2017;3(7):800–11. This article outlines the possible use of nitroxide-based contrast agents for MRI. Google Scholar
  77. 77.
    • Bahrainwala JZ, Leonberg-Yoo AK, Rudnick MR. Use of radiocontrast agents in CKD and ESRD. Semin Dial. 2017;30(4):290–304. This article makes suggestions for using the low dose and newer macrocyclic GBCAs to prevent NSF. Google Scholar
  78. 78.
    • Halteh P, et al. Gadolinium-naive nephrogenic systemic fibrosis of breast mimicking inflammatory breast carcinoma. Am J Dermatopathol. 2017;39(4):322–24. This article describes a case of NSF where the patient had no known exposure to GBCA. Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Julian M. Hazelton
    • 1
    Email author
  • Michael K. Chiu
    • 1
  • Hani H. Abujudeh
    • 1
  1. 1.Department of RadiologyDetroit Medical CenterDetroitUSA

Personalised recommendations