Medicine:Nephrogenic systemic fibrosis

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Nephrogenic systemic fibrosis
Other namesNSF
Causesiatrogenic disease caused by exposure to gadolinium-based contrast agents
Risk factorsimpaired kidney function is the major risk factor

Nephrogenic systemic fibrosis is a rare syndrome that involves fibrosis of skin, joints, eyes, and internal organs. NSF is caused by exposure to gadolinium in gadolinium-based MRI contrast agents (GBCAs) in patients with impaired kidney function.[1][2] Epidemiological studies suggest that the incidence of NSF is unrelated to gender or ethnicity and it is not thought to have a genetic basis.[2][3] After GBCAs were identified as a cause of the disorder in 2006,[4] and screening and prevention measures put in place, it is now considered rare.[5]

Signs and symptoms

Clinical features of NSF develop within days to months following exposure to GBCA. The main symptoms are the thickening and hardening of the skin associated with brawny hyperpigmentation, typically presenting in a symmetric fashion. The skin gradually becomes fibrotic and adheres to the underlying fascia.[6][7] The symptoms initiate distally in the limbs and progress proximally, sometimes involving the trunk.[6] Joint contractures of the fingers, elbows and knees can develop secondary to skin involvement and can severely impair physical function.[6][8] While skin involvement is on the foreground, the process may involve any organ, e.g., the eye,[8] heart, diaphragm, pleura, pericardium, and kidneys,[6][9] as well as the lungs and liver.[10][11]

Causes

NSF is an iatrogenic disease caused by exposure to gadolinium-based contrast agents used in magnetic resonance imaging.[12]

Risk factors

Impaired kidney function reduces the clearance of GBCAs and is the major risk factor for the development of NSF. The etiology or duration of renal failure seems not to be relevant, but NSF risk greatly depends on the residual kidney function.[7] The majority of NSF cases have been identified in patients with stage 5 CKD,[8] but NSF has also developed in patients with stage 4 and 3 CKD, and those with acute kidney injury, even if kidney function subsequently returned to normal following GBCA administration.[13][14] Thus NSF should be considered as a differential diagnosis in any patient who has been exposed to a GBCA, regardless of the kidney function level.[8]

Three GBCAs have been principally implicated in NSF: gadodiamide, gadopentetate dimeglumine, and gadoversetamide, though cases have been reported with majority of GBCAs on the market.[15] High doses in individual GBCA administrations and high cumulative doses of GBCA over the lifetime of patients with renal dysfunction are associated with increased risk of NSF.[7]

Mechanism

De-chelation of Gd(III) is responsible for the toxicity associated with gadolinium complexes such as GBCAs, and the toxicity appears to be a consequence of Zn2+, Cu2+, and Ca2+ transmetallation in vivo.[12][15] This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd(III) complexes, all become lethally toxic when they release precisely the same quantity of Gd(III).[16] It is also supported by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn2+ deficiency.[16] Under the transmetallation hypothesis, we can expect that subtle changes in formulation can affect the intrinsic safety of gadolinium complexes, which is indeed observed.[12][15]

Diagnosis

There is no specific imaging finding for NSF, and the diagnosis is a clinicopathological one, based on presentation and histological findings.[7]

Microscopic pathology

At the microscopic level, NSF shows a proliferation of dermal fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and deposits of mucin.[17] More recent case reports have described the presence of sclerotic bodies (also known as elastocollagenous balls) in skin biopsies from NSF patients. While not universally present, this finding is believed to be unique to patients exposed to gadolinium, although not necessarily limited to areas involved by NSF.[18][19][20]

Differential diagnosis

The differential diagnoses for NSF include diffuse cutaneous or limited cutaneous systemic sclerosis, scleromyxedema, lipodermatosclerosis, scleroedema diabeticorum, graft versus host disease, eosinophilic fasciitis; eosinophilia-myalgia syndrome; porphyria cutanea tarda, and other disorders. The nearly universal absence of facial skin involvement in NSF, presence of yellow plaques on the sclera of the eyes, absence of Raynaud’s phenomenon, and other differences in presentation can aid the proper diagnosis. History of exposure to GBCAs would favor NSF as the differential diagnosis.[6][8]

Prevention

The only known measure for prevention of NSF is the non-use or cautious use of GBCAs in patients with renal impairment, including preferential use of safer, macrocyclic GBCAs. Performing dialysis immediately after the MRI exam is recommended for patients already in dialysis treatment, but there is no evidence for introducing dialysis in non-dialytic patients for prevention of NSF.[6] Screening for impaired kidney function is routinely conducted and has drastically reduced the incidence of NSF.[5]

Treatment

Multiple therapies for NSF have been attempted, with variable clinical improvement. None have been as effective as restoration of kidney function. Restoration of kidney function by treating the underlying disease process, recovery from acute kidney injury (AKI), or performing a kidney transplant can slow or hold the progression of NSF. A few cases of curative kidney transplantation have been reported, and it is appropriate to consider transplantation as treatment.[6][7]

Epidemiology

NSF affects males and females in approximately equal numbers and has been reported in patients of different ethnic and geographic regions. It most often affects middle-aged individuals, but there are reports of cases occurring from childhood to senescence.[6][7]

History

This condition was originally termed “nephrogenic fibrosing dermopathy” as initially only skin involvement in patients with impaired kidney function was observed, and later renamed “nephrogenic systemic fibrosis” to better describe its systemic nature.[12] The term "gadolinium-associated systemic fibrosis" has also been proposed to reflect the fact that impaired kidney function is not in itself the cause of NSF.[12]

The first cases of NSF were identified in 1997,[21] but it was first described as an independent disease entity in 2000.[22] In 2006, the link between NSF and gadolinium-based MRI contrast agents was made.[4][23][24] As a result, restrictions on use of GBCAs in patients with an estimated glomerular filtration rate (a measure of kidney function) under 60 and especially under 30 mL/min/1.73 m2 have been recommended and NSF is now considered rare.[5]

After several years of controversy, during which up to 100 Danish patients suffered gadolinium poisoning after use of the contrast agent Omniscan, the Norwegian medical company Nycomed admitted that they were aware of some dangers from using gadolinium-based agents in their product.[25]

With both Gadopentetic acid (gadopentetate dimegulumine (Magnevist)) and Gadodiamide (Omniscan) the risk was considered to outweigh the benefits and, as a result, the EMA recommended the licence for intravenous gadopentetic acid and Gadodiamide be suspended.[26]

Following a legally binding decision issued by The European Commission and applicable in all EU Member States (Commission decision date: 23/11/2017), Intravenous Magnevist and Omniscan is now no longer authorised for use in Europe. Magnavist is, however, still authorised in Europe as an intra-articular MR contrast medium. The authorised indication for the use of linear chelated media gadobenic acid (also known as gadobenate dimeglumine; MultiHance) and gadoxetic acid (Primovist) has been limited to delayed phase liver imaging only. [27]

References

  1. "Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Medium Safety Committee guidelines". European Radiology 23 (2): 307–18. February 2013. doi:10.1007/s00330-012-2597-9. PMID 22865271. 
  2. 2.0 2.1 "Nephrogenic systemic fibrosis: history and epidemiology". Radiologic Clinics of North America 47 (5): 827–31, vi. September 2009. doi:10.1016/j.rcl.2009.05.003. PMID 19744597. 
  3. "Nephrogenic systemic fibrosis: clinical spectrum of disease". Journal of Magnetic Resonance Imaging 30 (6): 1289–97. December 2009. doi:10.1002/jmri.21975. PMID 19937929. 
  4. 4.0 4.1 "Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?". Nephrology, Dialysis, Transplantation 21 (4): 1104–8. April 2006. doi:10.1093/ndt/gfk062. PMID 16431890. 
  5. 5.0 5.1 5.2 "Gadolinium-Based Contrast Agents in Kidney Disease: A Comprehensive Review and Clinical Practice Guideline Issued by the Canadian Association of Radiologists". Canadian Journal of Kidney Health and Disease 5: 2054358118778573. 2018. doi:10.1177/2054358118778573. PMID 29977584. 
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 "Nephrogenic systemic fibrosis: concepts and perspectives". Anais Brasileiros de Dermatologia 87 (4): 597–607. 2012. doi:10.1590/S0365-05962012000400013. PMID 22892775. 
  7. 7.0 7.1 7.2 7.3 7.4 7.5 "Current status of nephrogenic systemic fibrosis". Clinical Radiology 69 (7): 661–8. July 2014. doi:10.1016/j.crad.2014.01.003. PMID 24582176. 
  8. 8.0 8.1 8.2 8.3 8.4 "Nephrogenic systemic fibrosis: a systemic fibrosing disease resulting from gadolinium exposure". Best Practice & Research. Clinical Rheumatology 26 (4): 489–503. August 2012. doi:10.1016/j.berh.2012.07.008. PMID 23040363. 
  9. "Safety of magnetic resonance contrast media: a review with special focus on nephrogenic systemic fibrosis". Topics in Magnetic Resonance Imaging 24 (1): 57–65. February 2015. doi:10.1097/RMR.0b013e3182a14e79. PMID 25654421. 
  10. "Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis with diaphragmatic involvement in a patient with respiratory failure". Journal of the American Academy of Dermatology 54 (2 Suppl): S31–4. February 2006. doi:10.1016/j.jaad.2005.04.024. PMID 16427988. 
  11. "Nephrogenic systemic fibrosis with multiorgan involvement in a teenage male after lymphoma, Ewing's sarcoma, end-stage renal disease, and hemodialysis". Pediatric and Developmental Pathology 10 (5): 395–402. 2007. doi:10.2350/06-05-0093.1. PMID 17929984. 
  12. 12.0 12.1 12.2 12.3 12.4 "Pathophysiology of gadolinium-associated systemic fibrosis". American Journal of Physiology. Renal Physiology 311 (1): F1–F11. July 2016. doi:10.1152/ajprenal.00166.2016. PMID 27147669. 
  13. "Gadolinium-induced nephrogenic systemic fibrosis in a patient with an acute and transient kidney injury". The British Journal of Dermatology 158 (3): 607–10. March 2008. doi:10.1111/j.1365-2133.2007.08369.x. PMID 18076707. 
  14. "Nephrogenic systemic fibrosis following acute kidney injury and exposure to gadolinium". Indian Journal of Medical Sciences 64 (1): 33–6. January 2010. doi:10.4103/0019-5359.92485. PMID 22301807. 
  15. 15.0 15.1 15.2 "Gadolinium-based contrast agents: A comprehensive risk assessment". Journal of Magnetic Resonance Imaging 46 (2): 338–353. August 2017. doi:10.1002/jmri.25625. PMID 28083913. 
  16. 16.0 16.1 "The relationship between thermodynamics and the toxicity of gadolinium complexes". Magnetic Resonance Imaging 8 (4): 467–81. 1990. doi:10.1016/0730-725X(90)90055-7. PMID 2118207. 
  17. "Nephrogenic Systemic Fibrosis". Emedicine. 2019-02-02. http://www.emedicine.com/DERM/topic934.htm. 
  18. "Sclerotic bodies beyond nephrogenic systemic fibrosis". Journal of Cutaneous Pathology 40 (9): 812–7. September 2013. doi:10.1111/cup.12187. PMID 23808625. 
  19. "Sclerotic bodies in nephrogenic systemic fibrosis: a new histopathologic finding". Journal of Cutaneous Pathology 36 (5): 548–52. May 2009. doi:10.1111/j.1600-0560.2008.01111.x. PMID 19476523. 
  20. "The evolution of osseous metaplasia in localized cutaneous nephrogenic systemic fibrosis: a case report". The American Journal of Dermatopathology 31 (7): 674–81. October 2009. doi:10.1097/dad.0b013e3181a1fb55. PMID 19633532. 
  21. "Nephrogenic fibrosing dermopathy: the first 6 years". Current Opinion in Rheumatology 15 (6): 785–90. November 2003. doi:10.1097/00002281-200311000-00017. PMID 14569211. 
  22. "Scleromyxoedema-like cutaneous diseases in renal-dialysis patients". Lancet 356 (9234): 1000–1. September 2000. doi:10.1016/S0140-6736(00)02694-5. PMID 11041404. 
  23. "Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging". Journal of the American Society of Nephrology 17 (9): 2359–62. September 2006. doi:10.1681/ASN.2006060601. PMID 16885403. 
  24. Centers for Disease Control and Prevention (CDC) (February 2007). "Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents--St. Louis, Missouri, 2002-2006". MMWR. Morbidity and Mortality Weekly Report 56 (7): 137–41. PMID 17318112. 
  25. "Nyhedsavisen: Medicinalfirma fortiede at stof var farligt". http://avisen.dk/medicinalfirma-fortiede-at-stof-var-farligt_6742.aspx. 
  26. "Gadolinium-containing contrast agents". 2018-09-17. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Gadolinium-containing_contrast_agents/human_referral_prac_000056.jsp&mid=WC0b01ac05805c516f. 
  27. "Gadolinium-containing contrast agents: Removal of Omniscan and iv Magnevist, restrictions to the use of other linear agents". https://www.gov.uk/drug-safety-update/gadolinium-containing-contrast-agents-removal-of-omniscan-and-iv-magnevist-restrictions-to-the-use-of-other-linear-agents. 

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