Indian Journal of Radiology Indian Journal of Radiology  

   Login   | Users online: 1477

Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size     

 

EDITORIAL REVIEW Table of Contents   
Year : 2007  |  Volume : 17  |  Issue : 2  |  Page : 63-65
Nephrogenic systemic fibrosis and gadolinium: A matter of concern


Department of Radiology, KEM Hospital and Seth GS Medical College, Dr Acharya Dhonde Marg, Parel, Mumbai - 400 012, Maharashatra, India

Click here for correspondence address and email
 

Keywords: Gadolinium, NSF

How to cite this article:
Sanghvi DA. Nephrogenic systemic fibrosis and gadolinium: A matter of concern. Indian J Radiol Imaging 2007;17:63-5

How to cite this URL:
Sanghvi DA. Nephrogenic systemic fibrosis and gadolinium: A matter of concern. Indian J Radiol Imaging [serial online] 2007 [cited 2020 Jul 14];17:63-5. Available from: http://www.ijri.org/text.asp?2007/17/2/63/33609

   Introduction Top


There is now an overwhelming correlation in literature between gadolinium (Gd) and a rare but fatal and little known disorder called nephrogenic systemic fibrosis (NSF) that has been the subject of intense scrutiny in the radiology community worldwide, in the past few months.

In this article, we review the evidence for Gd as a cause of NSF and discuss current recommendations for its use in patients with renal failure.

It is of great importance that radiologists be aware of this serious disease and exercise caution when considering the use of Gd-based contrast media in patients with moderate (glomerular filtration rate<60 mL/min/1.73 m 2 ) to severe (glomerular filtration rate<15 mL/min/1.73 m 2 ) renal disease.


   What is NSF? Top


Nephrogenic systemic fibrosis (NSF), formerly referred to as nephrogenic fibrosing dermatopathy (NFD) is a little known fibrosing disorder that involves predominantly the skin but also affects systemic organs such as the liver, heart, lungs, diaphragm and skeletal muscle. This condition can be quite disabling because the resultant skin tightening and musculotendinous involvement cause contractures that can reduce the range of motion of joints. Some patients become severely disabled due to contractures, muscle weakness and arthralgia. [1] In addition to severe physical disability, it can also lead to death when multi-system disease supervenes. [2]

This entity was first recognized in several patients in 1997 and was first described in the literature in 2000. [3] It is a rare disease with about 200 cases reported worldwide till date. [4] Thus NSF is a largely unknown entity, likely due to the infrequency of incidence and relatively small cohort. Approximately 90% of the patients with NSF have end-stage renal disease (ESRD) and are on either hemodialysis or peritoneal dialysis. [5] The rest have chronic kidney disease (CKD) or develop NSF in the setting of acute kidney injury (AKI). Thus, underlying kidney disease is a requisite for NSF to occur. Because not all patients with kidney disease develop NSF, one must hypothesize that a trigger is required to set the "fibrosing process" into motion. [6]

There is increasing evidence that Gd-based contrast agents may be a culprit in the development of NSF in patients with renal disease. The official site of the nephrogenic fibrosing dermopathy (NFD/NSF) registry [5] states that all registry cases, in which records can be located, have at least one known exposure to Gd within two to eight weeks prior to clinical symptoms.

Gadolinium, a culprit? Is the evidence real?

It was noted that over a four year period, 20 patients in Denmark [7] and five in Austria [8] developed a very rare disease, seen only in patients with severely impaired renal function. Each one of these patients had been administered Omniscan (gadodiamide, GE Healthcare), a Gd - based MR contrast agent for MRI or MRI angiographic examination within a few weeks or months prior to the onset of the disease. Roughly 17,500 patients are examined using gadodiamide in Denmark each year. Since January 2002, about 400 patients with severely impaired renal function had been examined, of which 20 or 5%, to whom gadodiamide had been administered, eventually were diagnosed with this disease in that country.

Broome et al , [1] describe another 12 patients of renal disease who developed NSF 2-11 weeks following administration of double dose intravenous gadodiamide.

In a recent population based study, [9] Deo et al found 87 cases of ESRD who had undergone a total of 123 MRI studies with Gd during an 18-months study period from January 2005 to June 2006. Three cases of NSF were diagnosed in this population during the study period. All three cases occurred within two months of Gd exposure. Two of the three cases had a fatal course. One patient died as a direct consequence of NSF. In the other fatal case, NSF-related pulmonary fibrosis was complicated by recurrent respiratory infections and ventilatory failure. Thus, all three of the NSF cases occurred in patients after Gd exposure and no patient who had ESRD and was unexposed to Gd developed NSF. There was a highly significant association (P=0.006) between patient exposure to Gd and the subsequent development of NSF in this ESRD population. Thus according to this population-based study, the absolute risk for development of NSF was 3.4% when a member of the ESRD population received Gd.

It is interesting to note that the onset of first reported cases of NSF in 1997 coincides closely with the rapid rise in the use of high dose Gd injections for MRI and angiography in the last decade. [1] The first Medline indexed article describing the use of Gd-enhanced MRI angiography in renal patients was also published in 1997. [10] Approximately 200 worldwide cases of NSF, in those with renal impairment, have now been reported with Gd-containing MRI contrast agents, most of which are associated with the least-stable agents, [11] gadodiamide and gadoversatomide. A small number of cases have been associated with Gd-DTPA and in at least one patient, NSF was considered directly attributable to this agent.

Mechanisms:

The mechanism by which some Gd-containing contrast agents are more likely to trigger NSF than other agents is not understood fully, but is thought to be related to their different physico-chemical properties that affect the extent to which they release free Gd ions. [11],[12] Deposition of free Gd ions in tissues and organs might stimulate NSF through induction of fibrosis. [13]

Patients with severe renal impairment are at increased risk of NSF because they take longer to eliminate the contrast agent from the body - the half-life of gadodiamide increases from 1.3 hours in healthy volunteers to 34.3 hours in patients with ESRD. [14] There are no known cases of NSF in patients with normal renal function.

An overwhelming majority of renal failure patients reported in literature to have NSF attributed to Gd have been exposed to the agent gadodiamide. The gadodiamide formulation differs from most other non-tissue specific extracellular MR imaging agents by having an excess chelate (12 mg/ml) and being less stable. [15] The excess chelate is considered necessary because of the possibility of transmetallation with endogenous ions. [15] Transmetallation results in release of free Gd+++, which is extremely toxic, but it can also cause binding of other ions. Agents susceptible to transmetallation have the largest amount of excess chelate. Thus, it seems possible that transmetallation is easier with gadodiamide than with other Gd-based contrast agents. [16] Of course, transmetallation is more likely to occur when Gd-based agents remain inside the body for a long period as is the case in patients with renal failure. [17] Whether transmetallation plays a crucial role in the development of NSF in patients with renal failure remains unproven. [7]

Recommendations

The American College of Radiology (ACR) guidance document for safe MR practices dated June 2007 [18] recommends no special treatment or handling for kidney patients with stage 1 or stage 2 chronic kidney disease (defined as presence of kidney damage with GFR > 90 mL/min/1.73m 2 or GFR between 60 and 89 mL/min/1.73m 2) . The only exception to this is that patients with any level of renal disease should not receive gadodiamide for their contrast-enhanced MR examinations. [15] It is recommended that all requests for MRI be pre-screened, with an additional question inquiring about the presence of a history of "kidney disease or dialysis". The ACR guidelines recommend that for all patients with stage 3, 4 or 5 kidney disease or those with acute kidney disease (AKI) one must consider refraining from administering any Gd agent unless a risk-benefit assessment for that particular patient indicates that the benefit of doing so would clearly outweigh the potential risk(s).

There is no data to determine the utility of dialysis to prevent or treat NSF in patients with decreased renal function who receive Gd agents. However, prompt dialysis of these patients will eliminate circulating Gd, with average Gd excretory rates of 78%, 96% and 99% in the first to third hemodialysis sessions, respectively. [19]

Finally, it is recommended that for all patients identified as having moderate to severe kidney disease in whom Gd has to be administered, informed consent should be taken, when practical, with a review of known risks and benefits as well as the possible availability of alternative imaging modalities if any.


   Conclusions Top


Based on a few reports of Gd causing NSF in patients with renal failure, in August 2006, all members of the European Society of Urogenital Radiology (ESUR) received an electronic mail asking them to report cases of NSF. In Europe, it turned out that all patients who developed NSF had gadodiamide within a few weeks of developing NSF. In the United States, the overwhelming majority of patients who had a Gd agent had gadodiamide.Based on the obtained information, it was striking that many radiologists were unaware that NSF may be a serious late adverse reaction to Gd-based contrast media despite the fact that the Food and Drug Administration (FDA) issued a warning on 08 June 2006. [20] Furthermore, the warning from the vendor of gadodiamide, issued on 06 June 2006, [21] had not been distributed in several countries. No other vendors have issued a warning.

Based on the data available in literature, there is compelling evidence linking Gd to the development of NSF in patients with renal failure. It is of great importance that radiologists be aware of this serious disease and exercise caution when considering the use of Gd-based contrast media in patients with moderate (glomerular filtration rate < 60 mL/min/1.73 m 2 ) to severe (glomerular filtration rate < 15 mL/min/1.73 m 2 ) renal disease.

 
   References Top

1.Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic fibrosis: Why radiologists should be concerned. AJR Am J Roentgenol 2007;188:586-92.  Back to cited text no. 1    
2.Galan A, Cowper SE, Bucala R. Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy). Curr Opin Rheumatol 2006;18:614-7.  Back to cited text no. 2    
3.Cowper SE, Robin HS, Steinberg HM, Su LD, Gupta S, Leboit PE. Scleromyxedema-like cutaneous disease in renal-dialysis patients. Lancet 2000;356:1000-1.  Back to cited text no. 3    
4.Farlow JT. The enigma of nephrogenic systemic fibrosis. Nephrol Nurs J 2007;34:80-1.  Back to cited text no. 4    
5.Cowper SE: Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001-2006. Available from: http://www.icnfdr.org. [Last accessed on 2006 Dec 26].  Back to cited text no. 5    
6.Perazella MA. Nephrogenic systemic fibrosis, kidney disease and gadolinium: Is there a link? Clin J Am Soc Nephrol 2007;2:200-2.  Back to cited text no. 6    
7.Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, et al . Nephrogenic systemic fibrosis: Suspected causative role of Gadolinium. J Am Soc Nephrol 2006;17:2359-62.  Back to cited text no. 7    
8.Grobner T. Gadolinium a specific trigger for the development of nephrogenic fibrosing dermatopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006;21:1104-8.  Back to cited text no. 8    
9.Deo A, Fogel M, Cowper SE. Nephrogenic systemic fibrosis: A population study examining the relationship of disease development to Gadolinium exposure. Clin J Am Soc Nephrol 2007;2:264-7.  Back to cited text no. 9    
10.Johnson DB, Lerner CA, Prince MR, Kazanjian SN, Narasimham DL, Leichtman AB, et al . Gadolinium-enhanced magnetic resonance angiography of renal transplants. Magn Reson Imaging 1997;15:13-20.  Back to cited text no. 10    
11.Idιe JM, Port M, Schaefer M, Le Greneur S, Corot C. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: A review. Fundam Clin Pharmacol 2006;20:563-76.  Back to cited text no. 11    
12.Thomsen HS, Morcos SK, Dawson P. Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? Clin Radiol 2006;61:905-6.  Back to cited text no. 12    
13.Morcos SK. Nephrogenic systemic fibrosis following the administration of extracellular gadolinium based contrast agents: Is the stability of the contrast agent molecule an important factor in the pathogenesis of this condition? Br J Radiol 2007;80:73-6.  Back to cited text no. 13    
14.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.  Back to cited text no. 14    
15.Thomsen HS; European Society of Uroenital Radiology. European Society of Uroenital Radiology guidelines in contrast media application. Curr Opin Urol 2007;17:70-6.  Back to cited text no. 15    
16.Behra-Miellet J, Gressier B, Brunet C, Dine T, Luyckx M, Cazin M, 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;18:437-42.  Back to cited text no. 16    
17.Thomsen HS.NSF: A serious late reaction to NSF. Eur Radiol 2006;16:2619-21.  Back to cited text no. 17    
18.Kanal E, Barkovich JA, Bell C, Borgstede JP, Bradley WG Jr, Froelich JW, et al . ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol 2007;188:1447-74.  Back to cited text no. 18    
19.Okada S, Katagiri K, Kumazaki T, Yokoyama H. Safety of gadolinium contrast agent in hemodialysis patients. Acta Radiol 2001;42:339-41.  Back to cited text no. 19    
20.Food and Drug Administration. Public Health Advisory: gadolinium containing contrast agents for magnetic resonance imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance and MultiHance. 2006. Available from: http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm.th   Back to cited text no. 20    
21.Flaten H. (GE Healthcare) (2006). Dear Healthcare Professional. Available from: .  Back to cited text no. 21    

Top
Correspondence Address:
Darshana A Sanghvi
2nd Floor, Gopal Dham, Ash Lane, Gokhale Road (North), Dadar, Mumbai
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-3026.33609

Rights and Permissions




 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  


    Introduction
    What is NSF?
    Conclusions
    References

 Article Access Statistics
    Viewed5377    
    Printed1178    
    Emailed2    
    PDF Downloaded634    
    Comments [Add]    

Recommend this journal