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Group 2 gadolinium-based contrast agents seem to be safe even for patients with chronic kidney disease

(15.12.2019)


Background:
Nephrogenic systemic fibrosis (NSF) is a rare disorder that has been observed in some patients with impaired renal function after exposure to a gadolinium-based contrast agent (GBCA) for magnetic resonance imaging (MRI). The characteristic features of NSF include diffuse skin thickening and fibrosis. In severe cases, systemic involvement may affect the heart, lungs, liver, and skeletal muscle. The lesions are irreversible, progressive, and sometimes fatal. After GBCAs were identified as a cause of the disorder in 2006, rule makers in Europe banned some of the less stable agents from the marked, while in the US the Food and Drug Administration (FDA) issued an advisory about the association of GBCAs and NSF in 2006 and subsequently issued a black box warning in 2007, instructing physicians to avoid the use of all GBCAs in patients at risk for NSF.

Given that kidney failure greatly increases the elimination half-life of GBCAs, it was postulated that gadolinium ions dissociate from their underlying binding ligand during the prolonged retention period, allowing tissue deposition and the eventual development of NSF. In 2010 FDA updated its gadolinium warning, specifying that 3 agents (gadopentetate dimeglumine, gadodiamide, and gadoversetamide) were responsible for most cases of NSF and therefore contraindicated in CKD . In the same update, the FDA stated that other GBCAs could be used cautiously under certain circumstances. Since screening and prevention measures have been put in place, NSF is now considered rare. Anyhow, the risk for NSF to individual patients remains poorly understood.

 
The new study:
With this in mind, Woolen and colleagues assessed the incidence of NSF in patients with stage 4 or 5 CKD after exposure to a group II GBCA (gadobenate dimeglumine, gadobutrol, gadoterate meglumine, or gadoteridol). The researchers screened the literature for related studies, and excluded from the found citations (in total 2700) conference abstracts, retracted manuscripts, narrative reviews, editorials, case reports and all studies not reporting group II GBCA administration.

In total, sixteen unique studies with 4931 patients were finally included in this systematic review and meta-analysis. Most of the 16 studies were conducted in Europe (8 of 16; 50%) and the United States (7 of 16; 44%). Seven (44%) were multicenter studies.

The pooled incidence of NSF across all studies was 0 of 4931 (0%; upper bound of 95% CI, 0,07%). The authors conclude that "these data support recent updates to ACR [American College of Radiology] and European Society of Urogenital Radiology guidelines liberalizing use of low-risk GBCAs for indicated examinations" for patients with stage 4 or 5 CKD.

Commentary:
It has been reported, that some patients have developed NSF after extended time following administration of GBCA (up to 8 years !). Also, the guidelines to exclude patients at risk from the use of GBCA may have systematically excluded the highest risk patients from the studied group of patients. It therefore seems reasonable to continue to apply safety rules such as:
only use the lowest possible dose, avoid repeated exposure, and patients treated with hemodialysis receive it shortly after GBCA administration.

For the researchers working in the field there are still a lot of questions to be answered:
  • What is the reason for gadolinium retention in the human body ?
  • What is the gadolinium species retained ?
  • What is triggering the degradation of the GBCA ?
  • What are the health effects related to retained gadolinium ?
These are only some of the questions that need to be addressed for obtaining a full understanding of the effects observed around the administration of GBCAs.
Michael Sperling




The original publication:

Sean A. Woolen, Prasad R. Shankar, Joel J. Gagnier, Mark P. MacEachern, Lisa Singer, Matthew S. Davenport, Risk of Nephrogenic Systemic Fibrosis in Patients With Stage 4 or 5 Chronic Kidney Disease Receiving a Group II Gadolinium-Based Contrast Agent A Systematic Review and Meta-analysis, JAMA Inter. Med. (2019) DOI: 10.1001/jamainternmed.2019.5284




Related studies

L.K. Young, S.Z. Matthew, J.G. Houston, Absence of potential gadolinium toxicity symptoms following 22,897 gadoteric acid (Dotarem®) examinations, including 3,209 performed on renally insufficient individuals. Eur. Radiol., 29/4 (2019) 1922-1930. DOI: 10.1007/s00330-018-5737-z

Y. Tsushima, K. Awai, G. Shinoda, H. Miyoshi, M. Chosa, T. Sunaya, J. Endrikat, Post-marketing surveillance of gadobutrol for contrast-enhanced magnetic resonance imaging in
Japan
. Jpn. J. Radiol., 36/11 (2018) 676-685. DOI: 10.1007/s11604-018-0778-4

H.J. Michaely, M. Aschauer, H. Deutschmann, G. Bongartz, M. Gutberlet, R. Woitek, B. Ertl-Wagner, W. Kucharczyk, R. Hammerstingl, F. De Cobelli, M. Rosenberg, T. Balzer, J. Endrikat, Gadobutrol in renally impaired patients: results of the GRIP study. Invest. Radiol., 52/1 (2017) 55-60. DOI: 10.1097/RLI.0000000000000307

P. Soyer, A. Dohan, D. Patkar, A. Gottschalk, Observational study on the safety profile of gadoterate meglumine in 35,499 patients: the SECURE study. J. Magn. Reson. Imaging., 45/4 (2017) 988-997. DOI: 10.1002/jmri.25486

R. Bruce, A.L. Wentland, A.K. Haemel, R.W. Garrett, D.R. Sadowski, A. Djamali, E.A. Sadowski, Incidence of nephrogenic systemic fibrosis using gadobenate dimeglumine in 1423 patients with renal insufficiency compared with gadodiamide. Invest Radiol., 51/11 (2016) 701-705. DOI: 10.1097/RLI.0000000000000259

S.B. Nandwana, C.C. Moreno, M.T. Osipow, A. Sekhar, K.L. Cox. Gadobenate dimeglumine administration and nephrogenic systemic fibrosis: is there a real risk in patients with impaired renal function? Radiology., 276/3 (2015) 741-747. DOI: 10.1148/radiol.2015142423

E. Smorodinsky, D.S. Ansdell, Z.W. Foster, S.M. Mazhar, I. Cruite, T. Wolfson, S.B. Sugay, G. Iussich, M. Shiehmorteza, Y. Kono, A. Kuo, C.B. Sirlin, Risk of nephrogenic systemic fibrosis is low in patients with chronic liver disease exposed to gadolinium-based contrast agents. J. Magn. Reson. Imaging., 41/5 (2015) 1259-1267. DOI: 10.1002/jmri.24650

G. Soulez, D.C. Bloomgarden, N.M. Rofsky, M.P. Smith, H.H. Abujudeh,  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., 205/3 (2015) 469-478. DOI:10.2214/AJR.14.14268

S. Amet, V. Launay-Vacher, O. Clément,  C. Frances, A. Tricotel, B. Stengel, J.-Y. Gauvrit, N. Grenier, G. Reinhardt, N. Janus, G. Choukroun, M. Laville, G. Deray, Incidence of nephrogenic systemic fibrosis in patients undergoing dialysis after contrast-enhanced magnetic resonance imaging with gadolinium-based contrast agents: the Prospective Fibrose Nephrogénique Systémique study. Invest. Radiol., 49/2 (2014) 109-115. DOI: 10.1097/RLI.0000000000000000

A. Alhadad, G. Sterner, Å. Svensson, H. Alhadad, P. Leander, Incidence of nephrogenic systemic fibrosis at a large university hospital in Sweden. Scand. J. Urol. Nephrol., 46/1 (2012) 48-53. DOI: 10.3109/00365599.2011.621142

D.R. Martin, S.K. Krishnamoorthy, B. Kalb, K.N. Salman, P. Sharma, J.D. Carew, P.A. Martin, A.B. Chapman, G.L. Ray, C.P. Larsen, T.C. Pearson, Decreased incidence of NSF in patients on dialysis after changing gadolinium contrast-enhanced MRI protocols. J Magn Reson Imaging., 31/2 (2010) 440-446. DOI:10.1002/jmri.22024

C. Chrysochou, A. Power, A.E. Shurrab, S. Husain, S. Moser, J. Lay, A.D. Salaman, P.A. Kalra, Low risk for nephrogenic systemic fibrosis in nondialysis patients who have chronic kidney disease and are investigated with gadolinium-enhanced magnetic resonance imaging. Clin. J. Am. Soc. Nephrol., 5/3 (2010) 484-489. DOI:10.2215/CJN.06580909

G. Heinz-Peer, A. Neruda, B. Watschinger, A. Vychytil, A. Geusau, M. Haumer, M. Weber, Prevalence of NSF following intravenous gadolinium-contrast media administration in dialysis patients with endstage renal disease. Eur. J. Radiol., 76/1 (2010) 129-134. DOI:10.1016/j.ejrad.2009.06.028

N. Janus, V. Launay-Vacher, S. Karie, O. Clement, E. Ledneva, C. Frances, G. Choukroun, G. Deray, Prevalence of nephrogenic systemic fibrosis in renal insufficiency patients: results of the FINEST study. Eur. J. Radiol., 73/2 (2010) 357-359. DOI: 10.1016/j.ejrad.2008.11.021

H.H. Abujudeh, H. Rolls, R. Kaewlai, S. Agarwal, Z.A. Gebreananya, S. Saini, P.W. Schaefer, J. Kay, 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 formagnetic resonance examination in renally impaired patients. J Magn Reson Imaging., 30/6 (2009) 1335-1340. DOI:10.1002/jmri.21976

R.F. Reilly, Risk for nephrogenic systemic fibrosis with gadoteridol (ProHance) in patients who are on long-term hemodialysis. Clin. J. Am. Soc. Nephrol., 3/3 (2008) 747-751. DOI: 10.2215/CJN.05721207



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October 29, 2012: Identification and quantification of potential metabolites of Gd-based contrast agents 
October 18, 2012: The behavior of Gd-based contrast agents during wastewater treatment
September 15, 2010: US FDA Announces Gadolinium-Based MRI Contrast Agent Warning
July 22, 2010: Nanoscale Metal-Organic Frameworks (NMOFs): A new way to create better MRI Contrast Agents
March 25, 2010: Publication on the separation of Gd-based contrast agents awarded
May 4, 2009: Gadolinium speciation analysis in search for the cause of nephrogenic systemic fibrosis (NSF)
April 17, 2009: Gadolinium-based MRI contrast agents found intact in the outlet of a waste water treatment plant


last time modified: December 15, 2019




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