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NSF a Late Adverse Reaction

NSF a Late Adverse Reaction

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Published by gasfgd
Time has shown that two factors are important: (1) reduced renal function and (2) exposure to one of the less stable gadolinium based contrast agents….

The following co-factors have been suggested: high doses of EPO, metabolic acidosis, iron and ferritin, chronic inflammation, hypercoagulability, thrombotic events, recent vascular surgery, recent renal transplant failure, recent surgery, anion gap, or increased phosphate.
Time has shown that two factors are important: (1) reduced renal function and (2) exposure to one of the less stable gadolinium based contrast agents….

The following co-factors have been suggested: high doses of EPO, metabolic acidosis, iron and ferritin, chronic inflammation, hypercoagulability, thrombotic events, recent vascular surgery, recent renal transplant failure, recent surgery, anion gap, or increased phosphate.

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Published by: gasfgd on Jul 04, 2012
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Cancer Imaging 
130137DOI: 10.1102/1470-7330.2007.0019
Nephrogenic systemic fibrosis (NSF): a late adversereaction to some of the gadolinium based contrast agents
Henrik S. Thomsen
, Peter Marckmann
and Vibeke B. Logager
 Department of Diagnostic Radiology and 
 Department of Nephrology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark;
 Department of Diagnostic Sciences, Faculty of Health Sciences,University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark Corresponding address: Professor Henrik S. Thomsen, MD, Department of Diagnostic Radiology 54E2,Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark. Email:
Data accepted for publication 23 July 2007
Until recently it was believed that extracellular gadolinium based contrast agents were safe for both the kidneys and allother organs within the dose range up to 0.3mmol/kg body weight. However, in 2006, it was demonstrated that somegadolinium based contrast agents may trigger the development of nephrogenic systemic fibrosis, a generalised fibroticdisorder, in renal failure patients. Accordingly, the use of gadodiamide and gadopentate dimeglumine for renal failurepatients was banned in Europe in spring 2007. The same two compounds should only be used cautiously in patientswith moderate renal dysfunction. The current paper reviews the situation (July 2007) regarding gadolinium basedcontrast agent and the severe delayed reaction to some of these agents. The fear of nephrogenic systemic fibrosisshould not lead to a denial of a well indicated enhanced magnetic resonance imaging examination.
Gadolinium based contrast agents; late adverse reactions; nephrogenic systemic fibrosis.
Magnetic resonance imaging (MRI) contrast media areused to improve visualisation of abnormal structures orlesions in various parts of the body. The most commonMRI contrast media are based on paramagnetic com-pounds that contain metal ions from the transition orlanthanide series of the periodic table such as manga-nese, iron and gadolinium. These metal ions have alarge magnetic moment and can shorten the longitudinal(T1) and transverse (T2) relaxation times of protons inthe water of tissues. The lanthanide metal ion gadoliniumhas the strongest effect of all elements on T1 relationtime because it has seven unpaired electrons.Gadolinium alone is highly toxic in vivo because it isdistributed to bone, lymph nodes and the liver, whereit rapidly produces liver necrosis. It obstructscalcium ion passage through muscle cells (reducing neu-romuscular transmission), and interferes with intracel-lular enzymes and cell membranes by the process of transmetallation, a phenomenon whereby Gd
replacesendogenous metals such as zinc and copper. To preventthe harmful effects of Gd
, and make it usable inhumans, Gd
needs to sequestered by non-toxic sub-stances. At the same time its contrast enhancementmust be maintained. These two goals are achieved by binding Gd
to another agent, known generally as achelate. Chelates are large organic molecules thatform a more or less stable complex around the Gd
.The gadolinium ion has nine coordination sites, of whicheight are used for binding with the chelate. The variousgadolinium chelates have different physico-chemicalproperties (Table 1), including bonds between the gado-linium atom and the ligands which are of different sta-bility. Bonds between carboxyl groups and aminonitrogen atoms and the gadolinium ion are the strongest,whereas bonds involving amide carbonyl atoms are theweakest.Since early 2006 evidence has accumulated thatsome gadolinium based contrast agents, particularly 
This paper is available online at http://www.cancerimaging.org. In the event of a change in the URL address, please use the DOIprovided to locate the paper.
2007 International Cancer Imaging Society 
gadodiamide (Omniscan
, GE Healthcare, ChalfontSt. Giles, UK), may cause a potentially devastating oreven fatal scleroderma-like, fibrosing condition callednephrogenic systemic fibrosis (NSF) in patients withrenal failure
. Recently it has been shown that gado-pentetate dimeglumine (Magnevist
, Bayer Schering,Berlin, Germany) may also trigger NSF, but apparently not with the same high frequency as gadodiamide. TheEuropean Medicines Agency has decided that the use of both agents in patients with a glomerular filtration ratebelow 30ml/min per 1.72m
(CKD 4 and 5) is contra-indicated and that they should be used only with cautionin patients with moderately reduced kidney function(3060ml/min per 1.72m
(CKD 3)). In the UScases of NSF have been reported after exposure to gado- versetamide (OptiMARK 
, Covidien, St. Louis, USA).NSF has not been reported after gadoterate meglumine,gadoteridol, gadobenate dimeglumine or gadobutrol.Some of these agents have been used in many patientsin imaging departments serving nephrology centres.However, an absence of reports does not mean that itis impossible that they could induce NSF, but rathersuggests that the risk is significantly lower than for exam-ple after gadodiamide. In this review the current situation(July 2007) is presented.
NSF was first described in San Diego, California, USA,in 1997 as an idiopathic skin condition characterized by thickening and hardening of the skin of the extremitiesand sometimes the trunk, with an increase in the numberof dermal fibroblast-like cells associated with collagenremodelling and mucin deposition.The typical patient is middle-aged and has end-stagerenal disease (ESRD). Most, but not all, reportedpatients are on regular dialysis treatment. The firstsigns of NSF may be seen within hours of exposure togadolinium based contrast agents, but may occur as lateas 3 months after exposure. Typically, the conditionbegins with subacute swelling of distal extremities fol-lowed in subsequent weeks by severe skin indurationand sometimes extension to involve the thighs, forearms,and lower abdomen. The skin induration may be aggres-sive and associated with constant pain, muscle restless-ness, and loss of skin flexibility. In some cases, NSF leadsto serious physical disability including becoming wheel-chair bound. For many patients, the skin thickening inhi-bits the flexion and extension of joints, resulting incontractures. Those severely affected may be unable towalk or fully extend the upper and lower limb joints.Complaints of muscle weakness are common, and deepbone pain in the hips and ribs has been described.Radiography may show calcification of soft tissue.NSF was initially observed in and thought to affect theskin only, so it was called nephrogenic fibrosing dermo-pathy (NFD), but it is now known that it may involveorgans such as the liver, lungs, muscles and heart.Involvement of internal organs may explain the suspectedincreased mortality of NSF patients. About 50% of patients have a progressive severe disease course. NSFmay contribute to death by causing scarring of bodorgans (which impairs normal function), by restrictingeffective ventilation, or by restricting movement leadingto falls which may cause fractures or haemorrhage. Otherpatients have died as a result of renal disease or transplantsurgery. Eighteen month mortality was increased signifi-cantly as compared to those without NSF (40% versus16%, respectively), with an adjusted hazard ratio of 2.9(95% CI 1.36.5),
0.008) in one study from Boston.However, it is difficult in this high-risk group to differen-tiate deaths duetocomplications ofthe underlying diseaseand its treatment from those due to NSF.InseveralstudiestheincidenceofNSFafterexposuretogadodiamide has been reported to be between 3 and 7% inpatients with reduced renal function. In CKD 5 patients(GFR less than 15ml/min per 1.72m
) it may be closer to20%. The incidence after gadopentetate dimeglumine andgadoversetamide is unknown. Only one centre hasreported a large number (
10) of NSF cases after gado-pentetate dimeglumine, whereas many centres, includingour own, have reported more than 10 cases after gadodia-mide. This difference is not just a reflection of the marketshare of the two products because gadopentetate dimeglu-mine has been administered to as many as 45 times thenumber of patients that have had gadodiamide.
Table 1 The various gadolinium based agents
Brand name Generic name Acronym ChemicalstructureCharge Eliminationpathway ProteinbindingCasesof NSF
Omniscan Gadodiamide Gd-DTPA-BMA Linear Non-ionic Kidney None YesOptiMARK 
Gadoversetamide Gd-DTPA-BMEA Linear Non-ionic Kidney None YesMagnevist Gadopentetate dimeglumine Gd-DTPA Linear Ionic Kidney None YesMultiHance Gadobenate dimeglumine Gd-BOPTA Linear Ionic 97% kidney, 3% bile
5% NoPrimovist Gadoxetic acid disodium salt Gd-EOB-DTPA Linear Ionic 50% kidney, 50% bile
15% No Vasovist Gadofosveset trisodium Gd-DTPA Linear Ionic 91% kidney, 9% bile
85% NoProHance Gadoteridol Gd-HP-DO3A Cyclic Non-ionic Kidney None NoGadovist Gadobutrol Gd-BT-DO3A Cyclic Non-ionic Kidney None NoDotarem Gadoterate meglumine Gd-DOTA Cyclic Ionic Kidney None No
 Nephrogenic systemic fibrosis 131
Diagnosis is confirmed by the presence of specifichistopathological features on deep skin biopsy, whichis a prerequisite for the definite diagnosis of NSF.It is extremely important to differentiate NSF fromother fibrosing skin disorders. Histology shows infiltra-tion with dermal spindle cells, which are characterisedby the surface markers CD45RO, CD34 andProcollagen I. These cells have an immunologic profilewhich is identical to circulating fibrocytes, whichare known to participate in normal wound healing.Whenthere istissueinjury,thesecellsinfiltratetheinjuredtissues and are involved in wound healing and scar forma-tion. In NSF, these cells enter uninjured tissue.Renal impairment may be involved in the malfunction of these cells. Other typical features of NSF are plumpedcollagen bundles, mildly increased interstitial mucindeposition and absence of inflammation.
Validation of NSF cases
Because NSF may mimic other skin lesions that occur inpatients with end-stage renal failure, the diagnosis of NSFshould never be made without a histological evaluationby an experienced dermatopathologist.Correlation of the disease to exposure to drugs or con-trast media requires adequate documentation of whatthe patient has been exposed to. Not all radiology depart-ments have an adequate registration system for the doseand name of the contrast medium used. Sometimes nick-names are used independent of the product used as wellas continuation of use of the brand-name, despite the factthat a new vendor has been introduced. Also the patientsweight is often not recorded. The lack of a completerecord causes problems in retrospective studies whichwe have found in trying to detect unsuspected NSFcases. In the future it is very important that a record isalways kept of the type and amount of each injection of gadolinium based contrast agent given and that all new cases of NSF are reported to the appropriate NationalRegulatory Authority. Interestingly, no NationalMedicines Agency had any record of NSF when we sub-mitted the first 20 cases to the Danish Authorities inMarch 2006. The authorities only need four simplefacts: (1) initials, birth date and sex of the patient; (2)the adverse event; (3) name of the drug; and (4) name of the reporting person including occupation. When thisinformation is submitted it counts as a report inEurope, but it does not prove the presence of NSF.The information requires validation, which is the respon-sibility of the vendor. Validation becomes even more difficult when severalgadolinium products have been used in a short period of time. Thus, if two different gadolinium based contrastmedia have been injected within 8 weeks of each other(maybe longer), it is impossible to determine with cer-tainty which agent triggered the development of NSF andthe situation is described as confounded. However, theagent which is most likely to be responsible is the onewhich has triggered NSF in other unconfoundedsituations.
Co-factors in the development of NSF
Time has shown that two factors are important: (1)reduced renal function and (2) exposure to one of theless stable gadolinium based contrast agents. The severity of NSF may correlate with the dose that patients havebeen exposed to over time, but cases have also developedafter a single 0.1mmol/kg standard dose. Also, NSF doesnot develop in all at-risk patients after exposure to theless stable gadolinium based contrast agents. Thereforemany investigators had been looking for co-factors thatmay destabilise the agent.The following co-factors have been suggested: highdoses of EPO, metabolic acidosis, iron and ferritin,chronic inflammation, hypercoagulability, thromboticevents, recent vascular surgery, recent renal transplantfailure, recent surgery, anion gap, or increased phos-phate. However, no universal co-factor apart from renalfailure has been identified. Marckmann
et al 
. could notidentify any exposure/event other than gadodiamidecommon to more than a minority of the patients whodeveloped NSF. The Center for Disease Control andPrevention found that only exposure to gadolinium con-taining CM during the preceding 6 months or preceding year remained statistically significant in their casecon-trol study of 19 NSF cases.Our current knowledge suggests that there may be sev-eral co-factors that increase the risk of NSF after somegadolinium based CM. However, some of the factors may have been listed just by chance because enhanced MRIwas performed when the particular factors were present.For example, in some departments enhanced MRI isdone as part of the evaluation of thrombo-embolic symp-toms, post surgical complications, etc., whereas in otherdepartments MRI is not used in those situations.Therefore, one institution may report that NSF occursmore frequent in patients with particular conditions,but others cannot confirm it because they use enhancedMRI for different indications. At the University of Copenhagen, where the highestnumber of European NSF cases has been collected(27 cases as of July 2007), gadodiamide enhanced MRIwas mainly used as a part of pretransplant work-up. Thisgroup of patients only had signs and symptoms related totheir uraemia, leading us to question some of thesurgical co-factors. Indications for the examinationsshould always be given, when possible co-factors arebeing sought as they may bias the results. The sameapplies to whether or not NSF patients were on dialysis.Haemodialysis is said to predispose to NSF, but it could just be the fact that patients undergoing haemodialysishave more vascular problems requiring enhanced MRIfor evaluation than patients on continuous peritoneal
132 H.S. Thomsen et al.

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