13244_2015_420_article 1.6

Insights ImagingDOI 10.1007/s13244-015-0420-2 Revisiting the risks of MRI with Gadolinium based contrastagents—review of literature and guidelines Aurang Z. Khawaja 1 & Deirdre B. Cassidy2 & Julien Al Shakarchi 1 &Damian G. McGrogan1 & Nicholas G. Inston1 & Robert G. Jones3 Received: 22 April 2015 / Revised: 16 June 2015 / Accepted: 30 June 2015 # The Author(s) 2015. This article is published with open access at Springerlink.com • Post-scan dialysis should be arranged as soon as possible Gadolinium based contrast agents (GBCA) have been linked and feasible.
to the occurrence of nephrogenic systemic fibrosis (NSF) in • Pre-existing inflammatory state is a risk factor; liver insuf- renal impaired patients. The exact interaction between the var- ficiency is not a contraindication.
ious different available formulations and occurrence of NSF isnot completely understood, but has been postulated. This as- Keywords Magnetic resonance imaging . Contrast media .
sociation has triggered public health advisory bodies to issue Gadolinium/adverse effects . Nephrogenic fibrosing guidelines and best practice recommendations on its use. As a dermopathy . Renal insufficiency result, the reported incidence of NSF, as well as the publisheduse of GBCA-enhanced magnetic resonance imaging in renalimpairment, has seen a decline. Understanding of the eventsthat led to these recommendations can increase clinical aware- ness and the implications of their usage. We present a reviewof published literature and a brief overview of practice recom- Gadolinium-based contrast agents (GBCA) have been linked mendations, guidelines and manuals on contrast safety to aide to the occurrence of nephrogenic systemic fibrosis (NSF) in everyday imaging practice.
renal impaired patients. The majority of studies that report on their use in the renal impaired population were published prior • Low risk gadolinium based contrast agents should be the to the publications that prompted the alert on NSF [This choice in renal insufficiency.
association has triggered public health advisory bodies to is- • Higher doses have been linked to NSF development. Doses sue guidelines and best practice recommendations on its use in should be as low as possible.
renal insufficiency. Since then, this has all but halted the rapid • Clear documentation of date, dose and type of formulation progression and uptake of contrast-enhanced magnetic reso- used should be noted.
nance imaging (MRI) in this population that was seen in theearly to mid 2000s. Understanding of the events that led tothese recommendations can increase clinical awareness and * Aurang Z. Khawaja the implications of the use of GBCAs in daily imaging prac- tice. We conducted an electronic database search [PubMed/Medline, EMBASE] to collate the evidence in published lit- Department of Renal Transplant Surgery & Vascular Access, Queen erature on the occurance of NSF in the renal impaired. We also Elizabeth Hospital, University Hospitals Birmingham, Mindelsohn carried out a forward citation and bibliographic search of iden- Way, Birmingham B15 2GW, West Midlands, UK tified studies. Published studies were reviewed for reported Present address: Division of Diabetes and Cardiovascular Medicine, pathophysiological and clinical manifestations, proposed di- University of Dundee, Dundee DD19SY, UK agnostic pathway, treatments options and reported incidence.
Department of Radiology, Queen Elizabeth Hospital, University We also reviewed practice recommendations, guidelines and Hospitals Birmingham, Mindelsohn Way, Birmingham B152GW, West Midlands, UK published manuals on contrast safety.
Background and incidence In the year 2000, 15 patients with blistering or even ulceration [. Resultant manifestations chronic kidney disease were identified presenting with include pain, severe pruritus, paraesthesia and flexion con- scleromyxoedema-like cutaneous manifestations yet having tractures that can begin on the hands or feet and extend significant clinical and histo-pathological differences; the term proximally. Cutaneous calcifications maybe noted on a plain nephrogenic fibrosing dermopathy was initially proposed.
film radiograph and confirmed on biopsy Lesions are These clinical findings are now recognized as characteristic frequently symmetrical, often located on the lower limbs, of NSF []. Following this, case reports of similar findings and followed by the forearms. Idiopathic, rapid onset, unstable also significant systemic involvement found on autopsy were hypertension has been described prior to onset of skin le- reported Patients with end-stage renal disease were sions. Its systemic involvement of lungs, heart, diaphragm, reported to develop symptoms as early as two to four weeks liver or kidneys can vary. The international centre for re- after exposure to GBCAs for MRI Exact pathogenesis search on NSF, led by Prof. Dr. S.E. Cowper, states that remains unclear; however, postulation of likely early dermal approximately 5 % are reported to have a fulminant course manifestation of this gadolinium toxicity is proposed ]. A [The Girardi Score (Fig. , Table was proposed in strong association is observed in the presence of both acute 2011 based on reported clinical presentations and expert renal impairment and chronic dialysis dependent renal insuf- consensus, as no single laboratory test could be used as a ficiency and other influencing co-factors that may play a role, gold standard to diagnose NSF. This encompassed identifi- such as a background inflammatory process ]. As the cation of major and minor criteria on clinical findings, evidence in published literature increased, the United States coupled with histological findings.
Food and Drug Administration (FDA), followed by the Euro-pean Medicines Agency (EMA) issued an alert on the use of Pathophysiology Recent theory suggests that administration GBCAs in patients with renal insufficiency []. Since of large amounts of GBCAs, (solely excreted via kidneys for then, public health and practice guideline bodies have pub- earlier used formulations and again mainly excreted by kid- lished recommendations on its use [A 2008 multi- neys in the remainder) persist in the body and may dissociate centre retrospective review reported 15 cases of NSF in a total from their carrier ligands/chelates [, ]. These population of 83,121 (0.02 % incidence), all of whom re- may then bind with readily available phosphates, carbonates ceived at least one administration of a GBCA. All 15 of these or citrates, and form insoluble molecules. Several authors cases of NSF were found in patients who had received a mention histological findings of increased dermal collagen higher than standard dose, increasing the incidence to bundles, CD34+ fibroblast like cells, macrophages, mucin 0.17 % (15 of 8997 patients). A higher than normal dose and transforming growth factor beta (TGFβ) in this cohort was described as approximately between 0.2 to 0.4 mmol of patients [, , –Pre-existing renal disease per kilogram body weight. In the entire cohort, 265 patients has been the most prevalent patient characteristic.
were on haemodialysis, but only one of them was reported to Although the disassociated gadolinium theory has been the have developed NSF (incidence 0.4 %) ]. Another publica- widely acknowledged trigger of NSF, questions of chelated gad- tion retrospectively collating data from four centres set to de- olinium in combination with pre-existing cofactors have been termine the benchmark incidence of NSF related to the con- raised Cofactors such as high dose erythropoietin treat- firmed use of two GBCAs [. They reported an overall ment, pro-inflammatory state, high serum phosphate and calci- incidence of 0.04 % at two centres that used Gadodiamide um, and absence of ace inhibitor treatment, have also been (32 cases in 82,260 patients—administered total dose range linked to the appearance of NSF Chelated gadolinium 1 to 9.5 mmol), as compared to the 0.02 % from the previously such as gadodiamide and gadopentetate have been shown to publish study. The other two centres that used Gadopentate directly stimulate macrophages and monocytes in vitro to release dimeglumin reported an incidence of 0.003 % (four cases in profibrotic cytokines and growth factors capable of initiating 135,347 patients) with an administered dose ranging between and supporting the characteristic tissue fibrosis , ].
2.5 and 8.5.
Hepatic insufficiency As evidence in published literature in- Clinical findings As reported in the literature, specific cuta- creased following the initial June 2006 alert, manufacturers of neous findings on clinical examination with relevant past his- GBCAs were ordered by the FDA to add a Bblack box tory of GBCA exposure trigger a differential of NSF, but re- warning the following year This elaborated on the alert quire histological confirmation [–]. It has been postulated to extend caution of GBCA use in any acute or chronic renal that the deposition of disassociated free gadolinium causes insufficiency patient (GFR<30 mL/min/1.73 m2), or acute this fibrous connective tissue formation []. Patients may pres- renal insufficiency of any severity due to the hepato-renal ent with firm, erythematous and indurated plaques of skin syndrome or in the perioperative liver transplantation period.
associated with subcutaneous oedema. The presentation may A 2009 systematic review of NSF in liver disease patients range from hyperpigmentation, yellow papules or plaques, found no compelling evidence to suggest liver disease in itself Fig. 1 The Girardi Score using Clinical Score
clinical criteria and histologicalfindings for diagnosis of NSF Alternave Diagnosis
Alternave Diagnosis
as being a risk factor for developing NSF. The authors con- Excess chelate The vast majority of GBCA preparations con- cluded that NSF developed only in the setting of pre-existing tain excess chelates to reduce or ensure absence of free gado- severe renal insufficiency, irrespective of liver disease status linium in the solution, and some studies have suggested thepossibility of excess chelate to inhibit the collagenolytic prop-erties of matrix metalloproteinase 1. The addition of excess Pregnancy To date, very little data is available regarding GBCA chelate to non-ionic linear chelate dramatically reduces the administration in pregnancy. Most of the published studies are acute toxicity , Table summates the commonly either animal studies or patient cohorts that are understandably used GBCAs, their elimination pathway, reports of NSF and historic, and have small numbers and limited follow-up periods the amount of excess chelate within the preparations.
–]. As evidence of gadolinium retention after exposurecontinues to pile and taking into consideration immature foetalrenal function, recommendations are much more restrictive.
Guidelines recommend that GBCAs should only be given to pregnant women when there is a very strong clinical indication.
Breast feeding should be stopped for at least 24 hours. One of the Thus far, no consistently successful treatment for NSF has been more stable, macrocyclic gadolinium agents (gadoterate proposed. Improving renal function slows or arrests NSF to meglumine, gadoteridol, or gadobutrol) should be used in the allow for gradual reversal over time, and has been described lowest dose consistent with a diagnostic result ].
in patients who received renal transplantation []. Dialysishelps to remove the contrast agent, but it cannot reverse the Girardi score—definition and classification of clinical and fibrotic tissue formation that has already occurred as a result of histological findings gadolinium deposition [, ]. With a full 4-hour dialysis session after administration, concentration levels comparisonto predialysis have been shown to be to cleared to 88 % at 30 Clinical findings major Patterned plaques mins, 93 % at 90 mins, and 97 % respectively. After a third Joint contracturesBCobblestoning session, a 99.7 % clearance has been demonstrated Marked induration / Peaud'orange Whether this would still be associated with development of Clinical findings minor Puckering / linear banding NSF would require long-term follow-up of these patients. Oth- Superficial plaque / patch er treatments such as oral and topical steroids have been tried with varying results Extracorporeal photopheresishas Scleral plaques (<45 years) shown good results in a small case series and in three patients Histological findings Increased dermal cellularity (Score +1) who were also kidney/liver recipients CD34+ cells with tram tracking (Score+1) Thick & thin collagen bundles (Score+1) was also utilized with acceptable results , Anecdotal Preserved elastic fibres (Score -1, if absent) evidence has been reported in the use of Cytoxan, thalidomide, Septal involvement (Score +1) ultraviolet therapy, physical therapy including deep massage Osseous metaplasia (Score +3) technique, pentoxyfilline (at high doses), sodium thiosulphate, Gadolinium based contrast agents—elimination pathway, last reported total number of administrations, occurrences of NSF and volume of excess chelate quantity ] Gadolinium based contrast agents Elimination pathway Number of reports No. administrations Excess chelate in (Gadobenate dimeglumine) (Gadoxetic acid disodium salt) (Gadofosveset trisodium) *Case published on 5 October 2009 **9 years prior to Dotarem administration, the patient had received an unknown GBCA. Case is still under investigation alefacept, and imatinib mesylate, and intravenous immuno- precautions and recommendations on the use of GBCAs. Mul- globulin (also at high dose and after renal transplantation) tiple publications, have since been gathered to form the body ]. Not having mandatory reporting, the NSF Registry, led of evidence for NSF; however, the vast majority have been by Prof. Dr. S.E. Cowper, still mentioned over 380 cases in linked to the earlier types of contrast agents. The incidence of 2013 The highest incidence in Europe has been reported NSF has been reported to be on the decline after these recom- in Danish registry reports []. The true incidence of NSF may mendations were implemented.
likely be under-reported, but in cases of confirmed NSF, renal While various different formulations are available on the transplantation should be made a priority.
market, not all have been associated with NSF. Linear GBCAsare considered the least stable, and have been linked to mostcases of the development of NSF []. These have often been linked to the background of an inflammatory processMacrocyclic GBCAs for MRI have also been developed.
From 2006 onwards, international agencies such as the Euro- A recent systematic review of MRI studies in the renal pean Medicines Agency (EMA), the European Society for impaired noted that the majority of included studies were pub- Urological Radiology (ESUR), the US Federal Drugs Agency lished prior to the FDA alert []. Half of the studies reported (FDA), American College of Radiology (ACR) and the UK use of contrast types now mentioned by the EMA as having Royal College of Radiologists (RCR) have published alerts, high incidence of NSF (Table European Medicines Agency: categorisation of GBCAs according to NSF risk, based on their thermodynamic and kinetic properties ] A. Linear non-ionic chelates A. gadoversetamide (OptiMARK®), gadodiamide (Omniscan®) B. Linear non-ionic chelates B. gadopentetic acid (Magnevist®, Magnegita®, and Gado-MRT-ratiopharm*) Gadofosveset (Vasovist®), gadoxetic acid (Primovist®) and gadobenic acid (MultiHance®) Linear ionic chelates Gadoteric acid (Dotarem®), gadoteridol (ProHance®) and gadobutrol (Gadovist®) Macrocyclic chelates *Gadopentetic acid generics In December 2007, the EMA recognized that the risk of developing NSF depends on the type of gadolinium-containing contrast agent used, and advised that these agents Grobner T (2006) Erratum: Gadolinium—a specific trigger for the should be categorized into three groups. Following this cate- development of nephrogenic fibrosing dermopathy and nephrogenic gorization, if a GBCA is to be used in a high-risk patient, then systemic fibrosis? (Nephrology Dialysis Transplantation (2006) vol.
21 (1104–1108)). Nephrol Dial Transplant 21:1745 the low risk category agents should be used. Risk and benefit Sadowski EA, Bennett LK, Chan MR et al (2007) Nephrogenic analysis assessment and informed consent should be obtained.
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Chemistry education:

CHEMISTRY EDUCATION: THE PRACTICE OF CHEMISTRY EDUCATION RESEARCH AND PRACTICE IN EUROPE 2000, Vol. 1, No. 1, pp. 161-168 Chemical education in Europe: Curricula and policies Georgios TSAPARLIS University of Ioannina, Department of Chemistry THE STATES-OF-MATTER APPROACH (SOMA)


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