No / Contrast agents are used to enhance imaging examinations, however in magnetic resonance imaging (MRI) there is an association with nephrogenic systemic fibrosis (NSF). The risk is small, but elevated in patients with impaired renal function and screening of patients is advised prior to administration. This study examines adherence of UK hospitals to guidance on the use of gadolinium based contrast agents (GBCA) in MRI. This was a prospective study utilising an electronic survey. The sample comprised NHS Trusts in the UK (n = 174). An invitation was sent to all MRI lead radiographers including a link to the survey. 17.6% indicated they had no written protocol for the GBCA administration within radiology. 41.2% check blood test results for all patients undergoing a contrast MRI, whereas 45.6% only check those patients with known renal dysfunction or are high-risk. Comorbidities which categorised patients as high-risk included diabetes, cardiac or vascular disease and age, however the cut off varied from 65 to 75 years old. Six sites indicated point-of-care (POC) creatinine testing would be carried out where bloods were unavailable, a further 12 had considered POC testing and dismissed it as an adjunct to the patient pathway, the most commonly cited reason being the cost. Within the UK there is no consistent approach to renal function assessment prior to GBCA administration despite international guidance. POC testing may have a role to play, but a lack of evaluation in radiology has led to concerns that it may constrain capacity and increase costs.

Bakgrund: Kontrastmedel används inom medicinsk avbildning för att tolka anatomi och patologi. Gadolinium är den vanligaste typen av kontrastmedel som används inom magnetresonanstomografi (MRT). Eftersom gadolinium är ett läkemedel kan det orsaka biverkningar. Studier har visat att det finns ett samband mellan insjuknandet av nefrogen systemisk fibros (NSF) och gadoliniumkontrastmedel hos njursjuka patienter. Syfte: Att ta reda på vilka biverkningar som kan uppstå efter en gadoliniumkontrastmedelsinjektion och redogöra för hur vanligt förekommande de är. Utöver detta undersöka om patienter med nedsatt njurfunktion insjuknar i NSF av gadoliniumkontrastmedel. Metod: Studien genomfördes som en systematisk litteraturstudie. Resultat: Omtalade biverkningar är skelettsmärta, huvudvärk, illamående, kräkningar och hudförändringar. Ångest, oro, influensaliknande symptom, klåda, osammanhängande tankegång, metallsmak i munnen, ledstelhet och muskelspasm är mindre omtalade biverkningar. Svåra biverkningar förekommer såsom struphuvudsödem, anafylaktisk chock, andningssvårigheter, dyspné och medvetslöshet. Milda biverkningar är mest förekommande. Fyra fall av NSF konstateras i en studie med 261 njursjuka deltagare. I en annan studie med 571 dialyspatienter bekräftades inga fall av NSF. Slutsats: Förekomsten för en biverkning är sällsynt men både omtalade och mindre omtalade biverkningar kan inträffa. Det finns studier som visar ett tydligt samband mellan NSF och gadolinium hos patienter med nedsatt njurfunktion medan andra studier inte kan bekräfta det. Gadoliniumkontrastmedel är relativt riskfritt men observation av patienten bör alltid förekomma. / Background: Contrast media are used in medical imaging to picture anatomy and pathology. Gadolinium is the most common type of contrast media used in magnetic resonance imaging (MRI). The use of gadolinium may cause adverse effects. The association between gadolinium-based contrast media and nephrogenic systemic fibrosis (NSF) in patients with renal insufficiency has been described in earlier studies. Purpose: To describe the most frequent adverse effects caused by gadolinium-based contrast media and their incidence. The study also aims to explain the association between NSF and gadolinium in patients with renal insufficiency. Method: The study has been conducted as a systematic literature review. Results: The well-known adverse effects are bone pain, headache, nausea, vomiting, and skin lesions. Anxiety, flu-like symptoms, pruritus, clouded mentation, metallic taste in the mouth, joint stiffness and muscle spasm are less mentioned. Severe adverse effects also exist such as laryngeal-edema, anaphylactic shock, breathing difficulty, dyspnea and unconsciousness. Mild adverse effects are most common. Four cases of NSF were found in a study with 261 participants with renal disease. In another study 571 patients with dialysis treatment were included, no cases of NSF were confirmed. Conclusion: Both well-known adverse effects and less mentioned adverse effects exist but the occurrence of an adverse effect is rare. There are studies showing a clear association between NSF and gadolinium in patients with renal insufficiency, whilst others can´t confirm it. Gadolinium-based contrast media is relatively risk-free but observation of the patient should always occur.

La fibrose systémique néphrogénique (FSN) est une maladie rare et relativement récente, observée uniquement chez des patients souffrant d’insuffisance rénale sévère ou terminale. Elle est liée à l’administration d’une certaine catégorie de complexes de gadolinium (CG), les CGs thermodynamiquement moins stables, utilisés comme produits de contraste pour l’imagerie par résonance magnétique. L’hypothèse mécanistique la plus couramment citée concerne les effets profibrosants du Gd3+ « libre » après dissociation in vivo des CGs les moins stables mais il n’en existe pas de démonstration formelle. La physiopathologie de cette maladie reste mal connue, notamment par manque de modèles précliniques pertinents. Les travaux de cette thèse répondent donc à la nécessité d’approfondir nos connaissances concernant les relations entre les propriétés physicochimiques des CGs (structure, stabilité) et le risque de toxicité chronique, afin de mieux comprendre leur rôle dans le mécanisme de la FSN. Nous avons mis aux points plusieurs modèles de FSN chez le Rat. Nous avons aussi comparé les effets de toutes les catégories structurales des CGs sur ces modèles. Une toxicité systémique importante et la survenue de lésions cutanées macroscopiques et d’une fibrose du derme sont notées après administration de gadodiamide (un CG linéaire et ionique de faible stabilité), ce qui est cohérent avec le fait que la grande majorité des cas de FSN sont associés à cet agent. Nous avons aussi montré que cette toxicité dépend du degré d’insuffisance rénale et que l’hyperphosphatémie sensibilise les animaux aux effets profibrosants du gadodiamide. Nos données suggèrent donc que ces facteurs associés sont des facteurs de risque de la FSN. Nous avons observé la dissociation progressive in vivo de deux CGs linéaires présentant une faible stabilité, le gadodiamide et l’acide gadopentétique, après administration chez le Rat insuffisant rénal, avec libération de Gd3+ sous forme libre et soluble. Les CGs macrocycliques sont restés stables. Nous avons confirmé cette stabilité sur du sérum de Rat et du sérum humain alors que le gadodiamide se dissocie in vitro. Nos données suggèrent aussi une interaction entre l’ion Gd3+ dissocié à partir du gadodiamide et les protéines sériques. Cette libération de Gd3+ est accélérée en présence d’une forte concentration de phosphate. Globalement, nos résultats suggèrent ainsi un rôle causal du Gd3+ libre dans les lésions cutanées observées chez les animaux insuffisants rénaux. Enfin, nous avons observé l’implication de la voie de signalisation canonique de TGFβ, le marqueur clé de la fibrose, uniquement chez des rats ayant reçu le gadodiamide et dont l’insuffisance rénale est modérée. Nos travaux sont donc en faveur de l’hypothèse mécanistique d’une dissociation des CGs peu stables. / Nephrogenic systemic fibrosis (NSF) is a rare systemic fibrosing disorder which has been described in patients with severe or end stage renal failure. NSF is associated with prior administration of certain gadolinium complexes (GCs), used as magnetic resonance imaging contrast agents, particularly those which have the lowest thermodynamic stability. The most widely accepted hypothesis regarding the mechanism is based on profibrotic effects of free Gd3+ following in vivo dissociation of the less stable GCs. Nevertheless, there is no conclusive evidence so far. The pathophysiology is not completely understood, especially due to the lack of relevant non-clinical models. The purpose of our thesis was to investigate the relationship between physicochemical properties of GCs (molecular structure, thermodynamic stability) and the risk of chronic toxicity (especially fibrosis), in order to enhance our understanding of their role in the mechanism of NSF. We have set-up various non-clinical models of NSF in renally-impaired rats. We also compared the effects of all categories of GCs on these models. A high systemic toxicity, associated with macroscopic skin lesions and dermal fibrosis, was observed after the administration of gadodiamide (a linear and nonionic GC with a low thermodynamic stability). Whereas more stable, macrocyclic GCs were well tolerated. These findings seem clinically-relevant because the vast majority of NSF cases are associated with gadodiamide. We also showed that systemic and skin toxicities depend on the baseline renal function, and that hyperphosphataemia sensitizes renally-impaired rats to the fibrotic effects of gadodiamide. Our data suggest that these factors are, actually, risk factors for NSF. We observed in vivo dissociation of two linear GCs, gadodiamide and gadopentetic acid, with gradual release of soluble Gd3+, in renally-impaired rats. Macrocyclic agents remained stable. This observation was also confirmed both in rat and human serum by the relaxometry technique. Our results are also consistent with an interaction between dissociated Gd3+ and serum proteins. We also demonstrated that elevated serum phosphate levels accelerates the release of Gd3+. Taken all together, our results suggest a causal role of dissociated Gd3+ in gadodiamide-induced skin lesions in renally-impaired rats. Finally, we identified the involvement of the canonical signaling pathway of TGFβ, the central mediator of the fibrotic response, in gadodiamide-treated rats with a moderate renal failure. Our work is consistent with a causal role of dissociated Gd in the mechanism of NSF.