Gadolinium-based Magnetic Resonance Contrast Agents and Nephrogenic Systemic Fibrosis


Table 1: Generic Names, Trade Names, Physicochemical Characteristics and Scientifically Reported Cases of Nephrogenic Systemic Fibrosis of Nine Gd-based Contrast Agents


Generic Name Gadodiamide


Gadoversetamide


Trade Name Chemical Structure Ionicity Omniscan OptiMark


Gadopentetate dimeglumine Magnevist Gadobenate dimeglumine Gadoxetic acid disodium Gadofosveset trisodium Gadoteridol Gadobutrol


Gadoterate meglumine


MultiHance Primovist Vasovist ProHance Gadovist Dotarem


Linear Linear Linear Linear Linear Linear


Macrocyclic Macrocyclic Macrocyclic


Non-ionic Low Non-ionic Low Ionic Ionic Ionic Ionic


Medium High High High


High


Thermodynamic Stability at pH 7.4 Kinetic Stability NSF Cases Low Low Low


Non-ionic Medium Non-ionic Low Ionic


Medium Medium Medium High High High


+++ +++ ++ – – – –


+ (? – see text) –


NSF = nephrogenic systemic fibrosis. In the column ‘NSF cases’ the number of + indicates the frequency of observed NSF cases relative to the number of patients exposed to the individual agent. Source: modified from Idee et al., 2009.4


Table 2: Early and Late Symptoms of Nephrogenic Systemic Fibrosis Early Symptoms


Time-frame • Appears within two months of the NSF-eliciting GdBCA exposure


Late Symptoms • Gradually evolves more than two months after the NSF-eliciting GdBCA Skin


• A symptom-free interval of on average two weeks after the GdBCA exposure. Typically stabilises within six months. Flare-ups and worsening exposure is seen, but immediate onset of symptoms may also occur may be seen later on, in particular in association with comorbidities such • Some patients have no records of early symptoms • Swelling, erythema, burning sensation, itching, pain, heat • Localized to lower legs, forearms, hands, thighs at decreasing frequency; seldom trunk, almost never face involvement, striking anatomical symmetry


as infections


• Plaques, papules, nodules, or large confluent areas of hardening and inflexibility. Brown hyperpigmentation, scaling, or flaking, or shiny appearance of affected regions may be seen. Hair loss in affected regions


• Anatomical distribution similar to early symptoms. Itching and pain may continue. Wrinkled skin in a minority of patients


Non-skin


• Acute gastrointestinal discomfort with pain, vomiting, and diarrhea • Restricted joint motion of legs and arms, in severe cases leading to • Acute pneumonia symptoms—shortness of breath, hypoxia, lung infiltrates on chest X-ray • Diffuse hair loss


immobility and dependence on e.g. wheelchair • Lung insufficiency, signs of pulmonary fibrosis


• Dysesthesia/numbness of affected regions • Poor muscle strength and endurance • Weakening of legs and arms • Poor appetite and wasting


GdBCA = gadolinium (Gd)-based contrast agents; NSF = nephrogenic systemic fibrosis.


disorder in 15 renal dialysis patients had been identified during 1997 to 2000. The disease had several similarities with scleromyxedema, but differed from scleromyxedema by the absence of monoclonal plasma protein and extracutaneous mucin deposits. Cowper initially named the disease ‘scleromyxedema-like cutaneous disease of renal dialysis patients’, but soon after suggested renaming it to nephrogenic fibrosing dermopathy (NFD).8


Accordingly, the disease was renamed once more in 2005.12 Since then, the term nephrogenic systemic fibrosis has been used by most authors.


Clinical Presentation of Nephrogenic Systemic Fibrosis


Since the initial description of NSF, most papers have focused on skin manifestations. However, extracutaneous manifestations of NSF may predominate in a minority of NSF patients, and extracutaneous manifestations most likely explain the apparent excess mortality of NSF patients.13


There is a large variation in the type and intensity of symptoms US NEPHROLOGY


Reports from other researchers revealed that the disease was not limited to dialysis patients and also not limited to the skin: autopsy studies of affected patients demonstrated abnormal fibrosis of other tissues and organs, such as striated muscles, heart muscle and the conduction system, lungs, the thyroid gland, and dura mater.9–11


between NSF patients, and symptoms also vary between early and late stages of the disease.14–21


Common early symptoms include swelling, erythema, burning sensations, itching, and heat of the skin (see Table 2). Anatomically, the legs and in particular the lower legs are affected in 90 % or more of cases. Forearms, hands, and thighs are less frequently affected—figures range from 25 to 66 %. The skin of the trunk is seldom involved, and the face is almost always spared. Anatomical symmetry of the skin changes is a striking and general finding. In a minority of patients, atypical symptoms such as acute gastrointestinal discomfort with vomiting and diarrhea or acute respiratory distress with increased oxygen requirement and bilateral infiltrates on chest X-ray may predominate in the early stage of the disease.19,20,22


Weeks


to months later, patients develop the typical late symptoms: the skin is hardened and inflexible, may have a shiny appearance, or become hyperpigmented (brown), eventually with scaling. The late skin changes replace the early findings and are located in the same anatomical regions. A small group of patients may develop wrinkled skin (cutis laxa) as an atypical late skin manifestation.15


Extracutaneous symptoms may be seen


in a minor fraction of patients. They include limb numbness, weakness or pareses due to axonal degeneration of peripheral nerves, and lung insufficiency due to lung fibrosis.


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