Nephrogenic Systemic Fibrosis
Table 1: Generic Names, Trade Names, Physico-chemical Characteristics and Scientifically Reported Cases of Nephrogenic Systemic Fibrosis of Nine Gadolinium-based Contrast Agents
Generic Name Gadodiamide
Gadoversetamide
Trade Name Chemical Structure Omniscan OptiMark
Gadopentetate dimeglumine Magnevist Gadobenate dimeglumine Gadoxetic acid disodium Gadofosveset trisodium Gadoteridol Gadobutrol
Gadoterate meglumine 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 • Appear within two months of the NSF-eliciting GdBCA exposure Dotarem
Linear Linear Linear
MultiHance Linear Primovist Vasovist ProHance Gadovist
Linear Linear
Macrocyclic Macrocyclic
Macrocyclic Ionicity
Non-ionic Low Non-ionic Low Ionic Ionic Ionic Ionic
Medium High High High
Non-ionic Medium Non-ionic Low
Ionic High
Thermodynamic Stability at pH 7.4 Kinetic Stability NSF Cases Low Low Low
Medium Medium Medium High High
High
+++ +++ ++ – – – –
+ (? – see text) –
Late Symptoms • Gradually appear more than two months after the NSF-eliciting Skin
• A symptom-free interval of two weeks on average after the GdBCA GdBCA exposure. Typically stabilise within six months. Flare-ups exposure is seen, but immediate onset of symptoms may also occur and worsening may be seen later on, in particular in association • Some patients have no records of early symptoms • Swelling, erythema, burning sensation, itching, pain, heat • Localised to lower legs, forearms, hands and thighs at decreasing frequency. Seldom trunk, almost never face involvement. Striking anatomical symmetry
with co-morbidities such 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 diarrhoea • 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, for example, a wheelchair • Lung insufficiency, signs of pulmonary fibrosis
• Dysaesthesia/numbness of affected regions • Poor muscle strength and endurance • Weakening of legs and arms • Poor appetite and wasting
GdBCA = gadolinium (Gd)-based contrast agent; NSF = nephrogenic systemic fibrosis.
cutaneous disease of renal dialysis patients’, but soon after suggested renaming it to ‘nephrogenic fibrosing dermopathy’.8 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 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
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
the legs, 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. The 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 diarrhoea or acute respiratory distress with increased oxygen requirement and bilateral infiltrates on chest X-ray, may predominate in the early stages.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.
There is a large variation in the type and intensity of symptoms between NSF patients, and symptoms also vary between early and late stages of the disease.14–21
Common early symptoms include swelling, erythema, burning sensation, itching and heat of the skin (see Table 2). Anatomically,
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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.
EUROPEAN NEPHROLOGY
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