Editorial
Acta Radiologica
Nephrogenic systemic fibrosis:
a serious adverse reaction to
gadolinium – 1997–2006–2016. Part 1
Henrik S Thomsen
The first magnetic resonance (MR) scanners for ima-
ging the human body became commercially available in
the early 1980s. Early in the development of magnetic
resonance imaging (MRI) it was believed that contrast
medium would not be necessary because of the good
soft-tissue discrimination obtained, but before long it
became obvious that contrast agents could provide
additional diagnostic information. Currently, up to
nine gadolinium-based agents are available in most
countries (Table 1). Six agents are distributed in the
extracellular fluid and are excreted by glomerular filtra-
tion. The remaining three agents are so-called organ-
specific, protein-binding, or high relaxivity agents. The
currently available gadolinium-based contrast media
are only approved for intravenous injection, not for
intra-arterial or intra-cavitary injection. Because MRI
has better soft tissue resolution than computed tomog-
raphy (CT), the extracellular MR contrast agents are
on average only used in one-third of the MR examin-
ations whereas iodine-based contrast media are used
for around two-thirds of CT examinations. Also the
molar dose used for an average MR examination is
approximately eight times lower than for CT.
Since gadolinium-based contrast agents were intro-
duced, there have been rapid developments, both in
MR techniques and in the use of these agents, which
could not have been foreseen when most of the agents
were developed and underwent testing (phase I to III
trials). In the early 2000s gadolinium-based contrast
agents were considered to be one of the safest drugs
on the market and were used rather liberally, even in
patients with poor renal function. However, like all
drugs, gadolinium-based contrast media may cause
adverse events. Adverse events are divided into acute
(within 60 min the exposure to the contrast agent), late
(from 1 h to 7 days), and very late (occurring more than
7 days after the exposure to the agent) (1). Acute
adverse events can be either generalized (systemic) or
renal reactions. Generalized reactions may be mild,
moderate, or severe. Moderate and severe reactions
requiring medical treatment are infrequent (<0.2%) (2).
Renal adverse reactions, often called contrast-induced
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nephropathy (CIN), are rarely seen after gadolinium-
based contrast media in the doses used for MRI (3).
In 2006, it became apparent that some gadolinium-
based contrast media were responsible for a very late
adverse reaction, nephrogenic systemic fibrosis (NSF)
(4,5). In North America and Western Europe, NSF
appears to have been eliminated by no longer using
less stable gadolinium-based contrast agents in patients
with reduced renal function, or, in some countries, by
not using less stable agents at all. I have not been able
to find any reports of NSF in the peer-reviewed litera-
ture, where the patient received the agent after 2009;
however, the lack of cases in the peer-reviewed litera-
ture does not exclude that there are cases (5). The aim
of this review is to bring the reader up to date on this
devastating very late adverse reaction, which, up until
now, is estimated to have affected around 10,000
patients with reduced renal function since 1997 (6).
Clinical features of NSF
An idiopathic skin condition characterized by thicken-
ing and hardening of the skin of the extremities and
sometimes the trunk was first described in California
in 1997, but it took another 3 years before this obser-
vation and reports from three other centers were pub-
lished in the peer-reviewed literature (7). The diagnosis
of NSF requires systematic examination of the skin as
well as careful light-microscopy of a deep skin biopsy.
The NSF registry in New Haven (CT, USA) has pro-
posed a diagnostic scoring system to make this difficult
diagnosis easier and ensure similar evaluation/diagnosis
worldwide (8), and their criteria should be used when-
ever there is any suspicion of NSF.
Department of Diagnostic Radiology 54E2, Copenhagen University
Hospital Herlev-Gentofte, Herlev, Denmark
Corresponding author:
Henrik S Thomsen, Department of Diagnostic Radiology, Copenhagen
University Hospital Herlev – Gentofte, Herlev Ringvej 75, DK-2730
Herlev, Denmark.
Email: henrik.thomsen@regionh.dk
516
Table 1. The nine available gadolinium-based contrast media classified according to ionicity and chelate structure (three agents are
organ-specific, as indicated in brackets after their names).
Ionic
Linear Extracellular agents:
Gadopentetate (Magnevist) Gd-DTPA
High relaxivity, protein-binding agents:
Gadofosveset trisodium (Ablavar) Gd- EOB-DTPA (vascular agent)
Gadoxetate disodium (Primovist, Eovist) Gd-DTPA-DPCP (liver agent)
Gadobenate (Multihance), Gd-BOPTA (liver agent)
Cyclic Extracellular agent:
Gadoterate (Dotarem, Magnescope) Gd-DOTA
The availability of the different agents varies from country to country, e.g. all nine agents are approved by FDA for human use in the USA, whereas only
four agents (gadoterate, gadobutrol, gadoteridol, and gadobenate) are currently registered for human use by the Danish Medicines Agency.
NSF was initially observed in and thought to affect
the skin only, and was called nephrogenic fibrosing
dermopathy (NFD). It is now apparent that it may
involve organs such as the liver, lungs, muscles, and
heart and this involvement probably explains the sus-
pected increased mortality of NSF patients. NSF affects
all ages and races. The typical patient has absent or
poor renal function (9,10).
The first signs of NSF may be seen hours or years
after exposure to gadolinium-based contrast agents
(11). In most patients, NSF begins with subacute swel-
ling of the distal extremities, followed in subsequent
weeks by severe skin induration, which may extend to
involve the thighs, forearms, and lower abdomen
(9,11). The skin induration may be aggressive and
associated with constant pain, muscle restlessness,
and loss of skin flexibility (Fig. 1). In some cases,
NSF leads to serious physical disability, including
becoming wheelchair bound. For many patients, the
skin thickening inhibits flexion and extension of joints,
resulting in contractures. Severely affected patients
may be unable to walk or fully extend the upper
and lower limb joints. Complaints of muscle weakness
are common, and deep bone pain in the hips and ribs
has been described. Radiography may show soft tissue
calcification.
There is great variability. NSF severity may be
graded from 0 to 4: 0, no symptoms; 1, mild physical,
cosmetic, or neuropathic symptoms not causing any
kind of disability; 2, moderate physical and/or neuro-
pathic symptoms limiting physical performance to
some extent; 3, severe symptoms limiting daily physical
activities (walking, bathing, shopping, etc.); and 4,
severely disabling symptoms causing dependence on
aid or devices for common, daily activities (11).
Patients with grade 0, 1, or 2 disease are rarely included
in retrospective studies and this explains the low preva-
lence in such studies compared to those based on visual
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Acta Radiologica 57(5)
Non-ionic
Extracellular agents:
Gadodiamide (Omniscan) Gd-DTPA-BMA
Gadoversetamide (OptiMark) Gd-DTPA-BMEA
Extracellular agents:
Gadobutrol (Gadovist, Gadavist) Gd-BT-DO3A
Gadoteridol (ProHance) Gd-HP-DO3A
inspection of the skin of all patients exposed to a gado-
linium-based contrast agent.
In one study it was shown that 18-month mortality
of NSF patients was 40% compared to 16% for
patients without NSF, with an adjusted hazard ratio
of 2.9 (95%CI, 1.3–6.5; P ¼ 0.008) (12). In 32 patients
with nephrogenic systemic fibrosis, 10 died at a median
of 112 days after diagnosis (13). At autopsy (3 patients)
there were appreciable amounts of gadolinium, iron,
and aluminum, as measured by indirectly coupled
plasma-mass spectrometry and confirmed by X-ray
fluorescence, in the heart, blood vessels, and skin. In
this high-risk group, it is difficult to differentiate deaths
caused by complications of the underlying disease and
its treatment from those due to NSF. NSF without
exposure to a less stable gadolinium-based contrast
agent is very unlikely when one looks back on the pub-
lications from the last 8 years.
Preclinical indications of
gadolinium toxicity
In the early 1980s, MR contrast media were being
developed and there was also independent chemical
research being conducted on the lanthanides.
Research on potential MR contrast media suggested
that copper (Cu2þ), manganese (Mn2þ), and gadolin-
ium (Gd3þ) were possible paramagnetic ions for use in
MRI (14). Gadolinium (atomic number 64 and atomic
weight of 157) with seven unpaired electrons was the
most powerful and had the highest relaxivity per atom
of all those tested (15). Unfortunately, it was also the
most toxic of the ions tested. During research on the
lanthanides, Evans and Drouven noted that they could
cause changes in the collagen structure of skin (16).
They published a textbook about these ions,
Biochemistry of Lanthanides, in 1990, just 1 year after
the American Food and Drug Administration (FDA)
Thomsen 517

Fig. 1. An example of late, symmetrical skin changes in gadodiamide-related NSF. The patient has severe skin and subcutaneous
stiffness/induration, browny pigmentation, and contractures causing loss of walking ability. Photo by MS Fie Slok, Plastic Surgery
Department, Copenhagen University Hospital Herlev. Reprinted with permission from the Publisher (11).

approved the first gadolinium-based contrast agent for
intravenous use (17).
In 1991 a workshop on contrast-enhanced MRI was
organized by the Society of Magnetic Resonance in
Medicine (now the International Society of Magnetic
Resonance in Medicine [ISMRM]). The abstracts and
discussions were published in the Journal of the Society
of Magnetic Resonance in Medicine, but were not widely
read (18). At this meeting, the stability of non-ionic linear
chelated gadolinium agents was much debated. It was
noted that pathological changes, which occurred after
exposure to a non-ionic linear chelate gadolinium agent,
were not seen after exposure to an ionic linear agent. The
following year it was decided that a new non-ionic linear
chelate, gadopendiamide, should not be brought to the
market because of concerns about the safety findings,
which were similar to those seen after other non-ionic
linear chelates (19). Three years later, using relaxometry
it was shown that gadodiamide releases gadolinium in
serum over time (20); no other agents were studied.
Thirteen years later it was again shown that non-ionic
linear agents released much more of the toxic gadolinium
ion in serum than did the other agents (21).
The first major sign of a clinical problem with the
stability of the non-ionic linear agents came when
Prince et al. in 2003 reported that gadodiamide may
cause spurious hypocalcemia (22). Both gadodiamide
and gadoversetamide may interfere with calcium
measurement obtained by assays using the ‘‘wet’’
method but not the assays using the ‘‘dry’’ (23,24). The
false measurement of serum calcium levels did not occur
with gadopentetate dimeglumine or gadoteridol (25).
This was the first clinical sign to the radiological com-
munity about stability problems with the non-ionic
linear agents, but it was not recognized as such.
Why these various safety concerns did not receive
attention outside a small group of experts will never
be known, but this failure illustrates the importance
of transparency in all aspects of drug development.
Stability of gadolinium-based agents
The various gadolinium-based agents differ in their ten-
dency to release free gadolinium ions. In an ionic linear
molecule Gd3þ is coordinated with five carboxyl groups
and three amino nitrogen atoms. The three negatively
charged carboxyl groups neutralize the three positive
charges of the Gd ion and the remaining two carboxyl
groups are neutralized by two meglumine cations. In a
non-ionic linear molecule such as gadodiamide or gado-
versetamide, the number of carboxyl groups is reduced
to three because each of the other two carboxyl groups
has been replaced by a non-ionic methyl amide.
Although both amide carbonyl groups are directly
coordinated to Gd3þ, the binding is weaker compared
to that with the carboxyl groups. This weakens the grip

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518
of the non-ionic chelate on the Gd3þ and decreases the
stability of the complex (26).
The other feature influencing the binding between
the Gd3þ and the chelate is whether the configuration
of the molecule is cyclic or linear. The macrocyclic mol-
ecule offers better protection and binding of Gd3þ
because it is a pre-organized rigid ring of almost opti-
mal size to cage the gadolinium ion. In contrast, the
linear structure, which is a flexible open chain, provides
weaker protection of the gadolinium ion. The rates of
dissociation of gadolinium from macrocyclic ligands
are several orders of magnitude slower than their dis-
sociation from linear chelates (27).
A large amount of excess chelate is present in agents
of low stability. The excess chelate is included in the
preparation to ensure the absence of free Gd3þ in solu-
tion. The addition of excess chelate to gadodiamide, a
non-ionic linear chelate, dramatically reduces the acute
toxicity of non-formulated preparations, which have no
excess chelate, by a factor of 2.5 in acute toxicity studies
(intravenous LD50) (26,28).
Pathophysiology of NSF
Transmetallation of gadolinium-based contrast media
leads to release of free gadolinium by replacing the
Gd3þ within the chelate molecule by body cations
such as iron, copper, zinc, and calcium. Zinc is the
main cation which displaces Gd3þ, because of its high
concentration in the blood (55–125 mmol/L).
The elimination half-life of gadolinium-based con-
trast agents in patients with normal renal function is
around 90 min, but it can be prolonged to 24 h or more
in patients with advanced chronic kidney insufficiency
(29). In patients with advanced chronic kidney insuffi-
ciency, including those on dialysis, in whom the con-
trast agent remains in the body for a long time,
transmetallation may cause release of free Gd3þ from
gadolinium-based contrast agents (26). The free Gd3þ
ions become attached to endogenous anions particu-
larly phosphate and form insoluble salts that deposit
in tissues. Local macrophages engulf these insoluble
molecules and release a range of cytokines, including
TGFb1, which attract circulating fibrocytes and initiate
the process of fibrosis (26,30,31). The tissue fibrosis in
NSF is more likely caused by circulating fibrocytes
recruited from the circulation than by proliferation of
resident dendritic cells. In the skin and fascia of NSF
patients, hybridization studies have showed a marked
increase in TGFb1 mRNA levels (9,32).
Studies in rats have used a dose of 2.5 mmol/kg dose
of gadolinium-based agents, which is not a high dose
for rats because they clear the agents from the blood
very rapidly. It is considered that this 2.5 mmol/kg dose
in rats is equivalent to 0.3 mmol/kg (‘‘triple dose’’) in
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Acta Radiologica 57(5)
man. Rats with normal renal function were given
repeated injections of 2.5 mmol/kg of six different gado-
linium-based contrast agents over a 20-day period. Skin
lesions consistent with human NSF were seen as early
as 8 days after starting non-formulated gadodiamide
(without excess chelate) and 20 days after starting for-
mulated gadodiamide (gadodiamide plus the excess
chelate caldiamide, the commercial solution), but not
when gadopentetate was given (33). The highest Gd3þ
concentrations in the skin and the most advanced skin
lesions were found in animals that received the low sta-
bility agents. Skin changes occurred despite the rats’
normal renal function. In another rat study,
2.5 mmol/kg of six different gadolinium-based agents
was injected. The highest concentrations of gadolinium
in skin, liver, and bone occurred with gadodiamide.
With gadopentetate, skin gadolinium concentration
was 10 times less and with gadoterate and gadobutrol
30 times less (34). Already by 1992, it was known that
gadoterate was superior to gadopentetate, as indicated
by an 85% improvement in safety; the ratio of LD50 to
effective dose was 53 for gadoterate versus 28 for gado-
pentetate (35). Gadoterate also showed significantly
higher stability in serum based on metal retention,
with less than 2% of the gadolinium being released
after 150 h compared with 10–20% of the gadolinium
being released from gadopentetate. Gadolinium may
accumulate in tissues other than skin, such as bone
and liver, and greater amounts were found after linear
than after macrocyclic agents (36). Retention of gado-
linium in bone was greater in renally impaired mice than
in mice with normal renal function (37). Gd3þ retention
in human bone was 2–4 times more with gadodiamide
than with the macrocyclic agent gadoteridol in patients
with normal renal function (38). These studies suggest
that multiple large doses of low stability gadolinium-
based contrast agents may cause heavy metal toxicity
even in patients with normal renal function.
Serum from NSF patients stimulates fibroblast hya-
luron synthesis up to seven times and collagen by up to
2.4 times compared to control fibroblast cultures incu-
bated with serum from healthy volunteers and dialysis
patients not suffering from NSF. Proliferation of fibro-
blasts exposed to gadodiamide (1.0 mM) for up to 7 days
was stimulated significantly (39). Gadodiamide has also
induced the expression of a-smooth muscle actin stain-
ing, suggesting induction of a myofibroblast phenotype.
Further studies comparing various gadolinium-based
contrast agents are required to show whether they
have different effects on fibroblasts. In in vitro studies
of human fibroblasts in culture gadodiamide stimulated
fibroblast proliferation and collagen production but had
no significant effect on keratinocytes. The stable macro-
cyclic agent meglumine gadoterate had no effect, except
at very high (10 mM) concentrations (40).
Thomsen
The ultrastructural site of gadolinium retention in
the skin of rats with impaired renal function given
formulated gadodiamide (gadodiamide plus the
excess chelate caldiamide) has been evaluated.
Gadolinium was detected extracellularly around seg-
ments of the collagen fibrils and intracellularly
within fragments of collagen fibrils in fibroblasts and
in histiocytes (41). In rats given the same doses of
gadoterate, no gadolinium was detected within skin
collagen fibrils or fibroblasts and there were no skin
changes similar to NSF. Bone, liver, and kidney were
also examined and the greatest difference between
gadodiamide and gadoterate was in the skin, where
the concentration of gadolinium was 40 times greater
with gadodiamide than with gadoterate (41).
To be continued in the next issue of Acta Radiologica.
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‘Classic papers’ from the Acta Radiologica
archives
Arnulf Skjennald
When can a classic paper be considered ‘‘old’’?
In this so-called ‘‘Old Classics’’ series, we have until
now republished classical papers first published in 1921
from the first year of this journal.
In this issue a ‘‘classic’’ paper will be republished, a
paper that hardly can be characterized as ‘‘old’’, but
definitively classic.
In the previous issue of Acta Radiologica (1) we read
the obituary for Professor Torsten Almén who passed
in January this year. Torsten was a pioneer in the his-
tory of radiological contrast media, and did in fact
revolutionize angiographic procedures by the introduc-
tion of non-ionic contrast media. However, he did not
rest upon this discovery and went further on with
improvements of contrast media to be used in radi-
ology. In 1995 he published his review of the entire
development of contrast media (2) beginning with the
first real ‘‘angiographic’’ study of the arteries in the
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Acta Radiologica 57(5)
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(DTPA-BMA) (Omniscan) versus GD (HP-DO3A)
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copy. Invest Radiol 2006;41:272–278.
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41. Haylor J, Schroeder J, Wagner B, et al. Skin gadolinium
following MRI contrast agents in a rat model of nephro-
genic systemic fibrosis. Radiology 2012;263:107–116.
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hand of a corpse performed by Hasneck and
Lidenthal in 1896 in the laboratories of Professor
Franz Exner’s physiochemical institute in Vienna,
demonstrating his impressive knowledge about contrast
media chemistry. The contrast media used in this ori-
ginal old study consisted of a mixture of lime, mercury,
and petroleum, quite different from the ‘‘high-tech’’
composition of today’s contrast media.
References
1. Nyman U, Aspelin P, Boijsen E, et al. Obituary for Prof.
Torsten Almén. Acta Radiol 2016;57:387–388.
2. Almen T. Visipaque - A step forward. A historical review.
Acta Radiol Suppl 1995;399:2–18.
Chief editor
Corresponding author:
Arnulf Skjennald, Department of Radiology, Oslo, Norway
Email: a.skjennald@online.no