Nephrogenic systemic fibrosis cannot be induced by
administering Gadolinium bound contrast agents in rats
Poster No.:
C-1138
Congress:
ECR 2010
Type:
Scientific Exhibit
Topic:
Contrast Media
Authors:
R. D. Langer , D. E. Lorke , K. F. W. Neidl v Gorkom , G.
1
1
1
1
1
1
2 1
Petroianu , S. Azimullah , S. M. Nurulain , U. Speck ; Al Ain/AE,
2
Berlin/DE
Keywords:
Nephrogenic systemic fibrosis, Gadolinium bound contrast agents
(GBCA), Animal experiments
DOI:
10.1594/ecr2010/C-1138
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Page 1 of 23
Purpose
In 2000 Cowper (1) published the first case of 'nephrogenic fibrosing dermopathy' (NFD),
a systemic disorder with severe tissue fibrosis, predominantly in the skin, subcutaneous
tissues, and underlying muscles. Later the nomenclature was changed to nephrogenic
systemic fibrosis (NSF) (2-5).
The pathomechanism of the disease still remains unclear. Mainly patients with end
stage renal disease (ESRD) after intravenous (IV) injections of Gadolinium bound
contrast agents (GBCA) are affected, especially individuals undergoing dialysis, with preinflammatory conditions, after vascular surgery, and after liver transplantation (1-3, 5-23).
In 2008 Golding (24) described a significantly increased incidence of NSF in patients
with renal failure plus manifest infections rising from 0.26% to 6.7% in patients with renal
failure plus infection (24). Some NSF patients develop severe disabilities; some even
consequently die (2, 15, 16, 25-29).
Histologically a hypercellularity with an increase in fibroblasts, and an alteration of the
normal pattern of collagen can be detected in the skin and subcutis, frequently together
with deposits of mucin (2, 30, 31). The result is a thickening and hardening of the
skin, mainly at the extremities, with a 'wooden' appearance, and subsequently with
contractures of the involved joints (2).
In several NSF patients other organs, such as heart, lungs, diaphragms, esophagus,
and kidneys are affected. No effective therapy exists so far; however, rapid correction
of renal function is generally beneficial, resulting in a standstill of the NSF; in rare cases
symptoms and findings may even reverse (2, 16, 17, 25, 32). Dr. SE Cowper at Yale
University (New Haven, Connecticut, USA) is in charge of an international NSF registry.
To date it contains > 315 patients with NSF worldwide (2). More than 95% of all registered
NSF patients have been exposed to Gadolinium bound contrast agents within one - up
to eight weeks prior to the onset of symptoms (2, 5, 6, 12, 15, 17-19, 21, 23, 33, 34, 36).
The majority of patients (~ 90%) received gadodiamide (Omniscan®, GE Healthcare
Princeton, NJ, USA), followed by exposure to gadopentetate dimeglumine (Magnevist®,
Bayer Schering, Berlin, Germany), and in few cases to gadoversetamide (OptiMARK®,
Covidien Imaging Solutions, Hazelwood, MO, USA). Very few patients have been
registered after other GBCA injections, or after administration of different GBCA. As a
result the Food and Drug Administration (FDA) of the United States of America (USA)
issued a black box warning relating to the indications of GBCA (25). Specific guidelines
were also published by the European Society of Urogenital Radiology (4). At the
beginning of December 2009 a FDA panel suggested further restrictions for gadodiamide
and gadopentetate dimeglumine for use in patients with severe renal problems.
The underlying relationship between GBCA and NSF is not finally determined; however,
data exist to make these contrast agents suspicious (2, 5, 6, 9, 17-19, 21, 23, 31,
Page 2 of 23
35, 37-42). Recently Gadolinium (or Gadolinium chelate) deposition could be detected
in cutaneous and subcutaneous tissue biopsies from specimens of NSF patients (41,
43-48).
Circulating fibrocytes have also been associated with the pathogenesis of NSF (7). In
2008 Edward reported that these circulating fibrocytes are being activated by GBCA, and
cause an increased synthesis of collagen resulting in skin changes, typical for NSF (30).
No more NSF cases were recorded at big US centers after change of the type of the
administered GBCA, and after reduction of the dosage to 0.1 mmol/ kg BW in patients
with ESRD and other predisposing factors (6).
Several researchers conducted animal experiments in rodents (31, 38, 41, 42, 46, 49,
50), in order to establish an animal model to further elucidate the pathogenesis of
human NSF. Sieber carried out studies in rats, administering daily repeated high doses
of intravenously (IV) injected GBCA, i.e. 2.5 mmol Gadolinium per kilogram (kg) body
weight (BW), five IV injections per week for four weeks, compared with negative controls,
treated with IV saline. Further animal studies were conducted by Grant (38), administering
5-10 mmol/ kg BW Omniscan®, and 5 mmol/ kg BW Magnevist®, other Gadolinium
bound substances, and Gadolinium salts. Additionally, 5/6-nephrectomized rats were
investigated to mimic ERSD. During all rodent experiments, clinical signs were recorded.
After five weeks (31, 46, 50), or three weeks, respectively (38), rats were sacrificed,
and histological examinations of the skin, subcutis, muscles, and internal organs were
obtained.
In a subsequent study, Sieber investigated seven different GBCA. All rats were monitored
during the treatment, and some Han-Wistar rats (CRL: WI [GIx/BRL/HAN] IGS BR)
showed severe hair loss, and skin lesions after gadodiamide (Omniscan ®) (42). We
expected confirming these findings would allow us to investigate the pathomechanism of
Gd-chelates, and to obtain better knowledge of the pathophysiology of NSF.
Methods and Materials
The institutional animal review board approved the animal experiments (FMHS Animal
Research Ethics Committee; No. A8/ 07). All experiments were conducted according
to the 'guiding principles in the care of and use of laboratory animals' (Council of the
American Physiological Society).
Experimental animals: Wistar rats (HsdOla-WI) were purchased from Harlan Laboratories
(Harlan Laboratories, Oxon, England). All animals (HsdOla-WI) used, were subsequently
bred at our animal house from the original stock. 8-10 week-old male rats with an average
Page 3 of 23
3
weight (± SD) of 192g (± 28 g) were kept in polypropylene cages (43 x 22.5 x 20.5 cm ;
six rats per cage) in climate- and access-controlled rooms (23 ± 1°C; 50 ± 4% humidity).
The day/night cycle was 12h/12h; food and water were available ad libidum. The food
was standard maintenance diet from Emirates Feed Factory (Abu Dhabi, UAE).
To each of the experiments six rats were randomly assigned. They received
intraperitoneal (IP) injections of seven different GBCA at 2.5 mmol/kg, as published by
Sieber (42), and 5.0 mmol/kg, respectively. Numbers of rats allocated to the individual
experiments, the tested GBCA, and the number and time frame of the intraperitoneal (IP)
injections are listed in table 1. Intraperitoneal GBCA injections were chosen in order to
extend the animals' exposure to the compounds, and to mimic prolonged circulation and
tissue exposure to GBCA in patients with ESRD (13). After IP injection the GBCA must
be absorbed by the peritoneum before they reach the circulation and can be eventually
renally excreted.
Rats were weighted weekly; inspection and palpation of the skin and underlying tissue
was carried out twice per day to discover changes, like fur loss, reddening, ulceration,
thickening or induration.
After one additional week of observation without further IP GCBA injections all rats
were sacrificed. Specimens of multiple organs, such as skin, subcutis, skeletal muscles,
kidneys, lungs, heart, liver, spleen were dissected and fixed by immersion in 4% buffered
paraformaldehyde. Specimens were subsequently dehydrated in ascending series of
ethanol, and embedded in paraffin wax (Paraplast, Tyco Healthcare GmbH, Neustadt
Donau, Germany), using xylene as an intermedium. 5 µm sections of all organs were
obtained, rehydrated in descending series of ethanol, and stained with hematoxylin eosin
(H&E), and Masson trichrome to visualize collagen fibers. Examiners were blinded during
histological assessment.
A grading of the epidermis, dermis and subcutis with reference to the density of collagen
fibers, fibroblasts and leukocytes in the three layers was conducted: normal (grade 0)
observed in sham controls, mildly elevated (grade 1), moderately elevated (grade 2) and
severely elevated (grade 3). Likewise, vacuoles in renal tubules were graded as grade
0: normal (occasional, very small vacuoles), grade 1: mildly elevated (small vacuoles in
most tubules), grade 2: moderately elevated (large vacuoles occupying less than 50% of
the cytoplasm of all tubules), and grade 3: severely elevated (large vacuoles occupying
over 50% of the cytoplasm of all tubules).
Venous blood samples were drawn weekly for measurement of blood urea nitrogen
(BUN) and creatinine values.
All experiments were carried out with the doses, and the seven GBCA, listed in table
1. Dissections were equally performed for all groups as described above. Furthermore
IP injections of 5.0 mmol/kg BW per day were performed with six rats per group for
gadodiamide (Omniscan®), a non-ionic linear GBCA, and for gadopentetate dimeglumine
Page 4 of 23
(Magnevist®), an ionic linear compound (table 1). After IV administration of these two
GBCA most human NSF cases were reported in descending order.
Wistar
rats per
group (n)
GBCA
Dose
GBCA /
Concentration
day
GBCA
Injections/
week (n)
Time of
treatment
(weeks)
Total
injections
6
Gadodiamide 0.5mmol/
(Omniscan®)
ml
2.5 mmol/
kg BW
5
4
(n)
20
6
Gadodiamide 0.5mmol/
(Omniscan®)
ml
5.0 mmol/
kg BW
5
4
20
6
0.5mmol/
Gadopentetate
ml
dimeglumine
2.5 mmol/
kg BW
5
4
20
5.0 mmol/
kg BW
5
4
20
(Magnevist®)
6
0.5mmol/
Gadopentetate
ml
dimeglumine
(Magnevist®)
6
0.5mmol/
Gadoversetamide
ml
(OptiMARK®)
2.5 mmol/
kg BW
5
4
20
6
Gadobenate 0.5mmol/
ml
dimeglumine
2.5 mmol/
kg BW
5
4
20
(Multihance®)
6
Gadobutrol 1.0mmol/
ml
(Gadovist
®)
2.5 mmol/
kg BW
5
4
20
6
Gadoteridol 0.5mmol/
ml
(Prohance
®)
2.5 mmol/
kg BW
5
4
20
6
Gadoterate 0.5mmol/
ml
dimeglumine
2.5 mmol/
kg BW
5
4
20
(Dotarem
®)
Table 1: Animal experiments: GBCA, dosage and time frame
Page 5 of 23
Results
For the first seven experiments rats of each group received 2.5 mmol/kg BW per day of
the respective GBCA as intraperitoneal injections. During the entire surveillance period,
i.e. five weeks, not a single rat was diagnosed with fur loss, thickening, reddening of
the skin, ulcerations, scab formation, subcutaneous induration (Fig. 1), characteristic for
findings observed in human NSF, and also in recent animal experiments. Laboratory
results of BUN, creatinine, and the BUN/creatinine ratios were as follows: rats, treated
with Omniscan® at doses of 2.5 mmol, showed a mild elevation of creatinine during
week five, after 20 injections. The median creatinine value rose from the average of
0.5mg/dl to 1.2mg/dl, which is still in the upper normal range. All other rats did not show
any elevation of creatinine, with values between 0.4 and 0.7 mg/dl. BUN and the BUN/
creatinine ratio stayed also within normal ranges. In those rats treated with higher daily
doses of Omniscan® and Magnevist® (5.0 mmol/kg BW)), an increasing elevation of
creatinine, starting in week three, and dropping again in week five, after cessation of the
IP GBCA injections, was recorded. All laboratory values for creatinine and BUN, however,
stayed within upper normal ranges. After treatment with Omniscan® and Magnevist®
at 5.0 mmol/kg BW per day, all rats showed a significant weight loss (Fig. 2), most
pronounced in weeks three and four; all animals, however, regained weight in week five,
i.e. after cessation of the IP injections.
One rat with 5.0 mmol Magnevist® treatment unexpectedly expired during week four.
Histological examinations of the deceased rat did not show any epidermal, dermal or
subcutaneous pathology or changes at the inner organs, typical for human NSF.
Histological evaluation of all rats, sacrificed after five weeks (after 20 IP injections
at 2.5mmol/kg BW or 5.0 mmol/kg BW), did not reveal any pathology. Thickness of
the epidermis, dermis and subcutis was normal in all groups without any signs of
acanthosis, ulcerations or other changes in cutis, subcutis and underlying muscles (grade
0). Exemplary images demonstrate histological findings in rats, treated for four weeks
with gadodiamide (Fig 3, 4) and gadopentetate dimeglumine (Fig. 5, 6) at doses of 2.5
and 5.0 mmol/kg each, and with IP saline (Fig. 7).
Density of collagen fibers, number and shape of fibroblasts, and leucocytes were equal
in GBCA-treated animals, and in control rats. No signs of inflammation or fibrosis, like
increased cellularity, or leukocyte infiltration were detected. Histological specimens of all
inner organs, such as lungs, heart, diaphragms, liver, spleen, kidneys, did not show any
evidence of increased collagen deposit, fibroblastic proliferation, increase in numbers of
fibroblasts, edema, perivascular fibrosis, thrombi, or leukocyte infiltration, anticipated and
reported as characteristic NSF changes (26, 27, 34, 51).
Page 6 of 23
Evaluation of kidney specimens demonstrated vacuolization in the proximal tubules at
different degrees. Rats treated with 5.0 mmol/kg Omniscan® or Magnevist® showed
severe vacuolization of the proximal tubules in the cortex of the kidneys (grade 3)
(Fig. 8). Vacuolization of cortical renal proximal tubules was also severe (grade 3)
in animals treated with 2.5 mmol/kg Dotarem®. In rats treated with Omniscan® and
Magnevist®, OptiMARK®, Gadovist®, Prohance® or Multihance® at 2.5 mmol/ kg a
moderate increase in renal proximal tubular vacuoles was revealed (grade 2). Kidneys
of all sham control animals showed only occasionally very small vacuoles in the proximal
tubules after IP saline treatment (grade 0) (Fig. 9).
Limitations
Several limitations apply to our animal experiments. The principal limitation is the primary
question if an animal model using rodents is valid to stimulate NSF changes, equivalent
to human NSF findings. Histological changes in rat experiments carried out by Pietsch,
Sieber, and Hope appear to notably differ from histological skin findings in human NSF
(31, 38). It was already emphasized that non-human primates would be a more suitable
species for such experiments (38).
Moreover in our study intraperitoneal injections were chosen under the premise of
a longer exposure of the animals to the administered GBCA; however, this type of
injection is different from other animal experiments, applying intravenous injections. A
possible explanation might be that a high peak concentration is important for Gadolinium
accumulation in the skin which may be missing after IP injection; however, comparative
pharmacokinetic data on IV and IP injections are not available to date.
In addition our animals, in accordance with naïve rats in other experiments (31, 38, 41,
42), do not present with renal failure, nor with additional other predisposing factors for
NSF, nor with manifest infections (24, 31, 52), which have obviously been proven as
essential conditions for the development of human NSF.
Images for this section:
Page 7 of 23
Fig. 1: Rat after 20 IP injections of gadodiamide at 2.5 mmol/kg BW for 4 weeks; normal
aspect of the back skin (after shaving).
Page 8 of 23
Fig. 2: Two rats in supine position (sham control below; gadodiamide-treated rat above):
weight loss of the gadodiamide-treated rat at 5.0 mmol/kg BW (20 IP injections for 4
weeks), no weight loss of the saline-treated rat. No abnormalities at the abdominal skin
of both rats (after shaving).
Fig. 3: Histological section of epidermis, dermis, and underlying muscle of a rat after
4 weeks of IP treatment with gadodiamide at 2.5 mmol/kg BW: thickness of epidermis,
dermis, and density of collagen fibers are normal.
Page 9 of 23
Fig. 4: Histological section of epidermis, dermis, and underlying muscle of a rat after
4 weeks of IP treatment with gadodiamide at 5.0 mmol/kg BW: thickness of epidermis,
dermis, and density of collagen fibers are normal.
Page 10 of 23
Fig. 5: Histological section of epidermis, dermis, and underlying muscle of a rat after 4
weeks of IP treatment with gadopentetate dimeglumine at 2.5 mmol/kg BW: thickness of
epidermis, dermis, and density of collagen fibers are normal.
Page 11 of 23
Fig. 6: Histological section of epidermis, dermis, and underlying muscle of a rat after 4
weeks of IP treatment with gadopentetate dimeglumine at 5.0 mmol/kg BW: thickness of
epidermis, dermis, and density of collagen fibers are normal.
Page 12 of 23
Fig. 7: Histological section of epidermis, dermis, and underlying muscle of a rat after 4
weeks of IP treatment with saline solution (sham control): thickness of epidermis, dermis,
and density of collagen fibers are normal.
Page 13 of 23
Fig. 8: Histological section of a kidney of a gadodiamide-treated rat at 5.0 mmol/kg BW:
massive vacuolization of the cortical renal proximal tubules, grade 3.
Page 14 of 23
Fig. 9: Histological section of a kidney of a saline-treated rat (sham control): very small,
occasional vacuoles of cortical renal proximal tubules, grade 0.
Page 15 of 23
Conclusion
•
•
•
•
•
Our results indicate that macroscopic or histological findings, comparable
to human NSF, do not develop in rats after long-term intraperitoneal highdose injections of any of the seven tested GBCA at the applied doses.
The IP injected doses of the used GBCA stand for a 25- to 50-fold of the
recommended single doses of GBCA in humans.
Histological specimen of the cutis, subcutis and underlying skeletal muscles
did not reveal any pathology, as published by other authors, such as fur
loss, ulcerations, acanthosis, or crust formation.
Kidney specimens showed vacuolization in the proximal tubules after
treatment with 5.0mmol/kg gadodiamide and gadopentetate dimeglumine.
These vacuoles are well known after IV GBCA administration, and do not
correlate with any deficiency in renal function (53). Harpur found such
vacuolization of the proximal tubular cells in rodents already after a single
dose of >0.5 mmol/ kg BW gadodiamide (53).
All other examined inner organs did not show any pathological findings,
similar to those described in human NSF, neither macroscopically, nor
histologically.
In accordance with the statements of other authors (26, 38, 52) we conclude
that NSF development is most probably multifactorial so that chemicophysical characteristics of GBCA, such as stability constants alone, cannot
be the only reason for the development of NSF.
ACKNOWLEDGEMENT
•
•
•
The authors express their sincere gratitude to the FMHS Research Grant
Committee for funding this project under number NP/08/22.
Furthermore we would like to honestly thank Prof. Dr. U Speck, Charité,
Berlin, for the donation of the administered GBCA for all animal experiments.
We would like to kindly acknowledge Prof. Dr. M Agarwal, FMHS, for
conducting creatinine and BUN tests from the collected blood samples, and
Mr. S Singh, FMHS, for professional technical assistance.
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Personal Information
Presenting author:
Ruth D Langer MD PhD
Present position:
Professor of Radiology
Associate Dean for Clinical Affairs
Faculty of Medicine and Health Sciences [FMHS]/ UAE University
Senior Consultant at Tawam Hospital Al Ain UAE in Affiliation with Johns Hopkins Medical
International [FMHS Teaching Hospital]
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Tel/ Fax: +971 3 7137 124/ 235 / +971 3 767 2001
Mobile: +971 50 663 41 61
Email: [email protected]
Member of the FMHS Priority Research Groups 'Genetics' and 'Oncology'
Previous positions:
1994-1997 Full Professor and Chair of the Dept of Diagn Radiology at the University of
Essen/ Germany
1995-1997 medical Director of the center of Radiology at the University of Essen/
Germany
Images for this section:
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Fig. 1: Ruth D Langer Portrait
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