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JACC: CARDIOVASCULAR IMAGING
VOL. 1, NO. 4, 2008
© 2008 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/08/$34.00
PUBLISHED BY ELSEVIER INC.
DOI:10.1016/j.jcmg.2008.05.007
EDITORIAL COMMENT
Nephrogenic Systemic Fibrosis:
Considerations for the Cardiologist*
Neil M. Rofsky, MD
Boston, Massachusetts
The manuscript by Schietinger et al. (1) in this issue
of iJACC (JACC: Cardiovascular Imaging) assesses
patterns of late gadolinium enhancement (LGE) in
the myocardium of chronic hemodialysis patients.
The observation that the majority of LGE was not
infarct related but was tied to the degree of left
ventricular hypertrophy, particularly in dysfunctional
segments, led the authors to suggest that LGE patterns within the myocardium may be able to serve as a
clinical marker, perhaps for sudden death.
See page 450
However, the prospect for investigating such
potential has been quelled by the new reality of
nephrogenic systemic fibrosis (NSF). During the
course of the Schietinger et al. (1) study, an emerging awareness of NSF, particularly in this highestrisk chronic hemodialysis population, and the identification of a new NSF case within their cohort
forced its premature termination.
Nephrogenic systemic fibrosis is a systemic
fibrosing disorder strongly associated with the
administration of gadolinium-based contrast agents
(GBCAs) in patients with substantial renal disease
(2– 4). The available data suggest a 3% to 7%
prevalence in the vulnerable population (4,5), although prevalence determination is problematic (5).
First reported in 2000 by Cowper et al. (6) as a
unique fibrosing disorder that was recognized among
patients undergoing renal dialysis, an early term as*Editorials published in JACC: Cardiovascular Imaging reflect the views of
the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
From Harvard Medical School, Department of Radiology, Beth Israel
Deaconess Medical Center, Boston, Massachusetts. Dr. Rofsky is on the
Advisory Board and receives research support from GE Healthcare; is on
the Advisory Board and receives research support from Bayer Healthcare
Pharmaceuticals; and is a consultant for Epix Pharmaceuticals.
cribed to the condition, nephrogenic fibrosing dermopathy, emanated from its dermal manifestations.
The recognition of systemic involvement prompted
a change in the name of the disorder to NSF (7). The
clinical manifestations of NSF are highly variable
spanning from a tiny plaque on the lower extremities
to severe contractures and death. Not until 2006 was it
first suggested that some of the GBCAs may trigger
the development of NSF (2,3). The functional consequences of NSF are often debilitating and may be
fatal. Treatment is multidisciplinary, predominantly
supportive, and largely ineffective.
Nephrogenic systemic fibrosis is most commonly
observed in patients with at least stage 4 chronic
kidney disease (CKD), when the estimated glomerular filtration rate (eGFR) is ⬍30 ml/min per 1.73
m2, with a clear majority noted in dialysis patients.
While NSF has not been documented in CKD
patients having an eGFR ⬎30 ml/min per 1.73 m2,
it has been seen in acute renal failure patients with
higher eGFR values, particularly with concurrent
pro-inflammatory processes (4,8).
To highlight the risk posed to patients with
kidney problems, a black box warning on the
product labels of all 5 of the GBCAs approved in
the U.S. has been added in response to a request by
the U.S. Food and Drug Administration. A summary of some of the important observations regarding NSF follows. Most of the epidemiological data
have been gathered using the unreliable strategy of
self-reporting. Published studies are chiefly retrospective reviews of relatively small populations
(each typically ⬍40 individuals). The documentation of the type and dose of GBCA has been poor.
The largest number of cases is associated with
exposure to the GBCA, gadodiamide. The association between NSF and GBCA use is preponderant
but not universal (9). The onset of noticeable
disease is unpredictable with respect to the time of
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Rofsky
Editorial Comment
exposure, and there are relatively low numbers of
reported cases given the historical prolific use of
GBCAs in renal insufficiency patients.
The predominant mechanistic hypothesis for
NSF involves the liberation of free gadolinium (Gd)
from its binding molecule, thought to trigger an
inflammatory response. Support for this hypothesis
resides in data demonstrating gadolinium in skin
biopsy specimens of NSF patients (8) and in experimental studies in both humans (10) and animals
(11). However, an as yet unidentified cofactor may
be operative.
Gadolinium belongs to the lanthanide series, a
set of chemically related elements with atomic
numbers from 57 to 71 that have unpaired electrons. The interactions between the unpaired electrons of the gadolinium ion and the hydrogen nuclei
of water molecules in tissues augment image contrast.
However, the bare gadolinium metal ion is highly
toxic. Therefore, it is essential that it be bonded to
an organic moiety or ligand to provide a metal
chelate complex (e.g., Gd-DTPA, Gd-BOPTA,
Gd-DOTA, and so on) for altering image contrast.
The variable risk of NSF among the different
GBCAs may be attributable to differences in the
chemical stability of agents, a reflection of the
propensity with which they are likely to dissociate
and release free Gd3⫹ in vivo. The physical parameter that is most compelling to guide clinical practice from a chemistry perspective is the kinetic
stability of an agent (12). The greater the kinetic
stability, the less likely it is for an agent to dissociate. The biological relevance of the kinetic properties of several contrast agents was reported in a
study showing strong correlation between the dissociation rates of chelates in acid and the long-term
deposition of Gd3⫹ in rat tissues (11).
Given that the clinical and epidemiological data
are relatively sparse, the chemical and physical
considerations support the use of a subset of the
available Gd-chelates with strong kinetic stabilities,
the macrocyclic agents, since they are far less likely
to dissociate (12,13). This is particularly the case for
patients with an eGFR ⬍30 ml/min/1.73 m2. A
recent report showing no cases of NSF in long-term
hemodialysis patients after administration of the
macrocyclic agent (gadoteridol) supports this perspective (14).
Institutional policies and procedures are evolving
to address the exposure to GBCAs in patients at
risk for NSF. A variety of screening procedures to
identify patients with low eGFR rates, increased
attention to the types and doses of contrast agent
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 4, 2008
JULY 2008:457–9
administered, alterations in imaging strategies, and
education at all levels of the medical community are
important components to such initiatives. The use
of screening forms and routine venous sampling for
serum creatinine values before Gd-enhanced magnetic resonance imaging are becoming pervasive.
These procedures help address the limited awareness of kidney disease in patients with stage 4 and 5
CKD who are not yet on dialysis. However, circumstances in which a high-risk individual requires
a GBCA to facilitate their management will arise.
In this scenario, an informed consent process specifically addressing the risk for NSF should be
applied.
For myocardial scar and fibrosis imaging inversion recovery sequences with an inversion time
structured to null the normal myocardium are used
to optimize the contrast between the tissue retaining gadolinium (scar) and the healthy or viable
myocardium (15). Options to alter the time between contrast administration and imaging, to adjust inversion times, to use agents with high relaxivity (T1 “brightening” capability), and to image at
high field strength offer opportunities for dose
reduction with potential to reduce NSF risk
(16,17). Such optimization, coupled with the use of
macrocyclic agents, could broaden the opportunities
for efficacious imaging in patients at risk for NSF.
The increased imperative for contrast mediaindependent techniques capable of demonstrating
myocardial viability will revive important lines of
research in diffusion, phosphorus, and sodiumbased magnetic resonance evaluations (18 –20).
Prospective registries that have recently been
initiated or are soon to be, as mandated of the
manufacturers by the U.S. Food and Drug Administration, will likely generate more reliable data
regarding the incidence, prevalence, potential cofactors, and the degrees of severity of this disorder.
It is hoped that from such data refined strategies
will emerge to guide the best risk: benefit selections
for patients requiring GBCAs for their care.
Thus, the provocative data from Schietinger et al.
(1) cannot be further validated or advanced until
issues related to NSF in this population are adequately addressed. Knowledge regarding the risks of
NSF in this vulnerable group will help to minimize
this potentially devastating iatrogenic disorder.
Reprint requests and correspondence: Dr. Neil M. Rofsky,
Harvard Medical School, Department of Radiology, Beth
Israel Deaconess Medical Center, 330 Brookline Avenue,
Boston, Massachusetts 02215. E-mail: nrofsky@bidmc.
harvard.edu.
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 4, 2008
JULY 2008:457–9
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Rofsky
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Key Words: nephrogenic
systemic fibrosis y gadolinium y
safety y renal insufficiency y
contrast media.
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