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www.medscape.com
From Applied Radiology
Abstract and Introduction
Abstract
Kuo presents a thorough, fascinating, responsible and practical review of the history, epidemiology and etiology
of nephrogenic fibrosis. He identifies the populations at risk and makes useful recommendations in various
thorny practice situations. This superb article should be required reading for all involved with the practice of MRI.
Introduction
In the last 3 years, revelations linking gadolinium-based contrast agents(GBCAs) and nephrogenic systemic
fibrosis (NSF) have had atremendous impact on the utilization of enhanced magnetic resonance imaging (MRI)
in patients with kidney disease. Virtually unknown to the radiology community prior to 2006, NSF has generated
significant concern and confusion among radiologists, clinicians and patients.
NSF is a systemic fibrosing disorder with predominant skin involvement in most patients. In many patients, the
disease manifests as a rapidly progressive, crippling disorder akin to scleroderma. In the relatively brief period of
time since the emergence and recognition of NSF, policies have been developed, modified and remodified, as
physicians and regulatory agencies attempt to understand the magnitude of the problem and the risk-to-benefit
ratio of using GBCAs in patients with compromised renal function.
Since many physicians (including most radiologists) have not encountered a patient with NSF, the first goal of
this article is to familiarize the reader with the clinical manifestations of NSF. The second goal is to introduce a
strategy to reduce the risk of NSF. This strategy has three prongs: 1) defining those at risk; 2) identifying them in
practice, and; 3) minimizing their risk. This article reviews the controversies and proposes a strategy for NSF
risk reduction.
The Discovery and Evolution of NSF
Early in 1997, physicians at a Southern California medical center were confronted with a mysterious clinical
entity.[1,2] Several patients in their hemodialysis center began experiencing cutaneous induration and erythema
of the limbs unassociated with fever, but frequently accompanied by pruritus, and sometimes pain. These
patients experienced progressive hardening and thickening of the skin that did not resolve with dialysis.
Authors and Disclosures
Dr. Kuo is an Associate Professor, Department of Medicine, Section of Hematology/Oncology, University of
Arizona School of Medicine and a staff Radiologist at Southern Arizona Veterans Administration Hospital,
Tucson, AZ. Dr. Griffith is a Resident in Internal Medicine at the University of Chicago School of Medicine. Dr.
Abu-Alfa is an Associate Professor, Department of Internal Medicine, Section of Nephrology; Dr. Bucala is a
Professor, Department of Medicine, Section of Rheumatology; Ms. Carlson is a Physician Assistant,
Department of Dermatology; Dr. Girardi is an Associate Professor, Department of Dermatology; Dr. Weinreb is
a Professor, Department of Diagnostic Radiology; and, Dr. Cowper is an Associate Professor, Department of
Dermatology, Dermatopathology Service, Yale University School of Medicine, New Haven, CT.
MRI in the Era of Nephrogenic Systemic Fibrosis: Review,Controversies and Suggestions for Risk ReductionPhillip H. Kuo, MD, PhD; Ali Abu-Alfa, MD; Richard Bucala, MD, PhD; Jason Griffith, MD, PhD; Kacie Carlson, PA-C;
Michael Girardi, MD; Jeffrey Weinreb, MD; and Shawn Cowper, MD
Posted: 06/12/2009; Applied Radiology. 2009;38(4):22-33. 2009 Anderson Publishing, Ltd.
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investigation confirmed that nearly all patients with NSF (in whom records could be located) had been exposed
to GBCA in the weeks and months leading up to the development of NSF.
As these data were developing, additional evidence emerged in Europe, as Austrian researchers published their
first report of 5 cases of NSF associated with GBCA exposure. [10,11] This was followed within a few months by a
systematic survey carried out in Denmark[12] wherein the strength of the association between GBCA and NSF
became much clearer. Additional studies completed to date suggest the risk of a patient with renal disease
contracting NSF following exposure to GBCA ranges from 2%-6% [12-14] and that there may be differences in risk
between the GBCA available in the world today, as well as an associated increased risk among those with high-
dose exposures or high cumulative exposures.[15,16]
While the intricacies of the exposure and risk data are still being investigated, European and American medical
authorities havemoved to restrict the use of GBCA in patients with AKI or with stages 4 and 5 chronic kidney
disease. As additional analyses are completed it is expected that more specific recommendations will follow.
The current data support that minimization of dose and exposure to these agents will likely result in fewer and
less severe cases of NSF, and that selection of agents to avoid the possibility of dissociation of the gadolinium-
ligand complex will help to minimize the profound clinical effects of this devastating disease.
Clinical Presentation of NSF
NSF has been reported to affect individuals with ages that range from 8 to 87 years, including at least 10 cases
in the pediatric agerange.[17,18] NSF has been reported in the Americas, Europe and Asia, and it has been
documented among all ethnicities.[1,19-21] Numerous casereports and series have demonstrated that all patients
with NSF have renal insufficiency of varying severity.[22] The onset of NSF is variable and may occur days,
months or years after the onset of renal failure. There does not appear to be a relationship between cause of
renal impairment and NSF severity.[9] The relationship between degree of CKD and severity of NSF is not well
established. In cases associated with reversible renal dysfunction, including successful renal transplantation, the
return of normal renal function usually heralds an improvement in the cutaneous findings.[4,5,9,22,23]
Besides renal insufficiency, other associated factors have been suggested, including vascular procedures,[3,24]
hypercoagulabilty/thrombosis, [3,23-29] high-dose erythropoietin,[30] pulmonary fibrosis, local trauma and hepatic
disease.[6,30] Because of the sudden emergence and clustering of the initial cases, an infectious or toxic agent
was suspected but not readily identified.[2,31] It is now generally accepted that GBCAs used as contrast for
magnetic resonance imaging (MRI) studies are highly associated with the development ofNSF and in almost all
patients, the likely trigger.[10-12,32-35]
Patients with NSF may manifest a range of cutaneous lesions. The typical clinical course begins with swelling of
distal parts of the extremities and is usually followed in subsequent weeks by severe skin induration (Figure 1).
Involvement may extend to the more proximal extremities and lower abdomen. The skin induration may be
aggressive and associated with intermittent to constant pain, muscle restlessness and marked loss of skin
flexibility. In some cases, NSF progresses to marked physical disability characterized by almost complete loss ofrange of motion of all extremity joints (Figure 2).
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site of activation. Activation within the bone marrow may increase recruitment from the marrow into the
circulation. Activation in the circulation may increase extravasation of the CFs from the intravascular space into
the tissues. NSF is a systemic fibrosis, and the signals that would cause preferential fibrosis in one organ over
another remain unresolved. Activation in peripheral tissues/organs may result in increased proliferation of CFs,
release of cytokines and production of collagen. Perhaps not of coincidence, CFs are known to elaborate
fibrogenic growth factors such as TGF-1, which has been found in elevated levels in the involved skin of NSF
patients.[37]
Figure 3. The mechanism of activation of circulating fibrocytes (CF) by Gd/GBCA is unknown. The
Gd/GBCA may act directly on the CF or indirectly through other pathways involving cytokines or other
inflammatory mediators. Possible sites of CF activation include 1) within the bone marrow to increase
recruitment from the marrow into the circulation 2) in the circulation to increase extravasation from the
intravascular space to the tissues 3) in the peripheral tissues to proliferate, produce cytokines and increase
collagen production.
Other fibrotic diseases linked to circulating fibrocytes include idiopathic pulmonary fibrosis, [38] asthma,[39]
granuloma formation,[40,41] and hepatic fibrosis.[42] A better understanding of abnormal fibrocyte function in NSF
may facilitate the treatment of fibrotic diseases fromthe disease model of NSF and GBCA. [43]
NSF Prevention Strategy
Since there is no consistently effective therapy for the disease, it cannot be emphasized enough that prevention
is the best strategy. As disconcerting a thought as this is, radiologists are the vector for this disease. Different
GBCAs likely have varying propensitiesfor triggering NSF, but for the time being, every GBCA should be
considered capable of triggering NSF.
A prevention strategy has two major points:
Define and identify the population at risk in your practice.1.
Minimize risk to that susceptible population.2.
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Figure 4. Potential interventions to reduce the retention of Gd/GBCA can be divided into approaches that
reduce input and increase clearance.
Limited data suggest that coincident infection or inflammation at the time of GBCA administration increases the
risk for NSF.[48] These patients should be considered at greater risk when deciding to administer GBCA.
Are Some GBCAs Safer Than Others?
No GBCA can be considered absolutely free from the risk of triggering NSF. Both U.S. and European regulatory
agencies share this position. Therefore, until more definitive data become available, a conservative approach
would be to utilize similar preventive measures regardless of the GBCA given.
Currently, nine GBCAs are approved in the USA or Europe. The different structures of the ligands (shown in
Figure 5) bound to the gadolinium atom impart different imaging properties and stabilities. A comprehensive
review of the stabilities of the various GBCAs is beyond the scope of this article.
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Figure 5. Chemical structures of the gadolinium-based MR contrast agents approved in the USA or
Europe.
As displayed in Table 1 , GBCAs can be organized by the two most important structural factors for stability (ionic
versus nonionic and macrocyclic versus linear). The three linear ionic agents in orange are cleared both by
hepatic and renal mechanisms to varying degrees. The remainder of the agents are cleared nearly exclusively
by the kidney.
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Increasing epidemiologic and scientific data support that nonionic linear agents are more commonly associated
with the disease, which could be a function of a poorly understood mechanism involving their relatively lower
stabilities.[49-51] The macrocyclic agents are the most kinetically stable and are therefore expected to release the
least amount of free gadolinium under conditions of prolonged retention of GBCA in patients.[52] It also should be
noted that the two agents associated with the greatest number of NSF cases are also the two GBCAs that have
been used most extensively worldwide and that, in part, the disparity in the number of cases associated with the
various agents might be due to differences in usage and patient populations.
Three of the ionic linear agents (Gd-BOPTA, Gd-EOB-DTPA and Gadofosveset) are cleared by both renal and
hepatobiliary mechanisms to varying degrees. Gd-EOB-DTPA and Gadofosveset are approved in Europe and
are used for hepatic and blood pool imaging respectively. Hepatobiliary clearance derives from the protein-binding property of these agents. In comparison to the typical GBCA (with virtually exclusive dependence on
renal clearance), agents with a component of biliary excretion may decrease retention of Gd inpatients with
kidney disease. Unfortunately, the magnitude of this difference and the impact on the risk for NSF are unknown.
Therefore using an agent with both hepatobiliary and renal clearance properties is not recommended as a
method of reducing NSF risk.
Administering a lower dose of GBCA may increase the risk of a non-diagnostic scan and may result in a higher
total administered dose when a subsequent full dose is given to reach the diagnosis. Utilizing a high relaxivity
contrast agent (HRCA) like Gd-BOPTA, which has approximately twice the relaxivity as a conventional GBCA
with no protein binding, may allow reducing dose while maintaining efficacy.[53] However, lower doses have
been proven only for selected clinical applications, and one should be careful not to reduce the dose to
nondiagnostic levels in the interest of "safety."
Hemodialysis
Although GBCAs are rapidly cleared with a half-life of less than two hours in patients with normal renal function,
in chronic kidney disease half-life is prolonged and may exceed 30-120 hours.[12,54] Without immediate and
adequate dialysis, gadolinium chelate clearance from the serum is significantly prolonged after contrast-
enhanced MRI.[55] This prolonged residence time increases the likelihood of release of gadolinium from its
ligand. Free gadolinium ions can form complexes with anions such as phosphate and can then be retained in
tissues. Gadolinium in intracellular deposits has been detected in the skin of patients with NSF.[32,33]
At the Yale University School of Medicine, Gd-HP-DO3A is used in the rare dialysis patient who needs
intravenous contrast. It is absolutely not used in everyone because it is believed that there are more adverse
events other than NSF with this agent.
Table 1. GBCAs Approved in the USA or Europe Organized by Ionic vs. Nonionic and
Macrocyclic vs. Linear
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Initial controversy regarding the use of prompt hemodialysis for patients already on hemodialysis after
administration of GBCA hasessentially resolved. Initially, some experts recommended hemodialysis as soon as
possible (within 2-3 hours) as a potential means of decreasing the risk of NSF. [34]
The FDA and EU regulatory agencies recommend prompt hemodialysis. However, it is critical to understand that
there are limited data to support that hemodialysis will decrease the risk of NSF and therefore hemodialysis
should not be perceived as a reliable means of NSF prevention. The recommendation is based on the
hypothetical concept that hemodialysis would remove the GBCA from the bloodstream and therefore decrease
the dose that would remain in the body, potentially for years. Since most MRI studies are conducted in an
outpatient setting, coordination with hemodialysis centers to achieve this goal seems arduous but is achievable.
An early study demonstrated that patients who received hemodialysis within 24 hours still developed NSF.[52]
However, because of the absence of controls, investigators could not ascertain whether the risk and severity of
the NSF was reduced. Further, hemodialysis was not started until at least 9 hours postexposure. The time
window for effective hemodialysis of GBCA and the optimal hemodialysis regimen has not been rigorously
determined. From the limited available data it appears that if hemodialysis is going to be effective it needs to be
done as soon as possible after the GBCA exposure.[46]
Consider Alternative Imaging Without GBCA
Avoid the use of GBCA by utilizing alternative imaging that does not require GBCA. In consultation with the
ordering physician, we consider alternative imaging or nonimaging modalities that may provide the requested
clinical diagnostic data at a lower potential risk. The benefits and risks of an MR study with the addition of
contrast should be evaluated on an individual basis for each patient.
Table 2 illustrates decisions for alternative imaging in five case presentations with history and imaging protocols.
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If the potential benefit of the enhanced MRI is judged to outweigh the risk, then obtain informed consent and
administer the lowest dose necessary. Subsequent to the enhanced MRI, perform prompt hemodialysis in those
patients already on hemodialysis and possibly those with AKI and rising creatinine.[53] Monitoring of the patient
over the coming weeks and months also seems logical. If the patient develops NSF and is fortunate enough to
benefit from therapy, early intervention with physical therapy and other reported therapeutic measures might be
helpful.
Conclusion
NSF is a systemic fibrotic disease often associated with great morbidity, and in the most severe cases,
increased mortality. The greatest known risk factor for NSF is receiving a GBCA in a setting of diminished renal
function. Arguably, administration of GBCA is the sine quo non of NSF. Since there is no reliable therapy at this
time, prevention is the key.
Table 2. Case Examples of GBCA Imaging Alternatives
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Calculations of eGFR are inherently inaccurate for a small percentage of patients and are inappropriate in the
setting of acute kidney injury. At present, patients with stage 4 and 5 CKD are considered at risk. While patients
with stage 3 CKD are theoretically at risk, the risk is extremely low and in general the benefit of the enhanced
scan would outweigh the risk.
Infection or inflammation coincident with administration of GBCA may increase risk for NSF. No GBCA should
be considered completely free from the risk of causing NSF, but the macrocyclic class of GBCAs are likely safer.
Risk increases with increasing dose ofGBCA and therefore the lowest dose sufficient to answer the indication for
the MRI should be used. Physicians need to exercise caution in performing multiple enhanced MRIs in a short
period of time. Utilizing an HRCA may allow for decreased dose without compromising efficacy.
Prompt hemodialysis may hypothetically decrease the risk of NSF and is therefore recommended. There are no
data at this time to support this practice and therefore hemodialysis cannot be considered completely protective.
Consider the full-range of alternativesto enhanced MRI which may mean a less efficient work-up. Sometimes, an
enhanced MRI is the gold-standard and the benefits willoutweigh the risks.
Understanding of this issue is still rapidly evolving so it is imperative to keep abreast of this topic.
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Acknowledgments
The authors would like to thank Geri Mancini for her invaluable assistance preparing the figures for this article.
Applied Radiology. 2009;38(4):22-33. 2009 Anderson Publishing, Ltd.
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