mri in the era of nephrogenic systemic fibrosis- review, controversies and suggestions for risk...

7/31/2019 MRI in the Era of Nephrogenic Systemic Fibrosis- Review, Controversies and Suggestions for Risk Reduction

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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.

References

Cowper SE, Robin HS, Steinberg SM, et al. Scleromyxoedema-like cutaneous diseases in renal-dialysis

patients. Lancet. 2000;356:1000-1001.

1.

Cowper SE, Su LD, Bhawan J, et al. Nephrogenic fibrosing dermopathy. Am J Dermatopathol.

2001;23:383-393.

2.

Cowper SE. Nephrogenic fibrosing dermopathy: The first 6 years. Curr Opin Rheumatol. 2003;15: 785-

790.

3.

Cowper S. Nephrogenic Fibrosing Dermopathy Website. In, 2001-2007. Available at

http://www.pathmax.com/dermweb/.

4.

Fibrosing skin condition among patients with renal disease--United States and Europe 1997-2002.

MMWR. 2002;25-26

5.

DeHoratius DM, Cowper SE. Nephrogenic systemic fibrosis: An emerging threat among renal patients.

Semin Dial. 2006;19:191-194.

6.

Cowper SE, Bucala R. Nephrogenic fibrosing dermopathy: Suspect identified, motive unclear. Am J

Dermatopathol. 2003;25:358.

7.

Ting WW, Stone MS, Madison KC, Kurtz K. Nephrogenic fibrosing dermopathy with systemic

involvement. Arch Dermatol. 2003;139:903-906.

8.

Swartz RD, Crofford LJ, Phan SH, et al. Nephrogenic fibrosing dermopathy: A novel cutaneous fibrosing

disorder in patients with renal failure. Am J Med. 2003;114:563-572.

9.

Grobner T. Gadolinium--A specific trigger for the development of nephrogenic fibrosing dermopathy and

nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21:1104-1108.

10.

Grobner T. Gadolinium--A specific trigger for the development of nephrogenic fibrosing dermopathy and

nephrogenic systemic fibrosis? [erratum appears in Nephrol Dial Transplant. 2006;21(6):1745]. Nephrol

Dial Transplant. 2006; 21(4):1104-1108.

11.

Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: Suspected causative role of

gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol. 2006;17:2359

-2362.

12.

Deo A, Fogel M, Cowper SE. Nephrogenic systemic fibrosis: A population study examining the

relationship of disease development to gadolinium exposure. Clin J Am Soc Nephrol. 2007;2:264-267.

13.

Lauenstein TC, Salman K, Morreira R, et al. Nephrogenic systemic fibrosis: Center case review.J Magn

Reson Imaging. 2007;26:1198-1203.

14.

Collidge TA, Thomson PC, Mark PB, et al. Gadolinium-enhanced MR imaging and nephrogenic systemic

fibrosis: Retrospective study of a renal replacement therapy cohort.Radiology. 2007;245:168-175.

15.

Kanal E, Broome DR, Martin DR, Thomsen HS. Response to the FDA's May 23, 2007, nephrogenic

systemic fibrosis update. Radiology. 2008; 246:11-14.

16.




13/14


14/14

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.

Medicines and Healthcare Products Regulatory Agency (MHRA). Nephrogenic systemic fibrosis (NSF)

with gadolinium-containing magnetic resonance imaging (MRI) contrast agents--Update. June 26, 2007.

Available at http://www.mhra.gov.uk/Safetyinformation/index.htm

44.

Poggio ED, Nef PC, Wang X, et al. Performance of the Cockcroft-Gault and modification of diet in renal

disease equations in estimating GFR in ill hospitalized patients. Am J Kidney Dis. 2005; 46:242-252.

45.

Prince MR, Zhang H, Morris M, et al. Incidence of nephrogenic systemic fibrosis at two large medical

centers. Radiology. 2008; 248:807-816.

46.

Broome DR, Girguis MS, Baron PW, et al. Gadodiamide-associated nephrogenic systemic fibrosis: Why

radiologists should be concerned. AJR Am J Roentgenol. 2007;188:586-592.

47.

Golding LP, Provenzale JM. Nephrogenic systemic fibrosis: Possible association with a predisposing

infection. AJR Am J Roentgenol. 2008;190: 1069-1075.

48.

Edward M, Quinn JA, Mukherjee S, et al. Gadodiamide contrast agent 'activates' fibroblasts: a possible

cause of nephrogenic systemic fibrosis. J Pathol. 2008;214:584-593.

49.

Kuo PH. Gadolinium-containing MRI contrast agents: Important variations on a theme for NSF.J Am Coll

Radiol. 2008; 5:29-35.

50.

Sieber MA, Pietsch H, Walter J, et al. A preclinical study to investigate the development of nephrogenic

systemic fibrosis:A possible role for gadolinium-based contrastmedia. Invest Radiol. 2008;43:65-75.

51.

Idee JM, Port M, Raynal I, et al. Clinical and biological consequences of transmetallation induced by

contrast agents for magnetic resonance imaging: A review. Fundam Clin Pharmacol. 2006;20:563-576.

52.

Kirchin MA, Runge VM. Contrast agents for magnetic resonance imaging: Safety update. Top Magn

Reson Imaging. 2003;14:426-435.

53.

Abu-Alfa A. The impact of NSF on the care of patients with kidney disease. J Am Coll Radiol. 2008; 5:45-

52

54.

Joffe P,Thomsen HS, Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal

insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis.Acad

Radiol. 1998;5:491-502.

55.


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