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Nephrogenic Systemic Fibrosis: Clinical Review and Education for Nurse Practitioners
Nephrogenic Systemic Fibrosis: Clinical Review and Education for Nurse Practitioners Stefania Lew and Mirella Vasquez Brooks
ABSTRACT In the past decade, nephrogenic systemic fibrosis has emerged as a new, severe, painful, disabling, and fibrosing disease of the skin and systemic tissues associated with the common denominators, advanced renal insufficiency, and exposure to gadolinium, an element used in magnetic resonance procedures.This disease mimics other cutaneous diseases with thickening and hardening of the skin of the extremities, yet it uniquely affects numerous organ systems such as the lungs, liver, or muscles.There is no effective treatment, making prevention the priority. Practitioners must identify patients at risk and exercise extreme caution when ordering magnetic resonance procedures in those patients. Keywords: fibrosis, gadolinium, nephrogenic, NSF, systemic 344
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eginning March 1997, Cowper and colleagues1 angiography using magnetic resonance (MR) with conidentified 15 renal-dialysis patients across the trast medium containing gadolinium (Gd).These patients United States who had developed a disease showed the clinical evidence of NSF within 2 to 4 weeks characterized by cutaneous thickening and hardening following exposure to the contrast. Similarly, in 2006, of the skin that was associated with hyperpigmentation, Marckmann et al10 reported identification of 13 patients in papules, and subcutaneous nodules of the extremities. Denmark who had been exposed to contrast-enhanced They reported that the disease histologically and clinimagnetic resonance imaging (MRI) procedures with cally resembled scleromyxoedema. With several differgadodiamide prior to the onset of NSF symptoms. In a ences they were hesitant to label the disease such and retrospective cohort study (N = 190), Rydahl et al11 identherefore set forth a multi-center collaborative study to tified 18 patients with NSF, all with chronic kidney injury determine what might be responsible and if its emerwith glomerular filtration rate < 15 mL/min/1.73 m2 or gence was related to renal-dialysis treatments. on dialysis at time of exposure to gadodiamide.They Nephrogenic systemic fibrosis (NSF) was originally report that the patients received doses of gadodiamide termed nephrogenic fibrosing dermopathy (NFD) because typically at 0.3 mmol/kg. Since the first reported emerof the fibrosing cutaneous findings gence of this new phenomenon 2,3 in patients receiving dialysis. by Cowper et al1 in 2001, more Subsequent studies showed some than 215 patients with NSF In response to reported patients had deeper fibrosis have been reported to the involving muscles, fascia, lungs, NFD/NSF Registry Project at findings, the FDA has issued and heart.4 It was decided a name Yale University, the Food and a public health advisory representing systemic disease was Drug Administration (FDA), revealing the epidemiological needed; henceforth, the term the American College of association of NSF and Gdnephrogenic systemic fibrosis.5 Radiology, the International NSF is a fibrosing disorder Center for Nephrogenic containing contrast agents that clinically features thickening Fibrosing Dermopathy during MR procedures. and hardening of the skin of the Research, and the European extremities and torso, showing Society of Urogenital expansion and fibrosis of the dermis that appears to be Radiology.12 With these subsequent reports, the epidemiassociated with circulating fibrocytes that may mobilize ology of NSF in patients with renal disease appeared to be in response to certain events such as surgery or tissue associated with Gd-containing contrast medium. Contrast injury.6 Nephrogenic systemic fibrosis predominantly agents Omniscan and Magnevist were identified as being occurs in patients who have advanced renal insufficiency, used and 85% of the cases reportedly received Omniscan.8 with approximately 90% being on either hemodialysis or In response to reported findings, the FDA has issued a peritoneal dialysis.7 With the remaining 10% of patients public health advisory revealing the epidemiological assowith renal insufficiency having not had any dialysis, it ciation of NSF and Gd-containing contrast agents during appeared that dialysis might not be causing the disorder MR procedures. As it has not yet been determined that 8 as once was originally thought. Given the high suspithese 2 agents directly cause NSF, it suggests a possible cion of the relationship between renal insufficiency and class effect.13 NSF, nurse practitioners (NPs) in primary care or subspecialties share an important role in prevention of the ETIOLOGY disease.The purpose of this paper is to introduce and There are 5 Gd-containing contrast agents approved by explore the theories behind NSF, describe risk factors the FDA for use during MRI: gadodiamide, gadoverseand clinical manifestations of the disease, and provide tamide, gadopentetate dimeglumine, gadobenate dimeginformation on possible prevention. lumine, and gadoteridol.13 Gadolinium is considered a paramagnetic rare earth metallic element that possesses a BACKGROUND ferromagnetic property, which is strongly attracted by a In 2006, Grobner9 described a series of cases in Austria magnet.8,14,15 This quality makes the agents with Gd usewhere 5 dialysis patients with NSF had undergone ful for magnetic resonance angiography (MRA) and
B
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MRI procedures to enhance visualization of abnormal with an elimination half-life of approximately 2 hours.9 structures throughout the body. Free Gd is toxic to tisGrobner9 reports that in patients with renal impairment 14,15 sues and has been identified as a precipitate in liver, the elimination half-life will range from 30 to 120 hours. lymph nodes, and bones, as well as shown to obstruct Saitoh et al18 evaluated dialyzability and safety of Gd in calcium-ion passage, and interfere with cell membrane patients on hemodialysis, finding an average of 73.8%, and intracellular processes.15,16 To prevent toxic effects of 92.4%, and 98.9% of the gadodiamide dose eliminated by Gd, it is sequestered by binding to a non-toxic substance days 1, 3, and 5, respectively.These data parallel that called a chelate; it is the disassociation of the gadolinium reported by Joffe et al19 in 1998, who demonstrated an from that chelate that is thought to participate in resultaverage of 65% of the gadodiamide dose removed via an ing adverse affects.14-16 initial hemodialysis session, with 98% and 99% removed Gadolinium-containing agents are classified on the during subsequent sessions. Peritoneal dialysis does not basis of the chelate biochemical structure and charge; effectively clear the gadodiamide, showing a 69% clear14-16 macrocyclic versus linear and ionic versus nonionic. ance after 22 days of continuous ambulatory peritoneal The macrocyclic ionic chelate bind more tightly to Gd dialysis.19 Interestingly, in a retrospective chart review by than do the linear; they are reportedly more stable and Broome et al,2 the development of NSF is reported in 10 therefore have a lower disassociation rate; whereas a nonof their 12 subjects despite the fact that they were diaionic linear chelate commonly disassociates.14,15 The Gdlyzed within 2 days of receiving Gd-containing contrast containing contrast agent gadodiamide, is reportedly medium. more likely than others to release the free Gd through During the past decade, it has been shown that varithe process called transmetallation.The disassociated Gd ous factors appear in the development of NSF; 2 of chelates become available to compete with iron, magnewhich appear predominant—reduced renal function and sium, zinc, copper, or calcium, leaving the free Gd to exposure to a Gd-containing contrast agent.The severity compete for binding with phosphate or carbonate.17 In a of NSF is speculated to be related to a correlation of the 3 small pilot study, High et al dose exposed over time; howassessed the presence of Gd and ever, cases have developed in other metals in a single histologthose after receiving only a ic section of soft tissue and skin minimal-single dose in addition During the past decade, it sampled from patients with NSF to not occurring in those who has been shown that various and Gd exposure versus a negaare in the same risk stratificafactors appear in the tive control. Gadolinium was tion after receiving the agent.20 development of NSF; two of detected in 4 of the 13 samples Many investigators have been from 7 patients with NSF as well looking for co-factors that may which appear predominant— as the presence of deposits of contribute to the development reduced renal function and other metals such as iron, copof NSF; for example, high doses exposure to a Gd-containing per, and zinc, leading to the idea of erythropoietin, iron, and fercontrast agent. of carrier molecule participation ritin,21,22 high levels of serum in the development of NSF. No ionized calcium and Gd was detected in the control phosphate,22 metabolic acidosis,9 23 subject who was not exposed. One patient sample anion gap, chronic inflammation,12 and recent renal showed the finding of Gd in an unaffected site, leading transplant failure.24 There appears to be no apparent unithe authors to speculate that certain tissues may retain versal co-factor.20 Gd in sites adjacent to inflammation or endothelial trauThe exact environment in which the process of transmetallation results or with which other concrete ma such as areas adjacent to peripherally inserted central factors contribute remains unclear. It is known that catheters (PICC) or dialysis fistula creation.3 The Gd-containing products are commonly used for when there is impaired renal function, the Gd chelates MRA at doses greater than needed for MRI, either remain in the body for a longer period of time. This, cumulatively or as a single dose.14,15 When these agents together with disturbed metabolic condition associated are used in healthy individuals, they are cleared rapidly with renal impairment, possibly set the environment 346
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DIAGNOSIS Laboratory findings reveal underlying renal insufficiency and any accompanying co-morbidities; these paired with the clinical presentation, NSF is established and confirmed histopathologically.4,8,21 A histological examination of a specimen from a deep biopsy of a lesion is considered the gold standard for diagnosis of NSF.4,8 On CLINICAL FEATURES a basic level, the tissue will reveal a proliferation of Swaminathan and Shah21 and Cowper8 describe an acute elongated fibrocytes (dermal spindal cells) with taperpresentation with the time frame varying widely. ing nuclei that form a dense connecting network of Features in the acute phase mimic systemic “inflammacollagen and elastin.8 tory response syndrome: fever, hypotension, acute kidDifferential diagnosis for NSF includes but is not limney injury, anemia, leukoerythroblastic picture, thrombo- ited to scleroderma, scleromyxedema, amyloidosis, calcicytopenia or thrombocytosis, phylaxis, carcinoid syndrome, leukocytosis, eosinophilia, borreliosis, and eosinophiliamonocytosis, elevated ␥-glumyalgia syndrome.4,8 The relatamyl peptidase, elevated lipase, tionship of Gd-containing Lack of definitive cause and and elevated D-dimer.”21(p.2636) contrast agents, presence of pathogenesis of NSF yields Swaminathan and Shah report renal insufficiency, absence of limited measures of the addition of elevated C-reacfacial lesion involvement, and treatment with proven tive protein, low serum albuthe absence of serum monomin, elevated serum ferritin, and clonal paraprotein helps to difefficacy. a decreased total iron-binding ferentiate NSF from the other capacity are regularly present in conditions.4,8,21 Additionally, this presentation, as well. Cowper8 points out, patients Appearance of early onset lesions is typically symmetric, recently exposed to gadodiamide (Omniscan) may developing predominantly on the limbs and torso, demonstrate falsely low serum calcium levels due to specifically between the ankles and mid thighs, and gadodiamide interference with some hospital laboratory between the wrists and mid upper arms. Areas of tests using colorimetry. involvement are edematous and sometimes warm to palpation. Patients may complain of pain in their limbs or TREATMENT muscle weakness. The primary lesions may be skin-colLack of definitive cause and pathogenesis of NSF yields ored or with erythema and papules that fuse together limited measures of treatment with proven efficacy.4 into erythematous plaques, eventually hardening, showLinfert et al27 report there have been several interventions ing a peau d’orange appearance with brawny plaques described, however, their effectiveness has not been reproresembling a thickened woody texture.4,8,21,25 Early cliniducible. It is thought that because all cases of NSF have cal presentation has been misdiagnosed as cellulitis, pan- been associated with renal impairment, recovery of renal niculitis, drug reactions, or edema.4,8 As joints become function would result in improvement.27 In some involved, contractures may develop, leading to decrease instances of acute kidney injury this has been the case; in use, which has led some patients to become wheelimprovement of the renal function has terminated the chair-bound within days or weeks, with the affected progression allowing slow resolution of the symptoms.8 areas possibly accompanied with pruritis, tingling, palpa- Swartz et al26 noted partial recovery in patient with acute ble warmth, and moderate to severe pain.4,21,25,26 Other kidney injury appearance of lesions, pain, and deformity; characteristics associated with NSF, seen in variations however, in the other patients, follow-up continued to among those diagnosed, include yellowish scleral nodshow pain, intermittent inflammation of the affected areas ules, hyperpigmentation of extremities,4,8,21 and multiple with persistent skin lesions, as well as progressive funcorgan involvement including development of acute pan- tional decline at 30 months.26 Goddard et al24 describes a creatitis and vascular thrombosis.4,21 patient with a case of NSF that resolved with successful to favorably lend transmetallation in this patient population, leading to the disassociation of Gd chelates, which leads to precipitation with other anions in the tissues, causing deposits.16 What causes some in this population to develop NSF while others do not is uncertain.
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transplantation and subsequently recurred after the graft 4, or 5 (GFR < 60 mL/min/1/73 m2),32 or in those with failed. Cowper8 and Linfert et al27 report extracorporeal acute injury unless the benefit or receiving it clearly outphotopheresis (ECP) as a widely, best-documented theraweighs the potential risks; when diagnostic information is py to date for patients with NSF who are not candidates essential and not obtainable with a non-contrastfor transplant.While the exact mechanism of this treatenhanced MR. Use in these circumstances constitutes ment is unclear, it is believed the procedure may involve receiving an educated-informed patient consent and decrease in cell-mediated immunity.27 In 2003, Baron et using the lowest possible dose (< 0.1 mmol/kg).7,8,31,34 The al28 describes successful treatment of NSF with plasmaACR guidelines also indicate that those patients on dialypheresis in 3 liver transplant recipients.Two of the sis receive hemodialysis within 2 hours after exposure to patients, however, were experiencing recovery in renal Gd-containing agents, as well as to consider a repeat dialfunction prior to the diagnosis of NSF. Other therapies ysis again within 24 hours. that resulted with anecdotal success include treatment with sodium thiosulfate to theoretically act as a chelator CONCLUSION of free Gd that has been released, pentoxifylline, glucoIn the past 10 years, there have been numerous investigacorticoids, intravenous immunoglobulin, thalidomide, tions into the accumulation of what is being considered phototherapy, intralesional interferon-a, and topical cala previously unknown disease. Given the potential dancipotriene with physical therapy.27 Ultimately, the goal ger of NSF, randomized controlled trials are not advocatshould be the return of renal function whenever ed, making the testing of strategies and treatments diffi8,27 possible. cult to assess. Despite the current recommendations, the The literature unanimously agrees that the best recliterature reports that there are no data to support that ommendation to date is prevention; however, the recomfollowing them will decrease the risk of developing NSF mendations regarding the avoidance of Gd-containing after exposure to Gd-containing media, even when treatagents vary.The FDA recomment with hemodialysis mends using an alternative nonimmediately follows.There is Gd-containing agent whenever no yet-proven linkage between possible in patients considered to Gd-based contrast media and When the diagnosis of NSF is have acute to severe chronic the development of NSF in suspected based on clinical renal impairment, being defined patients with impaired renal as a glomerular filtration rate function; however, there is the manifestations, it should be (GFR) < 30 mL/min/1/73 m2, notion of the use as a possible confirmed by biopsy and the with further recommendation to trigger.The diagnosis of NSF relationship between dialyze the individual promptly if is also associated with other suspected disease and (s)he does receive a Gd-containsuspected triggers associated ing agent.29 The European with inflammation; it may be contrast medium exposure Community Pharmacovigilance the coupling of these triggers should be investigated. Working Party states the use of that potentiates the developGd-containing agents is “strictly ment of the disease. If this is contraindicated” in patients with the possible case, identification renal failure and should not be used in those with GFR of renal impairment and these triggers in patients is pru< 30 mL/min/1/73 m2, or in those who have had or will dent in clinical practice. have liver transplantation.30 The American College of When the diagnosis of NSF is suspected based on Radiology (ACR) Guidance Document for Safe clinical manifestations, it should be confirmed by biopsy Magnetic Resonance Practices recommends that any and the relationship between suspected disease and conpatient with any level of renal impairment not to specifitrast medium exposure should be investigated.The specif31 cally receive gadodiamide for MR procedures. ic MR media needs to be documented and the temporal Additionally, they recommend avoidance of all Gd-contime line after exposure delineated. Possible cases of NSF taining media in patients with National Kidney should then be reported to the FDA through the Foundation (NKF) criteria for renal failure staging of 3, MedWatch33 program and to the International Center for 348
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Nephrogenic Fibrosing Dermopathy Research (ICNFDR).34 All physicians, nurse practitioners, patients, and other members of the health care team must be educated about this disease. Presently, there is no treatment for NSF; therefore, prevention is the priority. References 1. Cowper SE, Robin HS, Steinberg SM, et al. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet. 2001;356:1000-1001. 2. Broome DR, Girguis MS, Baron PW, et al. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. Am J Radiol. 2007;188:586-592. 3. High WA, Ayers RA, Chandler J, Zito G, Cowper SE. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol. 2007;56:21-26. 4. Galan A, Cowper SE, Bucala R. Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy). Curr Opin Rheumatol. 2007;18:614-617. 5. Cowper SE. Nephrogenic systemic fibrosis: the nosological and conceptual evolution of nephrogenic fibrosing dermopathy. Am J Kidney Dis. 2005;46(4):763-765. 6. Moreno-Romero JA, Segura S, Mascaró JM Jr, et al. Nephrogenic systemic fibrosis: a case series suggesting gadolinium as a possible aetiological factor. Br J Dermatol. 2007;157:783-787. 7. Grobner T, Prischl FC. Patient characteristics and risk factors for nephrogenic systemic fibrosis following gadolinium exposure. Semin. Dial. 2008;21(2):135-139. 8. Cowper SE. Nephrogenic systemic fibrosis: a review and exploration of the role of gadolinium. Adv Dermatol. 2007;23:131-54. 9. Grobner T. Gadolinium-a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006; 21:1104-1106. 10. Markmann 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. 11. Rydahl C, Thonsen HS, Marckmann P. High prevalence of nephrogenic fibrosis in chronic renal failure patients exposed to gadodiamide, a gadolinium-containing magnetic resonance contrast agent. Invest Radiol. 2008;43(2):141-144. 12. Sadowski EA, Bennett LK, Chan MR, et al. Nephrogenic systemic fibrosis: risk factors and incidence. Radiology. 2007;243(1):148-157. 13. U.S. Food and Drug Administration. Public Health Advisory. Gadoliniumcontaining contrast agents for magnetic resonance imaging (MRI): Omniscan, OpitiMARK, Magnevist, Prohance, and MultiHance. Available at: http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm. Accessed February 10, 2008. 14. Peak AS, Sheller A. Risk factors for developing gadolinium-induced nephrogenic systemic fibrosis. Ann Pharmacother. 2007;41:1481-1485. 15. Perazella MA, Rodby RA. Gadolinium use in patients with kidney disease: a cause for concern. Semin Dial. 2007;20(3):179-185. 16. Thakral C, Alhariri J, Abraham JL. Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications. Contrast Media Mol Imaging. 2007;2:199-205. 17. Ersoy H, Rybicki FJ. Biochemical safety profiles of gadolinium-based extracellular contrast agents and nephrogenic systemic fibrosis. J Magn Reson Imaging. 2007;26:1190-1197. 18. Saitoh T, Hayasaka K, Tanaka Y, Kuno T, Nagura Y. Dialyzability of gadodiamide in hemodialysis patients. Radiat Med. 2006;24(6):445-451. 19. 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(7):491-502. 20. Thomsen HS, Marckmann P, Logager VB. Nephrogenic systemic fibrosis (NSF): a late adverse reaction to some of the gadolinium based contrast agents. Cancer Imag. 2007;7:130-137. 21. Swaminathan S, Shah SV. New insights into nephrogenic systemic fibrosis. J Am Soc Nephrol. 2007;18:2636-2643. 22. Markmann P, Skov L, Rossen K, Heaf JG, Thomsen HS. Case-control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant. 2007 22(11):3174-3178. 23. Khurana A, Runge VM, Narayanan M, Greene JF, Nickel AE. Nephrogenic systemic fibrosis, a review of 6 cases temporarily related to gadodiamide injection (Omniscan). Invest Radiol. 2007;42(2):139-145. 24. Goddard DS, Magee CC, Lazar AJ, Miller DM. Nephrogenic fibrosing dermopathy with recurrence after allograft failure. J Am Acad Dermatol. 2007;56(5 Suppl):S109-111.
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25. Knopp EA, Cowper SE. Nephrogenic systemic fibrosis: early recognition and treatment. Semin Dial. 2008;21(2):123-128. 26. Swartz RD, Crofford LJ, Phan SH, Ike RW, Su LD. Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure. Am J Med. 2003;114(7):563-572. 27. Linfert DR, Schell JO, Fine DM. Treatment of nephrogenic systemic fibrosis: limited options but hope for the future. Semin Dial. 2008;21(2):155-159. 28. Baron PW, Cantos K, Hillebrand DJ, et al. Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis. Am J Dermatopathol. 2003;25(3):204-209. 29. U.S. Food and Drug Administration. Information for health care professionals. Gadolinium-based contrast agents for magnetic resonance imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, ProHance) Available at: http://www.fda.gov/cder/drug/InfoSheets/ HCP/gcca_200705.htm. Accessed February 10, 2008. 30. Medicines and Healthcare Products Regulatory Agency. Increased risk of nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis and gadolinium-containing MRI contrast agents. Public Assessment Report. Available at: http://www.mhra.gov.uk/Safetyinformation/ Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/ CON2030229. Accessed March 26, 2008. 31. Kanel E, Barkovich AJ, Bell C, et al. ACR guidance document for safe MR practices: 2007. Am J Radiol. 2007;188:1-27. Available at: http://www.acr.org/ SecondaryMainMenuCategories/quality_safety/MRSafety/safe_mr07.aspx. Accessed February 10, 2008. 32. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, of Stages of Chronic Kidney Disease. Available at: http://www.kidney.org/professionals/KDOQI/ guidelines_ckd/p4_class_g1.htm. Accessed March 3, 2008. 33. FDA MedWatch reporting system. Available at: http://www.fda.gov/ medwatch/report/hcp.htm. Accessed March 3, 2008. 34. International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR). Available at: http://www.icnfdr.org. Accessed March 3, 2008.
Stefania Lew, BSN, RN, ANP-BC, is the clinical coordinator at the Fresenius Medical Care Dialysis Clinic in Kaneoher, HI. She can be reached at [email protected]. Mirella Vasquez Brooks, PhD, FNP-BC, APRN, is an associate professor in the graduate division at the University of Hawaii at Manoa. In compliance with national ethical guidelines, the authors report no relationships with business or industry that would pose a conflict of interest. 1555-4155/09/$ see front matter © 2009 American College of Nurse Practitioners doi:10.1016/j.nurpra.2008.10.011
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ABSTRACT In the past decade, nephrogenic systemic fibrosis has emerged as a new, severe, painful, disabling, and fibrosing disease of the skin and systemic tissues associated with the common denominators, advanced renal insufficiency, and exposure to gadolinium, an element used in magnetic resonance procedures.This disease mimics other cutaneous diseases with thickening and hardening of the skin of the extremities, yet it uniquely affects numerous organ systems such as the lungs, liver, or muscles.There is no effective treatment, making prevention the priority. Practitioners must identify patients at risk and exercise extreme caution when ordering magnetic resonance procedures in those patients. Keywords: fibrosis, gadolinium, nephrogenic, NSF, systemic 344
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eginning March 1997, Cowper and colleagues1 angiography using magnetic resonance (MR) with conidentified 15 renal-dialysis patients across the trast medium containing gadolinium (Gd).These patients United States who had developed a disease showed the clinical evidence of NSF within 2 to 4 weeks characterized by cutaneous thickening and hardening following exposure to the contrast. Similarly, in 2006, of the skin that was associated with hyperpigmentation, Marckmann et al10 reported identification of 13 patients in papules, and subcutaneous nodules of the extremities. Denmark who had been exposed to contrast-enhanced They reported that the disease histologically and clinimagnetic resonance imaging (MRI) procedures with cally resembled scleromyxoedema. With several differgadodiamide prior to the onset of NSF symptoms. In a ences they were hesitant to label the disease such and retrospective cohort study (N = 190), Rydahl et al11 identherefore set forth a multi-center collaborative study to tified 18 patients with NSF, all with chronic kidney injury determine what might be responsible and if its emerwith glomerular filtration rate < 15 mL/min/1.73 m2 or gence was related to renal-dialysis treatments. on dialysis at time of exposure to gadodiamide.They Nephrogenic systemic fibrosis (NSF) was originally report that the patients received doses of gadodiamide termed nephrogenic fibrosing dermopathy (NFD) because typically at 0.3 mmol/kg. Since the first reported emerof the fibrosing cutaneous findings gence of this new phenomenon 2,3 in patients receiving dialysis. by Cowper et al1 in 2001, more Subsequent studies showed some than 215 patients with NSF In response to reported patients had deeper fibrosis have been reported to the involving muscles, fascia, lungs, NFD/NSF Registry Project at findings, the FDA has issued and heart.4 It was decided a name Yale University, the Food and a public health advisory representing systemic disease was Drug Administration (FDA), revealing the epidemiological needed; henceforth, the term the American College of association of NSF and Gdnephrogenic systemic fibrosis.5 Radiology, the International NSF is a fibrosing disorder Center for Nephrogenic containing contrast agents that clinically features thickening Fibrosing Dermopathy during MR procedures. and hardening of the skin of the Research, and the European extremities and torso, showing Society of Urogenital expansion and fibrosis of the dermis that appears to be Radiology.12 With these subsequent reports, the epidemiassociated with circulating fibrocytes that may mobilize ology of NSF in patients with renal disease appeared to be in response to certain events such as surgery or tissue associated with Gd-containing contrast medium. Contrast injury.6 Nephrogenic systemic fibrosis predominantly agents Omniscan and Magnevist were identified as being occurs in patients who have advanced renal insufficiency, used and 85% of the cases reportedly received Omniscan.8 with approximately 90% being on either hemodialysis or In response to reported findings, the FDA has issued a peritoneal dialysis.7 With the remaining 10% of patients public health advisory revealing the epidemiological assowith renal insufficiency having not had any dialysis, it ciation of NSF and Gd-containing contrast agents during appeared that dialysis might not be causing the disorder MR procedures. As it has not yet been determined that 8 as once was originally thought. Given the high suspithese 2 agents directly cause NSF, it suggests a possible cion of the relationship between renal insufficiency and class effect.13 NSF, nurse practitioners (NPs) in primary care or subspecialties share an important role in prevention of the ETIOLOGY disease.The purpose of this paper is to introduce and There are 5 Gd-containing contrast agents approved by explore the theories behind NSF, describe risk factors the FDA for use during MRI: gadodiamide, gadoverseand clinical manifestations of the disease, and provide tamide, gadopentetate dimeglumine, gadobenate dimeginformation on possible prevention. lumine, and gadoteridol.13 Gadolinium is considered a paramagnetic rare earth metallic element that possesses a BACKGROUND ferromagnetic property, which is strongly attracted by a In 2006, Grobner9 described a series of cases in Austria magnet.8,14,15 This quality makes the agents with Gd usewhere 5 dialysis patients with NSF had undergone ful for magnetic resonance angiography (MRA) and
B
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MRI procedures to enhance visualization of abnormal with an elimination half-life of approximately 2 hours.9 structures throughout the body. Free Gd is toxic to tisGrobner9 reports that in patients with renal impairment 14,15 sues and has been identified as a precipitate in liver, the elimination half-life will range from 30 to 120 hours. lymph nodes, and bones, as well as shown to obstruct Saitoh et al18 evaluated dialyzability and safety of Gd in calcium-ion passage, and interfere with cell membrane patients on hemodialysis, finding an average of 73.8%, and intracellular processes.15,16 To prevent toxic effects of 92.4%, and 98.9% of the gadodiamide dose eliminated by Gd, it is sequestered by binding to a non-toxic substance days 1, 3, and 5, respectively.These data parallel that called a chelate; it is the disassociation of the gadolinium reported by Joffe et al19 in 1998, who demonstrated an from that chelate that is thought to participate in resultaverage of 65% of the gadodiamide dose removed via an ing adverse affects.14-16 initial hemodialysis session, with 98% and 99% removed Gadolinium-containing agents are classified on the during subsequent sessions. Peritoneal dialysis does not basis of the chelate biochemical structure and charge; effectively clear the gadodiamide, showing a 69% clear14-16 macrocyclic versus linear and ionic versus nonionic. ance after 22 days of continuous ambulatory peritoneal The macrocyclic ionic chelate bind more tightly to Gd dialysis.19 Interestingly, in a retrospective chart review by than do the linear; they are reportedly more stable and Broome et al,2 the development of NSF is reported in 10 therefore have a lower disassociation rate; whereas a nonof their 12 subjects despite the fact that they were diaionic linear chelate commonly disassociates.14,15 The Gdlyzed within 2 days of receiving Gd-containing contrast containing contrast agent gadodiamide, is reportedly medium. more likely than others to release the free Gd through During the past decade, it has been shown that varithe process called transmetallation.The disassociated Gd ous factors appear in the development of NSF; 2 of chelates become available to compete with iron, magnewhich appear predominant—reduced renal function and sium, zinc, copper, or calcium, leaving the free Gd to exposure to a Gd-containing contrast agent.The severity compete for binding with phosphate or carbonate.17 In a of NSF is speculated to be related to a correlation of the 3 small pilot study, High et al dose exposed over time; howassessed the presence of Gd and ever, cases have developed in other metals in a single histologthose after receiving only a ic section of soft tissue and skin minimal-single dose in addition During the past decade, it sampled from patients with NSF to not occurring in those who has been shown that various and Gd exposure versus a negaare in the same risk stratificafactors appear in the tive control. Gadolinium was tion after receiving the agent.20 development of NSF; two of detected in 4 of the 13 samples Many investigators have been from 7 patients with NSF as well looking for co-factors that may which appear predominant— as the presence of deposits of contribute to the development reduced renal function and other metals such as iron, copof NSF; for example, high doses exposure to a Gd-containing per, and zinc, leading to the idea of erythropoietin, iron, and fercontrast agent. of carrier molecule participation ritin,21,22 high levels of serum in the development of NSF. No ionized calcium and Gd was detected in the control phosphate,22 metabolic acidosis,9 23 subject who was not exposed. One patient sample anion gap, chronic inflammation,12 and recent renal showed the finding of Gd in an unaffected site, leading transplant failure.24 There appears to be no apparent unithe authors to speculate that certain tissues may retain versal co-factor.20 Gd in sites adjacent to inflammation or endothelial trauThe exact environment in which the process of transmetallation results or with which other concrete ma such as areas adjacent to peripherally inserted central factors contribute remains unclear. It is known that catheters (PICC) or dialysis fistula creation.3 The Gd-containing products are commonly used for when there is impaired renal function, the Gd chelates MRA at doses greater than needed for MRI, either remain in the body for a longer period of time. This, cumulatively or as a single dose.14,15 When these agents together with disturbed metabolic condition associated are used in healthy individuals, they are cleared rapidly with renal impairment, possibly set the environment 346
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DIAGNOSIS Laboratory findings reveal underlying renal insufficiency and any accompanying co-morbidities; these paired with the clinical presentation, NSF is established and confirmed histopathologically.4,8,21 A histological examination of a specimen from a deep biopsy of a lesion is considered the gold standard for diagnosis of NSF.4,8 On CLINICAL FEATURES a basic level, the tissue will reveal a proliferation of Swaminathan and Shah21 and Cowper8 describe an acute elongated fibrocytes (dermal spindal cells) with taperpresentation with the time frame varying widely. ing nuclei that form a dense connecting network of Features in the acute phase mimic systemic “inflammacollagen and elastin.8 tory response syndrome: fever, hypotension, acute kidDifferential diagnosis for NSF includes but is not limney injury, anemia, leukoerythroblastic picture, thrombo- ited to scleroderma, scleromyxedema, amyloidosis, calcicytopenia or thrombocytosis, phylaxis, carcinoid syndrome, leukocytosis, eosinophilia, borreliosis, and eosinophiliamonocytosis, elevated ␥-glumyalgia syndrome.4,8 The relatamyl peptidase, elevated lipase, tionship of Gd-containing Lack of definitive cause and and elevated D-dimer.”21(p.2636) contrast agents, presence of pathogenesis of NSF yields Swaminathan and Shah report renal insufficiency, absence of limited measures of the addition of elevated C-reacfacial lesion involvement, and treatment with proven tive protein, low serum albuthe absence of serum monomin, elevated serum ferritin, and clonal paraprotein helps to difefficacy. a decreased total iron-binding ferentiate NSF from the other capacity are regularly present in conditions.4,8,21 Additionally, this presentation, as well. Cowper8 points out, patients Appearance of early onset lesions is typically symmetric, recently exposed to gadodiamide (Omniscan) may developing predominantly on the limbs and torso, demonstrate falsely low serum calcium levels due to specifically between the ankles and mid thighs, and gadodiamide interference with some hospital laboratory between the wrists and mid upper arms. Areas of tests using colorimetry. involvement are edematous and sometimes warm to palpation. Patients may complain of pain in their limbs or TREATMENT muscle weakness. The primary lesions may be skin-colLack of definitive cause and pathogenesis of NSF yields ored or with erythema and papules that fuse together limited measures of treatment with proven efficacy.4 into erythematous plaques, eventually hardening, showLinfert et al27 report there have been several interventions ing a peau d’orange appearance with brawny plaques described, however, their effectiveness has not been reproresembling a thickened woody texture.4,8,21,25 Early cliniducible. It is thought that because all cases of NSF have cal presentation has been misdiagnosed as cellulitis, pan- been associated with renal impairment, recovery of renal niculitis, drug reactions, or edema.4,8 As joints become function would result in improvement.27 In some involved, contractures may develop, leading to decrease instances of acute kidney injury this has been the case; in use, which has led some patients to become wheelimprovement of the renal function has terminated the chair-bound within days or weeks, with the affected progression allowing slow resolution of the symptoms.8 areas possibly accompanied with pruritis, tingling, palpa- Swartz et al26 noted partial recovery in patient with acute ble warmth, and moderate to severe pain.4,21,25,26 Other kidney injury appearance of lesions, pain, and deformity; characteristics associated with NSF, seen in variations however, in the other patients, follow-up continued to among those diagnosed, include yellowish scleral nodshow pain, intermittent inflammation of the affected areas ules, hyperpigmentation of extremities,4,8,21 and multiple with persistent skin lesions, as well as progressive funcorgan involvement including development of acute pan- tional decline at 30 months.26 Goddard et al24 describes a creatitis and vascular thrombosis.4,21 patient with a case of NSF that resolved with successful to favorably lend transmetallation in this patient population, leading to the disassociation of Gd chelates, which leads to precipitation with other anions in the tissues, causing deposits.16 What causes some in this population to develop NSF while others do not is uncertain.
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transplantation and subsequently recurred after the graft 4, or 5 (GFR < 60 mL/min/1/73 m2),32 or in those with failed. Cowper8 and Linfert et al27 report extracorporeal acute injury unless the benefit or receiving it clearly outphotopheresis (ECP) as a widely, best-documented theraweighs the potential risks; when diagnostic information is py to date for patients with NSF who are not candidates essential and not obtainable with a non-contrastfor transplant.While the exact mechanism of this treatenhanced MR. Use in these circumstances constitutes ment is unclear, it is believed the procedure may involve receiving an educated-informed patient consent and decrease in cell-mediated immunity.27 In 2003, Baron et using the lowest possible dose (< 0.1 mmol/kg).7,8,31,34 The al28 describes successful treatment of NSF with plasmaACR guidelines also indicate that those patients on dialypheresis in 3 liver transplant recipients.Two of the sis receive hemodialysis within 2 hours after exposure to patients, however, were experiencing recovery in renal Gd-containing agents, as well as to consider a repeat dialfunction prior to the diagnosis of NSF. Other therapies ysis again within 24 hours. that resulted with anecdotal success include treatment with sodium thiosulfate to theoretically act as a chelator CONCLUSION of free Gd that has been released, pentoxifylline, glucoIn the past 10 years, there have been numerous investigacorticoids, intravenous immunoglobulin, thalidomide, tions into the accumulation of what is being considered phototherapy, intralesional interferon-a, and topical cala previously unknown disease. Given the potential dancipotriene with physical therapy.27 Ultimately, the goal ger of NSF, randomized controlled trials are not advocatshould be the return of renal function whenever ed, making the testing of strategies and treatments diffi8,27 possible. cult to assess. Despite the current recommendations, the The literature unanimously agrees that the best recliterature reports that there are no data to support that ommendation to date is prevention; however, the recomfollowing them will decrease the risk of developing NSF mendations regarding the avoidance of Gd-containing after exposure to Gd-containing media, even when treatagents vary.The FDA recomment with hemodialysis mends using an alternative nonimmediately follows.There is Gd-containing agent whenever no yet-proven linkage between possible in patients considered to Gd-based contrast media and When the diagnosis of NSF is have acute to severe chronic the development of NSF in suspected based on clinical renal impairment, being defined patients with impaired renal as a glomerular filtration rate function; however, there is the manifestations, it should be (GFR) < 30 mL/min/1/73 m2, notion of the use as a possible confirmed by biopsy and the with further recommendation to trigger.The diagnosis of NSF relationship between dialyze the individual promptly if is also associated with other suspected disease and (s)he does receive a Gd-containsuspected triggers associated ing agent.29 The European with inflammation; it may be contrast medium exposure Community Pharmacovigilance the coupling of these triggers should be investigated. Working Party states the use of that potentiates the developGd-containing agents is “strictly ment of the disease. If this is contraindicated” in patients with the possible case, identification renal failure and should not be used in those with GFR of renal impairment and these triggers in patients is pru< 30 mL/min/1/73 m2, or in those who have had or will dent in clinical practice. have liver transplantation.30 The American College of When the diagnosis of NSF is suspected based on Radiology (ACR) Guidance Document for Safe clinical manifestations, it should be confirmed by biopsy Magnetic Resonance Practices recommends that any and the relationship between suspected disease and conpatient with any level of renal impairment not to specifitrast medium exposure should be investigated.The specif31 cally receive gadodiamide for MR procedures. ic MR media needs to be documented and the temporal Additionally, they recommend avoidance of all Gd-contime line after exposure delineated. Possible cases of NSF taining media in patients with National Kidney should then be reported to the FDA through the Foundation (NKF) criteria for renal failure staging of 3, MedWatch33 program and to the International Center for 348
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Nephrogenic Fibrosing Dermopathy Research (ICNFDR).34 All physicians, nurse practitioners, patients, and other members of the health care team must be educated about this disease. Presently, there is no treatment for NSF; therefore, prevention is the priority. References 1. Cowper SE, Robin HS, Steinberg SM, et al. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet. 2001;356:1000-1001. 2. Broome DR, Girguis MS, Baron PW, et al. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. Am J Radiol. 2007;188:586-592. 3. High WA, Ayers RA, Chandler J, Zito G, Cowper SE. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol. 2007;56:21-26. 4. Galan A, Cowper SE, Bucala R. Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy). Curr Opin Rheumatol. 2007;18:614-617. 5. Cowper SE. Nephrogenic systemic fibrosis: the nosological and conceptual evolution of nephrogenic fibrosing dermopathy. Am J Kidney Dis. 2005;46(4):763-765. 6. Moreno-Romero JA, Segura S, Mascaró JM Jr, et al. Nephrogenic systemic fibrosis: a case series suggesting gadolinium as a possible aetiological factor. Br J Dermatol. 2007;157:783-787. 7. Grobner T, Prischl FC. Patient characteristics and risk factors for nephrogenic systemic fibrosis following gadolinium exposure. Semin. Dial. 2008;21(2):135-139. 8. Cowper SE. Nephrogenic systemic fibrosis: a review and exploration of the role of gadolinium. Adv Dermatol. 2007;23:131-54. 9. Grobner T. Gadolinium-a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006; 21:1104-1106. 10. Markmann 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. 11. Rydahl C, Thonsen HS, Marckmann P. High prevalence of nephrogenic fibrosis in chronic renal failure patients exposed to gadodiamide, a gadolinium-containing magnetic resonance contrast agent. Invest Radiol. 2008;43(2):141-144. 12. Sadowski EA, Bennett LK, Chan MR, et al. Nephrogenic systemic fibrosis: risk factors and incidence. Radiology. 2007;243(1):148-157. 13. U.S. Food and Drug Administration. Public Health Advisory. Gadoliniumcontaining contrast agents for magnetic resonance imaging (MRI): Omniscan, OpitiMARK, Magnevist, Prohance, and MultiHance. Available at: http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm. Accessed February 10, 2008. 14. Peak AS, Sheller A. Risk factors for developing gadolinium-induced nephrogenic systemic fibrosis. Ann Pharmacother. 2007;41:1481-1485. 15. Perazella MA, Rodby RA. Gadolinium use in patients with kidney disease: a cause for concern. Semin Dial. 2007;20(3):179-185. 16. Thakral C, Alhariri J, Abraham JL. Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications. Contrast Media Mol Imaging. 2007;2:199-205. 17. Ersoy H, Rybicki FJ. Biochemical safety profiles of gadolinium-based extracellular contrast agents and nephrogenic systemic fibrosis. J Magn Reson Imaging. 2007;26:1190-1197. 18. Saitoh T, Hayasaka K, Tanaka Y, Kuno T, Nagura Y. Dialyzability of gadodiamide in hemodialysis patients. Radiat Med. 2006;24(6):445-451. 19. 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(7):491-502. 20. Thomsen HS, Marckmann P, Logager VB. Nephrogenic systemic fibrosis (NSF): a late adverse reaction to some of the gadolinium based contrast agents. Cancer Imag. 2007;7:130-137. 21. Swaminathan S, Shah SV. New insights into nephrogenic systemic fibrosis. J Am Soc Nephrol. 2007;18:2636-2643. 22. Markmann P, Skov L, Rossen K, Heaf JG, Thomsen HS. Case-control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant. 2007 22(11):3174-3178. 23. Khurana A, Runge VM, Narayanan M, Greene JF, Nickel AE. Nephrogenic systemic fibrosis, a review of 6 cases temporarily related to gadodiamide injection (Omniscan). Invest Radiol. 2007;42(2):139-145. 24. Goddard DS, Magee CC, Lazar AJ, Miller DM. Nephrogenic fibrosing dermopathy with recurrence after allograft failure. J Am Acad Dermatol. 2007;56(5 Suppl):S109-111.
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25. Knopp EA, Cowper SE. Nephrogenic systemic fibrosis: early recognition and treatment. Semin Dial. 2008;21(2):123-128. 26. Swartz RD, Crofford LJ, Phan SH, Ike RW, Su LD. Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure. Am J Med. 2003;114(7):563-572. 27. Linfert DR, Schell JO, Fine DM. Treatment of nephrogenic systemic fibrosis: limited options but hope for the future. Semin Dial. 2008;21(2):155-159. 28. Baron PW, Cantos K, Hillebrand DJ, et al. Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis. Am J Dermatopathol. 2003;25(3):204-209. 29. U.S. Food and Drug Administration. Information for health care professionals. Gadolinium-based contrast agents for magnetic resonance imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, ProHance) Available at: http://www.fda.gov/cder/drug/InfoSheets/ HCP/gcca_200705.htm. Accessed February 10, 2008. 30. Medicines and Healthcare Products Regulatory Agency. Increased risk of nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis and gadolinium-containing MRI contrast agents. Public Assessment Report. Available at: http://www.mhra.gov.uk/Safetyinformation/ Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/ CON2030229. Accessed March 26, 2008. 31. Kanel E, Barkovich AJ, Bell C, et al. ACR guidance document for safe MR practices: 2007. Am J Radiol. 2007;188:1-27. Available at: http://www.acr.org/ SecondaryMainMenuCategories/quality_safety/MRSafety/safe_mr07.aspx. Accessed February 10, 2008. 32. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, of Stages of Chronic Kidney Disease. Available at: http://www.kidney.org/professionals/KDOQI/ guidelines_ckd/p4_class_g1.htm. Accessed March 3, 2008. 33. FDA MedWatch reporting system. Available at: http://www.fda.gov/ medwatch/report/hcp.htm. Accessed March 3, 2008. 34. International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR). Available at: http://www.icnfdr.org. Accessed March 3, 2008.
Stefania Lew, BSN, RN, ANP-BC, is the clinical coordinator at the Fresenius Medical Care Dialysis Clinic in Kaneoher, HI. She can be reached at [email protected]. Mirella Vasquez Brooks, PhD, FNP-BC, APRN, is an associate professor in the graduate division at the University of Hawaii at Manoa. In compliance with national ethical guidelines, the authors report no relationships with business or industry that would pose a conflict of interest. 1555-4155/09/$ see front matter © 2009 American College of Nurse Practitioners doi:10.1016/j.nurpra.2008.10.011
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