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BRIEF REVIEW

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New Insights into Nephrogenic Systemic Fibrosis
Sundararaman Swaminathan and Sudhir V. Shah
Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas

ABSTRACT
Nephrogenic systemic fibrosis is a new disorder reported almost exclusively in patients who have renal insufficiency and are exposed to contrast media formulated with gadolinium. High morbidity and mortality are associated with this severely disabling and painful condition. The acute phase begins upon exposure to gadolinium contrast media, characterized by a systemic inflammatory response involving iron mobilization, and then as a progressive, chronic phase in which fibrosis develops. Proposed is a unifying model of cumulative risk factors in which the interplay of systemic inflammation and stimulated hematopoietic environment associated with hyperparathyroidism and erythropoietin may tie to a common pathogenic mechanism of fibrogenesis. Because there are no uniformly effective interventions to treat nephrogenic systemic fibrosis other than successful renal transplantation, prevention by avoiding gadolinium contrast media in patients with chronic kidney disease is vital. On the basis of suspected pathogenesis, it is also reasonable to limit erythropoietin and iron therapy to dosages ensuring recommended targets and adequately control hyperparathyroidism. Herein is reviewed what is currently known about this subject.
J Am Soc Nephrol 18: 2636 –2643, 2007. doi: 10.1681/ASN.2007060645

Table 1. Components of NSF
Acute phase: Systemic inflammatory response fever hypotension acute kidney injury elevated D-dimer elevated lipase anemia, thrombocytopenia, or thrombocytosis leukoerythroblastic picture monocytosis high serum ferritin, low total iron-binding capacity high C-reactive protein Chronic phase: Edema and fibrosis edema woody induration scleral plaques

Nephrogenic systemic fibrosis (NSF) is a recently described systemic fibrosing disorder that has been reported almost exclusively in patients with renal insufficiency. It was first described by Cowper et al.1 in 2000 as a cutaneous scleromyxedema-like disorder in patients with ESRD and was initially called nephrogenic fibrosing dermopathy.2 Clinical and autopsy data now suggest the presence of a systemic fibrogenic reaction with evidence of involvement of muscle, tendons, diaphragm, testes, cardiac atrium, lungs, and duramater.3 The disease henceforth has been referred to as nephrogenic systemic fibrosis.4 More than 200 cases of NSF have been reported to the Food and Drug Administration and to the NSF registry at Yale University. The estimated prevalence of
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ISSN : 1046-6673/1810-2636

NSF, however, is likely to be inaccurate because it still is not a widely recognized clinical entity. In addition, subclinical forms of NSF that could be recognized only with a skin biopsy might remain undiagnosed. In this review, we describe novel clinical manifestations of NSF and discuss our views on its pathogenesis. Specifically, we present a general paradigm in which different risk factors may be tied to a common pathogenic mechanism.

features of NSF may include an acute phase that immediately follows exposure to gadolinium-based contrast media (GBCM) and an overlapping chronic phase characterized by progressive fibrosis (Table 1). Features in the acute phase are variably present and mimic systemic inflammatory response syndrome: Fever, hypotension, acute kidney injury, anemia, leukoerythroblastic picture, thrombocytopenia or thrombocytosis, leukocytosis, eosinophilia, monocytosis, elevated -glutamyl peptidase, elevated lipase,
Published online ahead of print. Publication date available at www.jasn.org.

CLINICAL AND LABORATORY FEATURES

NSF is a severely disabling systemic fibrosing condition associated with increased morbidity and mortality.5–7 Our observations suggest that clinical

Correspondence to: Dr. Sundararaman Swaminathan, Division of Nephrology, University of Arkansas for Medical Sciences, 4301 W Markham Street #501, Little Rock, AR 72205. Phone: 501-686-5295; Fax: 501-686-7878; E-mail: sswaminathan@ uams.edu Copyright © 2007 by the American Society of Nephrology

J Am Soc Nephrol 18: 2636 –2643, 2007

edema. and elevated C-reactive protein are invariably present. personal observation). Note the induration. and joint contractures. such as the skin overlying an arteriovenous dialysis fistula. (A) NSF involving legs and hand. hyperpigmentation of extremities. plaque-like rash. acute pancreatitis. 2006.8 Decreased total iron-binding capacity.www.org BRIEF REVIEW and elevated D-dimer. and yellowish discoloration of facial skin are observed in some patients. 2007 Nephrogenic Systemic Fibrosis 2637 .6 Facial involvement is very un- usual except in severe. advanced cases in which temporal regions of the face may be involved (S. such as extremities or the presacral area.7 Because many patients have critical illnesses such as sepsis. yellowish scleral nodules. vas- Figure 1. the acute phase of systemic fibrogenesis may go unrecognized.jasn.5. or acute graft dysfunction that precedes NSF. low serum albumin. (B) Histopathologic appearance of NSF characterized by dermal spindle cell proliferation with extension into subcutaneous tissue. Alopecia. Swaminathan. hepatorenal syndrome. elevated serum ferritin. Onset of the chronic phase is also variable: As early as 4 d or as late as several months after GBCM exposure. Moderate to severe pain is more typical. Additional systemic findings that have been observed in patients with NSF include the development of acute pancreatitis. J Am Soc Nephrol 18: 2636 –2643. or high blood-flow areas.9 Early cutaneous manifestations in the chronic phase are usually limited to generalized edema followed closely by the development of a plaque-like skin rash with woody induration (Figure 1A). The condition tends to affect either dependent parts of the body.

variable infiltration of CD68 macrophages. NSF is seen in patients receiving either hemodialysis or peritoneal dialysis as well as in patients with posttransplantation allograft dysfunction. and the appropriate clinical context helps in differentiating NSF from these other conditions.and fat-suppressed T2-weighted images show symmetric skin thickening and soft tissue edema. Third. Singularly. temporal relation to GBCM exposure.10 The disease is severely disabling.16. suggest that gadolinium might have undergone transmetallation in vivo. we have observed. and calciphylaxis can be seen in some NSF biopsies. our ability to interpret these findings18 or arrive at a precise and safe cutoff of GFR above which the risk for NSF is negligible.17 and antiphospholipid antibodies. Biopsy findings (Figure 1B) that confirm NSF include dermal spindle cell (fibroblast) proliferation (usually CD34 ) with frequent extension into subcutaneous tissue.BRIEF REVIEW www. a low GFR is a major prerequisite for NSF to develop. and presence of broad collagen bundles with clefts and fragmented elastin. In our personal experience. and in their series.21.10. and many patients become wheelchair dependent or bed bound. where formula-based estimates for GFR cannot be used.9. overt NSF develops in only 3 to 5% of patients after GBCM exposure. after GBCM exposure. Osseous metaplasia. No specific cause of kidney disease except hepatorenal syndrome15 has been associated with heightened risk. imprecision of formula-based eGFR in accurately predicting renal function in stage 3 CKD limits In addition to several reports on the epidemiologic association of GBCM exposure and NSF.14.17 On the basis of current understanding. However.17 Significant vascular disease is also a risk factor.7 hypothyroidism. model” proposed by us and detailed in the following section. First. scleromyxedema. even when they were previously exposed to GBCM.17 high-dosage erythropoietin (EPO) therapy. axial T1.jasn.16. 2007 Journal of the American Society of Nephrology . vascular disease. In this “cumulative risk factor 2638 Figure 2.16 Second. and frequent infection. that NSF can develop in patients with an eGFR as high as 40 ml/min.15 The differential diagnoses of NSF include scleroderma. eosinophilic fasciitis.7 elevated parathyroid hormone (PTH).5. the risk for NSF seems to be limited to those with stage 3 or worse CKD (GFR 60 ml/min). some patients with NSF do not manifest any clinical signs. J Am Soc Nephrol 18: 2636 –2643. all NSF cases reported thus far have been associated with linear magnetic resonance contrast agents9. The diagnosis of NSF is established by performing a deep-skin biopsy from affected areas. and graft-versus-host disease. NSF developed predominantly in those with eGFR 30 ml/min. several important clues appear from current published literature. areas of increased uptake can be observed in muscles. In patients with CKD.22 that have inferior thermodynamic stability23–26 and a kinetic or conditional sta- The major risk factors associated with NSF include exposure to GBCM. Severe depressive illness often ensues. months after GBCM exposure and after extensive tissue processing. Recently.10 NSF also developed in two patients with an apparently higher eGFR in the setting of acute kidney injury. Sadowski et al. Cumulative risk factor model of NSF: Conceptual inverse interaction between gadolinium dosage and risk factors in the pathogenesis of NSF.org cular thrombosis. osteoclastlike giant cells. and systemic inflammation seem necessary for the development of NSF in the majority of cases.11–13 On a technetium99-diphosphosphonate scan.9. demonstration of gadolinium in NSF tissues has strengthened the causal link between the two. patients with more cumulative risk (risk factor load) may only need low dosages of GBCM to trigger NSF or vice versa (Figure 2). on the basis of current reports as well as personal observations.19 A higher dosage and multiple repeated exposures to GBCM increase the risk for NSF. An absence of facial involvement and circulating paraprotein.10 The mechanisms through which administration of GBCM results in toxicity and NSF are still evolving. and a significant number of patients quit dialysis. demonstration of significant quantities of insoluble gadolinium in the skin of patients with NSF.15 On magnetic resonance imaging. and presence of additional risk factors such as high-dosage EPO. exposure to GBCM. IMPAIRED RENAL FUNCTION GADOLINIUM TOXICITY: ROLE OF IRON AND TRANSMETALLATION RISK FACTORS FOR NSF NSF is seen in patients both with acute kidney injury and with chronic kidney disease (CKD). This finding is of significance because free gadolinium is toxic. However. reported the risk for NSF after gadolinium exposure at various levels of estimated GFR (eGFR). presence of dermal mucin. elevated PTH. an interaction of low GFR.20 Supporting the importance of transmetallation.

It is possible that endogenous EPO released during stress-in- duced erythropoiesis.30 additional exogenous treatment with parenteral iron and low total iron-binding capacity secondary to malnutrition. Collectively. . acidosis was thought to induce gadolinium’s dissociation from its chelate16.8 In patients with renal insufficiency. On the basis of our clinical experience with 70 patients with NSF and other available large case series.17. these observations suggest the development of NSF after GBCM exposure needs not only a prolonged retention of GBCM but also a process by which GBCM induces toxicity. mild.9 1021. a process whereby iron may play an important role. EPO is a potent cytokine with stimulatory effects on vascular endothelium.43 smooth muscle cells.50 Furthermore. cell proliferation. In addition. .47 endothelin-1.10 and oxidative stress may result in initial injury and a subsequent systemic-fibrosing illness characteristic of NSF. urinary protein (transferrin) loss. .40 recently reported that patients with NSF also receive higher dosages of EPO. and systemic inflammation.52 as well as wound-healing responses53 that are reminiscent of histologic Table 3. and selectin. a combination of free gadolinium.29. moderate. EPO is a potent stimulant of endothelial and progenitor cell proliferation.org BRIEF REVIEW bility that favors transmetallation.45. it has been suggested that its free concentration is insufficient to induce transmetallation of GBCM25.9) far exceeds the thermodynamic stability constant of gadolinium-DTPA-BMA (1016.2 h versus 1. lytic iron released by systemic inflammation35 and gadolinium-mediated cellular acquisition of catalytic iron might contribute to the development of NSF. AND VASCULAR INJURY We and others7. systemic inflammation.31–33 Available data suggest that iron is most potent in inducing transmetallation of GBCM because the thermodynamic stability of Fe3 -DTPA-BMA (1021. n/a. The plus and minus symbols refer to the degree of potency. thereby increasing asymmetric dimethyl arginine. ROLE OF EPO.9 Administration of magnetic resonance contrast agents is widely known to cause transient (up to 72 h) elevations in serum iron. The mechanism by which GBCM may undergo transmetallation in vivo or cause toxicity is still under investigation. catalytic iron. suggesting that EPO might play a role in pathogenesis. profound transferrin oversaturation.35–38 Thus. Recent descriptions19. however.41 or other growth factors that synergize with EPO42 might be important in patients who do not receive exogenous EPO before a diagnosis of NSF.49 It can also induce endothelial dysfunction by inhibiting dimethylarginine dimethylaminohydrolase. a subsequent report failed to confirm this. however.8. which could be several hundred-fold.35 In addition.39 of significant iron and gadolinium deposition in NSF tissues support our findings. There are many compelling reasons for why EPO might participate in the pathogenesis of NSF.www.9 Transmetallation Potency a Ktherm is a thermodynamic stability constant. even in 15 to 30% of healthy volunteers. several factors may aggravate free iron release.7.4 to 89.28 Because iron is tightly bound to ferritin and hemosiderin.17 it is uncommon that patients do not receive any EPO before NSF diagnosis.48 thromboxane A2. 2007 Nephrogenic Systemic Fibrosis 2639 .46 EPO administration induces a release of vasoactive factors such as monocyte chemoattractant protein-1.2 1012 1013 1016.45 and platelets. Theoretically. Potency of various endogenous cations in inducing transmetallation of gadolinium-DTPA-BMAa Cation-DTPA-BMA Calcium Zinc Copper Gadolinium Iron Log Ktherm 107. Potential role of EPO in the pathogenesis of NSF Endothelial dysfunction increases endothelin-1 asymmetric dimethyl arginine Proinflammatory increases monocyte chemoattractant protein-1 Cell proliferation increases endothelial cells smooth muscle cells endothelial progenitor cells Table 2.27. INFLAMMATION. J Am Soc Nephrol 18: 2636 –2643. strong. iron mobilization.9)34 (Table 2). Its pleiotropic biologic effects and/or systemic inflammation associated with an EPO-resistant state may be important (Table 3). we recently reported that GBCM administration in patients who have CKD and subsequently develop NSF results in a marked decrease in total iron-binding capacity.44.46. inflammation.5 h controls). exogenous EPO may not be a necessary prerequisite in all cases. including prolonged retention of GBCM (t ⁄ 13. and wound healing. Transmetallation of gadolinium chelates by endogenous ions: The role of iron. cata12 Figure 3.jasn. In an initial report. and chronic inflammation. . EPO therapy influences all key elements of the pathogenesis of NSF: Endothelial dysfunction. in applying the cumulative risk model (Figure 1). sepsis.51. Gadolinium-mobilized iron can also be directly toxic to tissues through the induction of oxidative stress by Fenton reaction (Figure 3).

BRIEF REVIEW www. In patients who are on hemodialysis. EPO.69 2640 may thus contribute to fibrosis through increased production of tissue myofibroblasts. to prevent its associated high mortality.jasn. they observed a role for local dermal cells and endothelial progenitor cells in dermal wound healing. Treatment of NSF involves a multidisciJ Am Soc Nephrol 18: 2636 –2643. hypertension.51. As with any other systemic fibrosing condition. history of renal disease. This occurrence possibly relates to the concept of a “persistently activated fibroblast phenotype. patients should go directly to the hemodialysis unit for initiation of dialysis. and an oxidative stress-induced “stimulated hematopoietic environment”41. Even though the presence of these markers suggests a contribution from circulating fibrocytes.55.65 and monocyte-derived cell fibrocytes. epithelial-to-mesenchymal transition of local epithelia. Avoid intravenous iron immediately before or after GBCM exposure.71 TREATMENT There are no good therapies for the cutaneous symptoms of NSF or. At the completion of imaging. then use low dosages of GBCM (preferably macrocyclic agents) in patients with an eGFR of 40 to 60 ml/ min. Any contribution of epithelial-to-mesenchymal transition to fibrogenesis in NSF. Like other chronic fibrosing disorders. using tissue reconstitution experiments with single hematopoietic stem cells (HSC).67 using crosstransplantation (bone marrow) experiments in an EGFP transgenic mouse model. chronic inflammation62 associated with an EPO-resistant state and highdosage EPO45. PTH. therefore. Supporting this. whether fibrocytes are a necessary intermediate in this process of transformation of HSC into myofibroblasts in vivo. CELLULAR BASIS FOR THE PERSISTENCE OF FIBROSIS IN NSF Figure 4. Ogawa et al. fibrocyte’s contribution to fibrosis is highly variable in different organs66 and is affected by additional factors such as cell turnover rates. It is unknown. Cowper and Bucala64 demonstrated that the spindle cells in NSF skin lesions express CD34 and procollagen 1 and suggested that circulating fibrocytes mediate the fibrosis in NSF. or liver disease. and critically ill patients). has not been evaluated.59 and in this setting.41. diabetes. 2007 Journal of the American Society of Nephrology . may lead to NSF. however.org changes seen in NSF. EPO51. which are known to participate in wound healing.56 –58 Vascular endothelial cell injury could similarly contribute to the pathogenesis of NSF by inducing the release of vasoactive factors and CD34 progenitors.68. and dialysis treatment should be administered for 3 consecutive days. therefore.” which could be mediated by factors such as ongoing chronic endothelial injury in uremia. we recommend the following measures for NSF prevention: Renal function should be checked in all high-risk patients before GBCM administration (age 50 yr.61 In addition. GBCM is absolutely contraindicated in patients who are on peritoneal dialysis. it is important to note that these markers are not unique to fibrocytes65. endothelial progenitor cells. although potentially possible. EPO’s detrimental effect on endothelia is further aggravated. In addition. Fathke et al. because gadolinium is poorly cleared by the peritoneum. persistent or progressive fibrosis. On the basis of the available data and our personal experience. infants.54 and PTH55 are also strong stimuli for a systemic release of CD34 progenitor cells. nicely demonstrated that both CD45 and CD45 bone marrow– derived stem cells contribute to dermal collagen deposition and wound repair. and bone marrow– derived cells. mesenchymal precursors.63 possible origins of fibroblasts in NSF include resident mesenchymal cell populations.60. it is likely that both resident fibroblasts and diverse types of bone marrow– derived cells that are released in response to injury and cytokines such as EPO.52. If clinically indicated and benefits outweigh risks.. including HSC (likely to be the most significant contributor). Similarly.47 might also contribute to the fibrogenesis seen in NSF. even after the original trigger is removed.64 contribute to fibrogenesis in NSF (Figure 4). Cellular basis for fibrosis in NSF: Interaction of multiple risk factors and central role of hematopoietic stem cells. Avoid GBCM in patients with an eGFR 40 ml/min.56 showed that HSC significantly contribute to myofibroblast population in tissues. GBCM should be administered only if the benefits of obtaining a contrast-enhanced magnetic resonance image substantially outweigh the risk. our first recommendation is prevention.70. more important.

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