Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
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{at}uams.edu
Nephrogenic systemic fibrosis is a new disorder reported almostexclusively in patients who have renal insufficiency and areexposed to contrast media formulated with gadolinium. High morbidityand mortality are associated with this severely disabling andpainful condition. The acute phase begins upon exposure to gadoliniumcontrast media, characterized by a systemic inflammatory responseinvolving iron mobilization, and then as a progressive, chronicphase in which fibrosis develops. Proposed is a unifying modelof cumulative risk factors in which the interplay of systemicinflammation and stimulated hematopoietic environment associatedwith hyperparathyroidism and erythropoietin may tie to a commonpathogenic mechanism of fibrogenesis. Because there are no uniformlyeffective interventions to treat nephrogenic systemic fibrosisother than successful renal transplantation, prevention by avoidinggadolinium contrast media in patients with chronic kidney diseaseis vital. On the basis of suspected pathogenesis, it is alsoreasonable to limit erythropoietin and iron therapy to dosagesensuring recommended targets and adequately control hyperparathyroidism.Herein is reviewed what is currently known about this subject.
Nephrogenic systemic fibrosis (NSF) is a recently describedsystemic fibrosing disorder that has been reported almost exclusivelyin patients with renal insufficiency. It was first describedby Cowper et al.1 in 2000 as a cutaneous scleromyxedema-likedisorder in patients with ESRD and was initially called nephrogenicfibrosing dermopathy.2 Clinical and autopsy data now suggestthe presence of a systemic fibrogenic reaction with evidenceof involvement of muscle, tendons, diaphragm, testes, cardiacatrium, lungs, and duramater.3 The disease henceforth has beenreferred to as nephrogenic systemic fibrosis.4
More than 200 cases of NSF have been reported to the Food andDrug Administration and to the NSF registry at Yale University.The estimated prevalence of NSF, however, is likely to be inaccuratebecause it still is not a widely recognized clinical entity.In addition, subclinical forms of NSF that could be recognizedonly with a skin biopsy might remain undiagnosed. In this review,we describe novel clinical manifestations of NSF and discussour views on its pathogenesis. Specifically, we present a generalparadigm in which different risk factors may be tied to a commonpathogenic mechanism.
NSF is a severely disabling systemic fibrosing condition associatedwith increased morbidity and mortality.5–7 Our observationssuggest that clinical features of NSF may include an acute phasethat immediately follows exposure to gadolinium-based contrastmedia (GBCM) and an overlapping chronic phase characterizedby progressive fibrosis (Table 1). Features in the acute phaseare variably present and mimic systemic inflammatory responsesyndrome: Fever, hypotension,acute kidney injury, anemia, leukoerythroblasticpicture, thrombocytopenia or thrombocytosis, leukocytosis, eosinophilia,monocytosis, elevated -glutamyl peptidase, elevated lipase,and elevated D-dimer.8 Decreased total iron-binding capacity,elevated serum ferritin, low serum albumin, and elevated C-reactiveprotein are invariably present.7 Because many patients havecritical illnesses such as sepsis, acute pancreatitis, hepatorenalsyndrome, or acute graft dysfunction that precedes NSF, theacute phase of systemic fibrogenesis may go unrecognized. Onsetof the chronic phase is also variable: As early as 4 d or aslate as several months after GBCM exposure.9 Early cutaneousmanifestations in the chronic phase are usually limited to generalizededema followed closely by the development of a plaque-like skinrash with woody induration (Figure 1A). The condition tendsto affect either dependent parts of the body, such as extremitiesor the presacral area, or high blood-flow areas, such as theskin overlying an arteriovenous dialysis fistula.5,6 Facialinvolvement is very unusual except in severe, advanced casesin which temporal regions of the face may be involved (S. Swaminathan,2006, personal observation). Moderate to severe pain is moretypical. Alopecia, yellowish scleral nodules, hyperpigmentationof extremities, and yellowish discoloration of facial skin areobserved in some patients. Additional systemic findings thathave been observed in patients with NSF include the developmentof acute pancreatitis, vascular thrombosis, and frequent infection.5,10The disease is severely disabling, and many patients becomewheelchair dependent or bed bound. Severe depressive illnessoften ensues, and a significant number of patients quit dialysis.
Figure 1. (A) NSF involving legs and hand. Note the induration, edema, plaque-like rash, and joint contractures. (B) Histopathologic appearance of NSF characterized by dermal spindle cell proliferation with extension into subcutaneous tissue.
The diagnosis of NSF is established by performing a deep-skinbiopsy from affected areas. Biopsy findings (Figure 1B) thatconfirm NSF include dermal spindle cell (fibroblast) proliferation(usually CD34+) with frequent extension into subcutaneous tissue,presence of dermal mucin, variable infiltration of CD68+ macrophages,and presence of broad collagen bundles with clefts and fragmentedelastin. Osseous metaplasia, osteoclast-like giant cells, andcalciphylaxis can be seen in some NSF biopsies.11–13 Ona technetium99-diphosphosphonate scan, areas of increased uptakecan be observed in muscles.14,15 On magnetic resonance imaging,axial T1- and fat-suppressed T2-weighted images show symmetricskin thickening and soft tissue edema.15
The differential diagnoses of NSF include scleroderma, scleromyxedema,eosinophilic fasciitis, and graft-versus-host disease. An absenceof facial involvement and circulating paraprotein, temporalrelation to GBCM exposure, and the appropriate clinical contexthelps in differentiating NSF from these other conditions.
The major risk factors associated with NSF include exposureto GBCM,9,16,17 high-dosage erythropoietin (EPO) therapy,7 elevatedparathyroid hormone (PTH),7 hypothyroidism,17 and antiphospholipidantibodies.17 Significant vascular disease is also a risk factor.17On the basis of current understanding, an interaction of lowGFR; exposure to GBCM; and presence of additional risk factorssuch as high-dosage EPO, elevated PTH, vascular disease, andsystemic inflammation seem necessary for the development ofNSF in the majority of cases. In this "cumulative risk factormodel" proposed by us and detailed in the following section,patients with more cumulative risk (risk factor load) may onlyneed low dosages of GBCM to trigger NSF or vice versa (Figure 2).
NSF is seen in patients both with acute kidney injury and withchronic kidney disease (CKD). No specific cause of kidney diseaseexcept hepatorenal syndrome15 has been associated with heightenedrisk. NSF is seen in patients receiving either hemodialysisor peritoneal dialysis as well as in patients with posttransplantationallograft dysfunction. Singularly, a low GFR is a major prerequisitefor NSF to develop. In patients with CKD, on the basis of currentreports as well as personal observations, the risk for NSF seemsto be limited to those with stage 3 or worse CKD (GFR 60 ml/min).Recently, Sadowski et al. reported the risk for NSF after gadoliniumexposure at various levels of estimated GFR (eGFR), and in theirseries, NSF developed predominantly in those with eGFR <30ml/min.10 NSF also developed in two patients with an apparentlyhigher eGFR in the setting of acute kidney injury, where formula-basedestimates for GFR cannot be used. In our personal experience,we have observed, after GBCM exposure, that NSF can developin patients with an eGFR as high as 40 ml/min. However, imprecisionof formula-based eGFR in accurately predicting renal functionin stage 3 CKD limits our ability to interpret these findings18or arrive at a precise and safe cutoff of GFR above which therisk for NSF is negligible.
GADOLINIUM TOXICITY: ROLE OF IRON AND TRANSMETALLATION
In addition to several reports on the epidemiologic associationof GBCM exposure and NSF, demonstration of gadolinium in NSFtissues has strengthened the causal link between the two.19A higher dosage and multiple repeated exposures to GBCM increasethe risk for NSF.10 The mechanisms through which administrationof GBCM results in toxicity and NSF are still evolving. However,several important clues appear from current published literature.First, overt NSF develops in only 3 to 5% of patients afterGBCM exposure.9,10,16 Second, some patients with NSF do notmanifest any clinical signs, even when they were previouslyexposed to GBCM. Third, demonstration of significant quantitiesof insoluble gadolinium in the skin of patients with NSF, monthsafter GBCM exposure and after extensive tissue processing, suggestthat gadolinium might have undergone transmetallation in vivo.This finding is of significance because free gadolinium is toxic.20
Supporting the importance of transmetallation, all NSF casesreported thus far have been associated with linear magneticresonance contrast agents9,16,21,22 that have inferior thermodynamicstability23–26 and a kinetic or conditional stabilitythat favors transmetallation. The mechanism by which GBCM mayundergo transmetallation in vivo or cause toxicity is stillunder investigation. In an initial report, acidosis was thoughtto induce gadolinium's dissociation from its chelate16; however,a subsequent report failed to confirm this.9 Administrationof magnetic resonance contrast agents is widely known to causetransient (up to 72 h) elevations in serum iron, even in 15to 30% of healthy volunteers.27,28 Because iron is tightly boundto ferritin and hemosiderin, it has been suggested that itsfree concentration is insufficient to induce transmetallationof GBCM25,29; however, we recently reported that GBCM administrationin patients who have CKD and subsequently develop NSF resultsin a marked decrease in total iron-binding capacity, iron mobilization,profound transferrin oversaturation, and systemic inflammation.8In patients with renal insufficiency, several factors may aggravatefree iron release, including prolonged retention of GBCM (t13.4 to 89.2 h versus 1.5 h controls),30 additional exogenoustreatment with parenteral iron and low total iron-binding capacitysecondary to malnutrition, urinary protein (transferrin) loss,sepsis, and chronic inflammation.31–33 Available datasuggest that iron is most potent in inducing transmetallationof GBCM because the thermodynamic stability of Fe3+-DTPA-BMA(1021.9) far exceeds the thermodynamic stability constant ofgadolinium-DTPA-BMA (1016.9)34 (Table 2).
Table 2. Potency of various endogenous cations in inducing transmetallation of gadolinium-DTPA-BMAa
Gadolinium-mobilized iron can also be directly toxic to tissuesthrough the induction of oxidative stress by Fenton reaction(Figure 3).35 In addition, catalytic iron released by systemicinflammation35 and gadolinium-mediated cellular acquisitionof catalytic iron might contribute to the development of NSF.35–38Thus, a combination of free gadolinium, catalytic iron, systemicinflammation,10 and oxidative stress may result in initial injuryand a subsequent systemic-fibrosing illness characteristic ofNSF. Recent descriptions19,39 of significant iron and gadoliniumdeposition in NSF tissues support our findings. Collectively,these observations suggest the development of NSF after GBCMexposure needs not only a prolonged retention of GBCM but alsoa process by which GBCM induces toxicity, a process wherebyiron may play an important role.
We and others7,17,40 recently reported that patients with NSFalso receive higher dosages of EPO, suggesting that EPO mightplay a role in pathogenesis. On the basis of our clinical experiencewith 70 patients with NSF and other available large case series,7,8,17it is uncommon that patients do not receive any EPO before NSFdiagnosis. It is possible that endogenous EPO released duringstress-induced erythropoiesis, which could be several hundred-fold,41or other growth factors that synergize with EPO42 might be importantin patients who do not receive exogenous EPO before a diagnosisof NSF. In addition, in applying the cumulative risk model (Figure 1),exogenous EPO may not be a necessary prerequisite in all cases.
There are many compelling reasons for why EPO might participatein the pathogenesis of NSF. Its pleiotropic biologic effectsand/or systemic inflammation associated with an EPO-resistantstate may be important (Table 3). Theoretically, EPO therapyinfluences all key elements of the pathogenesis of NSF: Endothelialdysfunction, inflammation, cell proliferation, and wound healing.EPO is a potent cytokine with stimulatory effects on vascularendothelium,43 smooth muscle cells,44,45 and platelets.46 EPOadministration induces a release of vasoactive factors suchas monocyte chemoattractant protein-1,45,47 endothelin-1,48thromboxane A2, and selectin.46,49 It can also induce endothelialdysfunction by inhibiting dimethylarginine dimethylaminohydrolase,thereby increasing asymmetric dimethyl arginine.50 Furthermore,EPO is a potent stimulant of endothelial and progenitor cellproliferation,51,52 as well as wound-healing responses53 thatare reminiscent of histologic changes seen in NSF. EPO51,52,54and PTH55 are also strong stimuli for a systemic release ofCD34+ progenitor cells, which are known to participate in woundhealing.56–58 Vascular endothelial cell injury could similarlycontribute to the pathogenesis of NSF by inducing the releaseof vasoactive factors and CD34+ progenitors,41,59 and in thissetting, EPO's detrimental effect on endothelia is further aggravated.60,61In addition, chronic inflammation62 associated with an EPO-resistantstate and high-dosage EPO45,47 might also contribute to thefibrogenesis seen in NSF.
As with any other systemic fibrosing condition,63 possible originsof fibroblasts in NSF include resident mesenchymal cell populations,epithelial-to-mesenchymal transition of local epithelia, andbone marrow–derived cells. Cowper and Bucala64 demonstratedthat the spindle cells in NSF skin lesions express CD34 andprocollagen 1 and suggested that circulating fibrocytes mediatethe fibrosis in NSF. Even though the presence of these markerssuggests a contribution from circulating fibrocytes, it is importantto note that these markers are not unique to fibrocytes65; fibrocyte'scontribution to fibrosis is highly variable in different organs66and is affected by additional factors such as cell turnoverrates. Supporting this, Fathke et al.,67 using cross-transplantation(bone marrow) experiments in an EGFP transgenic mouse model,nicely demonstrated that both CD45+ and CD45– bone marrow–derivedstem cells contribute to dermal collagen deposition and woundrepair. In addition, they observed a role for local dermal cellsand endothelial progenitor cells in dermal wound healing. Similarly,using tissue reconstitution experiments with single hematopoieticstem cells (HSC), Ogawa et al.56 showed that HSC significantlycontribute to myofibroblast population in tissues. EPO, PTH,and an oxidative stress-induced "stimulated hematopoietic environment"41,51,55,68,69may thus contribute to fibrosis through increased productionof tissue myofibroblasts. It is unknown, however, whether fibrocytesare a necessary intermediate in this process of transformationof HSC into myofibroblasts in vivo; therefore, it is likelythat both resident fibroblasts and diverse types of bone marrow–derivedcells that are released in response to injury and cytokinessuch as EPO, including HSC (likely to be the most significantcontributor), endothelial progenitor cells, mesenchymal precursors,65and monocyte-derived cell fibrocytes,64 contribute to fibrogenesisin NSF (Figure 4). Any contribution of epithelial-to-mesenchymaltransition to fibrogenesis in NSF, although potentially possible,has not been evaluated. Like other chronic fibrosing disorders,persistent or progressive fibrosis, even after the originaltrigger is removed, may lead to NSF. This occurrence possiblyrelates to the concept of a "persistently activated fibroblastphenotype," which could be mediated by factors such as ongoingchronic endothelial injury in uremia.70,71
There are no good therapies for the cutaneous symptoms of NSFor, more important, to prevent its associated high mortality;therefore, our first recommendation is prevention. On the basisof the available data and our personal experience, we recommendthe following measures for NSF prevention:
Renal function should be checked in all high-risk patients beforeGBCM administration (age >50 yr; infants; history of renaldisease, diabetes, hypertension, or liver disease; and criticallyill patients).
Avoid GBCM in patients with an eGFR <40 ml/min.
If clinically indicated and benefits outweigh risks, then uselow dosages of GBCM (preferably macrocyclic agents) in patientswith an eGFR of 40 to 60 ml/min.
GBCM is absolutely contraindicated in patients who are on peritonealdialysis, because gadolinium is poorly cleared by the peritoneum.
In patients who are on hemodialysis, GBCM should be administeredonly if the benefits of obtaining a contrast-enhanced magneticresonance image substantially outweigh the risk. At the completionof imaging, patients should go directly to the hemodialysisunit for initiation of dialysis, and dialysis treatment shouldbe administered for 3 consecutive days.
Avoid intravenous iron immediately before or after GBCM exposure.
Treatment of NSF involves a multidisciplinary approach. Aggressivephysical therapy, pain control, and psychologic support areessential cornerstones of therapy in this severely disablingdisease. The severity of pain usually necessitates opiate analgesics.Topical treatments include the use of moisturizers, emollients,and anti-inflammatory creams. Deep tissue massage and hydrotherapymay be helpful. On the basis of potential pathogenic mechanisms,control of PTH levels and limiting administration of EPO andintravenous iron enough to maintain recommended hemoglobin targetsare likely to help. Limiting systemic inflammation by decreasinginfection episodes such as catheter-related bacteremia may alsobe beneficial. Other treatment approaches that could resultin variable and modest improvements include a combination ofhydroxychloroquine and low-dosage steroids (S. Swaminathan,2006, personal observation), extracorporeal photopheresis, andtopical ultraviolet-A therapy. However, none of these optionshas been uniformly effective in patients with NSF. Renal transplantationthat results in a well-functioning allograft usually leads toa substantial resolution of the disease, and maintaining lowercyclosporine and tacrolimus targets may also potentially helpin limiting fibrogenesis.72–74 Secondary worsening ofNSF after initial improvement but without new GBCM exposurecan occur, but the mechanisms involved in these relapses areunclear. No data are available on the benefit of using chelationtherapy to remove gadolinium in NSF. A better understandingof the pathogenesis in this devastating disease may lead tonew interventions, which may be relevant not only to NSF butother fibrosing conditions.
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-glutamyl peptidase, elevated lipase, and elevated D-dimer.8 Decreased total iron-binding capacity, elevated serum ferritin, low serum albumin, and elevated C-reactive protein are invariably present.7 Because many patients have critical illnesses such as sepsis, acute pancreatitis, hepatorenal syndrome, or acute graft dysfunction that precedes NSF, the acute phase of systemic fibrogenesis may go unrecognized. Onset of the chronic phase is also variable: As early as 4 d or as late as several months after GBCM exposure.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, such as extremities or the presacral area, or high blood-flow areas, such as the skin overlying an arteriovenous dialysis fistula.5,6 Facial involvement is very unusual except in severe, advanced cases in which temporal regions of the face may be involved (S. Swaminathan, 2006, personal observation). Moderate to severe pain is more typical. Alopecia, yellowish scleral nodules, hyperpigmentation of extremities, and yellowish discoloration of facial skin are observed in some patients. Additional systemic findings that have been observed in patients with NSF include the development of acute pancreatitis, vascular thrombosis, and frequent infection.5,10 The disease is severely disabling, and many patients become wheelchair dependent or bed bound. Severe depressive illness often ensues, and a significant number of patients quit dialysis. 
60 ml/min). Recently, Sadowski et al. reported the risk for NSF after gadolinium exposure at various levels of estimated GFR (eGFR), and in their series, NSF developed predominantly in those with eGFR <30 ml/min.10 NSF also developed in two patients with an apparently higher eGFR in the setting of acute kidney injury, where formula-based estimates for GFR cannot be used. In our personal experience, we have observed, after GBCM exposure, that NSF can develop in patients with an eGFR as high as 40 ml/min. However, imprecision of formula-based eGFR in accurately predicting renal function in stage 3 CKD limits our ability to interpret these findings18 or arrive at a precise and safe cutoff of GFR above which the risk for NSF is negligible. 
13.4 to 89.2 h versus 1.5 h controls),30 additional exogenous treatment with parenteral iron and low total iron-binding capacity secondary to malnutrition, urinary protein (transferrin) loss, sepsis, and chronic inflammation.31–33 Available data suggest that iron is most potent in inducing transmetallation of GBCM because the thermodynamic stability of Fe3+-DTPA-BMA (1021.9) far exceeds the thermodynamic stability constant of gadolinium-DTPA-BMA (1016.9)34 (Table 2). 
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Abstract
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