Transcript
Page 1: NSF Clinical Picture & Treatment

Nephrogenic SystemicFibrosis : Clinical Pictureand Treatment

Peter Marckmann, MD, DMSca,*, Lone Skov, MD, DMScb

KEYWORDS� Nephrogenic systemic fibrosis � Clinical picture� Treatment � Gadolinium � Chronic kidney disease� Renal failure � Diagnosis

Nephrogenic systemic fibrosis (NSF) was identi-fied well before anyone knew what the cause ofthis feared disease is.1,2 Today, it is beyond doubtthat gadolinium (Gd)-based contrast agents(GBCA) have caused the large majority, if not allcases of NSF. The typical NSF case is character-ized by a history of exposure to GBCA before theappearance of first signs of NSF and detection ofGd deposits in affected tissues.3–6 Supportingevidence of the causal relationship betweenGBCA and NSF comes from ex vivo and animalstudies demonstrating that Gd-salts and someGBCAs cause histologic and clinical effectsresembling what is seen in NSF.7–9 Therefore, itmay be time to consider renaming NSF to what itreally seems to be, which is Gd-induced systemicfibrosis. This article outlines the clinical picture andtreatment possibilities of NSF.

CLINICAL PICTURE

The clinical picture of NSF is diversified.10,11 Itvaries from one patient to another and it variesover time. Although the histology of deep skinbiopsies most often gives important clues to thediagnosis,12 affected skin may show panniculitis- orvasculitis-like changes in the first few weeks andnonspecific fibrosis in late stages of thedisease.13–15 Unusual clinical presentation andnonspecific histology means that it may be veryhard to come to the NSF diagnosis in somepatients. In practice, the diagnosis of NSF

a Department of Nephrology, Odense University Hospitab Department of Dermatology KA1502, Copenhagen UnVej 65, DK-2900 Hellerup, Denmark* Corresponding author.E-mail address: [email protected] (P. Marckm

Radiol Clin N Am 47 (2009) 833–840doi:10.1016/j.rcl.2009.05.0040033-8389/09/$ – see front matter ª 2009 Elsevier Inc. All

therefore sometimes has to be based primarilyon patient history of GBCA-exposures, subse-quent appearance of otherwise unexplainedsymptoms from the skin, the limbs, or otherorgans, and the exclusion of relevant differentialdiagnoses.

This article gives a description of the classicpresentation of NSF and highlights the differencesbetween early and late manifestations of thedisease. It also provides information on atypicalGBCA-associated symptoms that should lead tothe suspicion of NSF.

General Characteristics of NephrogenicSystemic Fibrosis Patients

All published GBCA-associated NSF cases hadacute or chronic renal insufficiency when theywere exposed to GBCA.3,12 The large majority(more than 95%) of cases had chronic kidneydisease stage 5; that is, they had estimatedglomerular filtration rates (eGFR) lower than15 mL per minute per 1.73 m2. There have beenno reports of NSF cases among patients witheGFR greater than 60 mL per minute per 1.73 m2.

The disease may affect pediatric and adultpatients, but most patients are middle-aged, prob-ably reflecting an increased use of imaging proce-dures for this age group.5,16 The two sexes anddifferent ethnicities seem to be equally affected.The primary renal disease and the duration of renalinsufficiency apparently have no impact on the risk

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of NSF. Hemodialysis patients appear to have anincreased risk of NSF in its most severe formwhen compared with peritoneal dialysis patientsand predialytic patients, probably reflecting thathemodialysis patients more frequently have themost advanced, anuric form of renaldysfunction.17

On the basis of published NSF case stories andcohort studies, personal clinical experiences, andretrospective scrutiny of medical records, physicalexaminations, and personal interviews of NSFvictims, it has become clear that the course ofa typical NSF case may be divided into threephases: early inflammatory, intermediate, anda late fibrotic phase (Table 1).

Early Nephrogenic Systemic FibrosisSymptoms (Less than 2 Months AfterGadolinium-Based Contrast Agent Exposure)

In the authors’ experience, virtually all patients willhave their initial NSF-symptoms within 2 monthsafter the culprit GBCA exposure. The mean delay(the latent phase) from GBCA exposure to onset ofclinical symptoms was 14 days in the authors’detailed study of the clinical manifestations ofNSF.10 However, some patients (around 10%)experienced their first reaction to GBCA withinminutes or hours (immediate onset), whereas othershad a latent phase of 4 weeks or even more (delayedonset). Similar observations have been reported byothers.18–22 According to the authors’ observations,skin changes and neuropathic symptoms predom-inate the early phase of NSF.10

Skin changesAround 90% of the patients develop an erythema-tous rash with or without hemorrhagic elements.The skin turns skin reddish, bluish, or brownish incolor.10,13 Some 80% of the patients have marked,nonpitting swelling of the same areas. The swell-ings may be misinterpreted by the clinicians assigns of over-hydration, but respond poorly to

Table1The clinical course of GBCA-induced NSFmay be divided ian intermediate, and a late fibrotic phase

Phase of NSFTiming Relative to GBCA(Days After Exposure)

Latent 0–14 (range 0–60)

Early 14–60 (range 0–60)

Intermediate 60–180

Late 1180

restricted fluid intake, raised dosing of diuretics,and increased dialytic ultrafiltration. The swellingsare warm, relatively firm, and frequently very pain-ful. There is an intense itching of the affected areasin most cases (70%). The skin changes are almostalways localized to the limbs, primarily lower legs,in a symmetric pattern, but may extend to involvethighs and lower trunk. An estimated 10% to 20%of the patients have early involvement of hands orforearms.

Neuropathic symptomsAlmost 80% of the patients complain of pain, dys-esthesia, or hyperalgesia. A minority may presentwith restless legs syndrome. The anatomic predi-lection of the neuropathy is similar to that of theskin changes. The neuropathic symptoms maybe so intense that the patient becomes physicallydisabled. In particular, walking may become verypainful.

Other symptomsBesides skin changes and neuropathy, it is impor-tant to recognize that other body compartmentsand organs may be affected as part of the earlyphase of NSF, which includes:

nto a

Hair: Transient, diffuse hair loss may be seenin up to 50% of the patients.

Intestines: One-third of the patients maydevelop culture-negative signs of gastro-enteritis with abdominal cramps, vomitingand diarrhea within the first few days afterthe GBCA exposure.

Eyes: One-fifth of the patients or more maypresent with red eyes as sign of noninfec-tious conjunctivitis.

Lungs: In the authors’ material, 15% devel-oped serious culture-negative lung symp-toms, including shortness of breath,oxygen requirement, and bilateral infil-trates on chest X-ray within a few daysafter their GBCA exposure.

latent, an early inflammatory,

Predominant Symptoms

None

Erythema, swelling, pain, itching,neuropathy

Mixture of early and late symptoms

Skin thickening and hardening,contractures, disabilities

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Kidneys: Although GBCA were previouslyconsidered to have no toxic effects onkidney function, more recent reviewshave concluded that nephrotoxicity maybe seen with some GBCAs at a rate similarto that seen with iodine-based contrastagents.23

Inflammatory system: The initial phase of NSFfrequently includes signs of systemicinflammation with fever, elevated C-reac-tive protein, elevated ferritin, anemia, andthrombocytosis or thrombocytopenia.24,25

Fig.1. Young, female hemodialysis patient with neph-rogenic systemic fibrosis and classic thickening, hard-ening, and hyperpigmentation of the legs withflexion contractures of knees and ankles. Scaling wasalso prominent. The patient became dependentupon a wheelchair and died in her thirties.

The early phase may vary tremendously fromone patient to the other. A minority of patientshave no or very mild symptoms, whereas othersmay present with very dramatic symptoms fromone or more organs. In case of severe early-phasesymptoms, patients may suffer from associatedproblems, such as sleeplessness, depression,anorexia, and weight loss that may further deterio-rate their situation.

In the authors’ experience, some GBCA-exposed patients may develop some of theearly-phase symptoms of NSF without progress-ing into the late and chronic phase of NSF. Theauthors propose that such cases might be consid-ered and named ‘‘abortive or subclinical’’ NSF.

Late and Chronic Nephrogenic SystemicFibrosis Symptoms (Greater than 6 MonthsAfter Gadolinium-Based Contrast AgentExposure)

The early-symptom complex dominates the firstweeks to months, but is then gradually replacedby the late and chronic symptoms of fibrosis thatare used for finally diagnosing the patient as beinga NSF case. The late-symptom complex is typi-cally stabilized 6 to 12 months after the GBCAexposure. Some case reports indicate that symp-toms may appear and progress even later. In theauthors’ experience, late-symptom progressionmay indeed occur as a consequence of insufficientphysiotherapy or prolonged bed rest caused byintercurrent comorbidity. The classic, hallmarksigns of late stages of NSF are skin changes andcontractures.10,12

Skin changesThe typical skin changes include islets or confluentareas of thickened and hardened dermis andsubcutis, with or without sharp demarcation tothe surrounding normally appearing tissues(Fig. 1). The anatomic distribution is similar tothat of the early skin changes. The affected areasmay have a peau d’orange appearance, andhave a woody texture in the worst cases. Pinching

of the affected skin is hampered. The epidermis istypically atrophic, shiny, and hairless. However,extensive brown scaling may be seen. Hyperpig-mentation (brown or dark brown) is common, buthypopigmentation is also seen. Some of thepatients have discrete, superficial hemorrhagesat the border of lesions on feet and toes. In theauthors’ cases, lower legs (from above ankles tobelow knees) were affected in 95%, knees andfeet were affected in 50%, hands and forearmsin 33%, and thighs in 25% of the NSF patients. Asimilar pattern of lesion distribution was reportedby Cowper and colleagues.12 The swellings thatare characteristic of the early phase of NSF arevirtually absent in the late phase, and the painand itching are less prominent in most cases.

ContracturesThe joint motion may be seriously reduced inanatomic regions of severe skin changes. Thelimited motion is primarily explained by mechan-ical skin forces, but it may lead to complicatingjoint-capsule shrinkage. Joint contractures of theankles and knees may be seen in more than 50%of the patients, whereas wrists and elbows wereaffected in 33% of the authors’ patients. Thecontractures may lead to significant disabilities,

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including loss of walking ability and dependenceupon a wheelchair.

Although thickened, hardened skin and contrac-tures certainly are major diagnostic criteria forNSF, it is important to acknowledge the existenceof other GBCA-associated symptoms that havenot received the same attention, but still may beconsidered part of the NSF syndrome. The otherlate manifestations of NSF that have markedimpact on the life quality of the patient include:

Fig. 2lateformand

Atypical skin changes: In contrast to the hard-ened skin of the classical NSF patient,some patients may present with sharplydemarcated slack skin because of loss ofdermal elastic fibers and subcutaneousatrophy. The anatomic distribution of theseatypical skin changes is similar to that ofclassical skin changes but contracturesare absent (Fig. 2).

Neuropathic symptoms: The common earlyneuropathic symptoms resolve to someextent in most patients. However, a consid-erable fraction of the patients may developlate signs of sensory and motor axonalneuropathy in the form of reduced sensi-bility and physical weakness of feet, legs,hands and arms. These symptoms maybe disabling and limit the patients’ physical

. Female peritoneal dialysis patient with atypical,symptoms of nephrogenic systemic fibrosis in theof slack skin appearance explained by elastolysis

subcutaneous atrophy.

performance and working ability. The earlyand late neurologic symptoms indicatethat the fibrotic process of NSF involvesthe nervous tissue.10,16

Lungs: In parallel to the early signs of pneu-monitis, respiratory insufficiency causedby lung fibrosis may occur as a late mani-festation of NSF in some patients.16

Eyes: Yellow scleral plaques with preservedvision have been reported in variousproportions of NSF patients.12

Muscles: Muscular atrophy of the limbs maybe seen secondary to contractures,reduced mobility, axonal neuropathy, andmalnutrition.

Other organs: The clinical evaluation of someNSF patients from Denmark (unpublishedcase reports) indicate that late NSF symp-toms might also include cardiac arrhythmiaand portal hypertension. However, corre-lating these clinical features to NSFremains speculative.

In severe cases, malnutrition is frequent andmortality is raised. Depression is also a frequentaccompanying symptom of severe NSF. In spiteof the multiorgan involvement, the authors havenot identified any examples of reduced intellectualcapacity among their NSF patients. Thus, thecentral nervous system seems to be spared inNSF.

The intensity and the pattern of late-NSF symp-toms vary enormously among NSF cases. Theauthors have previously proposed a severityscoring scale of NSF that may help to distinguishmild from severe cases.10 The scale ranges fromscore 0 (no symptoms) to score 4 (severelydisabling symptoms causing dependence of aidor devices for common daily activities) (Table 2).In the authors’ population of 22 NSF cases, 45%received a score of 4, demonstrating that a largeproportion of NSF patients suffer from significantoverall disability.

In general, the late-NSF symptoms can beconsidered stable and chronic after 12 to 24months. Spontaneous remission of advancedchronic symptoms is unusual and cannot beexpected.

RISK FACTORS

GBCA leads to NSF in only a minority of exposedpatients. The reported risk of NSF after GBCAexposure ranges from 0% to 55%.3 The large vari-ation is partly explained by the fact that thedifferent GBCAs are not equally risky. The nonioniclinear GBCAs, in particular gadodiamide, are

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Table 2Severity grading (0^4) of NSF in its late phase

Grade Clinical Presentation Comments

0 No symptoms NSF cases with full symptom remission

1 Mild physical, cosmetic, or neuropathicsymptoms not causing any kind ofdisability

These cases are easily overlooked

2 Moderate physical or neuropathicsymptoms limiting physical performanceto some extent

May remain mis- or undiagnosed

3 Severe symptoms limiting daily physicalactivities (walking, bathing, shopping,and so forth)

May remain mis- or undiagnosed

4 Severely disabling symptoms causingdependence of aid or devices forcommon, daily activities

These cases are likely to be diagnosed andincluded in registry studies of NSF incontrast to patients with NSF grade 0–3

Nephrogenic Systemic Fibrosis 837

high-risk agents, whereas the cyclic agents arelow-risk agents.4,22,23,26–28 So far, there has beenno scientifically verified report of NSF caused bya cyclic GBCA. Differences in study populationcharacteristics are another reason for the largevariability. Obviously, risk estimates derived fromstudy populations with mild-to-moderate renalinsufficiency will be lower than estimates derivedfrom studies of patients with end-stage renaldisease. Risk may also vary between predialyticpatients, dialysis patients with residual kidneyfunction, and anuric dialysis patients, and betweenpatients treated with peritoneal dialysis versushemodialysis. The risk of NSF varies even amongpatients with similarly poor renal function exposedto the same high-risk GBCA: some will end up asNSF victims whereas other will not. These obser-vations illustrate that the NSF risk of an individualis modified by more factors than just type ofGBCA and kidney function.

Several studies have tried to identify the riskmodifiers such as acidosis18,29 and the dose ofthe GBCA.20,26,29 In the authors’ case-controlledstudy published in 2007, it was concluded thatthe risk of NSF is increased with increasing cumu-lative GBCA exposure (ie, repeated exposures) inpatients with stage 5 chronic kidney disease, andwith increased serum concentration of ionizedcalcium and phosphate. The report also observedthat high-dose erythropoietin treatment andregular hemodialysis therapy was associatedwith the more severe course of NSF.17 Princeand colleagues29 similarly found phosphate levelsto modify NSF risk. Their study also suggestedinflammation as a risk modifier similar to whatwas reported by others. Swaminathan andShah24 suggested a NSF promoting effect of iron

(ie, iron status and therapy). Other risk modifiershave been proposed but results have beenequivocal.

In summary, GBCA exposure and advancedrenal insufficiency are the two necessary causalfactors in NSF pathogenesis (Box 1). Residualkidney function, and certain metabolic conditions,clinical states, and pharmacologic treatmentsseem to be risk modifiers. These risk modifiersmost certainly interact mutually and with the twocausal factors in a complex manner that remainsto be understood. However, current best evidencesuggests that states of inflammation (for example,because of malnutrition, infection, or surgery),hyperphosphatemia, and high-dose erythropoietintreatment are important promoters of NSF.

DIFFERENTIAL DIAGNOSIS

The diagnosis of NSF can be easily reached insome patients, but NSF cases with little or atypicalskin manifestations might be difficult to identify.Important differential diagnoses of NSF includescleromyxoedema, morphea, systemic sclerosis,eosinophilic fasciitis, and lipodermatosclerosis.The differential diagnoses most often can beexcluded from the clinical findings as describedbelow.

Scleromyxedema

Scleromyxedema is a rare, idiopathic disease withnumerous, firm and closely spaced papules of2 mm to 3 mm in size. The skin lesions are primarilyseen on hands, arms, upper trunk, neck, and face,unlike the anatomic predilection of lower legs andabsent involvement of upper trunk, neck, and facein NSF. Affected areas are erythematous, with

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Box1Causal factors and risk modifiers of NSF

Causal factors

Acute or chronic renal insufficiency withglomerular filtration rate below 30 mL perminute per 1.73 m2 in combination with

Exposure to intravascularly administeredGd-based contrast agents

Risk modifiers associated with raised risk orincreased severity of NSF

Increasingly poor renal function

High cumulated dose exposure to Gd-basedcontrast agents

High dose single exposure to Gd-based contrastagents

Linear nonionic > linear ionic > cyclic Gd-basedcontrast agents

Hyperphosphatemia

Hypercalcemia

Erythropoietin analog treatment

Inflammatory states

Risk modifiers possibly associated with raisedrisk of NSF

Iron status

Hypercoagulability

Surgery

Acidosis

Marckmann & Skov838

scleroderma-like induration. In contrast to NSF,paraproteinemia is a frequent finding inscleromyxedema.

Morphea

Morphea is characterized by circumscribedwhitish sclerotic plaques with a shiny, cicatricialcenter. A violaceous border may be seen in activestages. The color of the morphea elementscontrasts with that of NSF elements (erythematouswith or without hemorrhagic elements in the earlyphase, and mostly brown in late stages). In NSF,there are no specific characteristics of the centerof the elements.

Systemic Sclerosis

In systemic sclerosis, the skin lesions may closelyresemble those of NSF. However, systemic scle-rosis typically includes marked Raynaud phenom-enons, truncal and facial involvement withdecreased oral aperture, significant atrophy of

fingertips, and painful digital ulcerations. Thesefindings are unusual in NSF patients. Differentfrom NSF, systemic sclerosis is frequently charac-terized by marked digestive tract involvementcausing dysphagia. Similar to NSF, lung fibrosisis seen. In 90% or more of systemic sclerosispatients there are antinuclear antibodies, a charac-teristic that is not observed with NSF.

Eosinophilic Fasciitis

Eosinophilic fasciitis initially presents as pain,erythema, warmth, swelling, and induration of theextremities. Later sclerotic changes and contrac-tures predominate. The skin changes are typicallyseen over the inside of the arms and the front ofthe legs. The skin of the face, chest, and abdomenmay also be occasionally affected. Patients witheosinophilic fasciitis have peripheral blood eosino-philia, which is not a feature of NSF.

Lipodermatosclerosis

Lipodermatosclerosis is characterized by well-cir-cumscribed indurated, inflamed and sometimeshyperpigmented plaques and dermatitis on thelower legs in patients with longstanding venousinsufficiency and stasis. The neuropathic symp-toms of NSF and contractures are not seen.

In uncertain cases, information about exposureto GBCA before skin changes is important.Furthermore, skin histology would provide diag-nostic clues. The histologic features of NSF aredescribed elsewhere in this issue.

TREATMENT

The serious clinical problems of NSF patients haveforced physicians dealing with these patients toinstitute empiric treatment. Several approacheshave been tried, including systemic steroid, imati-nib, chelating treatment with intravenous sodiumthiosulfate, extracorporeal photopheresis, ultravi-olet-A phototherapy, plasmapheresis, andmore.5,16 To the authors’ knowledge, none ofthese treatments have been tested in controlledtrials. Some of these treatments were reported tohelp some NSF patients in single reports, but con-trasting observations were made by others. There-fore, there is still no proven curative medicaltreatment that can be offered to the NSF patients.However, there seems to be wide consensus thatintensive physiotherapy may be of benefit in main-taining physical abilities and may even reverse lostjoin motion and disabilities in some cases. Symp-tomatic treatment with painkillers, moisturizingskin lotions, psychologic assistance, and aiding

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Nephrogenic Systemic Fibrosis 839

devices are important and should be consideredas needed.

The only really promising solution for NSFpatients is to recover their renal function. Thismay be obtained spontaneously in patients withacute renal failure, but requires renal transplanta-tion in cases of chronic renal failure. Several anec-dotal reports, including the authors’ ownexperience with three transplanted NSF patientsand a recent observational study indicate thatsignificant remission of NSF symptoms may beseen after successful transplantation.30

SUMMARY

The objective of this article was to providea comprehensive description of the clinical historyand signs that should raise the suspicion of NSF ina patient. The NSF diagnosis may be based onhistory of GBCA-exposure, temporally relatedspecific symptoms from the skin or other organs,histology of affected skin, and the exclusion ofcertain differential diagnoses. The present articledefines early and late phases of NSF, describesearly- and late-NSF symptoms, underlines thevariation in NSF severity between patients, andemphasizes the existence of atypical skin changesand extra-cutaneous manifestations related toGBCA exposure in uremic patients. NSF symp-toms may resolve with recovery of renal functionspontaneously or as a result of transplantation.

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