KIDNEY DISEASE AND GADOLINIUM: IS THERE A LINK?

KIDNEY DISEASE KIDNEY DISEASE

AND AND

GADOLINIUM:GADOLINIUM:

IS THERE A LINK?IS THERE A LINK?

Nephrogenic Nephrogenic

SystemicSystemic Fibrosis Fibrosis

New Disease.New Disease.

All Should Know.All Should Know.

Nephrogenic Systemic FibrosisNephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis (NSF) is aNephrogenic systemic fibrosis (NSF) is a

recently identified fibrosing disorder seenrecently identified fibrosing disorder seen

only in patient with kidney failure.only in patient with kidney failure.

It is characterized by two primary featuresIt is characterized by two primary features

1.1. Thickening and hardening of the skin Thickening and hardening of the skin overlying the extermities and trunk.overlying the extermities and trunk.

2.2. Marked expansion and fibrosis of the Marked expansion and fibrosis of the dermis in association with CD34-positive dermis in association with CD34-positive fibrocytes.fibrocytes.

TerminologyTerminology

1.1. Nephrogenic fibrosing dermopath Nephrogenic fibrosing dermopath (NFD)(NFD)

2. Dialysis – associated systemic 2. Dialysis – associated systemic fibrosisfibrosis

EpidemiologyEpidemiology

NSF occurs exclusively in patients NSF occurs exclusively in patients withwith

kidney failure.kidney failure.

The first cases were noted The first cases were noted between between

1997 and 2000.1997 and 2000.

No Predilection to NSF by gender,No Predilection to NSF by gender,

race, or age, etiology of kidney race, or age, etiology of kidney disease or duration of renal failure.disease or duration of renal failure.

Peritoneal dialysis, May be at Peritoneal dialysis, May be at HigherHigher

risk than hemodialysis.risk than hemodialysis.

EtiologyEtiology

A retrospective analysis of two large tissueA retrospective analysis of two large tissue repositories failed to identify any casesrepositories failed to identify any cases presenting before 1997.presenting before 1997.

A case matched study undertaken by the A case matched study undertaken by the centers for disease control failed to isolate a centers for disease control failed to isolate a single mediator (drug, medical technique, single mediator (drug, medical technique, chemical or infectious agent) that could chemical or infectious agent) that could explain every case of NSF. explain every case of NSF.

Increasing epidemlologic evidence has Increasing epidemlologic evidence has implicated gadolinium-containing contrast implicated gadolinium-containing contrast agents. agents.

GadoliniumGadolinium

Gadolinium chelaes are excreted unchangedGadolinium chelaes are excreted unchanged exclusively by the kidney.exclusively by the kidney.

Its half-life is 1.3hours in healthy.Its half-life is 1.3hours in healthy.

10 hours at an estimated. (GFR) of 20 to 40 10 hours at an estimated. (GFR) of 20 to 40

ML/min.ML/min.

34 hours in patients with end-stage renal 34 hours in patients with end-stage renal disease.disease.

1.9 to 2.6 hours if hemodialysis follows the 1.9 to 2.6 hours if hemodialysis follows the administration of gadoliniumadministration of gadolinium

1.1. Dose-response relationship Dose-response relationship exists.exists.

2.2. Erythropoietin therapyErythropoietin therapy

RiskRisk

Clinical ManifestationsClinical Manifestations

The latent period between The latent period between exposure and disease onset is exposure and disease onset is usually two to four weeks.usually two to four weeks.

The range is as short as two days The range is as short as two days and as long as 18 moths and as long as 18 moths

Skin disease in NSF symmetrical.Skin disease in NSF symmetrical.

Bilateral fibrotic indurated papules, Bilateral fibrotic indurated papules, plaques.plaques.

Subcutaneous nodules may be Subcutaneous nodules may be erythematous.erythematous.

Skin involvementSkin involvement

The lesions first develop on the The lesions first develop on the lower legs, ankles, feet, wrist, hand.lower legs, ankles, feet, wrist, hand.

Common distribution patterns Common distribution patterns involve the ankles up to mid-thighs. involve the ankles up to mid-thighs.

Skin between the wrists and mid-Skin between the wrists and mid-upper arms, bilaterally.upper arms, bilaterally.

Unusual distribution patterns Unusual distribution patterns overlying the mid and lower overlying the mid and lower abdomen.abdomen.

The head is spared.The head is spared.

The lesion preceded by edema and The lesion preceded by edema and may initially be misdiagnosed as may initially be misdiagnosed as cellulitis.cellulitis.

The edema usually resolves and The edema usually resolves and skin retains a thickened and firm skin retains a thickened and firm texture.texture.

The skin may have a cobblestone The skin may have a cobblestone woody or peau d’ orange woody or peau d’ orange appearance.appearance.

The lesions may be pruritic and The lesions may be pruritic and sharp pain or a burning sensation.sharp pain or a burning sensation.

Movement of the joints may be so Movement of the joints may be so limited and flexibility is lost.limited and flexibility is lost.

Systemic involvementSystemic involvement

Movement of the joints may be so Movement of the joints may be so limited and flexibility is lost.limited and flexibility is lost.

Muscle induration but strength is Muscle induration but strength is normal joint contractures.normal joint contractures.

Fibrosis of internal organs, diaphragm , Fibrosis of internal organs, diaphragm , myocardium, pericardium and pleura myocardium, pericardium and pleura and dura mater.and dura mater.

Yellow asymptoatic scleral plaques Yellow asymptoatic scleral plaques similar to pinguicula.similar to pinguicula.

DiagnosisDiagnosis

Marked ESR and CRPMarked ESR and CRP Histopathologic examination of a Histopathologic examination of a

biopsy.biopsy.

BiopsyBiopsy

1.1. Light microscopy varies with Light microscopy varies with disease severity, ranging from disease severity, ranging from proliferation of dermal fibrocytes proliferation of dermal fibrocytes in early lesions, to marked in early lesions, to marked thickening of the dermis with thickening of the dermis with florid proliferation of fibrocytes florid proliferation of fibrocytes with long dendritic processes in with long dendritic processes in fully developed cases.fully developed cases.

2.2. Associated with histiocytes and Associated with histiocytes and factor XIIIa+drmal dendritic cells factor XIIIa+drmal dendritic cells

3. Thick collagen bundles with3. Thick collagen bundles with

surrounding clefts are a prominent surrounding clefts are a prominent finding.finding.

4. Immunohistochemical staining 4. Immunohistochemical staining reveals.reveals.

CD34+dermal cells, with the CD34+dermal cells, with the dendritic processes.dendritic processes.

5. Elastic fibers and around collagen5. Elastic fibers and around collagen

bundles in a dense network bundles in a dense network

6. Increased number of CD68+and 6. Increased number of CD68+and factor factor

XIII+dendritic cells XIII+dendritic cells

7. Special tasting may reveal 7. Special tasting may reveal gadolinium.gadolinium.

Laboratory testsLaboratory tests Elevations in serum C-reactive Elevations in serum C-reactive

protein, serum ferritin, reduction in protein, serum ferritin, reduction in serum albumin serum albumin

Normal or absent are the Normal or absent are the eosinophil count, serum and urine eosinophil count, serum and urine protein electrophoresis, thyroid protein electrophoresis, thyroid function tests are normal.function tests are normal.

Pulmonary function tests reveal Pulmonary function tests reveal reductions in total lung capacity reductions in total lung capacity and volume and diffusing capacity.and volume and diffusing capacity.

Echocardiography is suggested Echocardiography is suggested possible cardiomyopathy.possible cardiomyopathy.

Muscle biopsyMuscle biopsy

Differential DiagnosisDifferential Diagnosis

1.1. SclerodermaScleroderma

2.2. Scleromyxedema Scleromyxedema

3.3. Eosinophilic Eosinophilic

4.4. CalciphylaxisCalciphylaxis

In a review of the published In a review of the published literature, literature,

1.1. 28% of patients had no 28% of patients had no improvementimprovement

2.2. 28% of patients died28% of patients died

3.3. 20% had modest improvement20% had modest improvement

Improvement in or remission of Improvement in or remission of NSF has been described, NSF has been described, primarlly in patients who primarlly in patients who recovered renal funtion.recovered renal funtion.

1.1. Prevention Prevention

2.2. Avoidance of gadoliniumAvoidance of gadolinium

1.1. Gadolinium at high doses should Gadolinium at high doses should be used only if clearly necessary be used only if clearly necessary

2.2. Should be avoided in patients Should be avoided in patients with a diagnosis or clinical with a diagnosis or clinical suspicion of NSF.suspicion of NSF.

3.3. Institute prompt hemodialysis Institute prompt hemodialysis after the imaging study if after the imaging study if gadolinium is givengadolinium is given

4. the average rates of gadolinium 4. the average rates of gadolinium removal were 78, 96, and 99removal were 78, 96, and 99 percent percent in the first, second, and third every –in the first, second, and third every –other-day dialysis sessions respectivelyother-day dialysis sessions respectively

5. No evidence that hemodialysis 5. No evidence that hemodialysis immediately after exposure lowers the immediately after exposure lowers the risk or severity of NSF.risk or severity of NSF.

6. Gadolinium is cleared much more 6. Gadolinium is cleared much more slowly with peritoneal dialysis slowly with peritoneal dialysis hemodialysis after the procedure is hemodialysis after the procedure is advisable.advisable.

TreatmentTreatment

No proven therapy for NSF other No proven therapy for NSF other than recovery of renal function.than recovery of renal function.

1.1. Intensive physical therapy is Intensive physical therapy is recommended in all patients to recommended in all patients to prevent or reverse disabilityprevent or reverse disability

2.2. Renal transplantationRenal transplantation

3. Extracorporeal photopheresis3. Extracorporeal photopheresis

4. Ultraviolet A phototherapy4. Ultraviolet A phototherapy

5. Plasmapheresis5. Plasmapheresis

6. Other modalities photodynamic 6. Other modalities photodynamic therapy, pentoxifylline, sodium therapy, pentoxifylline, sodium thiosulfate, intravenous immune thiosulfate, intravenous immune globulin.globulin.