KIDNEY DISEASE KIDNEY DISEASE AND GADOLINIUM: GADOLINIUM: IS THERE A LINK?

Nephrogenic Systemic Fibrosis New Disease. All Should Know.

Nephrogenic Systemic Fibrosis Nephrogenic systemic fibrosis (NSF) is a Nephrogenic systemic fibrosis (NSF) is a recently identified fibrosing disorder seen recently identified fibrosing disorder seen only in patient with kidney failure. only in patient with kidney failure. It is characterized by two primary features It is characterized by two primary features 1. Thickening and hardening of the skin overlying the extermities and trunk. 2. Marked expansion and fibrosis of the dermis in association with CD34-positive fibrocytes.

Terminology 1. Nephrogenic fibrosing dermopath (NFD) 2. Dialysis – associated systemic fibrosis

Epidemiology NSF occurs exclusively in patients with NSF occurs exclusively in patients with kidney failure. kidney failure. The first cases were noted between The first cases were noted between 1997 and and 2000.

No Predilection to NSF by gender, No Predilection to NSF by gender, race, or age, etiology of kidney disease or duration of renal failure. race, or age, etiology of kidney disease or duration of renal failure. Peritoneal dialysis, May be at Higher Peritoneal dialysis, May be at Higher risk than hemodialysis. risk than hemodialysis.

Etiology A retrospective analysis of two large tissue A retrospective analysis of two large tissue repositories failed to identify any cases repositories failed to identify any cases presenting before presenting before A case matched study undertaken by the centers for disease control failed to isolate a single mediator (drug, medical technique, chemical or infectious agent) that could explain every case of NSF. A case matched study undertaken by the centers for disease control failed to isolate a single mediator (drug, medical technique, chemical or infectious agent) that could explain every case of NSF. Increasing epidemlologic evidence has implicated gadolinium-containing contrast agents. Increasing epidemlologic evidence has implicated gadolinium-containing contrast agents.

Gadolinium Gadolinium chelaes are excreted unchanged Gadolinium 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 hours at an estimated. (GFR) of 20 to 40 ML/min. ML/min. 34 hours in patients with end-stage renal disease. 34 hours in patients with end-stage renal disease. 1.9 to 2.6 hours if hemodialysis follows the 1.9 to 2.6 hours if hemodialysis follows the administration of gadolinium administration of gadolinium

1. Dose-response relationship exists. 2. Erythropoietin therapy Risk

Clinical Manifestations The latent period between exposure and disease onset is usually two to four weeks. The latent period between exposure and disease onset is usually two to four weeks. The range is as short as two days and as long as 18 moths The range is as short as two days and as long as 18 moths

Skin disease in NSF symmetrical. Skin disease in NSF symmetrical. Bilateral fibrotic indurated papules, plaques. Bilateral fibrotic indurated papules, plaques. Subcutaneous nodules may be erythematous. Subcutaneous nodules may be erythematous. Skin involvement

The lesions first develop on the lower legs, ankles, feet, wrist, hand. The lesions first develop on the lower legs, ankles, feet, wrist, hand. Common distribution patterns involve the ankles up to mid-thighs. Common distribution patterns involve the ankles up to mid-thighs. Skin between the wrists and mid-upper arms, bilaterally. Skin between the wrists and mid-upper arms, bilaterally. Unusual distribution patterns overlying the mid and lower abdomen. Unusual distribution patterns overlying the mid and lower abdomen.

The head is spared. The head is spared. The lesion preceded by edema and may initially be misdiagnosed as cellulitis. The lesion preceded by edema and may initially be misdiagnosed as cellulitis. The edema usually resolves and skin retains a thickened and firm texture. The edema usually resolves and skin retains a thickened and firm texture.

The skin may have a cobblestone woody or peau d ’ orange appearance. The skin may have a cobblestone woody or peau d ’ orange appearance. The lesions may be pruritic and sharp pain or a burning sensation. The lesions may be pruritic and sharp pain or a burning sensation. Movement of the joints may be so limited and flexibility is lost. Movement of the joints may be so limited and flexibility is lost.

Systemic involvement Movement of the joints may be so limited and flexibility is lost. Movement of the joints may be so limited and flexibility is lost. Muscle induration but strength is normal joint contractures. Muscle induration but strength is normal joint contractures. Fibrosis of internal organs, diaphragm, myocardium, pericardium and pleura and dura mater. Fibrosis of internal organs, diaphragm, myocardium, pericardium and pleura and dura mater. Yellow asymptoatic scleral plaques similar to pinguicula. Yellow asymptoatic scleral plaques similar to pinguicula.

Diagnosis Marked ESR and CRP Marked ESR and CRP Histopathologic examination of a biopsy. Histopathologic examination of a biopsy.

Biopsy 1. Light microscopy varies with disease severity, ranging from proliferation of dermal fibrocytes in early lesions, to marked thickening of the dermis with florid proliferation of fibrocytes with long dendritic processes in fully developed cases. 2. Associated with histiocytes and factor XIIIa+drmal dendritic cells

3. Thick collagen bundles with surrounding clefts are a prominent finding. surrounding clefts are a prominent finding. 4. Immunohistochemical staining reveals. CD34+dermal cells, with the dendritic processes. CD34+dermal cells, with the dendritic processes. 5. Elastic fibers and around collagen bundles in a dense network bundles in a dense network

6. Increased number of CD68+and factor XIII+dendritic cells XIII+dendritic cells 7. Special tasting may reveal gadolinium.

Laboratory tests Elevations in serum C-reactive protein, serum ferritin, reduction in serum albumin Elevations in serum C-reactive protein, serum ferritin, reduction in serum albumin Normal or absent are the eosinophil count, serum and urine protein electrophoresis, thyroid function tests are normal. Normal or absent are the eosinophil count, serum and urine protein electrophoresis, thyroid function tests are normal.

Pulmonary function tests reveal reductions in total lung capacity and volume and diffusing capacity. Pulmonary function tests reveal reductions in total lung capacity and volume and diffusing capacity. Echocardiography is suggested possible cardiomyopathy. Echocardiography is suggested possible cardiomyopathy. Muscle biopsy Muscle biopsy

Differential Diagnosis 1. Scleroderma 2. Scleromyxedema 3. Eosinophilic 4. Calciphylaxis

In a review of the published literature, In a review of the published literature, 1. 28% of patients had no improvement 2. 28% of patients died 3. 20% had modest improvement

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

1. Prevention 2. Avoidance of gadolinium

1. Gadolinium at high doses should be used only if clearly necessary 2. Should be avoided in patients with a diagnosis or clinical suspicion of NSF. 3. Institute prompt hemodialysis after the imaging study if gadolinium is given

4. the average rates of gadolinium removal were 78, 96, and 99 percent in the first, second, and third every – other-day dialysis sessions respectively 5. No evidence that hemodialysis immediately after exposure lowers the risk or severity of NSF. 6. Gadolinium is cleared much more slowly with peritoneal dialysis hemodialysis after the procedure is advisable.

Treatment No proven therapy for NSF other than recovery of renal function. No proven therapy for NSF other than recovery of renal function. 1. Intensive physical therapy is recommended in all patients to prevent or reverse disability 2. Renal transplantation

3. Extracorporeal photopheresis 4. Ultraviolet A phototherapy 5. Plasmapheresis 6. Other modalities photodynamic therapy, pentoxifylline, sodium thiosulfate, intravenous immune globulin.