Nephrogenic systemic fibrosis (NSF)

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What is nephrogenic systemic fibrosis (NSF)?

Nephrogenic systemic fibrosis previously known as nephrogenic fibrosing dermopathy, is characterized by progressive fibrosis and thickening of the skin (similar to scleroderma), which is particularly painful, and also fibrosis in other organs (e.g., pleura, diaphragm).

A rare but debilitating or fatal fibrosing condition that most often affects the skin but may involve multiple organs.

NSF is a progressive fibrosing disorder occurring in patients with severe renal disease who have received gadolinium-containing contrast during an MRI procedure.

Most patients are dialysis-dependent or have a glomerular filtration rate of <15 mL/minute (stage 5 chronic kidney disease [CKD]). Rarely, patients may develop NSF with less severe kidney disease.

Nephrogenic systemic fibrosis occurs in the presence of kidney failure following the administration of gadolinium-based MR contrast agents.

It was first described in 1997 and was called nephrogenic fibrosing dermopathy; the nomenclature was changed to Nephrogenic systemic fibrosis in 2005.

What are the risk factors for developing Nephrogenic systemic fibrosis?

• High doses of gadolinium-based contrast agents

• Decreased glomerular filtration rate (below 30 mL/min, although almost all documented cases have been dialysis dependent)

• Vascular injury

• Venous thrombosis

• Coagulopathy

In patients with acute kidney injury, the use of gadolinium-based contrast agent should be avoided.

For patients with chronic kidney disease, the Federal Drug Administration (FDA) has determined that the risk is greatest when the eGFR is less than 30 mL/min per 1.73 m 2 .

In this setting, it should be determined whether use of a gadolinium-based contrast agent is essential for diagnosis, and alternative imaging techniques and tests should be considered.

For patients receiving hemodialysis when MRI is essential, it is recommended that hemodialysis be performed immediately after gadolinium-based contrast agent administration and again 24 hours later. However, the efficacy of dialysis is debated.

Peritoneal dialysis clears gadolinium very slowly so gadolinium-based contrast agents should be avoided in these patients.

Symptoms of Nephrogenic systemic fibrosis

The skin lesions appear as plaques, papules, or nodules distributed in an asymmetric fashion over the distal extremities.

Pathophysiology

The pathogenesis is deposition of gadolinium (contrast material used in magnetic resonance imaging), which does not get cleared in the presence of severe chronic kidney disease or acute kidney injury.

The interval between exposure to gadolinium and the early manifestations of Nephrogenic systemic fibrosis can range from 2 days to 18 months.

This variability is attributed to mobilization of gadolinium from bone over time. The risk of Nephrogenic systemic fibrosis appears to be higher with the linear molecules (e.g., gadodiamide) compared with macro cyclic gadolinium molecules.

How is Nephrogenic systemic fibrosis treated?

NSF has no effective treatment and a high fatality rate, so the primary focus is on prevention.

Gadolinium-enhanced scans should be avoided in patients with severe chronic kidney disease or acute kidney injury.

When gadolinium-enhanced scans are necessary, prophylactic measures that have been described include the use of hemodialysis (HD; eliminates 92% of gadolinium after two HD sessions; 99% after three HD sessions) in patients with advanced chronic kidney disease.

Similarly, an intensified regimen of peritoneal dialysis (PD) can remove gadolinium (90% of the gadolinium in 2 days with a regimen of 10 to 15 exchanges per day of PD).

The effectiveness of these measures is not clear.

Typical course of a patient with Nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis typically presents within 2 to 4 weeks of an at risk patient receiving gadolinium-containing contrast during MRI. Cutaneous features first involve lower extremities and extend proximally, with predominant extremity involvement.

The face is not involved. Patients first experience itching or burning, followed by development of papules and plaques.

Skin may develop a peau d’orange appearance and “cobblestone” texture over the upper arms, back, and thighs. Skin is very indurated and may develop hyperpigmentation. Flexion deformities of fingers, elbows, and knees are commonly disabling. Fibrosis of any visceral organ can occur and may be symptomatic. Raynaud’s phenomenon does not occur.

What are the characteristic laboratory abnormalities and histologic features in a patient with Nephrogenic systemic fibrosis?

There are no diagnostic laboratory tests. Paraproteinemia and scleroderma-associated autoantibodies are not present, which helps separate NSF from scleromyxedema and SSc, respectively.

Therefore, the diagnosis is made by the clinical evaluation and confirmed by a deep skin biopsy. The biopsy in NSF is characterized by increased number of dermal fibroblasts, increased dermal collagen, increased mucin deposition, no inflammatory cells, and increased CD34+ fibrocytes and CD68+ monocytes from the circulation. Gadolinium has been demonstrated in the tissue by mass spectrometry. Of note, the histology of Nephrogenic systemic fibrosis and scleromyxedema is very similar; the absence of a monoclonal gammopathy and sparing of face involvement in NSF (along with characteristic gadolinium exposure in a high-risk patient) can help separate the two.

Prognosis of Nephrogenic systemic fibrosis

The best therapy for Nephrogenic systemic fibrosis is prevention.

Patients with stage 4 and 5 CKD should not receive gadolinium-containing contrast during MRI. In patients with milder forms of renal insufficiency, use of lower-risk gadolinium-based contrast agents is recommended (macrocyclic chelates) as they may result in lower concentrations of free gadolinium (Gd +3 ) ions.

Once Nephrogenic systemic fibrosis is present, there is no effective therapy. Early renal transplantation has helped some patients.

Phototherapy with UVA1, extracorporeal photopheresis, plasmapheresis, and oral imatinib mesylate have been anecdotally reported as being effective.

Patients with Nephrogenic systemic fibrosis have a three-fold increased mortality.

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