Nephrogenic fibrosing dermopathy

Assistant Editor-in-Chief: Brian Blank

Overview
Nephrogenic fibrosing dermopathy or nephrogenic systemic fibrosis is a rare and serious syndrome that involves fibrosis of skin, joints, eyes, and internal organs. Its cause is not fully understood, but it seems to be associated with exposure to gadolinium (which is frequently used as a contrast substance for MRIs) in patients with severe kidney failure. It does not have a genetic basis.

Historical Background
The first cases of NFD have been identified in 1997 as a fibrotic disorder of the skin in patients with renal failure. As an independent disease entity, NFD was first described in 2000. Since then, systemic involvement has been described in some patients with NFD, resulting in use of the term nephrogenic systemic fibrosis (NSF); NFD and NSF have been used to describe the same condition. No clear etiology has been established for NFD, and little is known about its pathogenesis or natural history. This report describes the largest geographic cluster of NFD that has been identified and provides evidence that exposure to a gadolinium-containing contrast agent is a risk factor for the development of the disease. While skin involvement is on the foreground, the process may involve any organ and resembles diffuse scleroderma or systemic sclerosis.

In 2006, the link between NFD and gadolinium-containing contrast agents was made. As a result, gadolinium-containing contrast is now considered contraindicated in patients with an estimated glomerular filtration rate (a measure of renal function) under 60 and especially under 30.

Classification
The European authorities have classified the gadolinium-containing contrast agents in three groups:
 * Least likely (safest) to release free gadolinium ions Gd3+ in the body have a cyclical structure: Dotarem, Gadovist and ProHance
 * Intermediate have a ionic linear structure: Magnevist, MultiHance, Primovist and Vasovist
 * Most likely to release Gd3+ have a linear non-ionic structure: Omniscan and OptiMARK

It can be noted that this classification was released after another proposition would have left the safest category (ionic cyclical structure) with only one agent (Dotarem). The intermediate category would have been either ionic linear structure or non-ionic cyclical structure. The third category most at risk was unchanged (linear non-ionic).

Risk Factors
Although risk factors for NFD have not been studied extensively, possible correlations with severity of renal  failure, thrombotic episodes, edema, and vascular procedures have been reported. Recently, medication exposures such as erythropoietin and gadolinium-containing contrast agents have been identified as potential risk factors for NFD  In May 2006, the Danish Medicines Agency reported 25 cases of NFD diagnosed in Europe among patients with recent exposure  to gadolinium-containing contrast. In response, the Food and Drug Administration (FDA) issued a public health advisory in June 2006 regarding the use of these contrast agents ([gadopentetate dimeglumine (Magnevist), gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadoversetamide (OptiMARK), gadoteridol (ProHance)] in patients with moderate to end-stage renal disease . As of December 25, 2006, the FDA MedWatch system had received 90 reports of NFD possibly related to gadolinium-containing contrast agents. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease.

Appearance of the patient
Characteristics of NFD can include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. Patients develop large areas of hardened skin with fibrotic nodules and plaques. Flexion contractures with an accompanying limitation of range of motion can also occur. NFD resembles scleromyxedema at the histologic (microscopic) level; it shows a proliferation of dermal fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and deposits of mucin.

Pathogenesis
Intravenously administered contrast agents are used routinely for MRI studies; the contrast agents contain gadolinium (a paramagnetic heavy metal), which is bound to a chelating agent. The mechanism for possible gadolinium-associated NFD is unknown; however, one hypothesis is that the gadolinium ions might dissociate from the chelate and result in a fibrotic reaction. Five gadolinium-based contrast agents are available in the United States; the first was approved for use in 1988. Adverse events associated with these agents typically are minor (e.g., nausea); severe effects such as allergic reactions or tissue necrosis as a result of extravasation are rare. In addition, gadolinium-containing contrast agents are believed to be less nephrotoxic than iodinated contrast agents used for computed tomography (CT) imaging. Excretion of gadolinium-containing contrast agents primarily occurs renally; the amount of contrast eliminated from the body after dialysis has not been well-evaluated. Two studies suggest that 65%-78% of gadolinium-containing contrast might be cleared after one hemodialysis session and 98% after three sessions. Peritoneal dialysis might achieve less effective gadolinium-contrast clearance than hemodialysis. In one study, 69% of total gadolinium-containing contrast was excreted after 22 days in patients undergoing continuous ambulatory peritoneal dialysis. Delayed clearance might prolong the duration of gadolinium-containing contrast exposure among patients undergoing peritoneal dialysis. However, patients undergoing peritoneal dialysis have not been previously reported to be at higher risk for NFD than patients undergoing hemodialysis. The chronic peritoneal dialysis outpatients in this investigation had higher estimated NFD attack rates than chronic hemodialysis outpatients. No controls who had gadolinium-containing contrast exposure underwent primarily peritoneal dialysis.

Treatment
Most patients with NFD have undergone hemodialysis for renal failure, some have never undergone dialysis and others have received only peritoneal dialysis. Many patients have taken immunosuppressive medications and have other diseases, such as hepatitis C. Four of the five FDA-approved gadolinium contrast agents have been principally implicated in NFD, including Omniscan, Multihance, Magnevist, and OptiMARK.

Source

 * CDC

Nephrogene systemische Fibrose