Nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy is a rare and serious syndrome that involves fibrosis of skin, joints, eyes, and internal organs. The first cases were identified in 1997 and its cause is not fully understood. However, there is much evidence to suggest that it is associated with exposure to gadolinium (with gadolinium-based MRI contrast agents being frequently used as contrast agents for magnetic resonance imaging) in patients with severe kidney failure.^[1] Epidemiological studies suggest that the incidence of NSF is unrelated to gender, race, or age and it is not thought to have a genetic basis. A registry for NSF has identified about 335 cases as of 2011.^[2]

Most patients with NSF 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 seven gadolinium contrast agents approved by the U.S. Food and Drug Administration have been principally implicated in NSF, including Omniscan, MultiHance, Magnevist, and OptiMARK.

Systemic symptoms

In NSF, patients develop large areas of hardened skin with fibrotic nodules and plaques. NSF may also cause joint contractures resulting in joint pain and limitation in range of motion. In its most severe form, NSF may cause severe systemic fibrosis affecting internal organs including the lungs, heart and liver.^[3][4]

Microscopic pathology

At the microscopic level, NSF resembles scleromyxedema. Both conditions show a proliferation of dermal fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and deposits of mucin.^[5] More recent case reports have described the presence of sclerotic bodies (also known as elastocollagenous balls) in skin biopsies from NSF patients. While not universally present, this finding is believed to be unique to patients exposed to gadolinium, although not necessarily limited to areas involved by NSF ^{[6] [7][8]}

History

The first cases of NSF were identified in 1997,^[9] but NSF was first described as an independent disease entity in 2000.^[10] While skin involvement is on the foreground, the process may involve any organ and resembles diffuse scleroderma or systemic sclerosis.^[11] In 2006, the link between NSF and gadolinium-containing contrast agents was made.^[12][13][14] 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 ml/mn.^[15] One retrospective study of the Veterans Affairs Electronic Medical Record found no cases of NSF among 141 patients receiving hemodialysis for chronic kidney disease who received gadoteridol (ProHance).^[16]

Classification of gadolinium contrast agents as to risk

The European Medicines Agency has classified the gadolinium-containing contrast agents into three risk groups:^[17]

• Least likely (safest) to release free gadolinium ions Gd(III) (also written Gd^{3+) in the body have a cyclical structure: Dotarem, Gadovist and ProHance}
• Intermediate have an ionic linear structure: Magnevist, MultiHance, Primovist (Eovist in the U.S.) and Vasovist
• Most likely to release Gd (III) have a linear non-ionic structure: Omniscan and OptiMARK

The suitability of gadolinium complexes as magnetic resonance imaging contrast agents depends on a number of factors. A thermodynamic relationship to toxicity exists if one assumes that the chemotoxicity of the intact complex is minimal but that the toxicity of the components of the complex (free metal and uncomplexed ligands) is substantial.

Release of Gd(III) from the complex is responsible for the toxicity associated with gadolinium complexes; this release appears to be a consequence of Zn²⁺, Cu²⁺, and Ca²⁺ transmetallation in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd(III) complexes, all become lethally toxic when they release precisely the same quantity of Gd(III). It is also supported by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn²⁺ deficiency. Finally, this hypothesis predicts that subtle changes in formulation can further enhance the intrinsic safety of these complexes. The added Ca²⁺ salt of the ligand must have a favorable toxicity so that the decrease in toxicity from in vivo transmetallation is not offset, or overcome, by the addition of a toxic component to the formulation.^[18]

Relation to acute kidney injury

NSF has also developed in patients with acute kidney injury [14], even if renal function subsequently returned to normal following GBCM administration [15]. In one series, up to 20% of NSF cases were diagnosed in patients who had been in some element of transient acute renal failure (often, but not always, superimposed upon chronic kidney disease) at the time of GBCM administration [16].^[19]

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, not sold in North America). The intermediate category would have been both ionic linear structure and non-ionic cyclical structure. The third category most at risk was unchanged (linear non-ionic).^[20]

References