Nephrogenic systemic fibrosis
Encyclopedia
Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy is a rare and serious syndrome
that involves fibrosis
of skin, joints, eyes, and internal organs. 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
. 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.
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.
At the microscopic level, NSF resembles scleromyxedema. Both conditions show a proliferation of dermal fibroblast
s and dendritic cells, thickened collagen
bundles, increased elastic fibers, and deposits of mucin
. 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 NSF
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
.
The first cases of NSF were identified in 1997, but NSF was first described as an independent disease entity in 2000. 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 NSF 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 ml/mn. 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).
The European Medicines Agency
has classified the gadolinium-containing contrast agents in three groups:
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 Gd3+ from the complex is responsible for the toxicity associated with gadoliium complexes; this release appears to be a consequence of Zn2+, Cu2+, and Ca2+ transmetallatiou in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd complexes, all become lethally toxic when they release precisely the same quantity of Gd3+, and 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.
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].
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).
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
that involves fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
of skin, joints, eyes, and internal organs. Its cause is not fully understood. However, there is much evidence to suggest that it is associated with exposure to gadolinium
Gadolinium
Gadolinium is a chemical element with the symbol Gd and atomic number 64. It is a silvery-white, malleable and ductile rare-earth metal. It is found in nature only in combined form. Gadolinium was first detected spectroscopically in 1880 by de Marignac who separated its oxide and is credited with...
(with gadolinium-based MRI contrast agents being frequently used as contrast agents for magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
) in patients with severe kidney failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. 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.
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.
At the microscopic level, NSF resembles scleromyxedema. Both conditions show a proliferation of dermal fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s and dendritic cells, thickened collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
bundles, increased elastic fibers, and deposits of mucin
Mucin
Mucins are a family of high molecular weight, heavily glycosylated proteins produced by epithelial tissues in most metazoans. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most gel-like secretions, serving functions from lubrication to cell...
. 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 NSF
Most patients with NSF have undergone hemodialysis
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...
for renal failure, some have never undergone dialysis and others have received only peritoneal dialysis
Peritoneal dialysis
Peritoneal dialysis is a treatment for patients with severe chronic kidney disease. The process uses the patient's peritoneum in the abdomen as a membrane across which fluids and dissolved substances are exchanged from the blood...
. Many patients have taken immunosuppressive
Immunosuppressant
An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...
medications and have other diseases, such as hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
. 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
Gadoversetamide
Gadoversetamide is a gadolinium-based MRI contrast agent, particularly for imaging of the brain, spine and liver. It is marketed under the trade name OptiMARK....
.
The first cases of NSF were identified in 1997, but NSF was first described as an independent disease entity in 2000. 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 NSF 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
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
) under 60 and especially under 30 ml/mn. 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).
The European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
has classified the gadolinium-containing contrast agents in three groups:
- Least likely (safest) to release free gadolinium ionIonAn ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s Gd3+ in the body have a cyclical structureMolecular geometryMolecular geometry or molecular structure is the three-dimensional arrangement of the atoms that constitute a molecule. It determines several properties of a substance including its reactivity, polarity, phase of matter, color, magnetism, and biological activity.- Molecular geometry determination...
: Dotarem, Gadovist and ProHance - Intermediate have an ionic linear structure: Magnevist, MultiHance, Primovist (Eovist in the U.S.) and Vasovist
- Most likely to release Gd3+ 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 Gd3+ from the complex is responsible for the toxicity associated with gadoliium complexes; this release appears to be a consequence of Zn2+, Cu2+, and Ca2+ transmetallatiou in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd complexes, all become lethally toxic when they release precisely the same quantity of Gd3+, and 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.
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].
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).