Nephrogenic systemic fibrosis

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Nephrogenic systemic fibrosis
Other namesNSF
Specialty Dermatology   OOjs UI icon edit-ltr-progressive.svg
Causesiatrogenic disease caused by exposure to gadolinium-based contrast agents
Risk factors impaired kidney function is the major risk factor

Nephrogenic systemic fibrosis is a rare syndrome that involves fibrosis of the skin, joints, eyes, and internal organs. NSF is caused by exposure to gadolinium in gadolinium-based MRI contrast agents (GBCAs) in patients with impaired kidney function. [1] [2] Epidemiological studies suggest that the incidence of NSF is unrelated to gender or ethnicity and it is not thought to have a genetic basis. [2] [3] After GBCAs were identified as a cause of the disorder in 2006, [4] and screening and prevention measures put in place, it is now considered rare. [5]

Contents

Signs and symptoms

Clinical features of NSF develop within days to months and, in some cases, years following exposure to some GBCAs. The main symptoms are the thickening and hardening of the skin associated with brawny hyperpigmentation, typically presenting in a symmetric fashion. The skin gradually becomes fibrotic and adheres to the underlying fascia. [6] [7] The symptoms initiate distally in the limbs and progress proximally, sometimes involving the trunk. [6] Joint contractures of the fingers, elbows and knees can develop secondary to skin involvement and can severely impair physical function. [6] [8] While skin involvement is on the foreground, the process may involve any organ, e.g., the eye, [8] heart, diaphragm, pleura, pericardium, and kidneys, [6] [9] as well as the lungs and liver. [10] [11]

Causes

NSF is an iatrogenic disease caused by exposure to gadolinium-based contrast agents used in magnetic resonance imaging. [12]

Risk factors

Impaired kidney function reduces the clearance of GBCAs and is the major risk factor for the development of NSF. The etiology or duration of renal failure seems not to be relevant, but NSF risk greatly depends on the residual kidney function. [7] The majority of NSF cases have been identified in patients with stage 5 CKD, [8] but NSF has also developed in patients with stage 4 and 3 CKD, and those with acute kidney injury, even if kidney function subsequently returned to normal following GBCA administration. [13] [14] Thus NSF should be considered as a differential diagnosis in any patient who has been exposed to a GBCA, regardless of the kidney function level. [8]

Three GBCAs have been principally implicated in NSF: gadodiamide, gadopentetate dimeglumine, and gadoversetamide, though cases have been reported with majority of GBCAs on the market. [15] High doses in individual GBCA administrations and high cumulative doses of GBCA over the lifetime of patients with renal dysfunction are associated with increased risk of NSF. [7]

Mechanism

De-chelation of Gd(III) is responsible for the toxicity associated with gadolinium complexes such as GBCAs, and the toxicity appears to be a consequence of Zn2+, Cu2+, and Ca2+ transmetallation in vivo. [12] [15] 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). [16] 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. [16] Under the transmetallation hypothesis, we can expect that subtle changes in formulation can affect the intrinsic safety of gadolinium complexes, which is indeed observed. [12] [15]

Diagnosis

There is no specific imaging finding for NSF, and the diagnosis is a clinicopathological one, based on presentation and histological findings. [7]

Microscopic pathology

At the microscopic level, NSF shows a proliferation of dermal fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and deposits of mucin. [17] 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. [18] [19] [20]

Differential diagnosis

The differential diagnoses for NSF include diffuse cutaneous or limited cutaneous systemic sclerosis, scleromyxedema, lipodermatosclerosis, scleroedema diabeticorum, graft versus host disease, eosinophilic fasciitis; eosinophilia-myalgia syndrome; porphyria cutanea tarda, and other disorders. The nearly universal absence of facial skin involvement in NSF, presence of yellow plaques on the sclera of the eyes, absence of Raynaud's phenomenon, and other differences in presentation can aid the proper diagnosis. History of exposure to GBCAs would favor NSF as the differential diagnosis. [6] [8]

Prevention

The only known measure for prevention of NSF is the non-use or cautious use of GBCAs in patients with renal impairment, including preferential use of safer, macrocyclic GBCAs. Performing dialysis immediately after the MRI exam is recommended for patients already in dialysis treatment, but there is no evidence for introducing dialysis in non-dialytic patients for prevention of NSF. [6] Screening for impaired kidney function is routinely conducted and has drastically reduced the incidence of NSF. [5]

Treatment

Multiple therapies for NSF have been attempted, with variable clinical improvement. None have been as effective as restoration of kidney function. Restoration of kidney function by treating the underlying disease process, recovery from acute kidney injury (AKI), or performing a kidney transplant can slow or hold the progression of NSF. A few cases of curative kidney transplantation have been reported, and it is appropriate to consider transplantation as treatment. [6] [7]

Epidemiology

NSF affects males and females in approximately equal numbers and has been reported in patients of different ethnic and geographic regions. It most often affects middle-aged individuals, but there are reports of cases occurring from childhood to senescence. [6] [7]

History

This condition was originally termed "nephrogenic fibrosing dermopathy" as initially only skin involvement in patients with impaired kidney function was observed, and later renamed "nephrogenic systemic fibrosis" to better describe its systemic nature. [12] The term "gadolinium-associated systemic fibrosis" has also been proposed to reflect the fact that impaired kidney function is not in itself the cause of NSF. [12]

The first cases of NSF were identified in 1997, [21] but it was first described as an independent disease entity in 2000. [22] In 2006, the link between NSF and gadolinium-based MRI contrast agents was made. [4] [23] [24] As a result, restrictions on use of GBCAs in patients with an estimated glomerular filtration rate (a measure of kidney function) under 60 and especially under 30 mL/min/1.73 m2 have been recommended and NSF is now considered rare. [5]

After several years of controversy, during which up to 100 Danish patients developed gadolinium poisoning after use of the contrast agent Omniscan, the Norwegian medical company Nycomed admitted that they were aware of some dangers from using gadolinium-based agents in their product. [25]

With both Gadopentetic acid (gadopentetate dimegulumine (Magnevist)) and Gadodiamide (Omniscan) the risk was considered to outweigh the benefits and, as a result, the EMA recommended the licence for intravenous gadopentetic acid and Gadodiamide be suspended. [26]

Following a legally binding decision issued by The European Commission and applicable in all EU Member States (Commission decision date: 23/11/2017), Intravenous Magnevist and Omniscan is now no longer authorised for use in Europe. Magnavist is, however, still authorised in Europe as an intra-articular MR contrast medium. The authorised indication for the use of linear chelated media gadobenic acid (also known as gadobenate dimeglumine; MultiHance) and gadoxetic acid (Primovist) has been limited to delayed phase liver imaging only. [27]

Related Research Articles

<span class="mw-page-title-main">Gadolinium</span> Chemical element, symbol Gd and atomic number 64

Gadolinium is a chemical element; it has symbol Gd and atomic number 64. Gadolinium is a silvery-white metal when oxidation is removed. It is a malleable and ductile rare-earth element. Gadolinium reacts with atmospheric oxygen or moisture slowly to form a black coating. Gadolinium below its Curie point of 20 °C (68 °F) is ferromagnetic, with an attraction to a magnetic field higher than that of nickel. Above this temperature it is the most paramagnetic element. It is found in nature only in an oxidized form. When separated, it usually has impurities of the other rare-earths because of their similar chemical properties.

<span class="mw-page-title-main">Magnetic resonance imaging</span> Medical imaging technique

Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves to generate images of the organs in the body. MRI does not involve X-rays or the use of ionizing radiation, which distinguishes it from computed tomography (CT) and positron emission tomography (PET) scans. MRI is a medical application of nuclear magnetic resonance (NMR) which can also be used for imaging in other NMR applications, such as NMR spectroscopy.

<span class="mw-page-title-main">Nephrology</span> Medical study concerned with the kidneys

Nephrology is a specialty of adult internal medicine and pediatric medicine that concerns the study of the kidneys, specifically normal kidney function and kidney disease, the preservation of kidney health, and the treatment of kidney disease, from diet and medication to renal replacement therapy. The word "renal" is an adjective meaning "relating to the kidneys", and its roots are French or late Latin. Whereas according to some opinions, "renal" and "nephro" should be replaced with "kidney" in scientific writings such as "kidney medicine" or "kidney replacement therapy", other experts have advocated preserving the use of renal and nephro as appropriate including in "nephrology" and "renal replacement therapy", respectively.

<span class="mw-page-title-main">Systemic scleroderma</span> Medical condition

Systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterised by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. There are two major subgroups of systemic sclerosis based on the extent of skin involvement: limited and diffuse. The limited form affects areas below, but not above, the elbows and knees with or without involvement of the face. The diffuse form also affects the skin above the elbows and knees and can also spread to the torso. Visceral organs, including the kidneys, heart, lungs, and gastrointestinal tract can also be affected by the fibrotic process. Prognosis is determined by the form of the disease and the extent of visceral involvement. Patients with limited systemic sclerosis have a better prognosis than those with the diffuse form. Death is most often caused by lung, heart, and kidney involvement. The risk of cancer is increased slightly.

<span class="mw-page-title-main">Uremia</span> Type of kidney disease, urea in the blood

Uremia is the term for high levels of urea in the blood. Urea is one of the primary components of urine. It can be defined as an excess in the blood of amino acid and protein metabolism end products, such as urea and creatinine, which would be normally excreted in the urine. Uremic syndrome can be defined as the terminal clinical manifestation of kidney failure. It is the signs, symptoms and results from laboratory tests which result from inadequate excretory, regulatory, and endocrine function of the kidneys. Both uremia and uremic syndrome have been used interchangeably to denote a very high plasma urea concentration that is the result of renal failure. The former denotation will be used for the rest of the article.

<span class="mw-page-title-main">Acute kidney injury</span> Medical condition

Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both.

<span class="mw-page-title-main">Hepatorenal syndrome</span> Human disease

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<span class="mw-page-title-main">Magnetic resonance angiography</span> Group of techniques based on magnetic resonance imaging (MRI) to image blood vessels.

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<span class="mw-page-title-main">Gadopentetic acid</span> Complex of gadolinium by DTPA

Gadopentetic acid, sold under the brand name Magnevist, is a gadolinium-based MRI contrast agent.

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<span class="mw-page-title-main">Gadodiamide</span> Chemical compound

Gadodiamide, sold under the brand name Omniscan, is a gadolinium-based MRI contrast agent (GBCA), used in magnetic resonance imaging (MRI) procedures to assist in the visualization of blood vessels.

MRI contrast agents are contrast agents used to improve the visibility of internal body structures in magnetic resonance imaging (MRI). The most commonly used compounds for contrast enhancement are gadolinium-based contrast agents (GBCAs). Such MRI contrast agents shorten the relaxation times of nuclei within body tissues following oral or intravenous administration.

<span class="mw-page-title-main">Cardiac magnetic resonance imaging</span>

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<span class="mw-page-title-main">Gadopiclenol</span> MRI contrast agent

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References

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  24. ↑ Centers for Disease Control and Prevention (CDC) (February 2007). "Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents--St. Louis, Missouri, 2002-2006". MMWR. Morbidity and Mortality Weekly Report. 56 (7): 137–41. PMID   17318112.
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  27. ↑ "Gadolinium-containing contrast agents: Removal of Omniscan and iv Magnevist, restrictions to the use of other linear agents".

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