Nephrogenic Systemic Fibrosis

What is Nephrogenic Systemic Fibrosis?

Nephrogenic systemic fibrosis (NSF) is a condition that tends to worsen over time and involves hardening of tissues in multiple organs throughout the body. This usually happens because the patient has been exposed to a special type of contrast dye called gadolinium-based contrast agents (GBCAs). GBCAs are often used during magnetic resonance imaging (MRI) scans. The main symptom of NSF is thickening of the skin and the layer just below the skin, but other symptoms can occur as well, depending on which parts of the body are affected, such as the liver, heart, muscles, and lungs.

The severity of NSF can vary widely from patient to patient. Some may only see minor changes in their skin, while others could experience limited movement. It’s also possible, though rare, that the disease becomes severe enough to be fatal.

This condition was first identified in the year 2000, and since then, medical professionals have understood more about what causes it. Research has shown that NSF typically affects patients who have serious kidney problems, especially if their kidneys are functioning at less than 30% of their normal capacity.

Patients who have severe kidney problems are particularly at risk of developing NSF if they are given GBCAs during an MRI scan. Fortunately, the number of NSF cases has significantly decreased in recent years. This is because healthcare providers have been adhering strictly to guidelines that recommend not using certain types of GBCAs in patients who have severe kidney problems.

The connection between gadolinium and NSF was first proposed when a group of cases were studied in which every patient developed NSF after being exposed to gadolinium. Interestingly, one case even showed a patient developing NSF ten years after being exposed to gadolinium. Today, newer types of contrast dyes are being used which appear to carry a smaller risk of causing NSF, although more research is needed in this area.

Example of skin changes seen in nephrogenic systemic sclerosis.

What Causes Nephrogenic Systemic Fibrosis?

Nephrogenic systemic fibrosis is a rare condition that can develop in connection with the use of certain types of substances known as GBCAs, especially when the kidneys are not functioning properly. GBCAs, which stand for Gadolinium-Based Contrast Agents, were approved since 1988. They are substances that get injected into your body to help make the images in MRI scans clearer. Gadolinium, a heavy metal, is the main component in GBCAs and it is considered quite harmful for the body.

To lessen the chances of harming the body, gadolinium is made safe for use by being linked with other substances, or ligands. Some ligands are stronger and more stable, providing a stronger bond with the gadolinium, and they are called macrocyclic molecules. On the other hand, there are ligands that are weaker and considered high-risk because they are unstable; these are known as linear molecules.

The American College of Radiology (ACR) has categorized GBCAs into three groups: Group 1 includes gadopentetate dimeglumine, gadodiamide and gadoversetamide. Group 2 contains gadobenate dimeglumine, gadoterate meglumine, gadoteridol and gadobutrol. Lastly, Group 3 involves gadoxetic acid disodium.

It’s important to note that Nephrogenic systemic fibrosis (NSF) can occur due to the use of any type of GBCA. Regarding this, the US Food and Drug Administration (FDA) is conducting further investigations for each GBCA in order to fully understand the risk they each individually pose for NSF.

It’s not yet fully understood how much kidney dysfunction can lead to NSF. However, we do know that some of the risk factors involve severe stages of chronic kidney disease (Stage 4 and 5), as well as certain inflammatory conditions. Additionally, there are suggestions that using a common medication for diabetes called metformin could affect the risk of getting NSF, but this requires further research for confirmation.

Risk Factors and Frequency for Nephrogenic Systemic Fibrosis

Nephrogenic Systemic Fibrosis (NSF) is a condition that was first recognised in 2000. Every year, around 4.5 million Americans come into contact with GBCAs (Gadolinium-Based Contrast Agents), a substance which is linked to this disease. As per the US Food and Drug Administration, there were 3,094 instances of NSF and 742 deaths connected to it up until 2019. The US has the second highest rate of MRI scans in the world, following Germany, where Gadolinium is commonly used.

Neither race, gender, nor age affects the chances of getting NSF. Both adults and children can develop the condition. People with residual kidney function and those exposed to certain types of GBCAs have a higher risk. Similarly, people who receive a large initial dose or a high total dose of GBCAs may be more at risk. Despite this, very young or very old patients might be at a lower risk, although some dispute this claim. Individuals with severe chronic kidney diseases, especially those dependent on chronic dialysis or with a notably low kidney filtrating capacity, are also at a higher risk.

The risk was ever so high at 36.5 cases per 100,000 MRI scans using high-risk Gadolinium until preventative screening reduced it to 4 per 100,000 in 2007.
After 2008, only seven instances were reported with the use of Gadolinium exposure.
Once the use of lower-risk Gadolinium started, nobody developed NSF amongst 4,931 patients, making the risk less than 0.07%. This was consistent in another review involving over 80,000 patients.

In one study of patients with severe kidney failure in Connecticut, there were 4.3 cases of NSF per 1000 patient-years, equating to a 2.4% risk of NSF in each MRI scan using gadolinium. Another study showed a higher chance of developing skin symptoms of NSF if a patient was exposed to gadolinium. There was also a case of late-onset NSF in a patient from Korea who was exposed to Gadolinium at a much younger age.

On the other hand, Denmark reported 12 cases of NSF per million people, possibly the highest rate found globally. In contrast, France saw a decrease in NSF cases after implementing new guidelines for using gadolinium.

Signs and Symptoms of Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis (NSF) is a condition seen in patients with kidney problems who have been exposed to a type of contrast agent used in MRI scans called gadolinium. Symptoms can appear anywhere from a few days to years after exposure, but usually show up within 2-10 weeks. Not all patients have been through dialysis or a kidney transplant, so these treatments aren’t necessarily a precursor to developing NSF.

Early signs can include a painful, burning sensation, itching, tiredness, and small raised skin growths or patches often accompanied by swelling. Quite a few patients also have irregularities related to calcium in their bodies. These could include unusual deposits of calcium in the skin seen in patients who are on dialysis and have NSF, irregular bone growth and others conditions related to calcium imbalance associated with NSF.

Painful burning sensation
Itching
Tiredness
Small raised skin growths or patches
Swelling

The skin may tighten or thicken, leading to stiff hands and possible curling of the fingers. Some people may also observe that their skin looks glossier. These symptoms usually develop slowly. For many, the most noticeable symptoms can cause significant discomfort including pain or itching. In some cases, NSF related to being on dialysis has been noticed to affect the muscles.

As NSF advances, the skin might thicken and become darker in color. This can happen on both lower and upper parts of the body, spread from the hands and feet inwards, but it typically doesn’t affect the face. The skin can be shiny and hard to touch, sometimes described as having a ‘woody’ feel. Little bumps and firm lumps under the skin can occur. The skin can also resemble the texture of an orange peel, and patches of thickened skin might have an irregular, creeping border. Joint issues usually result in disability and curling of the fingers. Yellow plaques on the white parts of the eyes have been reported. NSF can also lead to fibrosis (scar-like tissue) in the kidney tubules, lungs, dura mater (thick membrane surrounding the brain and spinal cord), eye sclera, and skeletal and heart muscles. If it reaches the lungs, particularly the diaphragm, it can be life-threatening. Yellow spots that look like calcium deposits in the skin have been observed on the palms, and, as mentioned earlier, yellow plaques can appear on the whites of the eyes in patients with NSF.

Testing for Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis (NSF) is a medical condition that can’t be confirmed with a specific type of test. Often, healthcare providers will have to consider the patient’s medical history, physical symptoms, and other possible conditions before making a diagnosis. A common scenario among people with this condition involves significant kidney issues (specifically, when the eGFR kidney function test shows less than 30 mL/min/1.73 m^2) and exposure to a type of contrast agent, known as GBCAs, used in MRI scans. However, it’s important to note that patients with less severe kidney issues can also get this condition, usually when older, high-risk GBCAs were used. A tissue sample from the affected area, such as the skin, with typical disease characteristics can help support the diagnosis of NSF.

In order to get this tissue sample, a deep skin biopsy is usually performed. From this biopsy, the healthcare provider can ideally obtain a sample of the skin, underlying fat, and connective tissue. When examining these samples under a microscope, they could see several changes that suggest NSF. For instance, they might see large skin cells shaped like stars or epithelial cells – cells that line our body surfaces – which extend into the fatty tissue and cause it to widen. They might also see these skin cells spread out among thick collagen bundles – proteins that provide structure to the skin. In some cases, there might be traces of calcification, which is when calcium builds up in body tissues.

Some patients with NSF might also have certain findings in their blood test results, including higher levels of eosinophils – a type of white blood cells, antibodies attacking the body’s own tissues known as antinuclear antibodies, antibodies against a type of fat, namely anticardiolipin or antiphospholipid antibodies, or an increased tendency to form blood clots. Nerve conduction abnormalities, or problems with how signals travel along the nerves, have also been reported in some NSF patients.

Treatment Options for Nephrogenic Systemic Fibrosis

At this time, there aren’t any fully established cures for a condition known as nephrogenic systemic fibrosis (NSF). If a patient’s kidneys aren’t working properly, trying to restore kidney function is a crucial first step for slowing down or halting the progression of the disease.

Various treatment methods, while unable to fully cure NSF, have been known to sometimes improve skin symptoms. This includes the use of a bodily fluid known as immunoglobulin administered through an IV, a treatment process called photopheresis that is carried out using a special machine, or a locally applied medicine called interferon. Among these options, extracorporeal photopheresis seems to offer the best results but it’s costly.

Emerging research suggests that using combination treatments that involve steroids with a drug called methotrexate and a type of light therapy known as ultraviolet A (or UV-A) phototherapy can also help alleviate skin symptoms. UV-A phototherapy works by decreasing the hardness of the skin, while methotrexate helps to reduce bodily reactions that can cause inflammation and stiffness. A low dose of a medication called imatinib mesylate orally can improve the texture of the skin but might not have an impact on joint mobility.

Also, some topical treatments have been reported to give subjective improvements in a few cases, including calcipotriene alone and calcipotriene combined with betamethasone dipropionate. However, another treatment known as cyclophosphamide has not shown to be effective.

Pain from joint contraction can sometimes be managed with narcotic pain relievers. Physical therapy can play a crucial part in maintaining and improving joint movement and reducing the contractions.

Surgery to transplant a kidney may also bring improvements or reduce symptoms. In fact, any restoration of kidney function has shown symptomatic improvement.

There are also other treatments that have been viewed as successful for NSF, such as photodynamic therapy (a type of light therapy), UV-A1 (another type of light therapy), and the use of intravenous immunoglobulin. In fact, in some cases observed, UV light treatment alone also seems to be an effective treatment method.

Another report has shown an individual with NSF responding positively to intravenous sodium thiosulfate, especially if the person has been exposed to a substance known as gadolinium multiple times.

When trying to diagnose a condition called Nephrogenic systemic fibrosis (NSF), doctors must rule out other conditions that may have similar symptoms. These other conditions are known as differential diagnoses. Here are some diseases that doctors might consider when trying to diagnosis NSF:

β-microglobulin amyloidosis
Calciphylaxis
Chronic graft vs. host disease
Carcinoid syndrome
Borreliosis
Dermatofibrosarcoma protuberans
Lipodermatosclerosis
Early cellulitis
Early panniculitis
Eosinophilic fasciitis
Fibroblastic rheumatism
Drug-induced fibrosis
Radiation-induced fibrosis
Scleroderma
Scleromyxedema
Phenylketonuria
Porphyria cutanea tarda
Superficial fibromatosis

A key factor in the diagnosis of NSF is if the patient has recently had an MRI scan where they were exposed to a type of contrast dye known as GBCAs. Only one of these conditions, β2-microglobulin amyloidosis, is exclusive to those with severe kidney disease. However, it usually affects specific areas such as the shoulders, the inside of the wrist, and the tongue.

What to expect with Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis is a serious and quickly worsening disease. This health problem triggers fibrosis (abnormal growth of tissue) in the internal organs and skin of patients who have severe kidney problems and have been exposed to certain types of contrast agents used in MRIs, known as GBCAs.

Although skin changes tied with this disease can get better after the kidney function is improved, such as recovering from a sudden kidney injury, this condition does not usually get better on its own and often continues to get worse. Therefore, the outlook for these patients depends greatly on how much the fibrosis has affected their internal organs. Studies have shown that as the disease worsens, the death rate also increases. The high death rate is not due to the skin changes, but rather due to fibrosis affecting important internal organs, specifically the heart and lungs.

A study by Todd et al noticed that the 24-month death rate after examination was 48% in patients with skin changes, and 20% in cases where no skin changes were seen. Most patients become reliant on wheelchairs due to stiffness due to the disease within a few weeks of disease starting. A number of patients have reportedly died from falls and similar complications due to issues with moving around. Alongside this, many patients have reported experiencing chronic nerve pain and extreme itchiness. Lastly, patients may also suffer from flexion contractures, a condition where a joint becomes stuck in a bent position, if the disease affects a joint.

Possible Complications When Diagnosed with Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis (NSF) is a condition that can make existing kidney disease even worse. Here are some of the key complications:

Fibrosis, or scarring, of internal organs like the heart, lungs, renal tubes (the parts of the kidney where urine is created), and muscles. While this fibrosis is often symptomless, it can contribute to problems like high blood pressure in the lungs (pulmonary hypertension), a form of heart disease (cardiomyopathy), and general muscle weakness.
Individuals with NSF might also experience blood clotting in their veins (vascular thrombosis). As their condition progresses, significant low blood pressure can develop. This can make it difficult for them to tolerate the necessary dialysis treatments for their kidney disease.
The development of flexion contractures, a condition that causes joints to forcefully bend or deform due to the muscle tissue hardening, can result in becoming wheelchair-bound.
Falls become more frequent and can even lead to fractures.

Preventing Nephrogenic Systemic Fibrosis

When individuals are battling severe kidney disease and have been exposed to a type of contrast dye used for MRI scans, known as GBCAs (Gadolinium-Based Contrast Agents), they may develop a rare condition known as Nephrogenic Systemic Fibrosis (NSF). This condition unfortunately does not have any proven cures; medical treatments can only alleviate some symptoms. If NSF becomes more severe and leads to visceral fibrosis, a condition where tissues in the body become thick and hard, consistently taking medication may help improve one’s quality of life.

For those with severe kidney disease, it’s essential that healthcare providers explain the potential risks associated with using GBCAs. Physicians should discuss the benefits and drawbacks of using an MRI scan as compared to a contrast-enhanced CT (Computed Tomography) scan, which allows for detailed images of the body. Certain CT scans can contribute to a quicker loss of kidney function and sometimes even necessitate the initiation of dialysis, a treatment to remove waste products from the blood when the kidneys can’t do so on their own.

The use of a specific category of GBCAs, known as group 2, might be safer for individuals with advanced kidney disease or those already on dialysis. This is because these contrast dyes may provide better protection for remaining kidney function and could be linked with a survival benefit. However, patients who have already received group 1 GBCAs in the past should be extra cautious, as the effects can pile on over time.

Frequently asked questions

The prognosis for Nephrogenic Systemic Fibrosis (NSF) depends on how much the fibrosis has affected the internal organs. As the disease worsens, the death rate increases, primarily due to fibrosis affecting important internal organs like the heart and lungs. Skin changes tied to NSF may improve if kidney function is improved, but the condition usually does not get better on its own and often continues to worsen.

Nephrogenic Systemic Fibrosis can develop in connection with the use of certain types of substances known as GBCAs, especially when the kidneys are not functioning properly.

Signs and symptoms of Nephrogenic Systemic Fibrosis (NSF) include: - Painful burning sensation - Itching - Tiredness - Small raised skin growths or patches - Swelling Other symptoms and manifestations of NSF may include: - Skin tightening or thickening, leading to stiff hands and possible curling of the fingers - Glossy appearance of the skin - Slow development of symptoms - Significant discomfort, including pain or itching - Muscle abnormalities in some cases - Darkening of the skin, typically on the lower and upper parts of the body (excluding the face) - Shiny and hard-to-touch skin, sometimes described as having a 'woody' feel - Bumps and firm lumps under the skin - Skin texture resembling that of an orange peel - Patches of thickened skin with irregular, creeping borders - Joint issues leading to disability and curling of the fingers - Yellow plaques on the white parts of the eyes - Fibrosis (scar-like tissue) in various organs, including the kidney tubules, lungs, dura mater (thick membrane surrounding the brain and spinal cord), eye sclera, skeletal muscles, and heart muscles - Life-threatening complications if the lungs, particularly the diaphragm, are affected - Yellow spots resembling calcium deposits on the palms - Yellow plaques on the whites of the eyes in patients with NSF.

The types of tests that may be needed to diagnose Nephrogenic Systemic Fibrosis (NSF) include: 1. Medical history evaluation: Healthcare providers will consider the patient's medical history, including any kidney issues and exposure to contrast agents used in MRI scans. 2. Physical examination: A thorough physical examination will be conducted to assess the patient's symptoms and look for characteristic signs of NSF. 3. eGFR kidney function test: This test measures the glomerular filtration rate (GFR) to assess kidney function. A result of less than 30 mL/min/1.73 m^2 may indicate significant kidney issues associated with NSF. 4. Tissue sample (deep skin biopsy): A deep skin biopsy is usually performed to obtain a sample of the affected skin, underlying fat, and connective tissue. This sample can be examined under a microscope to look for changes that suggest NSF, such as star-shaped skin cells, thick collagen bundles, and calcification. 5. Blood tests: Blood tests may be done to check for certain findings that can support the diagnosis of NSF, including higher levels of eosinophils, antinuclear antibodies, anticardiolipin or antiphospholipid antibodies, and an increased tendency to form blood clots. Nerve conduction abnormalities may also be assessed. It's important to note that there is no specific test to confirm NSF, and a combination of these tests and evaluations is typically used to make a diagnosis.

β-microglobulin amyloidosis, Calciphylaxis, Chronic graft vs. host disease, Carcinoid syndrome, Borreliosis, Dermatofibrosarcoma protuberans, Lipodermatosclerosis, Early cellulitis, Early panniculitis, Eosinophilic fasciitis, Fibroblastic rheumatism, Drug-induced fibrosis, Radiation-induced fibrosis, Scleroderma, Scleromyxedema, Phenylketonuria, Porphyria cutanea tarda, Superficial fibromatosis.

When treating Nephrogenic Systemic Fibrosis (NSF), there can be several side effects and complications. These include: - Fibrosis or scarring of internal organs such as the heart, lungs, renal tubes, and muscles. This can lead to problems like high blood pressure in the lungs, heart disease, and muscle weakness. - Blood clotting in the veins (vascular thrombosis), which can cause low blood pressure and make it difficult to tolerate necessary dialysis treatments. - Development of flexion contractures, which causes joints to forcefully bend or deform due to muscle tissue hardening. This can result in becoming wheelchair-bound. - Increased frequency of falls, which can lead to fractures.

A dermatologist or a nephrologist.

Nephrogenic Systemic Fibrosis (NSF) is a rare condition.

Nephrogenic Systemic Fibrosis (NSF) is currently incurable, but there are various treatment methods that can help alleviate symptoms. Restoring kidney function is a crucial first step in slowing down or halting the progression of the disease. Treatment options include the use of immunoglobulin administered through an IV, photopheresis using a special machine, locally applied interferon, combination treatments involving steroids with methotrexate and UV-A phototherapy, low-dose imatinib mesylate, topical treatments such as calcipotriene alone or combined with betamethasone dipropionate, narcotic pain relievers for joint pain, physical therapy to improve joint movement, kidney transplantation, photodynamic therapy, UV-A1 therapy, intravenous immunoglobulin, and intravenous sodium thiosulfate in some cases.

Nephrogenic systemic fibrosis (NSF) is a condition characterized by the hardening of tissues in multiple organs throughout the body. It is typically caused by exposure to gadolinium-based contrast agents (GBCAs) used during magnetic resonance imaging (MRI) scans. The main symptom of NSF is thickening of the skin and the layer just below the skin, but it can also affect other organs such as the liver, heart, muscles, and lungs.