Nephrogenic Fibrosing Dermopathy: Causes, Symptoms & Treatment

Nephrogenic fibrosing dermopathy represents a very rare and new disease of connective tissue associated with the use of gadolinium-containing contrast agents in patients with kidney disease. In addition to the skin, the connective tissue of muscles and internal organs is often affected. The disease can lead to severe limitation of movement and even death.

What is nephrogenic fibrosing dermopathy?

Nephrogenic fibrosing dermopathy was first discovered in 1997 when individual patients with renal insufficiency were found to have an abnormal increase in the connective tissue of the skin. Fairly quickly, a connection with the use of gadolinium-containing contrast agents in MRI could be established. However, the name “nephrogenic fibrosing dermopathy” is already obsolete. The name was changed to nephrogenic systemic fibrosis (NSF) after it could be shown that often the musculature and many internal organs such as heart, liver or lungs are also involved. Another name is dialysis-associated systemic fibrosis, although it has recently been questioned whether only dialysis patients are affected. To date, approximately 315 cases have been observed. The exact mechanism of development of NSF is not yet known. According to previous observations, nephrogenic systemic fibrosis affects only renally insufficient patients, who, according to recent findings, do not necessarily require dialysis. The use of gadolinium-containing contrast agents in renally healthy patients has never led to NSF according to previous findings. Due to the small number of cases, it has not yet been possible to make a general statement on the chances of recovery. While there are individual cases with a very favorable course, no improvement could be achieved in other cases.

Causes

A prerequisite for the development of nephrogenic systemic fibrosis is renal insufficiency and the use of gadolinium-containing contrast agents in MRI, as mentioned above. Gadolinium is a chemical element from the rare earth group and belongs to the lanthanides. Due to its many unpaired electrons, it is paramagnetic and therefore very well suited for use in magnetic resonance imaging. Thus, gadolinium-containing contrast agent is used in imaging the brain or other organs during MRI examinations. The toxicity of free gadolinium ions is known. However, this element is fixed by complexation, so it can usually be used without problems. The acute toxicity of free gadolinium ions is due to the fact that they can be exchanged for calcium ions. In addition, contrast media containing iodine cannot be used in patients with renal insufficiency because they would impair renal function even more. Now, however, nephrogenic systemic fibrosis has been induced in some renal patients after the use of gadolinium-containing contrast media. The role played by the relationship between renal dysfunction and gadolinium is not yet known. It is assumed that in these patients even a small release of gadolinium ions from the chelate complex causes increased fibrosis of the connective tissue. Nephrogenic systemic fibrosis may develop two days to 18 months after contrast agent use. The risk of developing NSF is thought to be dependent on the degree of gadolinium ion release. Therefore, according to the European Committee for Medicinal Products for Human Use (CHMP), gadolinium-containing contrast agents are classified into three risk groups: low, moderate, or high.

Symptoms, complaints, and signs

Nephrogenic systemic fibrosis affects women and men equally. Within two days and 18 months after a gadolinium-containing contrast agent is used, red and dark nodules or spots may initially appear on the hands and feet. As this progresses, skin thickening develops. The skin hardens and then resembles an orange peel. These changes often affect the entire trunk of the body, leaving the neck and head mostly exposed. Muscles, ligaments and tendons contract. Movement becomes increasingly restricted. Some patients can eventually move around only with the aid of a wheelchair. If the heart or lungs are affected, the prognosis is often very unfavorable. Deaths have already been observed.

Diagnosis and course of the disease

Nephrogenic systemic fibrosis can be diagnosed by skin and muscle biopsy. However, the changes cannot be verified by specific abnormalities in laboratory values. Possible scleromyxedema is excluded as a differential diagnosis in the absence of paraproteins. Otherwise, tissue samples show significant thickening of the sclera. After an extensive history, an association with gadolinium-containing contrast agents is established.

Complications

Nephrogenic fibrosing dermopathy is already a very rare complication in patients with severely impaired renal function or in liver transplant recipients undergoing MRI examinations with gadolinium-containing contrast agents. The course of the disease cannot be predicted. In addition to very rare spontaneous cures, a progressive course causing severe disability is usually observed. Fatal courses can also occur. The gradual thickening of the skin can affect the heart muscle, lungs, diaphragm or skeletal muscles. In addition to limiting mobility, respiratory distress and severe cardiac problems may increasingly occur. In cases with complete recovery, renal insufficiency was usually successfully treated beforehand. It is not known whether nephrogenic fibrosing dermopathy always develops when the gadolinium-containing contrast agent is used for diagnosis in severe renal insufficiency. However, because the risk exists, other contrast agents should be used in these patients or dialysis should be immediately followed after contrast with gadolinium. Up to now, it has also not been sufficiently clarified whether an elimination of gadolinium with the aid of an intravenous administration of sodium thiosulfate always leads to an improvement of the symptoms. Treatment successes have been achieved here on various occasions, but there is no guarantee. The same is true of the chances of success with physical therapy to prevent contractures (shrinkage) of muscles, tendons, ligaments, and other parts of the connective tissues that lead to restricted movement.

When should you see a doctor?

People who are undergoing medical treatment for a kidney condition and have been exposed to the use of a contrast agent are in the Nephrogenic Fibrosing Dermopathy risk group. They should seek consultation with the treating physician as soon as various complaints develop after a session and the general state of health deteriorates significantly. Often, the first irregularities appear a few days after the treatment. In some cases, the first signs of irregularity may appear only after 1 ½ years. Changes in the appearance of the skin as well as the connective tissue indicate a disorder and should be presented to a physician. If there are limitations in mobility, a decrease in general muscle strength, and problems with locomotion, a physician is needed. Patients are often no longer able to move sufficiently without assistance. Since in severe cases the disease can lead to premature death of the affected person, a physician is needed at the first indication of an inconsistency. General dysfunction, a feeling of illness and malaise should be investigated. If already existing complaints increase significantly in scope and intensity, a physician is needed. If there is pain, sleep disturbances, as well as loss of appetite and irregularities in heart rhythm, medical attention is needed.

Treatment and therapy

The course of nephrogenic systemic fibrosis cannot be predicted. In very rare individual cases, complete regression of symptoms has occurred. In some patients, improvement was achieved by restoration of renal function. Spontaneous regression of skin lesions has also been observed in some cases after renal transplantation. It is also suspected that intravenous injection of sodium thiosulfate contributes to the improvement. Sodium thiosulfate forms chelate complexes with gadolinium ions, possibly promoting their elimination from the body. However, there is currently no effective therapy for most patients. Therefore, intensive physical therapy is recommended for symptomatic treatment of skin induration.

Outlook and prognosis

The prognosis of nephrogenic fibrosing dermopathy must be made according to individual circumstances.The general course of the disease is not predictable. In many cases, the decisive factor is the stage of the disease and the symptoms already present. If organic damage has already occurred, the further development is worsened. According to the current state of scientific knowledge, there is no uniform treatment measure that is generally used for this disease. Doctors decide which therapies are necessary according to individual developments. In some patients, spontaneous regressions of existing symptoms can be observed. However, these do not have to be permanent. More likely in the further course is the need for a donor organ as well as lifelong functional disorders. It is also to be expected that premature death of the affected person may occur. The development of a medical emergency has been documented in some patients. Without treatment, the life expectancy of the affected individual is reduced. At the same time, a reduction in quality of life can be observed. In contrast, with comprehensive medical care, there is a prospect of recovery. In the literature, cases can be found in which a successful cure of the disease took place. In them, renal insufficiency was previously treated. This seems to be a decisive factor in the course of the disease and thus in the prognosis.

Prevention

In renal insufficient patients, gadolinium-containing contrast agents should be avoided if possible. However, if this is not possible, preventive measures that prevent the release of gadolinium ions are very important. The German Federal Institute for Drugs and Medical Devices (BfArM) already reacted in May 2007. As a result of the incidents, it withdrew approval for risky gadolinium-containing contrast media such as Omniscan and Magnevist for patients with severe renal insufficiency or for liver transplant patients. Low-risk contrast agents should be used. These are gadolinium-containing substances with a cyclic structure that are less likely to release gadolinium.

Follow-up

There is no direct follow-up for nephrogenic fibrosing dermopathy. Because there is no known therapy for the condition, only symptoms can be monitored and treated. One way to reduce the hardening of the connective tissue is through regular treatments with heat and massage. Patients may be prescribed sodium sulfates to slow the progression of the disease. If a patient has received a kidney transplant, he or she must take immunosuppressants regularly and go for checkups. Among other things, these examinations determine whether kidney functions have improved. At the same time, the doctor checks whether new connective tissue has formed or whether the ability to move limbs has decreased. When the symptoms of nephrogenic fibrosing dermopathy worsen, patients gradually lose their mobility. They are then dependent on intensive care. Follow-up care is then mainly aimed at relieving ailments such as respiratory problems and pain. At this stage, therapeutic paths that would unnecessarily burden the patient are avoided. Supported physiotherapy with a very low load is only intended to prevent patients from getting bedsores. However, improvement in mobility is no longer possible.

Here’s what you can do yourself

The symptoms of nephrogenic fibrosing dermopathy should be closely observed in order to do something about it in time. Especially patients with renal insufficiency should point it out to the doctor to avoid problems with breathing or heart. Any irregularities may still appear 18 months later. If there are any changes in the appearance of the skin or connective tissue, it is important to see a doctor as soon as possible. Other indications of an exacerbation include limited mobility, weakening of the muscles and difficulty moving around. Patients should ask for help, if necessary, if they are unable to move properly. For loss of appetite, cardiac arrhythmias, pain and sleep problems, a doctor knows what to do. His advice helps patients to cope with everyday life and not to be too restricted by nephrogenic fibrosing dermopathy. The exact course and also the treatment methods are not always predictable.That is why close observation of one’s own body is so important. In addition to the treatment recommended by the doctor, those affected should also inform themselves about physical therapy. With consistent implementation of these methods, the hardening of the skin and connective tissue can be alleviated.