What is Nephrogenic Systemic Fibrosis (NSF)?

Nephrogenic Systemic Fibrosis (NSF), formerly known as nephrogenic fibrosing dermopathy (NFD), is a condition that, to date, has occurred only in people with kidney disease. NSF is a systemic disorder with its most prominent and visible effects in the skin, hence its original designation as a dermopathy (dermopathy=disorder of skin). With the further clarification of hundreds of additional cases and the continued recognition that kidney disease seems to be a prerequisite for developing NSF (nephrogenic=starting with the kidney), NSF has been accepted as the terminology most reflective of the reality of the disorder.

NSF affects males and females in approximately equal numbers. NSF has been confirmed in children and the elderly, but tends to affect the middle-aged most commonly. It has been identified in patients from a variety of ethnic backgrounds from North and South America, Europe, Asia and Australia. The majority of literature-reported cases have resided in the United States.

Some degree of kidney disease appears to be a common denominator in NSF. Neither the duration of kidney disease nor its underlying cause are related to the development of NSF. Some patients with NSF develop skin tightening in the earliest stages of kidney disease, and others may have had kidney disease for years. No specific form of dialysis has been linked to NSF, although most patients with NSF do undergo dialysis procedures. Some patients who have never been dialyzed have developed NSF.

MRI Contrast

Over the past several years, researchers have correlated the development of NSF with the increasing use of gadolinium-based MRI contrast agents in patients with kidney disease. Gadolinium, an element of the lanthanide series (atomic number 64) is the chief component of virtually all contrast agents administered for magnetic resonance imaging (MRI). While many MRI examinations do not require contrast enhancement, some studies, in particular those examining the blood vessels (angiography), benefit from the administration of one of these gadolinium-based contrast agents (GBCA).

Since gadolinium (Gd) is considered toxic, it is bound to other molecules (termed ligands) to exploit its superior imaging qualities while facilitating its safe transit through, and exit from, the body. GBCA are virtually entirely excreted via the kidneys. In patients with kidney disease, administered GBCA will require more time to exit the body. If there is no residual urine output, the only way such agents can exit the body is through diaysis procedures. While there are not many studies examining the excretion of GBCA via dialysis, there is no question that excretion is delayed (sometimes markedly so).

In patients with normal kidney function, GBCA are considered safe because the bond between the toxic Gd atom and its ligand molecule is extremely strong and because the GBCA molecule is flushed from the body so rapidly. There is a small risk that Gd atoms could dissociate (unbind) from their carrier ligands, but if this occurred, Gd (which acts much like calcium atoms in the body) would likely bind to readily-available phosphates and form insoluble molecules. In patients who receive large doses of GBCA and do not undergo rapid and effective dialysis, there is a risk that larger amounts of these gadolinium compounds could develop and remain in the body in a form that is not readily removable.

The recent focus on GBCA as a possible trigger for NSF derives from several observations:

1. GBCA were not widely used for angiography imaging in kidney patients prior to 1997. The earliest cases of NSF occurred in 1997.
2. Because of the long-recognized danger of contrast induced nephropathy (CIN) due to iodine-based contrast agents, GBCA were hailed as a way of avoiding CIN and thus preserving renal function (especially in those with diminished renal output). While the package inserts for these agents quite clearly indicated they were renally excreted--and users were warned that caution must be employed in those with reduced renal output--no specific warnings against their use were issued. During the 1997-2007 period no GBCA available in the USA was approved for MRA, although off-label use was widely adopted.
3. During this period, magnetic resonance angiography (MRA) also became widespread. MRA routinely employs 2-3x the usual dose of gadolinium based MRI contrast than does a standard MRI. MRA was commonly used in the pre-transplant setting to evaluate the renal vasculature.
4. Prior to warnings made by the FDA and European Medicines Agency regarding the association of GBCA with NSF, the incidence and recognition of NSF appeared to be rising. Following these announcements and widespread dissemination of the potential risk of NSF, the incidence of NSF appears to have dropped.
5. While many GBCA formulations exist in the world, only some of these have been associated with NSF, and only one has been associated with the vast majority of cases of NSF. Some have suggested that since this agent is slightly more likely to dissociate chemically, Gd dissociation (dechelation) might be the trigger of NSF at the cellular level. Some animal studies and cell culture studies seem to corroborate this hypothesis. Further study is ongoing.

Erythropoietin: Erythropoietin (Epo) is a hormone that controls red blood cell production. Many patients with kidney disease have anemia related to their kidney disease. Because of this, Epo is often administered to increase the output of red blood cells from the bone marrow. Because Epo gained widespread use among the renal population just as NSF emerged, some have suggested that Epo either triggers or facilitates the development of NSF. As Epo has so many applications beyond the treatment of anemia of chronic renal disease, and NSF is only seen among renal populations, Epo cannot be the sole trigger of NSF. In addition, the Yale NSF Registry has identified many persons with NSF who had never received Epo. Based on current data (especially very strong data implicating gadolinium based contrast agents) we cannot support Epo as a sole cause of NSF.

However, as Epo has the potential to affect the growth of other cells in the bone marrow, and as the cell responsible for producing much of the collagen deposition seen in NSF develops in the bone marrow, we find it an intriguing hypothesis that Epo could facilitate the development of NSF in some cases by increasing the number of circulating fibrocytes. At this time, this remains a hypothesis only.

Thrombosis/Endothelial Injury: Besides kidney disease, medical conditions that may be associated with NSF include hypercoagulation abnormalities and deep venous thrombosis, recent surgery (particularly vascular surgery), recent failure of a transplanted kidney, and sudden onset kidney disease with severe swelling of the extremities. It is very common for the NSF patient to have undergone a vascular surgical procedure (such as revision of an AV fistula, or angioplasty of a blood vessel) or to have experienced a thrombotic episode (thrombotic loss of a transplant or deep venous thrombosis) approximately two weeks before the onset of the skin changes.

The associated conditions enumerated in the preceding paragraph frequently justify the use of gadolinium-enhanced MRI or MRA studies. Whether there is an independent risk associated with endothelial damage or hypercoagulation remains an open question, although circulating fibrocyte migration from the blood is facilitated in both scenarios.

Images of NSF
Image 1 Image 2 Image 3

Patients with NSF describe swelling and tightening of the skin, usually limited to the extremities (images), but sometimes involving the trunk. The condition may develop over a period of days to several weeks. In many cases, the skin thickening inhibits the flexion and extension of joints, resulting in contractures. Severely affected patients may be unable to walk, or fully extend the joints of their arms, hands, legs, and feet. Complaints of muscle weakness are common. Approximately 5% of patients have a rapidly progressive (fulminant) course.

The skin changes may start as reddened or darkened patches, papules, or plaques. In time, the skin may feel “woody” and the surface may resemble the texture of the peel of an orange. Patients may experience burning, itching, or severe sharp pains in areas of involvement. Radiography may reveal calcifications of the soft tissue. Deep "bone pain" has been described in the hips and in the ribs.

The skin lesions are commonly symmetrical, with zones between the ankles and thighs most commonly involved, followed by involvement between the wrist and upper arms. Hand and foot swelling with blister-like lesions has also been reported. Some patients have reported yellow papules or plaques on or near the eyes. Rapid, new onset fluctuating hypertension of unknown cause has been described prior to the onset of the skin lesions.

Mortality/Morbidity

Nephrogenic systemic fibrosis appears linked to increased morbidity and mortality. Todd et al18 found that 24-month mortality rates following examination were 48% and 20% in patients with and those without cutaneous changes of nephrogenic systemic fibrosis, respectively. Within weeks of disease onset, many patients become dependent on a wheelchair because of contractures. Several patients have died because of complications from fractures after falls triggered by their mobility problems. Additionally, many patients report maddening pruritus and/or causalgia. Finally, some patients experience flexion contractures if the disorder occurs over a joint.

Click to See Report Before and After Treatment

I personally have seen gadolinium show up in my patient's toxic urine profiles and the link to the right with the report shows that gadolinium can be removed effectively. The effects of this agent are very clearly defined in the FDA report, but, as with any FDA report, the findings only show that this agent presents problems in people who already have chronic kidney disease.

You have to ask yourself if it makes any sense at all to inject a person with a radioactive substance and if there won't be repercussions even if not measured in death. Common sense dictates that ANY radioactive metal put in the body is eventually going to cause some type of problem.

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