Are You Confident of the Diagnosis?
What you should be alert for in the history
Nephrogenic systemic fibrosis (NSF) has a strong association with exposure to gadolinium-based contrast media during periods of either recognized or unrecognized, acute or chronic, renal insufficiency. The absence of exposure to gadolinum-based contrast material and/or the absence of signficant renal impairment at the time of exposure should cast doubt upon the likelihood of the diagnosis of NSF.
Characteristic features on physical examination
The disease is characterized by progressive and often debilitating fibrosis of the skin (Figure 1), and sometimes other organs including the heart, lungs, liver, reticuloendothelial system, and musculature, among others. Most often this soft tissue fibrosis occurs with resultant pain and joint contracture. Affected patients may become wheel-chair bound. The lower extremities are more often affected than are the upper extremities. The head and neck is often spared. In many classic cases, there is some subtle dyspigmenation and a peau d’range texture to affected skin, but deeper variants, without abnormalities apparent by visualization alone, exist. Yellow scleral plaques and dermal periocular nodules have been described in patients with NSF, and may represent important supportive findings for the dermatologist.
Expected results of diagnostic studies
For most cases, the biopsy of affected skin must occur via deep punch (or incisional biopsy), to include subcutis, and histologic findings include: fibrosis, widening of subctuaneous septae, a general lack of marked inflammation in most cases, variable mucin accumulation, general preservation of elastic tissue, and very often (but not requisite), an increased number of CD34/Procollagen I-dual positive dermal dendrocytes (Figure 2). Unusual sclerotic bodies are a relatively unique and specific finding in biopsy of NSF, but they are not present in many or even most cases. While it is not entirely clear what these sclerotic bodies represent, it is widely specultated that they represent some form of aberrant or abortic ossification process.
NSF is a diagnosis of clinicopathologic correlation. The diagnosis cannot often be rendered immutably by histologic or clinical means alone, and the totality of the clinical, histological, and even historical information, often must be considered to arrive at a certain diagnosis.
The differential diagnosis includes:
Scleromyxedema – while histologically similar to NSF in that there is hypercellularity of the dermis and mucin deposition, scleromyxedema is an connective tissue disorder of uncertain etiology that is strongly associated with a paraproteinemia (lacking in NSF) and there is often a lesser degree of true fibrosis.
Scleroderma – a rheumatologic/autoimmune condition that results in bound-down skin and soft tissue and joint contracture, but unlike NSF, scerloderma results in true scerlosis (glassy broad collagen with hypocellularity), whereas NSF is a fibrotic and hypercelluar condition.Scleroderma, like morphea, is often accompanied by loss of CD34-positive dendrocytes, rather than an increased number of such cells.
Scleredema – this condition of uncertain etiology results in a bound-down and tight feeling to the skin but it is caused by the deposition of mucin between and amongst collagen bundles, with splaying of dermal collagen, and without true fibrosis or hypercelluarity.
Volume overload – always a concern in patients with ESRD, this condition results from increased edema fluid splaying collagen bundles of the dermis, and resulting in tense skin, but there is neither fibrosis nor hypercellularity, as in in NSF.
Who is at Risk for Developing this Disease?
Nephrogenic systemic fibrosis is an uncommon condition strongly associated with dosing of gadolinium-containing radiographic contrast materials in the setting of renal disease. Gadolinium has been identified in tissue using a variety of techniques, including electron microscopy with energy dispersive spectroscopy, mass spectrometry, and synchrotronic x-ray fluoroscopy. In one study involving end-stage renal disease (ESRD), patients in Connecticut over an 18-month period, the incidence of nephrogenic systemic fibrosis was about 4.3 cases per 1000 patient-years.
The disease has been described in all races and in all age groups, and in many countries outside the United States. It seems highly likely that any human with poor renal clearance who is exposed to gadolinium can develop nephrogenic systemic fibrosis. It seems that exposure to gadolinium-based material in the setting of acute, chronic, and acute upon chronic renal disease may lead to nephrogenic systemic fibrosis. One study, by Saab et al demonstrated that peritoneal dialysis placed one at an even higher risk of disease development than hemodialysis, perhaps due to poorer overall clearance of exogenous materials.
What is the Cause of the Disease?
The exact etiology and pathophysiology of NSF is incompletely understood. There is a strong association between the developement of NSF and exposure to gadolinium-based radiographic contrast materials during period of renal insufficiency. While the disease was first described in 2000 (using tissue dating back to as late as 1997), the association between NSF and gadolinium-based contrast agents, which occurred in late 2006, was a product of several lines of evidence from several different research groups. This was a major advance in our understanding of this otherwise rather obscure and rare disorder.
While it is not settled definitively, several series have suggested a dose-response relationship in patients with ESRD who are exposed to gadolinium-based contrast and this may be why the first recognized cases occurred after magentic resonance angiogram, where the dose of contrast used, off-label, was often three-fold more than the dose used in a simple magentic resonance imaging study. Most cases of NSF have been associated with linear chelates, as opposed to the more complex non-linear chelates.
Indeed, with more judicious use of gadolinium-based contrast agents in the setting of renal insufficiency, the incidence of NSF at one tertiary hospital in Maryland went from approximately 44 cases per 100,000 contrast-enhanced examinations (before the discoveries of 2006), to approximately 4 cases per 100,000 contast enhanced examinations (after the discoveries of 2006).
It is also possible that NSF is a multi-factorial process. Other factors possibly implicated in the development of the disease, include, among others: iron supplementation, use of high-dose erythropoietin, pro-inflammatory or pro-thrombotic events occuring concomitantly, exposure to various blood pressure medications (such as ACE inhibitors or beta-blockers), or even accumulation of hyaluronic acid due to poor renal clearance in the setting of kidney disease. In fact, it is possible that NSF represents some threshold illness, where in theory, various insults in differing proportions may result in the same final clinical and histologic enpoint.
Systemic Implications and Complications
Deposition of gadolinium has been detected in a variety of organ systems, including the liver, the reticuloendothelial system, the heart, the lungs, and the musculature, among other tissues. Fibrosis has been described in many of these organs as well. Deaths have been described to be due to congestive heart failure and fibrosis of the diaphragm. Yellow scleral plaques and dermal periocular nodules have been described in patients with NSF, and may represent important supportive findings for the dermatologist.
There is no uniformly successful treatment for NSF and no clinical trials exist to date. Spontaneous partial improvement and remission has been described for reasons that are not entirely clear. All evidence for treating the disease is either based upon relatively small case series or is anecdotal in nature.
Reported therapuetic measures used to improve the condition include:
oral/intravenous high-dose gluococorticoids
topical calcipotriene under occlusion
psoralen plus UVA light treatment (PUVA)
intravenous sodium thiosulfate (chelating agent)
high-dose intravenous immunoglobulin
Optimal Therapeutic Approach for this Disease
As all evidence regarding the treatment of NSF is based upon either small series or anecdotal experience (case reports), management of the disease is without a firm standard. Physical therapy, being of some documented benefit, and also being without real negative consequences when professional managed, would seem an appropriate component of all NSF management strategies. Plasmapheresis and extracorporeal photophoresis have been reported effective in several small series, but these modalities are expensive, and could only reasonably be considered for those with strong financial options or by insitutions with generous charitable programs.
UVA-1 and PUVA treatment are modalities famailar to dermatologists, but they deal only with the superficial and cutaneous aspects of the disease, and are probably not effective with dealing with manifestations of the disease in other organ systems. Sodium thiosulfate was reported successful in one case report, but it is not without known toxicity, and in my own hands it has proven ineffective, and in one case led to temporary psychosis (a recognized side-effect). While I find the medication effective in calciphylaxis, another condition that effects patients with ESRD, I no longer offer it to my patients with NSF.
Imitanib meyslate, having recognized antifibrotic properties, is a drug of particular interest that I have found most effective in my own practice, but it is a difficult drug to use on those with many comorbidities, as it leads to side effects, including fluid-shifts and fatigue.
Lastly, there is increasing investigation into renal transplant as a treatment option, and some authorities are advocating earlier consideration of renal transplant and these experts cite cases of improvement after transplant, even when the graft function is less than optimal; however, it should be duly noted that NSF has even been described in patients after transplantation, so certainly the situation is complicated and imperfect.
It is estimated that over 250 million doses of gadolinium-based radiographic contrast have been utilized world-wide, and certainly the number of patients suffering from fulminant NSF, even if one considers some cases are unrecognized or unreported, probably is in the thousands or tens of thousands.
Therefore, one does not want to overly alarm those who do not have significant renal disease, yet have legitimate reasons for receiving gadolinium-based contrast materials. It is likely that the risk of NSF increases significantly as glomerular filtration rate (GFR) decreases and there is general agreement among experts that cases of NSF in patients with GFR > 30 ml/min are extraordinarily unusual and ulikely and the greatest risk occurs in those with a GFR < 30 ml/min, and particularly at risk are those with GFR < 15 ml/min.
With the FDA-mandated “black box” warning now imposed on all gadolinium-based radiographic materials, and with better screening of patients that may be at risk for unrecognized renal disease (hypertension, older age) and routine screening of creatinine-clearance prior to dosing, it would seem that the disease incidence and prevalence is falling rapidly.
Unusual Clinical Scenarios to Consider in Patient Management
Fibrosis of the skin, often with joint contracture and issue of pain and limited mobility, in the setting of past exposure to gadolinium-based contrast materials in patients with renal disease (either recognized or unrecognized) should prompt consideration of NSF. It is also possible that issues such as iron supplementation and high-dose erythropoietin use, which became more prevalent in 1997, the year in which this disease was first observed, may also play some contributory role, and these historical elements should be investigated as well.
What is the Evidence?
Cuffy, MC, Singh, M, Formica, R, Simmons, E, Abu Alfa, AK, Carlson, K. “Renal transplantation for nephrogenic systemic fibrosis: a case report and review of the literature”. Nephrol Dial Transplant. vol. 26. 2011. pp. 1099-1101. (This article describes a case of NSF that improved after renal transplant; a phenomenon that has been described. In this particular case, the patient improved even when the graft function was less than optimal. However cases of NSF developing in the setting of a failing renal transplant have also been reported, suggesting any improvement may be complex and multifactorial.)
Lemy, AA, del Marmol, V, Kolivras, A, High, WA, Matos, C, Laporte, M. “Revisiting nephrogenic systemic fibrosis in 6 kidney transplant recipients: a single-center experience”. J Am Acad Dermatol. vol. 63. 2010. pp. 389-99. (This case series reports of 6 cases of NSF that developed in patents that were status-post renal transplant with a poorly functioning graft, and it also contains a case that may be unassociated with gadolinium, as no such material was detected even with use of sensitive mass spectrometry to examing skin biopsy.)
High, WA, Ranville, JF, Brown, M, Punshon, T, Lanzirotti, A, Jackson, BP. “Gadolinium deposition in nephrogenic systemic fibrosis: an examination of tissue using synchrotron x-ray fluorescence spectroscopy”. J Am Acad Dermatol. vol. 62. 2010. pp. 38-44. (This small series demonstrated the presence of gadolinium in tissue by a third technique, in addition to electron microscopy/energy dispersive spectroscopy and mass spectrometry, and it also demonstrated a gradient of uneven deposition within affected skin.)
Bhawan, J, Swick, BL, Koff, AB, Stone, MS. “Sclerotic bodies in nephrogenic systemic fibrosis: a new histopathologic finding”. J Cutan Pathol. vol. 36. 2009. pp. 548-52. (This was the first report of relatively rare but rather specific sclerotic bodies that are present in some, but not all, cases of NSF. These bodies are thought to represent some form of aberrant or abortive ossification process occurring within the skin.)
Kay, J, High, WA. “Imatinib mesylate treatment of nephrogenic systemic fibrosis”. Arthritis Rheum. vol. 58. 2008. pp. 2543-8. (This series was the first report of imitanib mesylate, a tyrosine kinase inhibitor with recognized anti-fibrotic properties, in the treatment of NSF. The patients showed both histologic and clinical improvement while taking the drug and in one patient, who used the drug sporadically, there was worsening during holidays away from the medication.)
High, WA, Ayers, RA, Cowper, SE. “Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis”. J Am Acad Dermatol. vol. 56. 2007. pp. 710-2. (This was the first report of gadolinium quanitifcation in affected tissue of patients with NSF, showing that the levels in the tissue were often elevated, often with levels of 100 ppm or more, in affected skin.)
High, WA, Ayers, RA, Chandler, J, Zito, G, Cowper, SE. “Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis”. J Am Acad Dermatol. vol. 56. 2007. pp. 21-6. ((This was the first report of gadolinium actually being detected, with semiquantitative technology, within the skin of patients with NSF, and this further solidified and established an association that was, prior to this direct evidence, established only by two small series that detailed exposure to MRI/MRA in the weeks before development of disease.)
Marckmann, P, Skov, L, Rossen, K, Dupont, A, Damholt, MB, Heaf, JG, Thomsen, HS. “Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging”. J Am Soc Nephrol. vol. 17. 2006. pp. 2359-62. (Second report of 13 patients with end-stage renal disease who developed NSF, with all of the patients sharing exposure to an MRA in the weeks prior to development of disease as the only commonality among the small population.)
Grobner, T. “Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis”. Nephrol Dial Transplant. vol. 21. 2006. pp. 1104-8. (First description of nine patients with end-stage renal disease, five of whom developed NSF, all five of whom were exposed to gadolinium for MRA in the weeks proceeding the development of the disease.)
Streams, BN, Liu, V, Liégeois, N, Moschella, SM. “Clinical and pathologic features of nephrogenic fibrosing dermopathy: a report of two cases”. J Am Acad Dermatol. vol. 48. 2003. pp. 42-7. (Describes the occurrence of yellow scleral plaques in NSF as an addiitonal cutaneous finding that is present in some, but certainly not all, or even most, cases of NSF.)
Cowper, SE, Robin, HS, Steinberg, SM, Su, LD, Gupta, S, LeBoit, PE. “Scleromyxoedema-like cutaneous diseases in renal-dialysis patients”. Lancet. vol. 356. 2000. pp. 1000-1. (First report of the disease sui generis. It was published in 2000, but used tissue dating back to 1997, and futhermore the tissue was obtained from several different locations in five different states. At this point, the disease was likened to scleromyxedema, which shares some histological qualities with NSF, but the latter condition is more fibrotic and is not associated with paraproteinemia.)
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