This is a rare and recently described disease, occurring in patients with a history of renal disease. Initially described in patients with skin lesions, the disease has not expanded to include other organ systems and the term nephrogenic systemic fibrosis (NSF) is now preferred. Patients present with large areas of indurated and hardened fibrotic plaques, usually on the extremities and trunk. In long standing cases, flexion contractures may result. The pathologist is confronted with a biopsy that may resemble scleromyxedema, scleroderma or morphea. However, there are subtle differences and with the clinical context and chronic renal disease, the diagnosis can be made. In recent years, there is growing evidence that exposure to gadolinium-based radiological contrast agents may play a role.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE/
Rare, less than 100 cases reported in United States and Europe EPIDEMIOLOGIC ASSOCIATIONS MMWR Morb Mortal Wkly Rep 2002 Jan 18;51(2):25-6 Related Articles, Links
Fibrosing skin condition among patients with renal disease--United States and Europe, 1997-2002
MMWR Morb Mortal Wkly Rep 2002 Jan 18;51(2):25-6 Abstract quote
During May 1997-November 2000, eight (3%) of 265 kidney transplant recipients at a hospital in California developed an unusual skin condition posttransplant (Figure 1).
On clinical examination, the patients had fibrotic skin lesions histologically resembling scleromyxedema on their distal extremities and trunk, resulting in severe contractions and limited mobility. However, the usual IgG lambda paraprotein associated with scleromyxedema was not observed in these patients.
Personnel in the dermatopathology section at the University of California, San Francisco, reviewed the biopsies and concluded that this skin disorder had not been described previously. As a result, health-care providers at the hospital where the index patient was treated asked the California Department of Health Services (CDHS) and CDC to assist in the investigation.
This report summarizes preliminary findings from the investigation.
DISEASE ASSOCIATIONS CHARACTERIZATION CALCIPHYLAXIS
- J Cutan Pathol. 2006 Oct;33(10):695-700. Abstract quote
Nephrogenic fibrosing dermopathy (NFD) and calciphylaxis are rare conditions that are associated with chronic kidney disease.
Histopathologic changes, including dystrophic dermal calcification, often in association with elastic fibers have been observed in NFD and calciphylaxis. A pattern of dermal elastic fiber calcification that mimics pseudoxanthoma elasticum (PXE) has been previously reported as an incidental finding in the setting of calciphylaxis. Despite a shared association with renal disease and abnormal calcium deposits, however, NFD and calciphylaxis are discrete pathologic processes with distinct clinical and histopathologic features.
Criteria for each are reviewed through case presentation of a patient meeting the clinical and histopathologic criteria for both NFD and calciphylaxis with histologic features mimicking PXE.
Calciphylaxis and metastatic calcification associated with nephrogenic fibrosing dermopathy
Lisa C. Edsall, Joseph C. English III and James W. Patterson
Journal of Cutaneous Pathology
Volume 31 Issue 3 Page 247 - March 2004 Abstract quote
Background: Calciphylaxis and metastatic calcification are known complications of chronic renal failure. Recently, a sclerosing condition of the skin termed nephrogenic fibrosing dermopathy (NFD) has been described in patients with renal disease, many of whom have undergone hemodialysis and/or renal transplantation. To our knowledge, the simultaneous occurrence of both conditions in the same patient, in the same lesion, has not been previously reported.
Case report: We report the clinical, microscopic, and immunohistochemical features of two patients with chronic renal failure whose lesional skin biopsies showed both subcutaneous calcification and NFD. We consider the possible mechanisms that might explain the coexistence of these two disorders.
Results: Both patients presented with erythematous, indurated skin over the lower extremities. Purpuric, reticulated patches, necrosis, or ulceration were not observed. Microscopic examination showed the characteristic changes of NFD involving dermis and subcutaneous septa. In addition, biopsies of both individuals showed subcutaneous calcification, one in a diffuse distribution and the other involving the walls of subcutaneous vessels, as seen in calciphylaxis. Calcification was not suspected clinically in either case.
Conclusions: Metastatic calcification or calciphylaxis and NFD can occur simultaneously in patients with chronic renal failure and may be found together in the same lesion. Because subcutaneous calcification may not be suspected clinically in these cases, and in view of the adverse outcomes frequently associated with calciphylaxis, we recommend deep incisional biopsy of patients presenting with the clinical features of NFD. Both the fibrosis and the calcification of chronic renal failure may be related to the activity of transforming growth factor-/Smad signaling cascades
CHRONIC RENAL DISEASE Majority of cases are on hemodialysis but patients on peritoneal dialysis or renal insufficiency have been reported KIDNEY TRANSPLANTATION
Revisiting nephrogenic systemic fibrosis in 6 kidney transplant recipients: a single-center experience.
Lemy AA, del Marmol V, Kolivras A, High WA, Matos C, Laporte M, Nortier JL.
Department of Nephrology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
J Am Acad Dermatol. 2010 Sep;63(3):389-99. Epub 2010 Jul 8.
BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a fibrotic disorder occurring in patients with renal dysfunction. Exposure to gadolinium (Gd)-based contrast agents (GBCAs) during renal impairment is associated with development of NSF.
METHODS: A cross-referenced search of kidney transplantation and radiology databases at a single institution revealed the prevalence of NSF in the transplant population. Clinical records and skin biopsy specimens from 6 patients with kidney transplant given a diagnosis of NSF were reviewed to identify contributing factors.
RESULTS: Between January 1999 and December 2006, NSF was diagnosed in 6 of 705 patients with kidney transplant (0.9%). Renal function was impaired in all patients. Of 33 patients with kidney transplant exposed to GBCAs, 5 (15.2%) developed NSF. Disease onset ranged from 7 days to 11 months after exposure to GBCAs. All 5 patients exposed to GBCAs who developed NSF were also treated with a beta-blocker and clinical improvement was observed with discontinuation. The sixth case NSF appeared unrelated to Gd, without a known exposure, and testing of tissue via mass spectrometry revealed no Gd. Symptoms of NSF in this patient disappeared after administration of darbepoetin was switched from subcutaneous to intravenous injection. One patient with NSF who manifested the highest Gd level in tissue died 22 months after disease onset.
LIMITATIONS: The study represents the retrospective experience of only a single center.
CONCLUSIONS: NSF can develop in kidney transplant recipients with altered graft function. In these patients, exposure to GBCAs appears associated with development of NSF. The role of beta-blockers in the course of the disease merits further investigation.
Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis.
Baron PW, Cantos K, Hillebrand DJ, Hu KQ, Ojogho ON, Nehlsen-Cannarella S, Concepcion W.
Am J Dermatopathol. 2003 Jun;25(3):204-9. Abstract quote
Nephrogenic fibrosing dermopathy (NFD) is a recently described cutaneous fibrosing disorder associated with renal dysfunction. It appears similar to scleromyxedema but with some notable exceptions, including the lack of involvement of the face and absence of plasma cells on histology, systemic involvement, and paraproteinemia. Patients can present with thickened or edematous skin with indurated papules and plaques involving the extremities and the trunk.
We report the first three cases of NFD after liver transplantation successfully treated with plasmapheresis. Two patients underwent liver transplantation for hepatitis C virus-induced cirrhosis and one for hepatitis B virus-induced cirrhosis.
All the patients had encephalopathy, refractory ascites, and malnutrition prior to transplantation. Like those patients with NFD, all three of our patients had renal dysfunction and required hemodialysis before and after transplantation. Two were not dependent on dialysis at the time of diagnosis, however. These patients had excellent liver allograft function, but the other patient had allograft failure secondary to recurrent hepatitis C. Immunosuppression therapy consisted of basiliximab, mycophenolate mofetil, calcineurin inhibitor, and prednisone. The patients developed "woody" skin induration of the distal extremities, erythematous papules, and contractures at 1, 2, and 120 months after transplantation. Skin biopsies resembled NFD. No paraproteinemia was evident. One to three 5-day courses of plasmapheresis resulted in moderate to marked clinical improvement. The improvement of the kidney function in two of our patients did not appear to correlate with that of the skin disorder, because the kidney function was improving at the time the diagnosis of NFD was made.
In conclusion, we report the first three cases of NFD after liver transplantation. Plasmapheresis was moderately successful in resolving the skin-indurated papules, severe skin induration, and associated joint contractures. Preliminary studies (unpublished data) show that decreasing plasma levels of transforming growth factor-beta1 after plasmapheresis appear to correlate with the amelioration of this clinical condition.
Nephrogenic systemic fibrosis: a pathologic study of autopsy cases.
Koreishi AF, Nazarian RM, Saenz AJ, Klepeis VE, McDonald AG, Farris AB, Colvin RB, Duncan LM, Mandal RV, Kay J.
Department of Pathology, James Homer Wright Pathology Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
Arch Pathol Lab Med. 2009 Dec;133(12):1943-8. Abstract quote
CONTEXT: -Nephrogenic systemic fibrosis (NSF) is a rare but serious disorder initially described as a purely dermatologic process. Isolated autopsy reports have described multiorgan involvement by this disease.
OBJECTIVE: -To further illustrate the varied and systemic involvement of NSF by describing the autopsy experience at the Massachusetts General Hospital.
DESIGN: -We describe the findings in a series of 4 autopsy cases of patients diagnosed with NSF. This report describes the history of renal dysfunction, exposure to gadolinium-containing contrast agents, specific laboratory parameters, and the extent of systemic involvement identified by postmortem examination.
RESULTS: -Causes of death included systemic thromboembolic disease (n = 3) and pneumonia (n = 1). Laboratory parameters and type, dose, or timing of gadolinium-containing contrast-agent exposure did not correlate with clinical findings and outcomes. All patients demonstrated cutaneous manifestations of the disease and nephrocalcinosis, with some exhibiting calcification and fibrosis of the dura, thyroid, and heart including the cardiac conduction system, on postmortem examination. Soft tissue calcification was associated with concurrent hyperparathyroidism or high serum parathyroid hormone levels.
CONCLUSIONS: -Thromboembolic disease can be a significant clinical complication of NSF. Patients with NSF may also develop characteristic histologic features of fibrosis and calcification in multiple organs, with significant morbidity and mortality. This autopsy series highlights the variability of systemic manifestations of NSF.
PATHOGENESIS CHARACTERIZATION GADOLINIUM RADIOLOGIC CONTRAST
Gadolinium-induced nephrogenic systemic fibrosis is associated with insoluble Gd deposits in tissues: in vivo transmetallation confirmed by microanalysis.
Thakral C, Abraham JL.
Department of Pathology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
J Cutan Pathol. 2009 Dec;36(12):1244-54. Epub 2009 Jul 7. Abstract quote
BACKGROUND: Nephrogenic systemic fibrosis (NSF) is an extremely debilitating systemic fibrosing disorder affecting renal failure patients. The association of NSF with gadolinium (Gd) containing magnetic resonance contrast agents was noted in 2006. Gd deposition in skin biopsies was demonstrated shortly thereafter.
METHODS: We used automated scanning electron microscopy (SEM)/energy dispersive x-ray spectroscopy for in situ quantitative analysis of insoluble Gd-containing deposits, recording multi-elemental composition and spatial distribution of detected features.
RESULTS: Gd was detected in all 29 patients (53 of 57 skin biopsies) with NSF, biopsied from 2 weeks to 3 years after Gd exposure. Gd concentration ranged from 1 to 2270 cps/mm(2) and was detected predominantly in the deep dermis and subcutaneous fibrous septa. Gd was found associated with Ca, P and sometimes Fe or Zn. Patients with sequential biopsies showed persistence or increase of Gd in tissues (6 of 11). Transmission electron microscopy (TEM) identified the intracellular deposits in fibrocytes and macrophages.
CONCLUSIONS: The demonstration of insoluble tissue deposits of Gd with co-associated elements clearly confirms in vivo transmetallation and dissociation of soluble Gd-chelates. Toxic Gd(3+) may trigger fibrosis under permissive conditions, e.g., in renal insufficiency. Pathologists and clinicians need to be aware of this serious but preventable disease.
- J Am Acad Dermatol. 2007 Jan;56(1):21-6. Abstract quote
BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a disease of unknown etiology that affects a subset of patients with renal insufficiency. Recent publications suggested an association between exposure to gadolinium-containing contrast agents and subsequent development of NSF. We sought to detect gadolinium within the skin and soft tissue of patients with NSF who were exposed to gadolinium-based contrast.
METHODS: Paraffin-embedded skin and soft tissue from NSF patients exposed to gadolinium, and from negative controls, was provided by the NSF Registry (New Haven, Conn). The tissue was searched for metals using a field emission scanning electron microscope that was equipped with energy dispersive spectroscopy. The presence of gadolinium and other metals was verified through identification of unique and requisite X-ray emission spectra.
RESULTS: Gadolinium was detected in 4 of 13 tissue specimens from 7 patients with documented NSF who were exposed to gadolinium-based radiographic contrast. No gadolinium was detected in a paraffin-embedded specimen from a negative control. Based upon the known exposure history of patients with detectable gadolinium, a tissue residence time of 4 to 11 months was observed.
LIMITATIONS: As this was a pilot investigation, only a single control specimen and a single histological section from each block of tissue were utilized.
CONCLUSION: In this pilot investigation, gadolinium was detected in the tissue of a number of patients with NSF. Although neither dispositive of a pathophysiologic mechanism, nor proof of causation, the detection of gadolinium within tissue of NSF patients is supportive of an epidemiologic association between exposure to gadolinium-containing contrast material and development of disease.
- J Am Acad Dermatol. 2007 Jan;56(1):27-30. Abstract quote
There is growing recognition of the association between the use of gadolinium-containing radiocontrast agents for magnetic resonance imaging and the serious dermal and systemic disease nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis (NFD/NSF).
The pathogenesis of this entity remains unclear; however, our recent observations suggest a likely mechanism for the initial dermal manifestations of this gadolinium toxicity.
J Cutan Pathol. 2005 Oct;32(9):612-5. Abstract quote
Background: Patients with renal failure have been identified recently, some on dialysis, others with renal transplants, who have scleromyxedema-like skin changes. These lesions are characterized grossly by extensive thickening of skin, brawny pigmentation, papules, and subcutaneous nodules. Mucinous deposits are observed histologically that resemble those in scleromyxedema.
Methods: Biopsies of these lesions were stained with a biotinylated hyaluronan (HA)-binding protein coupled to an avidin-peroxidase reaction.
Results: These lesions are associated with marked deposition of HA in the papillary dermis.
Conclusions: HA turnover is cleared rapidly in the circulation by both liver and kidney. Evidence suggests that high molecular size HA chains, which are anti-inflammatory, antiangiogenic, and immuno-suppressive are cleared by the liver. By contrast, intermediate-size fragments, which are highly angiogenic, inflammatory, and a stimulus for fibrous deposition, are cleared by the kidney. The accumulation of such fragments in renal failure can account for HA deposition in the dermis and may be a mechanism for the nephrogenic fibrosing dermopathy that can accompany these lesions.
TRANSFORMING GROWTH FACTOR BETA
- Nephrogenic systemic fibrosis is associated with transforming growth factor beta and Smad without evidence of renin-angiotensin system involvement.
Department of Dermatology, University of Texas Medical Branch, Galveston, Texas 77555-0783, USA.
- J Am Acad Dermatol. 2008 Jun;58(6):1025-30. Abstract quote
BACKGROUND: The mechanisms of fibrosis associated with nephrogenic systemic fibrosis (NSF) are largely unknown. Transforming growth factor beta (TGF-beta), a known profibrotic cytokine, is theorized to play a central role. The renin-angiotensin system has been linked with both TGF-beta expression and fibrosis in other organ systems.
OBJECTIVE: We sought to investigate whether these mechanisms were involved with NSF.
METHOD: Eleven biopsy specimens from 8 patients with NSF were evaluated by immunohistochemistry for the expression of TGF-beta, Smad 2/3, angiotensin-converting enzyme (ACE), and angiotensin II receptor 1 (AT1).
RESULTS: TGF-beta was detected in 8 of 11 samples of NSF. Smad 2/3 nuclear staining was seen in 8 of 11 samples. Conversely, only faint staining for ACE was seen in 2 of the 11 specimens. No AT1 staining was seen.
LIMITATIONS: We did not perform our studies on a cohort of comparable patients with renal dysfunction without NSF. Our technique may not have been sufficiently sensitive to detect renin-angiotensin system involvement.
CONCLUSIONS: TGF-beta, as well as its second messengers, Smad 2/3, appears to be associated with the fibrosis seen in NSF. No definitive evidence of renin-angiotensin system involvement could be determined.
CHARACTERIZATION LABORATORY MARKERS No serum paraproteins
- Nephrogenic systemic fibrosis: a clinicopathologic study of six cases.
Department of Pathology, University of Rochester School of Medicine and Dentistry, NY, USA.
- J Am Acad Dermatol. 2007 Jul;57(1):105-11. Epub 2007 Apr 6. Abstract quote
BACKGROUND: Nephrogenic systemic fibrosis is a rare fibrosing condition that occurs in patients with renal insufficiency. While its histologic characteristics have been well described, the etiology and pathogenesis have not been fully characterized. Several recent studies support the theory that gadolinium-based contrast agents play a causative role in the development of the disease. Erythropoietin therapy and endothelial damage from surgical procedures have also been suggested as potential contributing factors.
OBJECTIVE: This study attempts to help contribute to the understanding of this novel disorder.
METHODS: We performed a retrospective chart review of 6 patients diagnosed with nephrogenic systemic fibrosis at our institution. Emphasis was placed on identification of potential putative etiologic agents including gadolinium, erythropoietin therapy, and previous surgical procedures.
RESULTS: All patients had documented exposure to gadolinium-based contrast agents. Three of the 6 patients were treated with erythropoietin, and all patients underwent a previous surgical procedure.
LIMITATIONS: This study is limited by its small size; therefore, the findings and results may not be applicable to all patients with this disorder.
CONCLUSION: Our data suggest that gadolinium plays a primary role in nephrogenic systemic fibrosis and that prior surgery may be a contributory factor.
- Nephrogenic fibrosing dermopathy: the first 6 years.
Dermatopathology Service, Yale University, New Haven, Connecticut, USA.
Curr Opin Rheumatol. 2003 Nov;15(6):785-90. Abstract quote
PURPOSE OF REVIEW: Nephrogenic fibrosing dermopathy (NFD) is a newly recognized scleroderma-like fibrosing skin condition. It develops in patients with renal insufficiency. This review summarizes recent case reports and examines theories of disease pathogenesis. Information from the Yale University NFD Registry Project, as well as published case reports, is included to provide a contextual framework upon which to base these theories.
RECENT FINDINGS: Recent studies have contributed to a clearer definition of the clinical spectrum, epidemiology, and pathogenesis of NFD. The findings of yellow scleral plaques and circulating antiphospholipid antibodies have been proposed as markers of NFD in recent case reports. In addition, epidemiologic data have yielded several distinct clinical patterns of disease onset. Lastly, dual immunohistochemical staining for CD34 and procollagen in the spindle cells of NFD suggest that the dermal cells of NFD may represent circulating fibrocytes recruited to the dermis-a finding previously undescribed in normal skin.
SUMMARY: Scenario classification of NFD is a means for simplifying the search for multifactorial disease triggers, and may be helpful in predicting prognosis and response to therapy. The technique of dual immunolabeling, although not yet fully characterized as a diagnostic test, may provide a sensitive and specific method of diagnosis, as well as a starting point in the investigation of other cutaneous fibrosing disorders. The postulate that NFD may represent a systemic disorder mediated by aberrantly functioning circulating fibroblast precursor fibrocytes is explored.
Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure.
Swartz RD, Crofford LJ, Phan SH, Ike RW, Su LD.
Division of Nephrology, University of Michigan Health Systems, Ann Arbor 48109-0364, USA.
Am J Med. 2003 May;114(7):563-72. Abstract quote
BACKGROUND: Nephrogenic fibrosing dermopathy is a newly recognized cutaneous fibrosing disorder marked by the acute onset of induration involving the upper and lower limbs in patients with acute or chronic renal failure. The etiology, pathogenesis, associated clinical conditions (other than renal failure), and ultimate course have not been defined in the few cases studied. Presently, there is no effective treatment, and the condition persists in most patients.
METHODS: Clinical and histopathologic data on 13 patients from our institution with the diagnosis of nephrogenic fibrosing dermopathy were reviewed. Several clinical and laboratory parameters were examined to see if any were consistently associated with the disease. Biopsy specimens were analyzed to determine if there was a pattern to the evolution of fibrosis in these patients.
RESULTS: All 13 patients had renal failure before disease onset: 8 were undergoing chronic hemodialysis, 2 were undergoing chronic peritoneal dialysis, and 3 with acute renal failure had never undergone dialysis before the development of dermopathy. Most patients had other serious underlying medical conditions. Many patients were taking erythropoietin, cyclosporine, or both before the onset of disease. In transplant patients, no histocompatibility antigens were found to be associated with the disease. There were various laboratory abnormalities, but none were consistently associated with the condition. In skin biopsy specimens taken 7 to 180 days after disease onset, there were histopathologic changes suggestive of a tissue reaction to injury, as well as the development of smooth muscle actin-positive myofibroblasts.
CONCLUSION: Nephrogenic fibrosing dermopathy is a novel cutaneous fibrosing disorder that is distinguished from other sclerosing or fibrosing skin disorders by distinctive clinical and histopathologic findings occurring in the setting of renal failure. There were no additional clinical risk factors or laboratory findings common to the 13 patients studied, other than renal failure. The resemblance to a tissue injury reaction and the presence of myofibroblasts in the tissue specimens suggest that fibrogenic cytokines may be involved in the evolution of the disease.
Clinical and pathologic features of nephrogenic fibrosing dermopathy: A report of two cases.
Streams BN, Liu V, Liegeois N, Moschella SM.
Departments of Dermatology and Dermatopathology, Massachusetts General Hospital and The Lahey Clinic, Harvard Medical School
J Am Acad Dermatol 2003 Jan;48(1):42-7 Abstract quote
Nephrogenic fibrosing dermopathy is a rare, recently described fibrotic skin condition that primarily affects patients with a history of renal disease.
We describe 2 patients on hemodialysis with the characteristic clinical and pathologic features.
Nephrogenic fibrosing dermopathy should be distinguished from other fibrotic disorders, such as scleromyxedema, systemic sclerosis, and eosinophilic fasciitis
Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease).
Mackay-Wiggan JM, Cohen DJ, Hardy MA, Knobler EH, Grossman ME.
Department of Dermatology; Division of Nephrology, Department of Internal Medicine; and Division of Transplant Surgery, Department of Surgery; Columbia University.
J Am Acad Dermatol 2003 Jan;48(1):55-60 Abstract quote
Nephrogenic fibrosing dermopathy or scleromyxedema-like illness of renal disease is a recently reported disorder. It manifests as scleromyxedema-like skin lesions without associated paraproteinemia, occurring in the setting of renal disease.
In the majority of cases skin lesions of nephrogenic fibrosing dermopathy develop after hemodialysis or renal transplantation; however, the origin is still unknown.
We report 4 new cases of nephrogenic fibrosing dermopathy and review the literature. The clinical and histopathologic features, differential diagnosis, possible etiology, and treatment options are reviewed.
- Localized nephrogenic fibrosing dermopathy: Aberrant dermal repairing?
Department of Dermatology, University of Maryland, School of Medicine, Baltimore, Maryland 21201, USA.
- J Am Acad Dermatol. 2008 Feb;58(2):336-9. Abstract quote
Nephrogenic fibrosing dermopathy (NFD) has emerged as a clinicopathologic entity since 2000 and was recently renamed nephrogenic systemic fibrosis. The cause and pathogenesis remain uncertain. The classic clinical presentation is diffuse thickening and hardening of the skin that occurs in patients with renal insufficiency, with or without systemic involvement.
We report a patient with renal failure who presented to our dermatology clinic with a localized plaque on the left forearm along the vein that was traumatized during the infusion of erythropoietin. Histologic examination revealed a dermal proliferation of CD34(+) fibrocytes with collagen fibers and interstitial mucin accumulation, features characteristic for NFD.
We conclude that NFD may present as a localized, scarlike plaque after trauma and exhibit overlapping histopathologic features resembling cicatrix and other dermal reparative/regenerative processes. NFD may, in fact, be a disorder of aberrant extracellular matrix remodeling in patients with renal insufficiency. This is a single case observation with discussion of literature and attempted hypothesis on pathogenesis. No experimental evidence is provided.
SCLEROTIC BODIES Sclerotic bodies in nephrogenic systemic fibrosis: a new histopathologic finding
Jag Bhawan 1 , Brian L. Swick 2 , Amy B. Koff 3 and Mary S. Stone 2
J Cutan Pathol 2009;36:548-552 Abstract quote
Nephrogenic systemic fibrosis (NSF – known previously as nephrogenic fibrosing dermopathy) is a systemic disorder observed exclusively in patients with a history of kidney disease associated with renal failure. Reported histopathologic findings of NSF include spindle-shaped fibroblast-like cells with fibrosis, thickened collagen bundles with surrounding spindled and epithelioid cells, increased number of elastic fibers, sparse inflammatory infiltrate and increased stromal mucin. Two populations of multinucleated giant cells (Factor XIIIa and CD68 positive) have also been observed.
We observed the presence of sclerotic bodies with entrapped elastic fibers in two cases of NSF, which we interpreted to be collagenous in nature, a finding not previously reported. These bodies should not be confused with osseous metaplasia previously seen in association with NSF, which show lacunae and cells within the osseous bodies that may or may not be calcified.
We did not observe lacunae or cells within the sclerotic bodies in our cases. Furthermore, the sclerotic bodies in our cases stained blue on Masson trichrome, whereas previous investigators observed the osseous metaplasia to be red. We suggest that sclerotic bodies may be an additional clue to the diagnosis of NSF.
Arch Pathol Lab Med. 2006 Feb;130(2):209-12. Abstract quote
Nephrogenic fibrosing dermopathy is a recently recognized, scleromyxedema-like fibrosing skin condition that occurs in individuals with acute or chronic renal failure.
Although the early descriptions of this disorder describe a purely cutaneous disease process, 2 recent autopsy reports have identified apparent multiorgan fibrosis with involvement of skeletal muscle, myocardium, lungs, kidneys, and testes.
We describe a 23-year-old man with nephrogenic fibrosing dermopathy and significant fibrosis of the atrial myocardium and dura mater, which was identified at autopsy. Dural fibrosis is a previously undescribed systemic manifestation of nephrogenic fibrosing dermopathy. The literature is reviewed.
Nephrogenic fibrosing dermopathy with systemic involvement.
Ting WW, Stone MS, Madison KC, Kurtz K.
Department of Dermatology, University of Iowa College of Medicine, Iowa City, USA.
Arch Dermatol. 2003 Jul;139(7):903-6. Abstract quote
BACKGROUND: There is a growing literature regarding sclerotic and panniculitic cutaneous conditions seen in patients with end-stage renal disease (eg, calciphylaxis and soft tissue calcification). Nephrogenic fibrosing dermopathy (NFD) is a recent designation to describe cutaneous findings in patients with end-stage renal disease who developed sclerotic plaques with scleromyxedema-like histologic features. Soft tissue calcification is rare in patients with NFD and systemic involvement has not been reported.
OBSERVATIONS: We describe a patient with end-stage renal disease who developed diffuse indurated woody plaques consistent with NFD in association with soft tissue calcification with catastrophic sequelae. A deep excisional biopsy specimen from the patient revealed thickened collagen bundles in the reticular dermis, plump bipolar spindle cells, and increased mucin. Focally, there were zones of calcium deposition in dermal collagen without vessel calcification. Autopsy of the patient revealed extensive fibrosis and calcification of the diaphragm, psoas muscle, renal tubules, and rete testes. The patient died 11 months after developing NFD.
CONCLUSION: A subset of patients with NFD may have significant systemic involvement.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
Nephrogenic systemic fibrosis with a spectrum of clinical and histopathological presentation: a disorder of aberrant dermal remodeling.
Deng A, Martin DB, Spillane A, Chwalek J, St Surin-Lord S, Brooks S, Petrali J, Sina B, Gaspari A, Kao G.
1Department of Dermatology, University of Maryland, School of Medicine, Baltimore, Maryland, USA.
J Cutan Pathol. 2010 Feb;37(2):204-10. Abstract quote
BACKGROUND: Nephrogenic fibrosing dermopathy (NFD) has emerged as a clinicopathologic entity since 1997 and recently renamed as nephrogenic systemic fibrosis (NSF). The etiology and pathogenesis remain uncertain. Characteristic clinical presentation is described as diffuse thickening and hardening of the skin occurring in patients with renal insufficiency. Typical histological features include proliferation of CD34 positive fibrocytes, increased thick collagen bundles and mucin deposition, without significant inflammatory infiltrate. Variations in clinical presentations have been reported, including papular and plaque-like skin lesions, focal lesion only, as well as systemic involvement. Histological changes can be subtle and non-specific, overlapping with other disease processes and harboring features including calcification and osteoclast-like giant cells with osseous metaplasia.
METHODS: We reviewed patients with NSF that presented to our dermatology clinic by chart review, clinical examination and histological examination. Skin biopsy specimens were obtained from all cases. Histopathology evaluations were carried out by three dermatopathologists (AD, BS and GK) independently and the features were compared among all the cases. Special stains and immunohistochemistry study were also performed to highlight the histological features.
RESULTS: Seven cases of NSF presented with a spectrum of clinical manifestations, from classic diffuse hardening of the skin to localized linear plaques. On histological examination, proliferation of CD34-positive fibrocytes ranged from sparse to dense, collagen bundles ranged from thin to thick, and the interstitial dermal mucin accumulation ranged from scant-patchy to abundant. In addition, the lesion displayed various degrees of vascular proliferation, inflammatory infiltrates and intensities of CD68 and Factor XIIIa staining. Two cases showed extensive dermal calcification and ossification.
CONCLUSION: NSF may present with a spectrum of clinical abnormalities, and exhibit overlapping histopathological features resembling cicatrix and other dermal reparative/regenerative processes. NSF may in fact to be a disorder of aberrant extracellular matrix remodeling in patients with renal insufficiency.
Nephrogenic Fibrosing Dermopathy
Shawn E. Cowper, M.D.; Lyndon D. Su, M.D.; Jag Bhawan, M.D.; Howard S. Robin, M.D.; Philip E. LeBoit, M.D.
From the Departments of Pathology and Dermatology (S.E.C., P.E.L.), University of California, San Francisco, California; Department of Pathology (L.D.S.), University of Michigan Medical Center, Ann Arbor, Michigan; Dermatopathology Section (J.B.), Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts; and Sharp Healthcare (H.S.R), San Diego, California, USA.
Am J Dermatopathol 2001;23:383-393 Abstract quote
This report details the histopathologic findings in a unique fibrosing disorder that recently emerged among patients with renal disease.
The affected patients were initially identified among recipients of renal transplants at a single institution, but later cases at other centers were identified, and included patients receiving renal dialysis for a variety of different kidney diseases. The cutaneous changes consisted largely of indurated plaques and papules on the extremities and trunk. Systemic findings seen in scleromyxedema, which the condition resembles in some respects, were absent.
By routine microscopy, the findings range from a very subtle proliferation of dermal fibroblasts in early lesions, to a florid proliferation of fibroblasts and dendritic cells in fully developed cases. Thick collagen bundles with surrounding clefts are a prominent finding, and a variable increase in dermal mucin and elastic fibers was usually evident with special stains. CD-34 positive dermal dendrocytes were floridly abundant, with dendritic processes aligned with elastic fibers and around collagen bundles in a dense network. Factor XIIIa and CD-68 positive mono-and multinucleated cells are also present in increased numbers. Electron microscopy highlighted increased elastic fibers closely apposed to dendritic cell processes. The entire dermis was commonly involved, with increased spindle cells, collagen, mucin, and elastic fibers extending through the subcutis along the septa of fatty lobules. In some instances, the process resembled a sarcoma on histopathologic examination. The recent emergence of this condition and the apparent clustering of cases in specific dialysis centers initially suggested a possible infectious and/or toxic agent. To date, however, no such agent has been identified.
We propose the term “nephrogenic fibrosing dermopathy (NFD)” until a specific cause can be identified.
VARIANTS GIANT CELLS
A variant of nephrogenic fibrosing dermopathy with osteoclast-like giant cells: a syndrome of dysregulated matrix remodeling?
Klilah Hershko, Cheryl Hull, Leila Ettefagh, Susan Nedorost, Senait Dyson, Thomas Horn and Anita C. Gilliam
Journal of Cutaneous Pathology
Volume 31 Issue 3 Page 262 - March 2004 Abstract quote
Nephrogenic fibrosing dermopathy (NFD) is a disorder characterized by dramatic thickening and hardening of skin in the extremities and trunk, which occurs in individuals on dialysis for renal disease. The pathophysiology is unknown. Increased transforming growth factor- (TGF-) and collagen deposition have been reported in a small group of patients studied by Jimenez et al. We report two patients with NFD and osteoclast-like giant cells in the fibrotic dermis; one patient also had dystrophic cutaneous calcification. These findings have been seen in a small percentage of NFD patients (estimated 2-5%) and may represent a variant of the disease.
The hypothesis of altered matrix dysregulation due to altered TGF- , metalloproteinases, and activation of osteoclasts as an explanation for this variant is proposed.
Nephrogenic systemic fibrosis: report of an additional case with granulomatous inflammation.
Wilford C, Fine JD, Boyd AS, Sanyal S, Abraham JL, Kantrow SM.
Division of Dermatology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Am J Dermatopathol. 2010 Feb;32(1):71-5. Abstract quote
Nephrogenic systemic fibrosis (NSF) is a novel disease entity described over the past 10 years. NSF is a progressive systemic fibrosing disorder that occurs arguably exclusively in patients with impaired renal function who have been exposed to gadolinium-containing contrast agents.
As no single clinical or histopathologic finding is diagnostic of NSF, a careful review of the cumulative characteristics of each case is essential in making a correct diagnosis. The spectrum of histologic variants of NSF continues to expand, including a report of NSF mimicking erythema nodosum and several case reports of NSF with giant cells and calcification.
We report an additional case of NSF with the uncommon pathologic features of granulomatous and lymphocytic inflammation in the fibrous septae similar to erythema nodosum.
- Osseous metaplasia in the setting of nephrogenic fibrosing dermopathy.
Ruiz-Genao DP, Pascual-Lopez MP, Fraga S, Aragues M, Garcia-Diez A.
Departments of Dermatology and *Pathology, Hospital Universitario de La Princesa, Madrid, Spain.
J Cutan Pathol. 2005 Feb;32(2):172-5. Abstract quote
Background: Nephrogenic fibrosing dermopathy (NFD) is a new skin-fibrosing disorder associated with renal dysfunction. It is marked by the acute onset of induration involving the upper and lower limbs, and it is characterized by distinctive histopathologic findings.
Methods: We report the case of a patient on hemodialysis who presented initially with the characteristic clinical and pathological features of NFD. The patient progressively developed painful hyperkeratotic spicules on both thighs and bone metaplasia was confirmed.
Results: Histological studies were performed at different stages of the disease showing an evolution from the well-known initial phase of NFD, characterized by thickening of the dermis, increased number of fibroblast-like cells, and mucin deposits, to an end stage characterized by the presence of dermal ossification.
Conclusions: We report the exceptional finding of bone metaplasia in the setting of a case of NFD.
CHARACTERIZATION SPECIAL STAINS Mucin stain may highlight interstitial mucin collections CD34
Am J Kidney Dis. 2005 Oct;46(4):754-9. Abstract quote
Nephrogenic fibrosing dermopathy (NFD) is a fibrosing condition of the skin that is being described increasingly in patients with renal diseases, many of whom are on dialysis therapy or have undergone renal transplantation. Its etiopathology is unknown, and no standard therapy currently exists.
We describe a patient with NFD for whom histopathologic studies indicated that the fibrotic process affected subcutaneous tissue, striated muscles, diaphragm, pleura, pericardium, great vessels of the heart, left ventricle and septum, and tunica albuginea in addition to the dermis. Fibroblast-like cells positive for CD34 and CD45RO and scattered CD68-positive cells were found in affected tissues. The presentation of our case is unusual in that the disease process started in the lower abdomen and upper extremities and involved the upper extremities to a greater extent than the lower extremities.
Our findings indicate that the fibrosis associated with NFD can extend beyond dermis and, as part of a systemic fibrosing disorder, can involve subcutaneous tissues, striated muscles, diaphragm, pleura, pericardium, and myocardium. We therefore suggest that "nephrogenic systemic fibrosis" would be a more appropriate term for this disease entity.
Br J Dermatol. 2004 May;150(5):1050-2
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES DERMAL FIBROSING DISORDERS ERYTHEMA NODOSUM
- Nephrogenic systemic fibrosis with septal panniculitis mimicking erythema nodosum.
Student Body, Brown Medical School, Providence, Rhode Island 02903, USA.
- J Am Acad Dermatol. 2008 Jan;58(1):149-50. Abstract quote
Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy is an idiopathic fibrosing disorder recently described in patients with renal disease.
The typical histology in nephrogenic systemic fibrosis consists of haphazardly arranged dermal collagen bundles with clefting, collagenous change which extends into the subcutaneous septa, mucin deposition, fibroblast proliferation, and increased elastic fibers with minimal inflammation.
We present a 65-year-old female with classic clinical features whose biopsy demonstrated unique histologic features of septal pannicilitis with lymphocytic aggregates and Miescher's radial granulomas mimicking erythema nodosum.
J Cutan Pathol. 2005 Aug;32(7):484-90. Abstract quote
Background: Nephrogenic fibrosing dermopathy (NFD) clinically presents as indurated plaques and papules in patients with renal dysfunction. The differential diagnosis generally includes scleromyxedema (SMX), an idiopathic systemic disorder with cutaneous manifestations, in which patients also develop indurated papules and plaques. The two entities can be extremely difficult to distinguish microscopically. Histopathologic differences with immunophenotypic comparison, to our knowledge, have not been thoroughly studied. We compared these two entities with an emphasis on immunohistochemistry.
Design: Nine biopsies diagnosed as NFD and seven biopsies diagnosed as SMX were retrospectively collected from the University of Pennsylvania Medical Center's surgical pathology and dermatopathology archives. Immunohistochemical staining for CD34, factor XIIIa, CD31, smooth muscle actin, CD68, and procollagen-I, as well as colloidal iron, were performed on each biopsy. Amount of expression for each of these markers, as well as degree of inflammation, for each biopsy was evaluated using a grading system of 0-3.
Results: Overall, NFD and SMX showed similar expression for all markers except procollagen-I, which showed increased expression in SMX.
Discussion: Although some immunophenotypic differences were found, our study did not demonstrate microscopic characteristics that can be easily used diagnostically to distinguish NFD from SMX. Clinical pathologic correlation is paramount in distinguishing these two entities.
PROGNOSIS CHARACTERIZATION RENAL FAILURE Rare patients may improve with correction of renal abnormalities
TREATMENT CHARACTERIZATION GENERAL No effective treatment
Thalidomide has been utilized on an experimental basis
PHOTOPHERESIS Nephrogenic Systemic Fibrosis
Relationship to Gadolinium and Response to Photopheresis
Heather Richmond, BA; Jeffrey Zwerner, MD, PhD; Youn Kim, MD; David Fiorentino, MD, PhD
Arch Dermatol. 2007;143:1025-1030. Abstract quote
Background Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy, is an idiopathic condition seen in patients with renal disease that is characterized by cutaneous sclerosis that can often result in contractures, pain, and functional disability as well as systemic complications. Recent reports have suggested a possible link with exposure to gadolinium, a commonly used radiocontrast agent. No current therapy has clearly demonstrated efficacy for NSF, although case reports suggest that extracorporeal photopheresis (ECP) may be of benefit. The purpose of this study was to explore the plausibility of a gadolinium linkage with NSF as well as to assess the efficacy of ECP in the treatment of a cohort of patients with NSF.
Observations We report our experience with 8 consecutive patients with NSF seen at the Stanford Medical Center, Palo Alta, California, from 2004 to 2006. Of the 8 patients, 6 had a history of arterial or venous thrombotic disease and 7 had a documented exposure to gadolinium within 1 week to several months prior to the onset of NSF. Specifically, all patients were exposed to gadodiamide. We treated 5 of the patients with ECP. After a mean number of 34 treatment sessions over a mean of 8.5 months, 3 patients experienced a mild improvement in skin tightening, range of motion, and/or functional capacity.
Conclusions Our data support the hypothesis that exposure to gadolinium, perhaps specifically gadodiamide, plays a role in the pathogenesis of NSF. Larger epidemiologic studies will be needed to confirm this association. In addition, our experience suggests that, if used for extended periods, ECP might have some mild benefit for patients with NSF. Larger, randomized, placebo-controlled trials of ECP should be performed to more specifically assess the benefit of ECP in the treatment of NSF.
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Last Updated September 13, 2010
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