Realizing that most patients (and many doctors) do not have the same level of access to the medical literature that I have on this subject, below is my attempt to summarize, chronologically, the articles published on NFD/NSF. This is necessarily a "subjective" exercise on my part -- as are all "editorial" exercises. Please keep this in mind as you read. Important "discoveries" are in bold, and personal editorial comments are inserted when I judge these need to be made (these are recognized as having a blue colored font). Also, an ongoing working hypothesis is indicated in red. NFD should be considered an equivalent terminology to NFD/NSF.
Article 1 September 2000
Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous disease in renal-dialysis patients. The Lancet 2000; 356(9234):1000-1 PubMed Abstract
This is the first verifiable report of what came to be known as nephrogenic fibrosing dermopathy.
14 dialysis patients in four US states with clinical and pathological findings resembling the disease scleromyxedema (Br. spelling "scleromyxoedema")
Nine patients were renal transplant recipients, one patient had acute renal disease
No gender or ethnic predilection was noted
No associated medical conditions (besides renal disease) were noted
No associated medicine or treatments were noted
Age range of patients (31-74)
Described cutaneous lesions as papules and nodules, generally on the extremities, typically sparing the torso, sometimes associated with contractures
Provided initial discussion of clinical diagnostic differentials to consider: Scleromyxedema, scleroderma, eosinophilc fasciitis, myositis, and calciphylaxis
Pointed out the absence of an IgG paraprotein in NFD (an important means of excluding scleromyxedema from consideration)
Provided initial discussion of histological diagnostic differentials to consider: Scleromyxedema, morphea (scleroderma), eosinophilia-myalgia
Provided first description of pathological findings
Haphazard dermal collagen bundles with surrounding clefts
Striking increase in dermal fibroblast-like cells
Increases in dermal mucin
Presence of some small multinucleated histiocytes
Involvement of the subcutaneous septa and fascia
All of this was important ground-breaking information that has essentially remained valid to date.
Of incidental interest was the fact that the search term "scleromyxoedema" did not map to "scleromyxedema" in the PubMed database, thereby leading many persons in the non-British-English speaking world to miss this important report when searching with the term "scleromyxedema." (see commentary in Article 9, below)
Article 2 October 2001
Cowper SE, Su L, Robin H, Bhawan J, LeBoit PE. Nephrogenic Fibrosing Dermopathy. Amer J Dermatopathol 2001; 23(5): 383-393 PubMed Abstract
This is an expansion of the previous report, with a deeper discussion of all issues related to the investigation.
Described initial case definition constructed in conjunction with the CDC
Points out that hemodialysis is not required for NFD. Some patients have never been dialyzed.
Introduction of the term "Nephrogenic Fibrosing Dermopathy"
Further described the original 14 dialysis patients noted above.
Tabulated causes of underlying renal disease in these cases
Tabulated lesional distribution
First documented association of vascular disease with NFD onset (leaking abdominal aneurysm)
Described some cutaneous lesions as plaques and bullae and rare involvement of the face
Described pruritis and causalgia (burning pain) in affected areas
Expanded clinical diagnostic differentials by adding: panniculitis, cellulitis and drug reactions
Provided in-depth discussion of histological diagnostic differentials and added several additional differentials: dermatofibrosarcoma protuberans, spindle cell melanoma, beta-2 microglobulin amyloidosis, interstitial granuloma annulare
Elaborated on pathological findings to include early and fully developed lesions, as well as one resolved lesion
Lesional cells found to be procollagen I positive by immunohistochemistry
Striking increase in CD34+ spindle cells, generally adjacent to collagen bundles, in a dense interconnecting network
Increased numbers of glassy dermal elastic fibers, reduced mucin in later lesions
Presence of angiogenesis
Presence of increased Factor XIIIa positive cells
Provided first description of electron microscopical findings
Described calcification of some lesions
Recognition of resemblance of NFD to normal wound healing microscopically
Perhaps most important here was the beginning of the immunohistochemical definition of the lesional cells and the beginning of the recognition that NFD resembles wound healing and is associated with vascular disease. Also important is the recognition that with resolution of acute renal disease, NFD may become a fully reversible process.
Article 3 January 2002
Fibrosing skin condition among patients with renal diseaseUnited States and Europe 1997-2002. MMWR/Morb Mortal Wkly Rep 2002; 51:25-6 Link to article
This is the first CDC issued report regarding the new disease entity, "NFD".
As of January 2002, 49 patients throughout the United States and Europe had been identified
Provided the results of a small case-controlled study of NFD patients in a transplant center in California
NFD cases were more likely than controls to have had poor renal function following transplantation
No clear association was identified between disease onset and specific medications, procedures, or infections
Proposed a larger follow-up study to investigate non-transplant cases
Of interest is the fact that no specific medication or procedure could be tied to the onset of NFD. The events of September 11, 2001 redirected the Centers for Disease Control, and control of the NFD Registry was returned to the University of California, San Francisco Department of Dermatopathology. The larger formal epidemiological evaluation was never completed.
Article 4 June 2002
McNeill AM, Barr RJ. Scleromyxedema-like fibromucinosis in a patient undergoing hemodialysis. Int J Dermatol 2002; 41(6): 364-7 PubMed Abstract
Case report of a 31 year old Hispanic female with NFD
First report of NFD in the dermatology literature
Disease onset followed 1 month after initiation of hemodialysis for end stage renal disease
Patient had 15 year history of renal disease and had failed two renal transplants
Further discussed lichen myxedema and scleromyxedema and suggested that NFD could be classified as a type of atypical lichen myxedematosus
Suggested that similar histopathological findings have been noted in three liver transplantation patients
Also suggested the possibility that liver disease or hepatitis C infection may be a comorbidity
Proposed the possibility that transforming growth factor-beta (TGF-B) could be responsible for the fibrosis
Clearly, the index case described here did not have liver disease, nor did the patients in the initial cohort. If liver disease was in any way to blame, it could not, by itself, explain all of the cases of NFD. Of interest, the three additional cases described here were more fully investigated and reported in a later paper by Baron, et al (see Article 12). TGF-beta, as a potent fibrogenic cytokine, remains a likely candidate in the development of NFD lesions.
News report from Pacific Northwest Dermatological Society interview with Debra Gillis of the California Department of Health Services
Stated 70 cases of NFD had been identified to date
Reported lack of consistent results with prednisone with and without plasmapheresis
This was more of a newspaper report than a formal report of results. By this date, the CDC and California Department of Health had passed the management of the investigation to Dr. Cowper, who had moved to Yale University in New Haven, Connecticut.
Article 6 January 2003
Bardin T. Musculoskeletal manifestations of chronic renal failure. Curr Opin Rheumatol 2003; 15(1): 48-54 PubMed Abstract
A brief mention of NFD at the end of an in-depth article on musculoskeletal disorders
First report of NFD in the rheumatology literature
Patient 1 noted to have antiphospholipid antibody syndrome and onset of NFD lesions before institution of hemodialysis
Treated with plasmapheresis and photopheresis with some evidence of improvement, but died due to infection
Patient known to have microocclusive disease
Patient 2 noted to have anticardiolipin antibody. He died due to complications related to lymphoma.
Patient 3 noted to have antiphospholipid antibody syndrome and history of deep venous thrombosis
Developed acute renal failure due to bilateral renal vein thrombi, short term hemodialysis instituted
Patient treated with photopheresis with improvement
Normal renal function returned following hemodialysis
Patient 4 noted to have antiphospholipid antibody syndrome and history of deep venous thrombosis
Onset of NFD 5 weeks post transplant
Patient noted to have antiphospholipid antibody syndrome
Lesions resolved without specific treatment over the next 12 months
First use of "amoeboid" projections to describe cutaneous plaques of NFD
Further discussed clinical and histopathological differentials
Suggested the antiphospholipid antibody, itself, was somehow causing the NFD
Many important points were made in this paper.
First, the clinical presentation, distribution of lesions and histpathology corroborate previous reports
Second, the authors identify that all four of their patients harbor a condition known to be related to hypercoagulability (antiphospholipid syndrome), three of whom had actually manifested clinically evident coagulation events
Third, one of these patients had onset of NFD before dialysis was initiated (further corroborating the fact that neither dialysis nor transplant are requirements for NFD).
Fourth, two of these patients were improving with a return to normal renal function. The contribution by photopheresis to the improvement in patient 3 is not clear, as renal function seemed to be improving concurrently. However, in patient 4, NFD lesions resolved without specific treatment over a period of 12 months.
Article 8 January 2003
Streams BN, Liu V, Liegeois N, Moschella SM. Clinical and pathological features of nephrogenic fibrosing dermopathy. Jour Amer Acad Dermatol. 2003; 48(1): 42-7 PubMed Abstract
Reports of two new patients with NFD
Patient 1 and 2 noted to have bilateral scleral plaques
Patient 2 noted to have previous history of pulmonary embolism.
Clinically, these authors describe palmar lesions resembling cutaneous calcinosis in one of their patients. The histology also showed some calcium deposition
Further discussed clinical and histopathological differentials, adding fibroblastic rheumatism to the list of differentials to be considered
Thalidomide was instituted in both cases, but the results of the therapy were not included
This article appeared in the same issue of JAAD as article 7 and included the very important clinical finding of scleral lesions. This finding has been corroborated by my own experience, but information regarding the specificity and sensitivity of this sign is lacking. Of great interest is that this is the first non-cutaneous lesion of NFD, beginning the evidence trail which would eventually conclude that NFD is in fact a systemic process, not solely a cutaneous one.
Of incidental interest is the fact that one of these two patients had a history of pulmonary embolism. In retrospect, this finding sits well with the later observation that many NFD patients have an underlying hypercoagulable state.
Thalidomide is first mentioned here as a possible treatment, but no results are provided.
Article 9 March 2003
Hubbard V, Davenport A, Jarmulowicz M, Rustin M. Scleromyxoedema-like change in four renal dialysis patients. Br J Dermatol. 2003; 148(3): 563-8 PubMed Abstract
Reports of four new patients with NFD, including first reports from patients residing outside the United States
Patient 1 developed NFD 2 weeks after renal graft nephrectomy for acute vascular rejection
The patient received 8 units of blood during the nephrectomy
Cutaneous lesions were noted to be particularly prominent over the site of his A-V fistula
Lesions of NFD improved over the next six months, but flexion deformities persisted
Patient 2 noted to have previous history of right atrial thrombus and acute vascular rejection of renal grafts on two prior occasions
Three months following her third kidney transplant NFD started in the vicinity of the A-V fistula, and ultimately involved all four limbs
Patient 3 noted to have previous history of intra-atrial thrombus and acute vascular rejection of a renal graft on one prior occasion
Patient 4 developed NFD while being hospitalized for treatment for an occluded femoral Goretex graft
The patients had no benefit from plasmapheresis or intralesional triamcinolone or intralesional methotrexate
Intralesional interferon alpha was tried in two patients with an initial improvement, however, it was abandoned in both due to complications unrelated to NFD
PUVA in one of these patients showed no improvement
Authors claimed there had been only one reported series of similar patients (referring to article 1, above)
Further discussed differentials noted in previous articles, with the addition of a discussion about vinyl chloride exposure
Further discussed, and logically excluded dialysates, dialysis filters, inferior water used for dialysis, and dialysis machine cleaning methods
This article suffered (I believe) from the authors' inability to find the most recent articles on NFD in PubMed because they searched using the British spelling "scleromyxoedema," missing the plethora of articles that could have been found by searching with "scleromyxedema." (see commentary in article 1, above)
Nevertheless, they make the interesting observation that in two of their patients, NFD lesions had a predilection for skin adjacent to the A-V fistula site. They attributed this to flow characteristics, and in retrospect, they may be right. NFD does typically manifest in areas with poor flow (legs with poor circulation or clotted venous returns for instance). More experience with this disease may well confirm this hypothesis.
Interestingly, two of their four patients also had histories of an intra-atrial thrombus, and one had an occluded Goretex vascular graft--further corroboration of a hypercoagulable state, perhaps? These incidental historical details, in combination with those mentioned above, form the beginnings of a hypothesis regarding "triggering events" in susceptible folks for NFD (thrombosis, vascular surgery, etc.)
Lastly, the authors do comment on therapies, but not in great detail (see above).
Article 10 May 2003
Swartz RD, Crofford LJ, Phan SH, Ike RW, Su LD. Nephrogenic Fibrosing Dermopathy: A novel cutaneous fibrosing disorder in patients with renal failure. Am J Med. 2003; 114(7): 563-72 PubMed Abstract
Reports of thirteen patients with NFD, four of whom were presented in previous publications
Three of these patients had never been dialyzed at the time of NFD onset
Four of the patients had known cardiomyopathy
One of the patients had known pulmonary fibrosis
Three of the patients had gout
Two of three patients tested were positive for the antiphospholipid antibody
One patient had renal failure due to the hepatorenal syndrome; two had renal failure secondary to atheroembolic complications
Hyperparathyroidism and calcium/phosphate abnormalities were noted in some of the patients, but appeared unassociated with NFD
One patient who had recovery of renal function showed partial improvement in the appearance of lesions, but no improvement in contractures
Further characterized the histopathology with an emphasis on the pathology as it varied depending on the perceived age of the lesion
Discussed the appearance of myofibroblasts in 3-4 week old lesions, and subsequent absence in older lesions
Discussed the modulation of dermal fibroblasts by TGF-beta to become myofibroblasts
Capillary proliferation was most marked with advancing lesional age
Reinforced the impression in article 2 that the histology of NFD resembles a wound healing reaction, and that NFD may represent an aberrant tissue injury reaction
Pointed out the shortcomings in interpreting lesional age and histology changes over time
Provided a list of treatments that did not seem to alter the course of NFD, but no details regarding dose or duration of therapy: topical steroids, histamine blockers, cyclosporine, oral prednisone
This article provides reinforcement of previously recognized ideas
NFD does not require dialysis, and if renal function is restored, some degree of recovery is possible
NFD is associated with disorders known to promote a hypercoagulable state (antiphospholipid, etc.)
NFD strongly resembles an aberrant wound healing reaction sans wound
NFD, in this paper, was also associated with cardiomyopathy (no elaboration provided) and pulmonary fibrosis (in one case)
Now that we understand NFD to be a systemic process, other organ systems should be scrutinized. The finding of pulmonary fibrosis is intriguing, as I am aware of its presence in at least two other unpublished cases, suggesting a possible increased incidence in patients with NFD. This still needs to be formally investigated.
Hepatorenal syndrome is described here and in several later cases of NFD. HRS seems to be over-represented in the NFD population, suggesting the possibility that decreased renal blood flow (and ischemia) which is present in HRS may be a common denominator in many of these patients
Described a fairly typical case of NFD from the point of view of a nephrologist
First report of NFD in the nephrology literature
Incorrectly stated that all patients with NFD have undergone hemodialysis
Elaborated on TGF-beta levels in renal disease
This article suffers from an incomplete background investigation. At the time of its publication much more could have been said about the "latest" findings, however, the authors relied almost exclusively on the first two articles and the MMWR report, ultimately incorrectly stating that all patients had undergone hemodialysis--not a message to impart to those who are in charge of performing hemodialysis.
Article 12 June 2003
Baron PW, Cantos K, Hillebrand DJ, H KQ, Ojogho ON, Nehlsen-Cannarella S, Concepcion W. Nephrogenic Fibrosing Dermopathy After Liver Transplantation Successfully Treated With Plasmapheresis. Amer J Dermatopathol 2003; 25(3):204-209 PubMed Abstract
Reported three cases of NFD in liver transplant recipients treated with plasmapheresis
Patient 1 had hepatorenal syndrome due to cirrhosis (due to alcohol and hepatitis C)
Underwent successful liver transplantation. Required hemodialysis for 1 week after transplantation
Four weeks after transplantation he developed NFD, and several days later he was wheelchair dependent
Each procedure removed 1.5 plasma volumes and replaced it with 5% albumin
Plasmapheresis was performed through a triple lumen central venous catheter
The patient improved remarkably and was able to ambulate with a walker
The patient was treated with an additional 5 day course of plasmapheresis one month later in response to a flare of NFD with improvement seen within 3 days
The patient currently has no evidence of skin lesions and ambulates without difficulty (24 months post-transplant)
Patient 2 had cirrhosis (due to alcohol and hepatitis C) and renal disease secondary to hypertension and cyclosporine toxicity
Developed NFD 2 months after starting hemodialysis
Treated with five days of plasmapheresis, which was repeated every 2-3 weeks for a total of three courses
Vascular access and replacement fluids were identical to those above
The patient improved partially, but was not able to ambulate and continued on hemodialysis
The patient died 3 months later due to worsening liver function
Patient 3 developed hepatorenal syndrome following an acute GI bleed in the setting of cirrhosis (hepatitis B)
Underwent successful liver transplantation. Required hemodialysis for 2 weeks after transplantation
Developed NFD 6 weeks after transplantation, mild renal dysfunction was still present
Treated with five days of plasmapheresis, a single course
Vascular access and replacement fluids were identical to those above
The patient improved partially, and at 27 months post-transplant was able to ambulate with a cane
Authors concluded that kidney function improvement did not influence the clinical course of NFD because the renal function was improving at the time the diagnosis was made
Decreased levels of serum levels of TGF-beta were noted in post-plasmapheresis samples when compared to pre-plasmapheresis samples
This is an important paper for many reasons and requires careful interpretation
All patients had chronic liver disease upon which a relatively recent onset renal dysfunction was superimposed
Patients 1 & 3 were similar in terms of the nature of the renal insult (hepatorenal syndrome) and the fact that they developed NFD 4-6 weeks post-transplant
In both cases the renal disease could be "cured" with correction of the liver disease
In both cases improvement in NFD was noted
In case 1, in whom renal disease was fully reversed, complete correction of the NFD occurred within 2 years
In case 3, in whom renal disease was not fully reversed, incomplete correction of the NFD occurred within 2 years
Since we know from ongoing experience that NFD is tied directly to renal function, these points make complete sense without considering plasmapheresis at all
While patients 1 & 3 received the same type of therapy, patient 1 received three courses (one which seemed to correct a late flare) and patient 3 received a single course
This may imply that a certain number of courses of therapy are necessary (perhaps a certain duration of therapy) to achieve complete clearing of NFD
Patient 2 was unlike 1 & 3, with onset of NFD following kidney toxicity and absence of a major transplant operation in the recent past
In case 3, the renal disease could not be "cured," yet improvement in NFD was noted
Unfortunately, no information regarding the patient's ongoing underlying renal function was provided, so we are unable to determine if there may have been transient improvement with medical treatment
If the improvements were solely because of plasmapheresis (and not renal function) one would expect this patient to experience improvements over time, but unfortunately this patient expired shortly after, leaving this question unanswered
Does plasmapheresis work?
Unfortunately, patient 2 does not contribute to an answer to this question
As clinical onset of NFD usually follows 4-8 weeks after the onset of renal disease, there is a lag period for the appearance of lesions
As clinical resolution of NFD follows in months to possibly years after the resolution of renal disease, there is a longer lag period for the disappearance of lesions
The observation that patient 1 had a late flare of NFD following a clinical improvement (which subsequently resolved with a third treatment) suggests that plasmapheresis is probably modifying the NFD in some way in this patient. This point is made with the assumption that the patient's renal function was stable and normal (which we cannot assess given the provided data)
In summary, the absence of documentation of renal function in patients who were being treated with plasmapheresis does not allow one to completely exclude an improvement in underlying renal function as the sole cause of the patients' improvement. The case of patient 1, however, is intriguing enough to urge continued research on this subject. And, as the investigators point out, TGF-beta levels may, as has been suggested, play a role in the development (and subsequent perpetuation) of NFD
Article 13 July 2003
Ting WW, Stone MS, Madison KC, Kurtz K. Nephrogenic Fibrosing Dermopathy with Systemic Involvement. Archiv Dermatol 2003; 139(7):903-6 PubMed Abstract
Describe a single case of NFD with prominent soft tissue calcification
Patient was a 60-year-old white male with ESRD due to hypertension
Cadaveric kidney transplant performed and acute vascular rejection ensued due to renal vein thrombosis (time elapsed before rejection not provided)
Five days rejection, patient required 10 units of blood during a resuscitation episode for hypovolemic shock
The next day, erythematous, painful, areas that rapidly became woody plaques were noted in dependent areas
Patient noted to have Antithrombin III deficiency and factor II deficiency and an elevated calcium-phosphate index and parathyroid hormone
Patient failed to respond to treatments which included: hydroxychloroquine, prednisone, cyclosporine, PUVA, photopheresis
Patient had severe shortness of breath, and his renal disease did not resolve
The patient chose to discontinue dialysis due to the morbidity associated with NFD and died 11 months after the disease onset
An autopsy was performed
Calcification was noted in large zones of the dermis among the collagen bundles. Vascular calcification was absent
The diaphragm was extensively involved, with vascular and extravascular calcification
The psoas muscle was similarly involved
Fibrosis without calcification was noted in the proximal esophagus
The myocardium contained a vessel in the left ventricle that was calcified and fibrosed
The vessels of the lungs and kidneys demonstrated intimal calcifications, and extravascular calcification was seen in the testes and renal tubules
Hyperplasia of three parathyroid glands and atrophy of the bilateral kidneys was noted
Authors conclude that a subset of NFD patients may have systemic disease
This too is a very important paper, the first autopsy report and the first definite proof of NFD as a truly systemic disease
The coagulation defects and the renal disease likely preceded the transplant. The renal vein thrombosis, possibly in concert with the surgery or the ischemic kidney, seem to have triggered NFD in this "susceptible" individual
The patient had factor II deficiency, almost assuredly acquired. The cause for this is not given, but since no liver disease was noted, the most likely agents are anticoagulant drugs, intestinal malabsorption, and the use of potent antimicrobials. None of these causes can be verified in the report.
The patient also had antithrombin III deficiency which was felt to be the cause of his renal vein thrombosis
The presence of three hyperplastic parathyroid glands with a normal calcium, elevated phosphorus and elevated PTH suggest secondary hyperparathyroidism.
This is a not uncommon complication in chronic renal disease, and can lead to excessive deposition of calcium in the tissues, particularly in areas that are fibrotic to begin with (metastatic calcification)
Conclusions cannot be made about the various medical treatments employed, as there is no documentation of duration or dosing. Clearly, none of them worked in a rapid or miraculous manner, however.
Article 14 July 2003
Leboit PE. What nephrogenic fibrosing dermopathy might be. Archiv Dermatol 2003; 139(7):928-30 PubMed Abstract
Discussed the early investigation of NFD from the point of view of the first person to recognize NFD -- Philip LeBoit!
Opined that a change in human behavior was likely the root cause of NFD
Suggested against thrombosis as a direct cause of NFD, as thrombi are not seen in the biopsy material
Suggested the possibility of minimizing erythropoietin dosage to the smallest amount possible
Suggested that observed early "clustering" of cases in certain centers was not merely observer bias
Comments: (with all due respect to my colleague and mentor, we differ in some of our opinions here!)
I agree that a change in human behavior has somehow brought NFD into our midst. The abrupt onset of cases in 1997 teamed with the association (early on) with very sick people suggests the use of a new medicine or technique, possibly one employed in certain centers
However, as time has passed, it becomes clear that this disease is present throughout the world, in many different populations
I believe thrombosis is related in some way to NFD onset--not necessarily directly, and not likely as microthrombi that would be visible in cutaneous biopsies. There is a strong possibility that hypoxia and/or ischemia releases local factors (cytokines) that are responsible for triggering NFD
Exogenously administered human recombinant erythropoietin cannot, itself, be the answer. While it is an intriguing hypothesis given its recent introduction and widespread use in the renal population, it is also used in a variety of other states (anemia related to malignancies, HIV infection, and Olympic athletes [oops]) and hasn't contributed to the development of NFD in these populations. Of interest, recent reports suggest that exogenously administered erythropoietin does increase the risk of clotting events in some patients (see my point above). So epo, may, in a roundabout way be a contributing factor to clotting in a population which is at risk for NFD. Time will tell.
Endogenously produced erythropoietin should also be considered in this discussion. In renal insufficiency, endogenous erythropoietin is typically low.
As time has passed and many more NFD patients have been seen (in small and large centers alike) I have concluded the clustering phenomenon was probably recognition bias, and not due to unusual medical, toxic or infectious exposure as initially thought. Again, time will tell.
Article 15 August 2003
Cowper SE, Bucala R. Nephrogenic Fibrosing Dermopathy: Suspect Identified, Motive Unclear.[Letter] Amer J Dermatopathol 2003; 25(4):358 PubMed Abstract
Pointed out the observation that CD34 and procollagen staining were occuring in the same spindled cell, and the very likely identification of that cell as a "circulating fibrocyte" (CF)
The clues leading to this observation were as follows:
The symmetry of NFD lesions in most cases suggests an intrinsic factor is involved
The rapidity of onset of the disease and the absence of mitotic figures in the dermal spindle cells suggests that spindle cells arrive via the circulation
The occurence of histiocytes in the lesions of NFD in varying proportions suggests a common origin for these cells (both histiocytes and CFs derive from circulating monocytic precursors)
The cellular composition of NFD resembles a wound healing reaction (including angiogenesis). CFs are known to be recruited to sites of wound healing
Resolved lesions of NFD are histologically indistinguishable from a healed wound site
While CFs are not fully understood, they are known to migrate to sites of tissue injury and are the only known circulating cell with the collagen I/CD34 dual positive immunophenotype
In the laboratory, the cells exhibit characteristics of connective tissue cells and leukocytes (including the ability to present antigen)
The CF provides a key missing link. With this piece in place, a global hypothesis of NFD emerges:
First unified hypothesis of NFD
Renal disease makes an individual suscepitble to NFD. Only a small number of patients go on to develop NFD.
Tissue injury (surgery, thrombosis and ischemia, worsening organ failure) elaborates cytokines that directly or indirectly recruit CFs from the bone marrow
CFs aberrantly target the skin and subcutaneous tissues (?preferentially)
CFs come out of circulation and begin to secrete additional cytokines that possibly recruit more CFs (self-perpetuating) and histiocytes, possibly also promoting angiogenesis (in a sense, building the foundation of a good wound healing reaction)
Most of these CFs assume a spindled morphology resembling a fibroblast, and begin producing collagen, mucin and elastic fibers
The reestablishment of a healthy kidney in some way interrupts this self-perpetuation, after which normal local remodelling (as occurs in a remodelling wound) takes over, softening the lesions of NFD over a long period of time
This theory also explains why well-established lesions of NFD may never fully resolve once contractures occur, and why short term renal failure, if reversed, may fully resolve before lesions are firmly established
This article, in combination with article 14, absolutely confirms that NFD is a systemic process
Article 16 October 2003
Hancox JG, Mengesha YM, Sangueza OP, Yosipovitch G. Nephrogenic fibrosing dermopathy after five days of hemodialysis. J Drugs Dermatol. 2003;2(5):550-3 PubMed Abstract
Reported on a single case of NFD in a 53-year-old female with acute renal disease due to renal artery stenosis
Patient required urgent renal artery bypass and stenting and five days of hemodialysis
Approximately one month post discharge she returned with NFD of upper and lower extremities
Patient also had elevated platelets and ESR
Treated with prednisone 40 mg po per day for 3 months without improvement
Authors specifically assert that NFD is associated with dialysis
This article reinforces the association of acute renal disease (associated with a thrombotic event) with NFD
The article also confirms the impression that in acute lesions, there is a lag time from the onset of renal disease, to the development of lesions (2-8 weeks is typical)
The article points out that dialysis is associated with NFD. It is associated in that NFD occurs in renal patients and dialysis is only administered in renal patients. Dialysis (for reasons elaborated on in the discussion of previous articles, does not cause NFD)
The authors also claimed prednisone was not effective at the dose of 40 mq po qd for a period of three months in this patient. We assume the patient was no longer renally insufficient, so on the basis of other cases presenting like this, we would expect to see spontaneous clearing after a few months. Whether the NFD persisted after this three month period would be very helpful to know.
Article 17 November 2003
Cowper SE. Nephrogenic Fibrosing Dermopathy: The First Six Years. Curr Opin Rheumatol. 2003;15(6):785-90 PubMed Abstract
Comprehensive summary of NFD as a disease entity up to that date
Over 100 cases in the NFD Registry at the time of publication
The only known commonality among all NFD patients is renal insufficiency
Introduced the concept that thrombosis and/or vascular surgical procedures might trigger NFD in susceptible individuals
Mentioned that brain tumors were present in two patients, and that hepatic and pulmonary disease were very common comorbidities in NFD
Discussed clinical, laboratory, and pathologic workup of possible cases of NFD
First description of neurological and muscular histopathological changes in one case
Briefly discussed treatments and called for better documentation of all treatments tried in the literature with special consideration given to the underlying renal status while undergoing treatment for NFD
Discussed a variety of scenarios that loosely classify NFD cases (with some overlap) and an initial impression regarding disease prognosis based on these scenarios
Type 1: New onset acute renal failure (ARF) or acute renal decompensation in a patient with chronic renal failure (CRF)
Type 2: Pneumonia-like disorder, distinct from pulmonary edema, followed by ARF
Type 3: Surgical procedure (often vascular) or acute blood loss, followed by ARF
Type 4: Kidney transplantation
Type 5: Chronic renal failure, unknown trigger
Type 6: Thrombotic event. Renal failure may predate or follow the event
Type 7: Brain tumor
Discussed theories of pathogenesis to date, including the idea that NFD patients may, in some way, be genetically predisposed to the condition
Discussed the possibility that the fundamental defect in NFD patients is fibrosis, with the kidney being an early, more susceptible target, and the skin a later, less commonly involved one
This article summarizes all of the comments above and is as comprehensive as the knowledge base was at the time of publication
In retrospect, as I look at the scenarios, it is clear to me that renal ischemia/infarction is likely the trigger in every case of NFD
I still am not sure what the apparent increased incidence of brain tumor is about, and cannot rule out mere chance
A very important point made in this article is that all potential therapies need to be carefully documented with respect to underlying renal function, dosing, and trial period. Without systematic studies, we will remain in a period of empiricism with NFD therapy
Article 18 November 2003
Jan F, Segal JM, Dyer J, Leboit P, Siegfried E, Frieden IJ. Nephrogenic Fibrosing Dermopathy: Two Pediatric Cases. J Pediatr. 2003; 143:678-81 PubMed Abstract
Reported on two cases of NFD in the pediatric population--the first discussion in the pediatric literature
Case 1: a 16-year-old white female with lifelong CRF; had previously rejected two transplanted kidneys
Presented with a 10 day history of erosive, pruritic, lesions on the trunk and extremities, 1 month following worsening of renal function necessitating hemodialysis (had previously been maintained with peritoneal dialysis)
Some lesions appeared as thick, linear plaques
Histology showed foci of mineralization consistent with calcinosis cutis. A follow up biopsy confirmed NFD.
The patient had some improvement of lesions with a switch to peritoneal dialysis, and discontinuing and restarting erythropoietin seemed to make no clinical difference
One year after NFD onset, she received a cadaveric kidney transplant
Within days the degree of pruritis and edema improved, and over time the skin has become much less indurated
Case 2: an 8-year-old white male with acute decompensation of CRF (the cause of the decline was unknown)
10 days post-admission he developed perianal erythema that (over a period of 10 weeks) became thickened and violaceous, with similar lesions developing on the extremities and back. Some of these were also linear in appearance
Treatment with high potency topical steroids under occlusion was ineffective
Two years after NFD onset, he received a cadaveric kidney transplant
After transplant the lesions softened and no new lesions appeared
Subsequently he rejected the kidney and was restarted on dialysis, but there was no worsening of the NFD
Further discussed the differentials discussed in the articles above
Concluded that therapy is supportive until renal disease can be corrected through transplantation
While "erosive" lesions of NFD have not been previously described, the linearity in the setting of pruritis suggest that both patients were scratching reachable areas. Therefore, linearity of lesions of NFD seem to suggest a Koebner-like reaction to scratching
Both patients had onset of NFD with renal insufficiency, and both showed improvement with reestablishment of renal function
The fact that the second patient did not get worse with loss of the transplanted kidney suggests the trigger event for NFD was not present later in his course
The treatment experience with steroids under occlusion suggests that no topical steroidal therapy is likely to work in NFD
Empiricism suggests erythropoietin may not be affecting the course of NFD (more study required!)
Calcification in at least one of these patients corroborates this finding in some other cases (see above). The etiology is not clear from the provided data, but has been related to metastatic calcification likely due to secondary hyperparathyroidism
Reported on a single case of NFD occurring in a 58-year-old man being treated with hemodialysis
First NFD report in the non-English medical literature
Comment: Apologies, I do not have an English translation, and I do not read Dutch! The abstract seems to be a case presentation similar to those mentioned above. If anybody can send me a translated version of the article, I will gladly review it here.
Article 20 January 2004
Dawn G, Holmes SC. Scleromyxoedema-like eruption following haemodialysis or Nephrogenic Fibrosing Dermopathy? [Letter] 2004; Br J Dermatol. 150(1):167-8 PubMed Abstract
This letter was written in response to article 9 (see above)
The authors reported a second British NFD case in a 48-year-old woman one month after beginning hemodialysis
The authors were aware of a third case in the UK as well
Comment: These authors were aware of the American literature on the subject and wanted to bring the British Dermatologists up to speed!
Article 21 February 2004
Evenepoel P, Zeegers M, Segaert S, Claes K, Kuypers D, Maes B, Flamen P, Fransis S, Vanrenterghem Y. Nephrogenic Fibrosing Dermopathy: A Novel Disabling Disorder in Patients with Renal Failure. Nephrol Dial Transplant. 2004; 19(2):469-73 PubMed Abstract
This is a report of two cases of NFD from Belgium
Case 1: a 56-year-old Caucasian man with NFD lesions appearing 3 weeks post kidney transplantation
8 days post-transplant the graft was removed due to diffuse cortical necrosis
Primary cause of renal disease was adult polycystic kidney disease, and the patient had been on dialysis for five years prior to transplant
The A-V fistula in the affected left arm was occluded
MRI changes resembled those seen in myositis and ultrasound showed thickening of the subcutaneous tissues
Whole body PET scanning showed increased metabolic activity in sites of all clinically-evident lesions
Immunohistochemistry noted increased Factor XIIIa staining in the tissues, with less prominent staining with CD34
Case 2: a 57-year-old Caucasian male liver transplant recipient developed renal failure 1 month after liver transplantation for hepatocellular carcinoma in the setting of hemochromatosis-induced cirrhosis. One month later he developed the lesions of NFD.
The cause of the renal failure was acute idiopathic membranoproliferative glomrulonephritis (resistant to plasmapheresis and pulsed steroids)
Whole body PET scanning showed increased metabolic activity in all clinically evident lesions
After five months, the skin lesions stabilized and softened somewhat (renal status not provided during this time)
Discussed the use of PET scanning and scintigraphy and their possible future use in quantitative measurement of inflammation
The first formal report of NFD on the European mainland
Patient 1 had a renal infarction which likely served as the trigger for NFD (lesional onset about 2 weeks post-infarction)
Patient 2 developed acute renal failure with NFD onset 4 weeks later
Reported Factor XIIIa staining as more prominent than CD34 staining in one patient. I have seen this pattern as well, but it seems to represent a minority of patients
The first report of radiological investigations and the possible utility, in particular, of PET scanning
PET scanning looks promising as a possible objective assessment of disease activity. Unfortunately it is expensive and hard to access in many parts of the world. Nevertheless, future investigation may prove very helpful
Article 22 February 2004
Jain SM, Wesson S, Hassanein A, Canova E, Hoy M, Fennell RS, Dharnidharka VR. Nephrogenic Fibrosing Dermopathy in pediatric patients. Pediatr Nephrol. 2004; 19(4):467-70 PubMed Abstract
This is a report of two more pediatric NFD cases
Case 1: a 19-year-old white male who had lost three previous renal transplants to thrombosis
The patient developed NFD 2-3 months prior to diagnosis (the medical history proximate to the NFD onset was not provided)
The patient had bilateral scleral plaques
The patient had a history of homocysteinemia and protein C deficiency; anti-phospholipid antibody testing was unremarkable
The patient was treated with daily systemic prednisone (25-30 mg; 7 months total) with some improvement in the cutaneous plaques
Case 2: a 9-year-old white male with NFD diagnosed 2 months after initiating chronic peritoneal dialysis
The patient had a history of pulmonary embolus at age 3 years
The patient had a renal transplant followed by cardiopulmonary arrest the second day (thought secondary to pulmonary embolism)
Autopsy was not performed
Both patients were using sevelamer hydrochloride (Renagel--Genzyme), and the authors suggest that since this medication came on the market in 1998, there might be a temporal association with the development of NFD, even though the medication has no known systemic absorption
Both patients had a known pre-existing hypercoagulable state
One patient had scleral plaques
Both patients were using Renagel. Whenever a drug is suggested as being causative, I always try to ask myself the following:
Are all NFD patients taking the drug? (keep in mind, the CDC identified no common medication among the study subjects in article 3)
Do all patients who take the suspected drug develop NFD? If not, why not?
Has the drug recently appeared on the market? Is it on the market in countries where NFD has been reported?
These are important questions to ask. Unfortunately, the level of detail provided about most of the agents being taken by the case report subjects is too low to draw conclusions at this point
Article 23 March 2004
Edsall LC, English JC, Patterson JW. Calciphylaxis and metastatic calcification associated with nephrogenic fibrosing dermopathy. J Cutan Pathol. 2004; 31(3):247-53 PubMed Abstract
This is a report of two NFD patients who manifested concurrent evidence of NFD and calciphylaxis
Case 1: a 29-year-old white female on chronic hemodialysis developed NFD in the bilateral lower legs simultaneously
The patient had a history of atrial thrombus and transient thrombocytopenic purpura and a prolonged PT/PTT
Histopathology contained striking calcifications within vessel walls and in the adjacent elastic tissue
Case 2: a 60-year-old african american male undergoing hemodialysis following loss of a previous transplant (for hypertensive renal disease) developed abrupt onset bilateral lower leg NFD
The patient also demonstrated a prolonged PT/PTT
Diffuse calcification was noted in the subcutis, but vascular calcification was not seen
The authors discuss the presence of calcification in lesions in several previous articles (see above)
The authors discuss, at length, the link which exists between TGF-beta and other cofactors which may influence calcification, including the known actions of these factors in the development of other fibrosing disorders
I am not certain either of these patients truly had "calciphylaxis," which typically manifests clinically as purpura and necrosis (not seen here)
In addition, I have seen calcification of the type described in lesions that were definitely not classic calciphylaxis; and I have seen small degrees of calcification in many cases of NFD (this will be a common theme in upcoming summaries) with deposits present in vessel walls, and more diffusely in areas of the ubiquitous fibrosis.
Calcification and ossification are also commonly seen within zones of normal wound healing as an incidental finding in non-NFD (and non calciphylaxis) settings
My personal opinion is that this is not "calciphylaxis" in the classic sense, but that calciphylaxis, as well as other pathological and incidental forms of calcium and bone deposition are absolutely tied to the process of fibrosis. As such, the calcification seen in some cases of NFD is probably best considered an epiphenomenon of fibrosing processes in general.
We look forward to future studies that may shed additional light on TGF-beta and the balance of procalcific and anti-calcific forces as they relate to NFD and the fibrosing disorders in general.
Please note, both patients had abnormal coagulation studies, and one had a demonstrable history of an atrial thrombus.
Article 24 March 2004
Hershko K, Hull C, Ettefagh L, Nedorost S, Dyson S, Horn T, Gilliam AC. A variant of nephrogenic fibrosing dermopathy with osteoclast-like giant cells: a syndrome of dysregulated matrix remodelling? J Cutan Pathol. 2004; 31(3):262-5 PubMed Abstract
This is a report of two NFD patients who both harbored a histologic variant of NFD with osteoclastic giant cells
Case 1: a 68-year-old white female who developed NFD one month after beginning hemodialysis for diabetic nephropathy
Noted typical histology of NFD including increased numbers of small blood vessels and osteoclast-like giant cells
Case 2: a 27-year-old white male with a history of renal transplantation in childhood developed NFD after rejecting his kidney
Similar histology to that described above, however, calcification was noted focally
Patient showed initial improvement with photopheresis
The authors were particularly intrigued by three issues:
Rapid tissue fibrosis: with clear similarities to findings seen in scleroderma
Osteoclast-like giant cells: and speculation that TGF-beta induces their recruitment
Dystrophic calcification: The authors discuss different types of calcification that can occur in the setting of renal failure
The authors discuss the possibility that altered calcium, phosphorous and/or Vitamin D may play a role, but admit that the laboratory results in these two patients are not consistent
Conclude that the effects of TGF-beta may affect extracellular matrix homeostasis, including osteoclast recruitment/activation
Coming on the heels of article 23, many of the same issues are raised related to TGF-beta, its role in NFD, and its precise mechanism of action in NFD in relation to matrix production, and in this case, osteoclast recruitment
As opined above, I am highly confident that TGF-beta is involved in NFD, and it is only a matter of time before its role is better understood.
To date, in the 150 or so cases of NFD I have seen, osteoclast-like giant cells remain rare (having only been observed in these two cases to my knowledge). I do not know what factors were at work in these two instances that were not also present in the many other cases of NFD I have seen without osteoclasts.
The authors referenced an article that I have been unable to find in the literature related to TGF-beta expression in NFD. It is not indexed in PubMed or in the issue of Arthritis and Rheumatism in which it is alleged to have appeared. If the authors know of the correct citation, I would like to include it in this chronological discussion. Please contact me.
The authors mentioned some therapeutic success with initial treatments with photopheresis. This mode of therapy is also mentioned in articles 7 and 13 above, however, insufficient detailed information was provided to form a clear conclusion about this modality. As will be seen, further publications corroborate in a clearer fashion the possible role of photopheresis in improving the lesions of NFD in the setting of ongoing chronic renal failure.
Article 25 March 2004
Chiu H, Wells G, Carag H, Canova E, Firpi RJ. Nephrogenic fibrosing dermopathy: A rare entity in patients awaiting liver transplantation Liver Transpl. 2004; 10(3):465-6 PubMed Abstract
This is a report of a patient with liver disease due to alpha-1 antitrypsin deficiency and concurrent renal failure who developed rapid onset anasarca associated with lower extremity NFD
The patient had no discernible deep venous thrombosis
An explanation for the worsening anasarca was not provided
The patient eventually underwent liver transplantation which was associated with some improvement in the lesions
This is a short report of another NFD patient with concurrent renal and liver disease
The cause of the acute anasarca which was evidently tied to the development of NFD is not clear. We cannot determine whether there was an acute worsening of chronic renal failure, or a worsening of liver failure, or another separate event that figured in the development of the NFD
While the lesions of NFD improved post liver transplant, we cannot determine whether there was any improvement in kidney function that could account for it, or whether the improvement was due to post-transplant steroids, as the authors imply.
This is a single case report of a 61-year-old NFD patient treated with high dose intravenous immunoglobulin (hdIVIg)
The patient had been on peritoneal dialysis for 8 months after suffering renal failure secondary to radiocontrast dye
He had NFD for four months at the time of his therapy
Therapy was hdIVIg, 0.4 g/kg qd for 5 days each month
Joint range of motion was evaluated each month for three months while on the treatment
The therapy was well-tolerated, and a noticeable improvement in joint ROM was seen after one month
After 2 and 3 months of therapy, no discernible improvement was seen
This case evidently occurred after peritoneal dialysis only
The onset of the NFD, at four months post-initiation of peritoneal dialysis, is not elaborated upon
The authors did a good job documenting ROM by objective measurements, however, it is not clear whether the improvement in NFD is completely related to the hdIVIg, as the ongoing renal function was not provided
The treatment appears to have been well tolerated.
Article 27 April 2004
Quan TE, Cowper S, Wu SP, Bockenstedt LK, Bucala R. Circulating fibrocytes: Collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol. 2004; 36(4):598-606 PubMed Abstract
This is an article more fully describing circulating fibrocytes (CFs), first recognized in article 15 as the culprit effector cell in NFD
CFs were first recognized in 1994 as a result of studies in a model system of wound repair
The possibility of a circulating fibroblast-like cell had been speculated upon for 150 years and wound healing models developed in the 1940s implied that cells capable of producing connective-tissue were indeed present in the circulation
Flow cytometric studies demonstrate the CF has a unique immunophenotype among circulating cells (CD34+/CD11b+/CD45+/HLA-DR+/CD71+/CD80+/CD86+/procollagen I+) [a more complete listing of antigens can be found in table I in the article]
CFs are bone marrow derived, and may have their origins in the bone marrow stroma (known also to be CD34+)
CFs derive from a CD14+ peripheral blood precursor under the influence of T-lymphocytes
The coexpression of collagen production and uniquely hematologic markers is likely sufficient to describe CFs in different pathologic lesions
The authors discuss in broad terms the process of wound repair
Phase 1 (Inflammatory):
Triggered by traumatic disruption of endothelium and other tissue elements
Neutrophils and monocytes serve to remove clot, cell debris and invading bacteria. Monocytes mature into macrophages and secrete chemoattractants
Phase 2 (Proliferative):
Epithelium covers the wound and fibroblasts produce collagen and matrix
Phase 3 (Maturation):
New matrix is slowly remodeled, providing tensile strength and structural integrity
Known capabilities of CFs include:
The production of alpha-smooth muscle actin (a myofibroblast marker) when induced by TGF-beta--with a concurrent loss of CD34 positivity
The production of numerous angiogenic factors
Fibrocytes produce matrix metalloproteinase (MMP-9) and numerous other growth factors: VEGF, PDGF-A, M-CSF, HGF, GM-CSF, b-FGF, CNTGF [A more complete listing of cytokines and growth factors is found in table 2]
Antigen primed CFs can migrate to lymph nodes and prime naive T-lymphocytes in a Class II-specific fashion
CFs contain receptors for several chemokines: CCR3, CCR5, CCR7, and CXCR4
In normal wound healing, CD34 positivity seems to be inversely related to collagen positivity, suggesting a phenotypic change from an immature to a mature cell type
The authors summarize the role CFs may play in a variety of disorders, including asthma, NFD, scleroderma
This is an important summary paper that helps to further characterize the functions of CFs, the effector cell in NFD
The ideas (and specifics) discussed in this article also provide likely suspects in the triggering and perpetuation of NFD, and therefore help to identify potential ways to prevent the onset of NFD in susceptible persons, as well as slow, and perhaps reverse, the NFD once it has begun
Another exciting prospect is the possibility that unraveling the processes underlying NFD may, in fact, have application in many other disease processes
First unified hypothesis of NFD, modified (from comments above, article 15)
First hit: Renal disease makes an individual susceptible to NFD. The renal disease may either remove a key controlling factor, or may allow a promoting factor to build up to high levels.
Caveat: Only a small number of renal patients go on to develop NFD, so hit 1, by itself, is not the sole cause of NFD.
Second hit: Tissue injury (vascular injury with thrombosis and ischemia, worsening organ failure) elaborates cytokines that directly or indirectly recruit CFs from the bone marrow (consider CCR3, CCR5, CCR7, and CXCR4 as possibilities). In this setting CFs are responding as they should--fulfilling their normal roles in phases 1 and 2 of classic wound healing
Caveat: Neither ischemia nor worsening organ failure is unusual in the setting of renal disease, yet NFD is highly unusual. So, both hits 1 and 2 together may still not be enough to explain why NFD is so unusual.
Third hit: CFs aberrantly (?preferentially) target the skin and subcutaneous tissues (again, consider CCR3, CCR5, CCR7, and CXCR4)
Comment: It is possible that this unusual targeting problem may, in fact, explain why NFD is so rare in the susceptible population.
CFs come out of circulation and begin to secrete additional cytokines that possibly recruit more CFs (see chemokines above, as well as numerous growth factors, including TGF-beta) and histiocytes, possibly also promoting angiogenesis (CFs, as noted in the article synopsis above, produce many angiogenic factors, and likely are responsible for the small new vessels noted in tissue samples from NFD skin)
Most of these CFs assume a spindled morphology resembling a fibroblast, and begin producing collagen, mucin and elastic fibers (CFs can produce collagen I and III as well as mucins and elastic fibers--correlating exactly with the findings seen on histology)
Some CFs mature to other forms (ie. myofibroblasts [alpha smooth muscle actin positive--see article 10] or terminally-differentiated fibroblast-like cells [procollagen positive, but CD34 negative]) and concurrently lose CD34 expression.
The reestablishment of a healthy kidney in some way interrupts this self-perpetuation, after which normal local remodelling (as occurs in a remodelling wound) takes over, softening the lesions of NFD over a long period of time--thus explaining the lag times in cutaneous lesion resolution observed when renal disease can be reversed.
Article 28 May 2004
Gambichler T, Paech V, Kreuter A, Wilmert M, Altmeyer P, Stucker M. Nephrogenic fibrosing dermopathy. Clin Exp Dermatol. 2004; 29(3):258-60 PubMed Abstract
This is a single case report of NFD developing in an 81-year-old caucasian male in which circulating autoantibodies were identified
Case 1: Abrupt onset of NFD in the seventh year of hemodialysis for analgesic-induced renal failure
Work-up paralleled typical NFD cases, however, this patient also had circulating immune complexes as well as high levels of anti-dsDNA antibodies
The authors point out that high levels of circulating immune complexes and antinuclear antibodies can be found in chronic renal patients undergoing dialysis, even in the absence of other autoimmune phenomena
This is an isolated case, also from mainland Europe.
This is an unusual case in that circulating antibodies of a variety of types were seen [in contrast to most NFD patients, who have no antibody complexes when specifically examined]
This is the only NFD patient reported (as of May 2004) to have had analgesic-induced renal disease. Whether this might be related to the observation of circulating antibodies is impossible to tell at this point.
There was no detail provided to suggest what may have triggered the patient's NFD seven years into his renal failure
At this time it is reasonable to assume this unusual finding is not causing his NFD
Article 29 May 2004
Lauchli S, Zortea-Caflisch C, Nestle FO, Burg G, Kempf W. Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis. Dermatology 2004; 208(3):278-80 PubMed Abstract
This is a single case report of NFD developing in an 40-year-old caucasian female and treated with photopheresis with some improvement
The patient had been on hemodialysis for over 20 years when she underwent renal transplantation in 2000.
She required continued hemodialysis post-transplant, and began developing NFD one month after transplantation
There was bilateral lower extremity involvement, as well as involvement in the vicinity of her shunt in her left arm
Laboratory evaluation was normal with the exception of a slightly elevated anti-cardiolipin. A bone marrow biopsy was also normal.
The patient was treated with retinoids and PUVA for 4 weeks without improvement (the patient developed muscle pain)
Photopheresis was then initiated, with marked softening of the indurated plaques noted after 4 cycles had been completed
No additional detail was provided regarding the therapy, and the patient's background renal function during this time was not described
A letter to the lead author clarified a few points:
Photopheresis was provided at intervals of every two weeks.
The patient had unchanging, poor renal function throughout the treatment period
Treatment had to be cancelled after four cycles, as the insurance company refused further treatment
The author had some success in a second NFD patient with photopheresis
This is another therapy that seems to have exerted a positive effect in a patient with NFD, and thanks to the follow-up response from the author, it appears the therapy worked in the setting of ongoing renal dysfunction--a strong argument that the observed effectiveness can be attributed to the treatment! Proving this will require more patients, as well as controls, in a prospective trial.
Of additional interest is the fact that the patient's fistula area seems to have been specifically involved. This pattern suggests the fistula site is a target of interest for circulating fibrocytes. Peculiar to the fistula site would be unusual flow dynamics, the possibility of ongoing endothelial trauma, and the mixing of arterial and venous blood. These factors, therefore may contribute in some way to cutaneous lesional development.
The authors also point out the presence of anticardiolipin antibodies in their patient (this has been a notable, but not universal, finding in NFD). The significance of this finding is not yet clear
Of interest, also, is that a bone marrow biopsy was unremarkable in this patient. This is important because the effector cell of NFD, the circulating fibrocyte, has its origin in the bone marrow, and to date, nobody had reported on bone marrow biopsy findings in this population.
Article 30 May 2004
Ortonne N, Lipsker D, Chantrel F, Boehm N, Grosshans E, Cribier B. Presence of CD45RO+ CD34+ cells with collagen synthesis activity in nephrogenic fibrosing dermopathy: a new pathogenic hypothesis [Letter] Br J Dermatol. 2004; 150(3):1050-2 PubMed Abstract
This letter opens by claiming that 24 total cases of NFD have been reported (clearly untrue -- see articles 1-29)
The letter also reports 2 additional cases of NFD
Cases 1 and 2 were both on chronic hemodialysis for renal insufficiency and had lesions clinically typical of NFD
No anticardiolipin antibodies were noted in either patient, however, one patient had high titer ANA which was interpreted as a false positive result due to chronic renal failure and dialysis
The authors point out that some of the lesions regressed spontaneously, while new lesions spontaneously appeared
Given this, the authors urged caution in the interpretation of results from any new therapy
The authors point out the finding of positive immunohistochemical staining with CD45RO among the spindle cells in their cases
Ultrastructural examination confirmed the production of collagen among these cells
The presence of numerous Langerhans' cells in their cases was also noted
The authors claim that the dendritic cells of NFD are thought to be derived from normal dermal dendritic cells (not a claim I have made!)
They hypothesize that the dermal dendritic cells, are in reality, probably so-called "circulating fibrocytes".
These researchers independently arrived at the same conclusion that was suggested in article 15--that the spindle cells of NFD are "circulating fibrocytes"
These authors reinforce their opinion with ultrastructural information (compare to ultrastructural information in article 2).
Nobody, to my knowledge, has opined that the NFD spindle cells are resident dermal dendrocytes. I do no believe anybody would in light of the assembled evidence.
The authors also suggest that lesions spontaneously disappear and reappear in NFD, making assessment of therpeutic measures complex. I am not aware of a great deal of lesional involution in NFD patients in the face of ongoing renal disease, but certainly agree that new lesions can develop. I agree completely that all prospective therapies need to be carefully assessed, as lesional involution may be related to other factors (ie. improving renal function). The renal status of the described patients over time, was not mentioned, although the nature of the disease would suggest chronicity in these cases.
The presence of an elevated ANA has been described (see article 28). The significance remains unknown, but chronic renal disease is the likely cause, as these authors suggest
Article 31 July 2004
Hauser C, Kaya G, Chizzolini C. Nephrogenic fibrosing dermopathy in a renal transplant recipient with tubulointerstitial nephritis and uveitis. Dermatol. 2004; 209(1):50-2 PubMed Abstract
This article reports a single case of NFD arising in a 53-year-old male with tubulointerstitial nephritis with uveitis syndrome (TINU)
The patient developed TINU 20-25 years prior to NFD onset, and worsening renal disease led to a transplant 15 years prior to NFD
Two years prior to NFD the patient had aortocoronary bypass surgery and the renal disease worsened
One month prior to NFD onset the patient developed acute renal failure
NFD onset was in the bilateral legs and associated with a fever, followed soon after by arm and thorax lesions
The clinical amd histological picture fit well with NFD, with the addition of smooth muscle actin positive spindle cells in the dermis focally
Lab tests were essentially unremarkable, and coagulation tests were reportedly normal
This is the first patient with NFD with a history of TINU, once more underscoring the impression that the underlying cause of the renal failure does not seem to be important in the devlopment of NFD
The authors point out that application of a classification scheme is difficult in this case, since the patient could be classified in several ways. However, it is the acute renal failure which preceded the development of lesions by one month that is most important, not the remote history of vascular surgery.
The finding of SMA positive cells focally parallels the findings described in article 10 (myofibroblastic differentiation). This would fit well with the concept of circulating fibrocytes progressing through specific differentiation pathways (in this case toward myofibroblasts).
Article 32 July 2004
Tan AW, Tan SH, Lian TY, Ng SK. A case of nephrogenic fibrosing dermopathy. Ann Acad Med Singapore. 2004; 33(4):527-9 PubMed Abstract
This article reports a single case of NFD arising in a 45-year-old Indian female in Singapore
The patient had a history of systemic lupus and the antiphospholipid syndrome and had developed ARF 5 months prior to developing NFD
She was treated with pulsed cyclophosphamide with no improvement of NFD after 8 months
Renal function has returned to normal, per the authors
This is the first case of NFD reported from Asia, and to my knowledge, the first one reported in a person of Indian background
This further substantiates the potential widespread nature of this disease in many ethnic groups and several countries
It would be very interesting to know when, precisely, the lesions began. It is typical to see onset no later than about 2 months post acute renal failure. The patient in this article presented 5 months post ARF, but appears to have been fully involved by NFD at the time.
It is intriguing that at 8 months, there is no improvement of the lesions despite a return of renal function. This is somewhat unusual. It would be important to know if she has any degree of ongoing renal dysfunction, and if not, precisely when her renal function normalized.
Follow-up will be sought and reported here
Per Dr. Audrey Tan, the NFD lesions may have been obscured by massive edema and the patient's dark skin.
The patient's renal function has normalized, and is stable. The NFD plaques are unchanged (at 2.5 years post-ARF).
Thank you, Dr. Tan, for the feedback
As the patient's plaques seem to have stabilized, there is no further progression of the NFD since the renal function has returned.
Why some people show gradual improvement and others do not is largely a matter of speculation at this time, but could possibly be related to the length of time active NFD was present before renal function was reestablished.
Additional investigation will be needed to see if this is indeed true
Article 33 August 2004
Jimenez SA, Artlett CM, Sandorfi N, Derk C, Latinis K, Sawaya H, Haddad R, Shanahan JC. Dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy): study of inflammatory cells and transforming growth factor beta1 expression in affected skin. Arthritis Rheum. 2004; 50(8):2660-6 PubMed Abstract
This article reports a series of nine NFD cases
All described patients had a fairly typical history for NFD; 4 of the patients had undergone previous transplantation (some multiple)
All patients were chronic renal patients, with an average of over 6 years of hemodialysis (range 2 mos to 22 years)
Lab tests were similar to those described above, including the occasional finding of low titer ANA
The histopathological findings were similar to those described above
The described thickened fibrous tissue tracts are the same as the widened subcutaneous septa noted above
Muscle involvement was described as endomysial and perimysial infiltration and muscle fiber atrophy
The authors also describe histopathological changes of fibrosis in the lung and heart of several patients
The authors describe dual positive CD68/factor XIIIa cells in muscle sections and increased TGF-beta staining by in-situ hybridization in the skin and fascia diffusely, and between muscle fibers
The authors suggest that the disease should be considered a systemic disorder (an opinion previously expressed in articles 13, 15 and 17 above)
The authors point out an important shortcoming of this work regarding the systemic findings (more below)
The authors suggest that the finding of ANA positivity may be an indication that the fibrosis is in itself may be in some way facilitating the development of these antibodies
The authors suggest CD68, Factor XIIIa and TGF-beta may be involved in this disorder, and that TGF-beta may be responsible for enhancing or initiating the antigen presenting functions of additional dendritic cells, establishing a vicious circle resulting in their accumulation in affected tissues
The authors explain their rationale for suggesting a new terminology for NFD (see below)
Most of this article is a restatement of information that had already been published
The authors provide additional corroboration of skeletal muscle biopsy findings (identical to those described in article 17, figure 4)
The authors point out the presence of fibrosis in other organ systems, and conclude that NFD is systemic. Both statements are true, but one does not necessarily follow the other logically.
First, convincing evidence has been provided elsewhere that NFD is a systemic process whose initial findings are typically recognized in the skin
Second, fibrosis has been noted in other organ systems in NFD patients (as established by the autopsy findings reported here, as well as those reported in article 13, above)
BUT, fibrosis is the endpoint of many chronic disease processes in persons without NFD
The only way to convincingly assert that NFD patients have more internal fibrosis than non-NFD patients is to study control patients with renal disease who do not have NFD and see if they lack the internal fibrosis alleged to be due to NFD. This was not done (the authors noted it themselves as a significant shortcoming), and to jump to the conclusion that NFD is causing ALL of the fibrosis in these patients is therefore not supported by the available evidence.
Alternatively, as we know the cutaneous findings of NFD are very rapid in onset, if one could establish the presence of a rapid fibrosing process in an internal organ -- where no previous fibrosis had been present -- and tie it to the development of fibrosis in the skin lesions of NFD, one could make a strong temporal association. This was also not done.
In conclusion, one could look at the data presented here and legitimately conclude that NFD patients seem to have a high incidence of pulmonary dysfunction (as evinced by a markedly reduced CO diffusion capacity). One could not (and should not), however, automatically assume that the processes at play are necessarily one and the same. This does not mean that one could not speculate about the possibility, however...
Of interest, the authors aver that the presence of ANA (rather than being a non-specific result of chronic renal disease and/or dialysis) may signify a developing autoimmune process, possibly triggered by the NFD. This is an intriguing hypothesis, and one that should be investigated.
The presence of CD68 and Factor XIIIa positive dermal dendritic cells has been discussed in the literature at great length (from the first histopathological descriptions).
I have specifically examined the expression of both of these markers in the cutaneous lesions of NFD by immunohistochemistry and saw no similarities in distribution that would suggest a large number of dual-positive cells.
On subsequent examination of tissue by dual immunohistochemical methods, I have not been able to duplicate the finding of a dual-positive CD68/Factor XIIIa cell, but admittedly, I am using slightly different techniques than those employed by the authors.
A high-magnification image of a dual-positive CD68/Factor XIIIa cell would go a long way in proving this assertion. Such an image was not published in this paper.
We have, however, been successful in demonstrating dual-positivity for CD34 and procollagen I, (article 15) leading to the identification of circulating fibrocytes as the effector cell in NFD. This was subsequently confirmed in article 30 by researchers in Europe, who came to the same conclusion via a slightly different methodology. The authors reported neither CD34 nor Procollagen I stains in this study, however.
The authors also speculate on the role of TGF-beta in the development of NFD lesions. I agree completely (as do many authors above).
This study shows the presence of TGF-beta diffusely in the dermal lesional spindle cells of NFD. While circulating fibrocytes (CF) are not the only cells known to produce TGF-beta, CFs are capable of producing TGF-beta, and have been shown to be the dominant spindle cell in NFD cases. It is no surprise, therefore, that diffuse TGF-beta expression was noted, and a further evaluation of techniques targeted at TGF-beta reduction recommended. It is quite possible that the improvements noted in plasmapheresis (article 12) are illustrative of this concept.
Coming soon: Why Dialysis-Associated Systemic Fibrosis is NOT a good name
Article 34 August 2004
Taylor EN, Henderson JM, Rennke HG, Magee CC. Traumatic calcinosis cutis in a dialysis patient. Am J Kidney Dis. 2004; 44(2):e6-9 PubMed Abstract
Article 35 August 2004
Obermoser G, Emberger M, Wieser M, Zelger B. Nephrogenic fibrosing dermopathy in two patients with systemic lupus erythematosus. Lupus. 2004; 13(8):609-12 PubMed Abstract
This article reports on two cases of NFD occurring in the setting of lupus erythematosus
Case 1: A 54-year-old woman with a 17 year history of renal insufficiency due to lupus nephritis
The patient developed NFD without ever having been dialyzed
NFD onset was associated with an undulating fever up to 38.4 degrees C, an elevated CRP, and a pleural effusion
The fever responded to elevation of prednisone up to 50 mg qd (but did not effect the skin changes)
ESR was elevated, and ANA, RNP, Sm, and anti-native DNA antibodies were positive
Anticardiolipin and the lupus anticoagulant were negative
Perivascular lymphocytes were noted on the biopsy, which was otherwise typical of NFD
Symptoms have gradually disappeared, and no new lesions have appeared
Case 2: A 50-year-old female with a 16 year history of lupus associated with the antiphospholipid syndrome (APS)
The patient had renal disease due to microthrombosis and bilateral renal artery stenosis.
She developed NFD 10 weeks after starting hemodialysis for worsening of compensated renal failure
CRP was elevated and IgG anticardiolipin antibody was positive.
The authors provide a review of the literature and theories to date.
These authors importantly present another patient with NFD who had never been dialyzed
The presence of significant numbers of lymphocytes is not typical of NFD, but can be typical of lupus.
I have previously encountered the unusual febrile syndrome described at the time of lesional onset in Case 1. It is by no means unique, but it does appear to be an unusual occurrence.
It is not completely clear from the article whether the NFD lesions disappeared in Case 1, or merely stabilized.
Case 2 describes a fairly typical course of NFD, once again associated with a thrombotic propensity
Article 36 November 2004
Levine JM, Taylor RA, Elman LB, Bird SJ, Lavi E, Stolzenberg ED, McGarvey ML, Asbury AK, Jimenez SA. Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy). Muscle Nerve. 2004; 30(5):569-77 PubMed Abstract
This article is the first to delve exclusively into the muscle and neural changes in NFD
Discussed five pts with NFD, all of whom had concurrent myopathy
All patients had chronic scleral injection and a uniformly high calcium-phosphate product
Three patients had secondary hyperparathyroidism
Three of the five had failed kidney grafts
All patients had skin changes over the affected muscles, except those that had jaw muscle involvement
Case 1: 55 year-old male with ESRD due to hypertension
AAA repair in 1994, chronic aortic dissection, mitral valve replaced in 2001 (patient noted onset of NFD in February or March of 2002).
Treated w/high dose IV steroids and plasmapheresis without benefit
Patient died of sepsis
Case 2: 37 year-old male with ESRD due to hypertension
Developed NFD shortly after failed cadaveric renal transplant.
Could not walk 1 month after surgery
Patient had had DVT and repair of an AV fistula pseudoaneurysm (no timing given)
Dialysate changed to low calcium dialysate bath and he was also treated with a calcium free phosphate binder
Eight months following surgery he had regained nearly normal ROM in the knees
Muscle electrophysiological studies
Three of four tested had evidence of mild to moderate sensory motor polyneuropathy
EMG findings: All patients had evidence of myopathy, and one showed evidence of neuropathy as well
Diffuse high attentuation material throughout the muscles and fascial planes of the entire body in the two most severely affected patients
No imaging abnormalities were noted in the three less affected patients
Muscle biopsy findings
Degree of fibrosis correlated with degree of clinical severity
Electron microscopy showed changes suggestive of denervation in one patient, and loss of thick filaments as is often seen in steroid myopathy
3 received steroids and plasmapheresis without effect
One patient improved slightly after treatment with phosphate binders
2 patients have had a static or slowly progressive course
Burning and sharp pains are neuropathic
All patients w/this complaint had evidence of neuropathy
Not clear whether this was due entirely to NFD, but temporal association suggests it may be
Cramping and aching pains are myopathic
There was no correlation between degree of pain and degree of involvement
These authors point out the high incidence of scleral injection in NFD patients (100% in this study)
In this setting, steroids and plasmapheresis were without effect
Case 2, interestingly, improved with efforts to reduce calcium and phosphate levels--no other therapy was described (this represents a unique occurrence, to my knowledge, and worthy of further investigation)
Article 37 November 2004
Gremmels JM, Kirk GA. Two Patients With Abnormal Skeletal Muscle Uptake of Tc-99m Hydroxymethylene Diphosphonate Following Liver Transplant: Nephrogenic Fibrosing Dermopathy and Graft vs Host Disease. Clin Nucl Med. 29(11):694-7. PubMed Abstract