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
    
    
• Comments:
• 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

Article 6
January 2003

A brief mention of NFD at the end of an in-depth article on musculoskeletal disorders

First report of NFD in the rheumatology literature

Article 7
January 2003

Mackay-Wiggan JM, Cohen DJ, Hardy MA, Knobler EH, Grossman ME. Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease). Jour Amer Acad Dermatol 2003; 48(1): 55-60
PubMed Abstract

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
    
    
• Comments:
• 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
    
    
• Comments:
• 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
  
  
• Comments:
• 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

Article 11
May-June 2003

Ishibe S, Perazella MA, Reilly RF. Nephrogenic Fibrosing Dermopathy: an unusual skin condition associated with kidney disease. Semin Dial. 2003; 16(3): 276-80
PubMed Abstract

• Report a single case of NFD
• 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
  
  
• Comments:
• 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
    
    
• Comments:
• 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
  
  
• Comments:
• 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)
    
    
• Comments:
• 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
  
  
• Comments:
• 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
  
  
• Comments:
• 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
  
  
• Comments:
  • 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

Article 19
December 2003

Engelen JW, Kooistra MP, Canninga-van Dijk MR, Toonstra J, Sigurdsson V. Nephrogenic Fibrosing Dermopathy [Dutch] 2003; Ned Tijdschr Geneeskd. 147(49):2435-8
PubMed Abstract

• 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
  
  
• Comments:
  • 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
  
  
• Comments:
  • 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
  
  
• Comments:
• 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
    
    
• Comments:
• 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
  
  
• Comments:
• 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.

Article 26
March 2004

Chung HJ, Chung KY. Nephrogenic fibrosing dermopathy: response to high-dose intravenous immunoglobulin [Letter] Br J Dermatol. 2004; 150(3):596-7
PubMed Abstract

• 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
    
    
• Comments:
• 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
    
    
  • Comments:
  • 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
    
    
  • Comments:
  • This is a