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NEPHROGENIC SYSTEMIC FIBROSIS: WHAT’S UP DOC?

  • HOSPITAL DAS CLÍNICAS DA UNIVERSIDADE FEDERAL DE PERNAMBUCO (UFPE)
  • RECIFE – PERNAMBUCO – BRAZIL
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AUTHORS
  • ADONIS MANZELLA - MD, MSc


  • PAULO BORBA FILHO - MD
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INTRODUCTION
  • Nephrogenic systemic fibrosis (NSF), initially called nephrogenic fibrosing dermopathy, is a relatively newly described, rare, and serious idiopathic disease that has been reported only in patients with severe renal disease (table 1) characterized by cutaneous sclerosis (1-6).


  • Since 1997, a steadily growing number of NSF cases have been identified around the world. The total number of NSF cases is probably approaching 1000 patients these days (5).


  • A few pediatric cases have been reported (7,8).
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Table 1-  CHRONIC KIDNEY DISEASE (CKD).
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EPIDEMIOLOGY
  • NSF affects male and female patients equally (6,13).


  • There is no apparent racial predilection and it has been documented in patients from 8 to 86 years of age (6,13).
  • Renal insufficiency is universal in NSF patients and may be acute or chronic (6).
  • The causes of the underlying renal disease are variable and 10% of patients with NSF have never been dialyzed (15).
  • Approximately 90% of the patients described in the registry have end-stage renal disease (ESRD) and are on either hemodialysis or peritoneal dialysis (16).


  • NSF patients frequently have numerous co-morbidity factors such as coagulation abnormalities and deep vein thrombosis, endothelial damage due to vascular surgery or renal/liver transplantation, chronic liver disease (1,9,17,18).
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Table 2- RISK FACTORS ASSOCIATED WITH NSF.
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PATHOGENESIS
  • The etiology is presently unknown and is likely to be multifactorial (18,20,25).


  • Because the majority of patients with renal insufficiency who have been exposed to these specific Gd chelates did not develop NSF, the existence of additional risk factors, has been proposed (1,3,17,18,26-33). Table 3 shows some clinical conditions possibly associated with NSF.


  • The cause of skin targeting is still unknown (7).


  • The current pathogenetic model for NSF supports the role of aberrantly functioning circulating fibrocytes coupled with the elaboration of fibrogenic factors (20,32).


  • Immunohistochemical studies reveal that perhaps a dual positive CD34/procollagen spindle cell is the dominant cell type induced in NSF.
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Figure 2- DIAGRAM OF POSSIBLE MECHANISM OF FIBROSIS IN NSF.
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PATHOPHYSIOLOGY
  • Pathophysiologically, NSF results in increased tissue deposition of collagen, commonly resulting in thickening and hardening of the skin of the extremities and often culminating in immobility and contractures of the joints (6,20).
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Table 4- Gd-BASED CONTRAST AGENTS, CHARACTERISTICS AND ASSOCIATION WITH NSF.
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Gd- RELATED NSF
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Gd- RELATED NSF
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CLINICAL MANIFESTATIONS
  • The clinical course of the disease is highly variable (table 9). It begins with subacute swelling of distal parts of the extremities and is followed in subsequent weeks by severe skin induration and sometimes anatomic extension to involve thighs, antebrachium, and lower abdomen (21,38,42).


  • The skin induration may be aggressive and associated with constant pain, muscle restlessness, and loss of skin flexibility (1,3,7,17,42).
  • Patients can also have hyperpigmentation of the extremities (figure 5) and/or the abdomen. Head and neck are usually spared. The skin lesions often take on a peau d’orange appearance (2,8,40, 44,45).



  • Painful contractures of the joints may progressively result in reduced mobility, and may be associated with paresthesias and/or severe pruritus (7,22).


  • In some cases, NSF leads to serious physical   disability, including wheelchair requirement (21).
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DIAGNOSIS
  • The definitive method of diagnosis of NSF is clinical assessment and a deep skin biopsy sufficient to sample the dermis, subcutaneous fat, and fascia (38,49).


  • There is no laboratory biomarker for NSF (49).
  • Histologically, skin lesions demonstrate dermal thickening with deep penetration of collagen bundles into the superficial fascia. Staining for dermal mucin is positive. Fibrous bundles contain CD34/procollagen-expressing fibroblast-like and CD68/factor VIIIa–expressing dendritic-like cells.  Most of the dermal spindle cells will stain positive for CD 34 and procollagen I (7,17,40,44,45).


  • One study (17) in which bone scintigraphy was obtained in patients with NSF showed symmetric increased uptake in the muscles, tendons, and skin involving upper-extremity (three patients) and abdominal wall (one) as well as chest wall (one).
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DIFFERENTIAL DIAGNOSIS
  • EOSINOPHILIC FASCIITIS (EF)-  It is an inflammatory fibrosing condition of the fascia involving the tissues around the muscles, and may have systemic involvement. Often, EF patients manifest peripheral eosinophilia, which can help make this diagnosis (38,42,49).


  • EOSINOPHILIA-MYALGIA SYNDROME (EMS)- It is linked to the ingestion of the amino acid L-tryptophan. Skin lesions range from erythema with edema, to papules, to diffuse thickening with a peau d’orange appearance (38,42).


  • LIPODERMATOSCLEROSIS – It is characterized by very painful induration of the distal lower extremities, particulaly medially and inferior to the knees. Involvement above the knee is very rare. Common in patients with edema (42).


  • SCLERODERMA - The skin changes may mimic progressive systemic sclerosis (PSS). But unlike PSS, NSF spares the face and lacks the serologic markers of scleroderma such as antinuclear antibodies and anticentromere antibobies (45).
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TREATMENT
  • Spontaneous remissions are not the rule, although improvement has been observed if a rapid correction of renal function can be obtained by medical or surgical means (renal transplantation).


  • There is no established treatment for NSF. No single treatment has proven effective (38,50).


  • A large panel of dermatological treatments, usually used in sclerodermal processes, has been proposed for the treatment of NSF, with varying degrees of success (7,9).


  • Therapeutic approaches including steroids, plasmapheresis, extracorporeal photopheresis, intravenous immunoglobulin, ultraviolet light therapy, physical therapy, and pentoxifylline have shown some promise (9,11,38,44).
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RECOMMENDATIONS
  • NSF is to be considered as a serious late adverse reaction in stages 4 or 5 CKD patients. Some of the current recommendations are as follows:
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RECOMMENDATIONS
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RECOMMENDATIONS
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CONCLUSION

  • Although NSF still remains an underreported condition, early recognition and diagnosis will be paramount in achieving a better understanding of this disease.
  • At present, avoiding the use of GBCAs in patients with CKD appears to be the best preventive strategy.


  • We believe that many radiologists, nephrologists, dermatologists and other physicians are still unaware that NSF may be a serious late adverse reaction to GBCAs and hope we have provided well-established as well as new information to ensure a better knowledge of this growing condition.
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"THANK YOU"

  • THANK YOU!
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