بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم

2. Nephrogenic Systemic FibrosisorNephrogenic Fibrosing Dermopathy Dr. Dalia Mahmoud Shaaban Ass. Prof. of Dermatology and Venereology

3. Skin Renal System

4. Nephrogenic Systemic Fibrosis (NSF), also known as nephrogenic fibrosing dermopathy (NFD), fibrosing dermopathy of dialysis, is a condition that, so far, has occurred only in people with kidney disease. • It is a systemic disorder with its most prominent and visible effects in the skin. For this reason, NSF is preferred in that it more accurately reflects the disorder. • First identified by Cowper in 2000. There have been no cases identified prior to early 1997.

5. Epidemiology • Age: NFD has been reported in all age groups (+ middle age). • Sex:No sexual predilection is recognized. Male-to-female ratio 1:1 (NFD Registry ). • Race: No racial predisposition is reported. Whites, African, Americans, and Asians have all been reported with this condition. • The development of NFD is not correlated with the durationof renal disease, and it can occur early as well as later.

6. Risk Factors • All patients with NSF have a history of renal insufficiency of varying severity and duration (glomerulonephritis, hypertensive nephropathy, pyelonephritis, renal dysplasia and diabetes). Most patients have had treatments that include hemodialysis, peritoneal dialysis, or renal transplantation. However, neither dialysis nor transplantation is a prerequisite for NFD.

7. Risk Factors • Many patients with NFD have calcium pathology (Traumatic calcinosis cutis, Osseous metaplasia, Calciphylaxis and metastatic calcification ). • A variant of NFD with osteoclast-like giant cells, which has been termed a syndrome of dysregulated matrix remodeling, has been noted.

8. Risk Factors • History of preceding episodes of severe anasarca, recent vascular surgery, or hypercoagulability. • Concurrent liver disease and/or neoplasia. • Immunosuppressive medications. • NFD has been reported in 2 patients with systemic lupus erythematosus.

9. Clinically:Symptoms • Patients with NSF describe swelling and tightening of the skin, usually limited to the extremities, occasionally the trunk, almost never the face. • Patients may experience burning, itching, or severe sharp pains in areas of involvement.

10. Appearance (Signs): • The skin changes may start as indurated, reddened or hyperpigmented patches, papules, or plaques. • Plaques may have amoeboid advancing edges. • Skin may feel woody / peau d’orange. • Lesions are often symmetrical, ankles to thighs most commonly involved, followed by wrists and upper arms followed by the trunk. • Hand and foot swelling with blister-like lesions has also been reported.

11. Cellulitis is commonly suspected. • Distinct papules and subcutaneous nodules can also be seen. • Some patients have reported yellow papules or plaques on or near the eyes.

12. Symptoms – Over time • Severely affected patients develop contractures and become immobile. Often, the skin thickening inhibits the flexion and extension of joints. • Complaints of muscle weakness are common. • Deep "bone pain" has been described.

16. Sclerotic slightly pigmented plaques with orange skin aspect located on the external face of the lower (A) and upper (B) extremities.

18. Sclerotic hyperpigmented plaques with the orange-skin aspect located on the thigh

20. Histologically • Histopathologically, NSF resembles scleromyxedema in that it manifests with a proliferation of dermal fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and mucin deposition

25. There is homogenous fibroblast proliferation and collagen deposits throughout the full thickness of the dermis (A). At higher magnification, the fuso-cellular myofibroblast component can be observed. No inflammatory infiltrate is seen (B).

26. Observe extensive collagen deposits with the thrichrome stain (A), and visible mucopolysaccharide with the Alcian blue stain (B).

28. Intense CD34 cells staining distributed in a fibrillary pattern, arranged around collagen fibers and blood vessels.

29. Not Just The Skin • There have also been reports involving the following organs: • Lungs • Myocardium • Striated muscle • Diaphragm • Meninges

30. Prognosis • The natural history of the disease is not well understood. Some patients report a gradual improvement in mobility and slight softening of the skin over time. Complete spontaneous healing in a patient with ongoing kidney disease has not yet been reported. • Within weeks of disease onset, many patients are wheelchair bound because of contractures. • Several patients with NSF have died as a result of complications of their kidney disease or transplant.

31. Some patients with NSF (5% or less) have an exceedingly rapid and fulminant disease course that may result in death. • NSF, by itself, is not a cause of death, but may contribute to death by restricting effective ventilation, or by restricting mobility to the point of causing an accidental fall that may be further exacerbated by fractures and clotting complications.

34. Pathophysiolgy UNKNOWN

35. Current Theory • Recent investigations suggest the cell responsible for the fibrosis seen in NSF is a recently characterized cell involved in wound healing and tissue remodeling. • This cell- a circulating fibrocyte (CF) -is a distinct from fibroblast in that it has a D34/procollagen dual positive profile and is blood-borne.

36. Current Theory • CF’s are thought to leave the circulation (aberrantly, or by passive diffusion in fluid overload states) and differentiate in the dermis into cells that functionally and histologically resemble dermal fibroblasts leading to fibrosis. • Because of the presence of these circulating cells, NSF is considered a systemic disorder.

37. Current Theory Reported “Triggers” • Hypercoagulability/DVT: APLA/SLE • Recent surgery (particularly vascular surgery) • Recent failure of a transplanted kidney • Sudden onset kidney disease with severe swelling of the extremities • Brain tumours ???

38. Triggers • It is very common for the patient to have undergone a vascular surgical procedure or to have experienced a thrombotic episode approximately two weeks before the onset of the skin changes.

39. HTN/Edema Triggers • Rapid, new onset fluctuating hypertension of unknown cause has been described prior to the onset of the skin lesions. • Sudden, severe edema may trigger a fibrotic and mucinous cutaneous reaction that results in this progressive scleromyxedema-like illness resulting in proliferation of fibroblastlike cells and mucin deposition in the dermis.

40. GADOLINIUM BAD!we think • One common denominator in all of these recognized co-morbidities is the frequent use of contrast agents for angiography (detecting clots, planning surgery, and evaluating the vascularity of brain neoplasms). • FDA: Gadolinium-based contrast agents have recently been linked to the development of NSF. • Peripherally deposited gadolinium might be a target for circulating fibrocytes.

41. FDA recommends that the use of gadolinium-containing contrast agents should be excluded to the greatest extent possible in patients with renal disease until these observations can be confirmed and clarified.

42. Diagnosis • NSF cannot be detected using a single diagnostic test. A confident diagnosis can usually be reached through the combination of a clinical history, a physical examination, and the histopathologic assessment. • Clinically: scleroderma, eosinophilic fascietis (spares the face). • May be histologically indistinguishable from scleromyxedema (Increased number of fibrocytes that are CD34-positive and procollagen I–positive)

43. Treatment (none) • Careful attention (impaired renal function) • While there is no consistently successful treatment for NSF, improving renal function (due to any modality) seems to slow or arrest NSF (and occasional reversal of the process). • Rare cases of partial-to-complete spontaneous resolution have been reported in the absence of specific therapy (with the return of renal function).

44. Treatment • Oral steroids (prednisone): Has had some efficacy in at 1 mg/kg po qd. It is not clear whether the prednisone is affecting the cutaneous vs renal disease (osteoporosis, muscle weakness). • Topical vit D analogue (under occlusion): The combination of occluded dovonex and clobetasol with vascular compression stockings may benefit.

45. Treatment • Extracorporeal photopheresis (ECP): A recent article describes three patients in Europe who responded with softening of plaques after several courses of ECP. Each of these patients had no improvement in renal function during the treatment. This report corroborates other anecdotal reports in the US that photopheresis is helpful in some patients.

46. Treatment • Plasmapheresis: One study from Loma Linda University reported improvement in three patients with liver/kidney transplant. Two of these patients were noted to have concurrent improving renal function. Several others have been reported who noted no improvement at all.

47. Treatment • Thalidomide:There are no formal reports on the success of this medication in NSF. However, some patients have reported subjective improvement. • Ultraviolet therapy: anecdotal ; single case in this report. PUVA in combination with prednisone has been anecdotally helpful in two patients

48. Treatment • Pentoxifylline (PXF): A recent report describes two NSF patients who received 1200 mg per day of oral pentoxifylline. Both patients stabilized, and the one with less severe disease improved somewhat. The use of PXF is theoretically justified as it has known antifibrotic activity (TNF alpha antagonism), improves circulation, decrease thrombosis.

49. Treatment • Renal transplantation: Several patients have improved significantly with a return to normal kidney function (either as a result of transplantation or medical therapy). In other cases, kidney transplant has resulted in no obvious improvement of the lesions, even with a fully functioning, successfully transplanted organ.

50. Treatment • Physical therapy (PT): Some patients have reported that physical therapy, in particular, swimming, may be helpful in slowing the progression of joint contractures.