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Nephrogenic fibrosing dermopathy (NFD) is an acquired, idiopathic, scleroderma-like disorder of the skin that affects patients with renal insufficiency that have under gone magnetic resonance imaging with gadolinium salt. It was first identified in 1997 and has been increasingly recognized since that time.

It resembles scleroderma and eosinophilic fasciitis clinically and scleromyxedema histo-pathologically. In NFD, large areas of indurated skin with fibrotic nodules and plaques develop. Flexion contractures with an accompanying limitation of range, of motion can also occur. Although most patients with NFD are on hemodialysis for renal failure, some have never undergone dialysis and others have received only peritoneal dialysis .Many patients have taken immunosuppressive medications and have other diseases, such as hepatitis C.

Histo-pathologically, NFD resembles scleromyxedema in that it manifests with a proliferation of dermal fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and mucin deposition.

Fibrotic process of NFD affects the subcutaneous tissue, fascia, striated muscles, lungs, and myocardium, in addition to the dermis. The skin contains large numbers of CD68+/factor XIIIa+ dendritic cells with increased expression of transforming growth factor-beta1. CD45RO+ CD34+ cells with increased collagen synthesis also play role in this fibrosis. Circulating fibrocytes (i.e. collagen-secreting cells of the peripheral blood) have also been implicated as a cause of NFD.

Mackay-Wiggan et al in his case series noticed that his patients had anticardiolipin or antiphospholipid antibodies detected on testing. This implied a role for these antibodies in the development of NFD. Although these antibodies occur in 10-29% of patients with end-stage renal disease, the antibodies are more common in patients with NFD. What role these antibodies play in fibrosis is still uncertain. Possibly, it interacts with the dialysis machine's filter or the tubing to stimulate fibroblast or mucin production. But this would not explain the occurrence of NFD in the small subset of CKD patients with an onset of the disorder before beginning dialysis.

An accumulated substance intrinsic to acute or chronic renal failure may interact with the antiphospholipid antibody. Sudden, severe edema may trigger a fibrotic and mucinous cutaneous reaction that results in this progressive scleromyxedema like illness. Edema coupled with immunosuppression in patients with antiphospholipid antibodies stimulate a physiologic response, resulting in proliferation of fibroblast like cells and mucin deposition in the dermis.

No infectious agents have been identified, despite comprehensive viral, serologic, electron microscopic, and attempted fibroblast culture studies.

Skin ulceration and degenerative lesion of the testicular germinal epithelium has been described after repeated administration of high doses of Gadodiamide and Gadoversetamide in rats during regulatory preclinical studies.

Patients with hepatitis C who were undergoing hemodialysis would be at increased risk for this disorder because of increased levels of basic fibroblast growth factor and/or transforming growth factor.

NFD occurs in the setting of renal disease. Thus, abnormal values of BUN and creatinine are typically present.

In some cases, a positive antinuclear antibody test result has been reported, but no linkage to lupus has been noted. Some patients with NFD have anticardiolipin or antiphospholipid antibodies.

Many patients have an associated hypercoagulable state. Some patients have hepatitis B or C.

Early Changes

(Within 20 wk of onset)

Late Changes

(>20 wk of onset)

Skin lesions are prominent large dermal reticular,

Microscopy shows epithelioid or stellate spindle cells. Spindle cells are diffusely arranged among thickened collagen bundles.

Skin lesions are less prominent with clefting, less mucin, and fewer cells

Calcification, described in some patients and which has been interpreted as dystrophic in nature, can be present.

Prevention
To prevent the occurrence of this disease it is important to know the renal function before deciding contrast-enhanced MRI as modality of investigation.

CKD Stage 5 or End-stage renal disease – It is advisable to choose Contrast enhanced CT instead MRI with Gadolinium as this group is at highest risk for developing NFD. If Gd – MRI contrast still needed, hemodialysis should be arranged in advance as Dialysis shortly after contrast-enhanced MRI may be important, with approximately 75% of agent removed with one session of Dialysis and 95% removed with three session of dialysis Though there is no evidence that this decline in blood levels of Gadolinium leads to lesser chances of NFD.

Medical Care: NFD is usually a chronic, progressive condition. Rare cases of partial-to-complete spontaneous resolution have been reported in the absence of specific therapy, with the return of renal function. A favorable response to medical intervention is anecdotal.

In few patients, treatment with photodynamic therapy was found beneficial. UV-A1 phototherapy also has been reported to improve NFD. A trial of localized psoralen plus ultraviolet A (PUVA) treatment in 1 patient produced no improvement.

A 40 years old female, a renal transplant recipient, developed sclero-dermiform brownish plaques on her extremities. The induration improved significantly after 4 cycles of extracorporeal photopheresis.

Also NFD responded to high-dose intravenous immunoglobulin in one report. Oral prednisone (60 mg PO qd) has been found effective in several cases, but it has been discontinued in some patients because of its adverse effects.

In 1 of 2 patients, intralesional alpha interferon (3 MU 3 times weekly) improved the skin, although in both patients, it had to be discontinued because of its adverse effects. In another patient, this therapy was associated with a worsening of lesions. It is suggested that decreasing the erythropoietin might improve NFD in some patients. Topical Dovonex (Calcipotrene) has resulted in subjective improvement in some patients. Pentoxyfyllin 1200mg orally per day seemed to slow or arrest the extension of skin changes in one patient.

Some medications have shown a benefit in small numbers of patients. NFD lesions may be treatable earlier in the disease course, becoming recalcitrant after significant fibrosis has occurred. Prednisone and Dovonex have been used with marginal success. Alpha interferon has been used, but its effects on the disease are unclear. Methotrexate, Cytoxan, and PUVA have been used without effect.

Plasmapheresis has shown some promise in the treatment of this condition, and is still being evaluated for its efficacy in persons who have not undergone transplantation.

Because NFD may restrict mobility, physical therapy might be helpful for some with this condition

Surgical Care: Surgical care has no role in the treatment of this condition. Although surgical care has no direct role in the treatment of this condition, patients who have undergone successful kidney transplantation may show resolution of the lesions. NFD is not a contraindication to transplantation; however, because of reports of associated thrombotic events and early graft loss, evaluation for hypercoagulability should be performed.

NFD can be disabling and restrict the patient's range of motion. Falls are not uncommon, and fractures frequently result.

Spontaneous resolution is described in some reports, typically coincident with improved/resolved renal disease. In most patients, NFD is a progressive condition. Many patients report stabilization and marginal improvement after years with the condition. Whether NFD is a localized or systemic disease is not yet clear.