Nephrogenic systemic fibrosis (NSF) is a rare disease typically found among individuals with severe renal impairment. The first cases thought to be NSF occurred as early as 1997 in renal dialysis patients having a “scleromyxedema-like cutaneous disease.”¹ Because early reports of NSF had multiple dermatologic findings, the condition was initially termed “nephrogenic fibrosing dermopathy.”^2,3,4,5 It soon became evident, however, that this emerging disease entity could affect multiple organ systems in addition to the skin, such as the heart, lungs, liver, and muscles, so the more descriptive term “nephrogenic systemic fibrosis” was adopted.

NSF affects men and women equally and cases have been reported in Caucasian, African, Asian, Indian, and Hispanic individuals. Most cases have been identified in the United States, followed by Europe and Asia.⁶ The lower incidence in Asians is hypothesized to be more likely because of the lower gadolinium contrast doses used in Asia rather than any racial differences. There is a strong connection between NSF and poor renal function. Grobner’s landmark observation connecting renal function, gadolinium contrast, and NSF found that five out of nine hemodialysis patients developed NSF after the administration of high-dose nonionic linear gadolinium contrast.

Skin involvement is usually the first symptom of NSF (Table 8.2).¹¹ Patients typically complain of pain, pruritus, tightness, and/or swelling of the skin in the extremities. Lesions appear to be symmetric and bilateral and also tend to be hyperpigmented or erythematous. Hypopigmented lesions are rare. NSF lesions are most frequent in the lower extremities, followed by the upper extremities and then the trunk (Fig. 8.1). The lesions can be as mild as plaques and papules limited to the superficial layers of the skin. NSF lesions may be deeper in the subcutaneous layers, however, where fibrosis can tether skin to the underlying fascia (Fig. 8.2). This may create patterns of skin dimpling or cobblestoning. Joint stiffness and contractures may interfere with normal mobility, and internal organ involvement has been found in autopsies.

Indurated plaques of the deep subcutaneous layers of the skin are often described as firm, thickened, “lumpy,” and shiny (Fig. 8.3).¹¹ A peau d’orange (“peel of orange”) appearance may result when there is extensive dermal involvement. Cobblestoning is commonly found in the thighs and banding is commonly found in the arms or legs.

A full-body skin examination should be performed in patients with suspected NSF by a dermatologist, rheumatologist, or other health care professional who is familiar with clinical features of NSF and how to distinguish them from other disorders that are in the differential diagnosis of NSF.¹² During the skin exam, lesions should be assessed to find ones that are the most suitable candidates for deep dermal biopsy. An examination of the joints should include assessment for loss of range of motion and flexion contractures (Fig. 8.4). An eye exam should also be performed to check for scleral plaques.

Determining the estimated GFR as an indicator of kidney dysfunction is essential in determining who is at risk for NSF. This is most commonly done by measuring a patient’s serum creatinine and incorporating it into the Modification of Diet in Renal Disease (MDRD) equation to calculate GFR.^13,14 This calculation also incorporates factors like a patient’s age, gender, and ethnicity when calculating the GFR. To increase the accuracy of the GFR calculation, serum creatinine needs to be collected during steady-state conditions (i.e., outside the setting of an acute kidney injury, perioperative period, etc.).

There are multiple other conditions with prominent dermatologic findings that are in the differential diagnosis of NSF. Among these are lipodermatosclerosis, scleroderma, scleromyxedema, and eosinophilic fasciitis.¹¹ Lipodermatosclerosis can be distinguished from NSF because lipodermatosclerosis is characterized by painful induration, which usually results from venous insufficiency and venous

stasis. Scleroderma is differentiated from NSF based on physical examination findings of a tapering of the fingertips (i.e., sclerodactyly) and serum autoantibodies SCL-70 and antinuclear antibody (ANA) in scleroderma. Scleromyxedema is distinguished from NSF because scleromyxedema usually involves fibrosis in the upper extremities and face, which are rarely affected by NSF. Although eosinophilic fasciitis may share some fibrosing patterns of NSF, peripheral eosinophilia is more commonly found in the blood of patients with eosinophilic fasciitis.

The histopathologic hallmark of NSF is excessive dermal fibrosis.¹¹ Fibrosis is caused by an increased number of fibrocytes in the dermis (Fig. 8.5). Fibrosis can be in focal areas or in the entirety of the dermis, with sparing of the epidermis. Fibrocytes show indistinct cytoplasmic borders on hematoxylin and eosin (H & E) stain. They lack mitotic figures and nuclear membrane abnormalities. In addition, granular material can be found within fibrocyte cytoplasm, which can be detected with Perls’ stain. Fibrocytes are also CD34 positive and procollagen I positive on immunohistochemical staining. Under normal conditions, fibrocytes, which are usually found in bone marrow, begin to circulate and deposit in areas that need wound repair. Through the use of specialized microscopic techniques and spectroscopy, gadolinium has been detected in the affected tissues of NSF patients. The deposition of gadolinium is hypothesized to trigger circulating
fibrocytes to produce inflammation and collagen inappropriately. Deep incisional biopsies sometimes demonstrate the extension of the fibrotic processes beyond the dermis through the underlying fascia, all the way to skeletal muscle.

Other histopathologic features of NSF include the absence of both microthrombi and vasculitis, despite being associated with a hypercoagulable state.¹¹ Neovascularization can be present at times and histiocytes are commonly seen. There are usually no excess neutrophils or eosinophils seen, and no inflammatory response occurs in NSF.