Gadolinium and nephrogenic systemic fibrosis: The evidence of things not seen
Now faith is the substance of things hoped for, the evidence of things not seen.
—HEBREWS 11:1
Since the first case appeared in 1997,1 nephrogenic systemic fibrosis (NSF) has been detected with increasing frequency in patients with chronic kidney disease. Recognition that this condition affects more than just the skin led to the change in its name from “nephrogenic fibrosing dermopathy” to “nephrogenic systemic fibrosis.”
In this issue, Issa and colleagues2 review this devastating new disease and discuss its association with gadolinium exposure.
NSF RESEMBLES OTHER FIBROSING DISORDERS
The clinical presentation of NSF most closely resembles that of scleromyxedema or scleroderma.1 However, the face is spared in patients with NSF except for yellow plaques on the sclerae, a frequent finding. Monoclonal gammopathy (which may be associated with scleromyxedema) and Raynaud’s phenomenon (which often is associated with scleroderma) usually are absent in NSF.3
A set of histologic findings differentiates NSF from other fibrosing disorders. Skin biopsy reveals fibrosis and elastosis, often with mucin deposition. If NSF is suspected, immunohistochemical stains for CD34, CD45RO, and type I procollagen should be performed to look for dermal spindle cells (presumably “circulating fibrocytes”) coexpressing these markers. Histiocytic cells and dermal dendrocytes expressing CD68 and factor XIIIa have also been described in NSF skin lesions, but other inflammatory cells usually are absent.4 However, the histologic changes of NSF are difficult to distinguish from those of scleromyxedema.5
Thus, as with scleroderma, the diagnosis of NSF remains clinical. Skin biopsy, even of an affected area, occasionally may yield non-diagnostic findings. Histologic findings serve to confirm the diagnosis of NSF in the appropriate clinical setting.
RISK FACTORS FOR NSF: POSSIBLE ASCERTAINMENT BIAS
Renal dysfunction
Because cases of NSF have been searched for only in patients with chronic kidney disease, reported cases have been found only in this patient population. A major limitation of most published case series is that cases have been gathered from among those with histologic confirmation of NSF, and “controls” have been gathered from the remainder of the population receiving dialysis treatment without confirmation by physical examination of the absence of cutaneous changes of NSF.
Most cases have been found in those with stage 5 chronic kidney disease (creatinine clearance < 15 mL/min or requiring dialysis). However, cases have been described in patients with stage 4 chronic kidney disease (creatinine clearance 15–29 mL/min) and, occasionally, in those with lesser degrees of impaired renal function.
Despite the ascertainment bias in identifying cases, this greater prevalence of NSF with lesser renal function suggests a role for renal dysfunction in the pathogenesis of NSF.
