Nephrogenic systemic fibrosis (NSF) is a rare debilitating disorder characterized by dermal plaques, joint contractures, and fibrosis of the skin with possible involvement of muscles and internal organs.1-3 Originally identified in 1997 as nephrogenic fibrosing dermopathy to describe its characteristic cutaneous thickening and hardening, the name was changed to NSF to more accurately reflect the noncutaneous manifestations present in other organ tissues.2,4,5 Nephrogenic systemic fibrosis occurs in patients with a history of renal insufficiency and exposure to gadolinium-based contrast agents (GBCAs) used in magnetic resonance angiography and magnetic resonance imaging. There is no predilection for age, sex, or ethnicity.
Nephrogenic systemic fibrosis may develop over a period of days to several weeks. However, there have been cases of NSF developing 10 years after gadolinium exposure.2 In most cases, patients have a history of severe chronic renal disease requiring hemodialysis. There have been a few reported cases of NSF occurring in patients with resolved acute kidney injury or resolved acute on chronic renal disease.1,6-10 We present a case of NSF occurring in a patient with resolved transient renal insufficiency and no history of chronic renal disease.
Case Report
A 68-year-old woman presented with new dark, painless, pink plaques on the right thigh and calf. The patient stated the condition started and got worse after she was hospitalized 12 years prior for lower extremity cellulitis, sepsis, and acute renal failure. The patient developed complications during that hospital stay and underwent a renal biopsy and renal artery embolization requiring use of a GBCA. After the procedure, she noticed skin hardening in the extremities and decreased mobility in both legs while she was still in the hospital. It was thought that the lower leg changes were due to cellulitis. Therefore, when the renal issues resolved, she was discharged. Her skin and joint changes remained stable until 6 years later when she noticed new pink plaques appearing. Her medical history was positive for breast cancer, which was surgically and medically treated 16 years prior to presentation.
On presentation, physical examination revealed dark pink, hyperpigmented plaques on the right leg and a firm hypopigmented broad linear plaque on the right forearm. Palpation of the legs revealed thickened sclerotic plaques from the thighs down to the ankles (Figure 1). The plaques were not tender to palpation. She did have a decreased range of motion with eversion and inversion of the feet and ankles.
FIGURE 1. Nephrogenic systemic fibrosis. A, Thickened sclerotic plaques from the thighs down to the ankles. B, Dark pink hyperpigmented plaques on the right leg.
Biopsies from the right medial leg and right volar forearm showed increased bland dermal spindle cellularity associated with numerous round to ovoid osteoid aggregates encircling elastic fibers and surrounded by osteoblasts (Figure 2). CD34 immunohistochemistry showed general retention of staining within the dermal fibroblast population, and elastin stain showed general retention of elastic fiber bundles and thickening.
FIGURE 2. A, A biopsy of the right medial leg showed increased bland dermal spindle cellularity (H&E, original magnification ×4). B, Bland dermal spindle cellularity with round to ovoid aggregates encircling elastic fibers (H&E, original magnification ×10). C, Bland dermal spindle cellularity with round to ovoid aggregates encircling elastic fibers (H&E, original magnification ×20).
Laboratory workup included a complete blood cell count, comprehensive metabolic panel, thyroid-stimulating hormone level, and serum protein electrophoresis; results were all within reference range. The patient also had a urine element profile from an outside provider 1 month after presenting to our office that showed an elevated urine gadolinium level of 4.146 μg/g (reference range, 0–0.019 μg/g). The patient’s skin lesions have remained stable, and she is now working with physical therapy to help with her range of motion.
Comment
Gadolinium Causing Fibrosis—The incidence of NSF varies according to the severity of renal impairment, dosage level of GBCA used, and the history of GBCA use. In patients with normal renal function, gadolinium is excreted within 90 minutes. In patients with severe renal disease, the half-life can increase to up to 34.3 hours.11 Reduced renal clearance and increased half-life of gadolinium lead to prolonged excretion, causing the GBCA to become unstable and dissociate into its constituents, leading to tissue deposition of Gd3+ cations. This dissociation is thought to be due to differences in the stability of the various chelation complexes among the different formulations of GBCAs.12 The mechanism by which the dissociated gadolinium causes the fibrosis in the skin or other organs of the body is still unknown. Furthermore, even patients with normal renal function who undergo repeated administration of GBCA have been found to have higher levels of Gd3+ in their tissues, even in the absence of symptoms.13