Nephrogenic systemic fibrosis

Did You Know?

• Clinical features develop within days to months, and sometimes years, after GBCA exposure.
• Skin thickening and hardening with brawny hyperpigmentation typically appears symmetrically, starting distally in the limbs and progressing proximally.
• Restoration of kidney function, whether by treating the underlying disease, recovery from acute kidney injury, or kidney transplant, can slow or halt progression; a few curative transplants have been reported.

Risk factors

Impaired kidney function is the major risk factor, as it reduces clearance of GBCAs. The risk depends on residual kidney function rather than the etiology or duration of renal failure. Most cases occur in stage 5 CKD, but NSF has also developed in stage 4 and 3 CKD and acute kidney injury, even if function later normalizes. Three GBCAs are principally implicated: gadodiamide, gadopentetate dimeglumine, and gadoversetamide. High single or cumulative doses increase risk.

Mechanism

De-chelation of Gd(III) from GBCAs is responsible for toxicity, likely through transmetallation with Zn2+, Cu2+, and Ca2+ in vivo. Acute toxicity experiments show that different gadolinium complexes become lethal when they release the same quantity of Gd(III). Subchronic rodent studies produce findings similar to zinc deficiency. Formulation changes can affect intrinsic safety.

Diagnosis

No specific imaging finding exists; diagnosis is clinicopathological based on presentation and histology. Microscopically, NSF shows dermal fibroblast and dendritic cell proliferation, thickened collagen bundles, increased elastic fibers, mucin deposits, and sometimes sclerotic bodies (elastocollagenous balls), which may be unique to gadolinium exposure. Differential diagnoses include systemic sclerosis, scleromyxedema, and others. Absence of facial skin involvement, presence of yellow scleral plaques, and absence of Raynaud's phenomenon aid differentiation. History of GBCA exposure favors NSF.

History

Originally termed nephrogenic fibrosing dermopathy because only skin involvement was observed in patients with impaired kidney function, it was later renamed nephrogenic systemic fibrosis to reflect systemic involvement. The term gadolinium-associated systemic fibrosis has also been proposed. First cases were identified in 1997, and it was described as an independent disease in 2000. The link to GBCAs was made in 2006, leading to restrictions on use in patients with low eGFR. After controversy involving up to 100 Danish patients poisoned by Omniscan, Nycomed admitted awareness of some dangers. The EMA recommended suspension of intravenous gadopentetic acid and gadodiamide. A 2017 European Commission decision banned intravenous Magnevist and Omniscan in Europe; Magnevist remains authorized for intra-articular use. Linear chelated media gadobenic acid and gadoxetic acid are limited to delayed phase liver imaging.