Gadolinium-induced nephrogenic systemic fibrosis is associated with insoluble Gd deposits in tissues: in vivo transmetallation confirmed by microanalysis.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is an extremely debilitating systemic fibrosing disorder affecting renal failure patients. The association of NSF with gadolinium (Gd) containing magnetic resonance contrast agents was noted in 2006. Gd deposition in skin biopsies was demonstrated shortly thereafter.
METHODS: We used automated scanning electron microscopy (SEM)/energy dispersive x-ray spectroscopy for in situ quantitative analysis of insoluble Gd-containing deposits, recording multi-elemental composition and spatial distribution of detected features.
RESULTS: Gd was detected in all 29 patients (53 of 57 skin biopsies) with NSF, biopsied from 2 weeks to 3 years after Gd exposure. Gd concentration ranged from 1 to 2270 cps/mm(2) and was detected predominantly in the deep dermis and subcutaneous fibrous septa. Gd was found associated with Ca, P and sometimes Fe or Zn. Patients with sequential biopsies showed persistence or increase of Gd in tissues (6 of 11). Transmission electron microscopy (TEM) identified the intracellular deposits in fibrocytes and macrophages.
CONCLUSIONS: The demonstration of insoluble tissue deposits of Gd with co-associated elements clearly confirms in vivo transmetallation and dissociation of soluble Gd-chelates. Toxic Gd(3+) may trigger fibrosis under permissive conditions, e.g., in renal insufficiency. Pathologists and clinicians need to be aware of this serious but preventable disease.