Synchrotron X-ray analyses demonstrate phosphate-bound gadolinium in skin in nephrogenic systemic fibrosis

Abstract

Nephrogenic systemic fibrosis (NSF) is an incurable, debilitating disease found exclusively in patients with decreased kidney function and comprises a fibrosing disorder of the skin and systemic tissues. The disease is associated with exposure to gadolinium (Gd)-based contrast agents (GBCA) used in magnetic resonance imaging (MRI). Tissue samples from many patients with NSF contain micron-sized insoluble Gd-containing deposits. However, the precise composition and chemical nature of these particles is unclear. To clarify the precise chemical structure of the Gd-containing deposits in NSF tissues. Autopsy skin tissues from a patient with NSF were examined in situ using synchrotron X-ray fluorescence (SXRF) microscopy and extended X-ray absorption fine structure (EXAFS) spectroscopy and in correlation with light microscopy and the results of scanning electron microscopy /energy dispersive spectroscopy analyses. The insoluble Gd deposits were shown to contain Gd no longer coordinated by GBCA chelator molecules but rather in a sodium calcium phosphate material. SXRF microscopy shows a clear correlation between Gd, Ca and P. EXAFS spectroscopy shows a very different spectrum from the GBCAs, with Gd–P distances at 3·11 A and 3·11 A as well as Gd–Gd distances at an average of 4·05 A, consistent with a GdPO4 structure. This is the first direct evidence for the chemical release of Gd from GBCA in human tissue. This supports the physical–chemical, clinical and epidemiological data indicating a link between stability and dose of GBCA to the development of NSF.