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

Abstract

Background 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 based contrast agents (GBCA) used in magnetic resonance imaging (MRI). Tissue samples from many NSF patients contain micron-sized insoluble Gd-containing deposits. However, the precise composition and chemical nature of these particles is unclear. Objectives To clarify the precise chemical structure of the Gd-containing deposits in NSF tissues. Methods Autopsy skin tissues from a NSF patient are examined in situ using synchrotron x-ray fluorescence (SXRF) microscopy and extended absorption fine structure (EXAFS) spectroscopy and in correlation with light microscopy and the results of SEM/EDS analyses. Results The insoluble Gd deposits are 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 Å and 3.72 Å as well as Gd-Gd distances at an average of 4.05 Å, consistent with a GdPO4 structure. Conclusions 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.

Hyperphosphataemia sensitizes renally impaired rats to the profibrotic effects of gadodiamide

“…The question of which Gd species is actually involved in the pathogenesis of the lesions observed remains unanswered. Several studies have demonstrated micron‐sized insoluble deposits containing Gd associated with calcium and phosphate in NSF patients (Thakral and Abraham, 2009; George et al ., 2010). The protocol used in our study was unable to distinguish precipitated insoluble Gd in tissues.…”

Gadolinium‐containing magnetic resonance contrast media: investigation on the possible transchelation of Gd3+ to the glycosaminoglycan heparin

“…injection, not interacting with substances in the body and being completely eliminated via the kidneys in unchanged form. However, ever since nephrogenic systemic fibrosis (NSF) in patients with advanced renal insufficiency (10,11) was linked to prior systemic administration of GdCM (12,13), the stability of GdCM complexes (14,15) and a possible release of Gd 3+ ions under certain circumstances have been subject to intensive investigation in both experimental (16)(17)(18)(19)(20) and clinical studies (21)(22)(23)(24)(25). NSF is altogether very rare with fewer than 500 cases registered by The International Center for Nephrogenic Systemic Fibrosis Research (26).…”

Quantification estimate methods for synchrotron radiation X-ray fluorescence spectroscopy

“…For a sample and reference geometry as shown in Fig. 4, and assuming a narrow beam such that the dimensions of the beam are much smaller than distance between the sample and the detector, then the equation for the sample or reference measurement is given by (5): detector solid angle, detection response, X-ray incident angle, X-ray incident energy, beam spot size, and material path lengths for both the sample and the reference measurements.…”

“…To obtain further insight or to maintain biological or medical relevance quantifying these localized elemental concentrations is becoming increasingly important [2][3][4][5][6]. Traditionally XRF has been combined with quantification methods such as inductively coupled plasma mass spectrometry (ICP-MS) [7] and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) [8].…”