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Abstract: FR-PO971

The Mechanisms of Gadolinium-Based Contrast Agent-Induced Nephrotoxicity

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Author

  • Wagner, Brent, Kidney Institute of New Mexico, Albuquerque, New Mexico, United States

Group or Team Name

  • Kidney Institute of New Mexico
Background

All classes of gadolinium-based contrast agent (GBCA) are nephrotoxic. This is well accepted from case reports, prospective studies, and prescriber information sheets.

Methods

Generation of chimeric transgenic mice provided a means of tracing myeloid-derived cellularity in the target organs. Groups were randomized to GBCA treatment versus none. Kidney sections were examined with a Hitachi HT7700 with an AMT 16 megapixel camera and a Jeol JEM 2010F field emission electron microscope at 200 kV with a GATAN Orius camera and Oxford Analytical ISIS energy-dispersive spectrometer (EDS).

Results

GBCA exposure caused significant renal fibrosis and podocyte injury associated with elevations in plasma creatinine and metabolic disorders as evidenced by dyslipidemia. Metabolomic analysis of flash-frozen renal cortex demonstrated that GBCA treatment—far from being inert—resulted in glycolytic switching—the Warburg effect—where glycolysis and lactate accumulation increased with suppression of the tricarboxylic acid cycle. In the treated group, the electron-dense deposits riddled the glomeruli and vacuoles of proximal tubular cells. By EDS, these contained high quantities of gadolinium (P < 0.01), calcium (P < 0.01), and phosphate (P < 0.05).

Conclusion

We provide the first evidence that GBCAs cause significant metabolic disorders and kidney injury in mice without pre-existent renal insufficiency. Accumulation of non-physiologic lanthanide heavy metals may be leaching phosphorous from lysosomal membranes, catalyzing the formation of calcium phosphates, and thwarting cellular energetics in this manner.

Transmission electron microscopy of proximal tubule (top) laden with electron-dense material. Energy-dispersive x-ray spectroscopy of the electron densities minus control and normalized counts in regions for gadolinium, calcium, and phosphate.

Funding

  • NIDDK Support