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Abstract: SA-PO786

Nephrogenic Systemic Fibrosis (NSF) Is Induced in High-Phosphate-Diet CKD Rats Exposed to Gadolinium Gd3+-Binding Contrast Agents: Role of Bone ASARM Peptides

Session Information

  • CKD: Mechanisms - III
    November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Rowe, Peter S. N., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Fields, Timothy A., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Gupta, Aditi, University of Kansas Medical Center, Kansas City, Kansas, United States
  • McCarthy, Ellen T., University of Kansas Medical Center, Kansas City, Kansas, United States
Background

High contrast Magnetic Resonance Imaging (MRI) requires the use of Gadolinium Binding Contrast Agents (GBCAs). Subsets of chronic kidney disease (CKD) patients exposed to GBCAs develop Nephrogenic Systemic Fibrosis (NSF), a progressive disease that leads to acute morbidity and death. Our previous work showed circulating ASARM-peptides bind to GBCAs and induce release of toxic Gd3+. Bone-derived ASARM peptides induce hypophosphatemia and bone-mineralization abnormalities. We hypothesize increased levels of acidic ASARM-peptide exacerbates release of free Gd3+ resulting in an NSF pathology with reduced ectopic mineralization defects.

Methods

To test our hypothesis, we used a rat 5/6 Nephrectomy CKD disease model (NEPHREX). Male rats (16 wk, 250 gm) were fed a high phosphate diet (2% P, 200IU Vit D and 0.8% Ca; TEKLAD 170496). ASARM peptide was infused continuously for 4 weeks using subcutaneous implantation of osmotic pumps. As controls, co-implanted osmotic pumps were used to co-infuse SPR4 peptide - a peptide that neutralizes ASARM. Sera collections were taken at the beginning and end of the study. Three consecutive, daily bolus injections of Gd3+-containing contrast agent (OmniscanTM, gadodiamide) were given 3 days after pump implantation through surgically implanted jugular-vascular-catheters.

Results

NEPHREX rats treated with OmniscanTM and ASARM developed severe skin pathology, behavioral abnormalities, and joint abnormalities that were consistent with NSF. Computed tomography (CT) showed renal, brain, heart dermal metastatic calcifications and bone defects in OmniscanTM treated Rats. ASARM peptide treatment corrected the OmniscanTM induced skin, bone and soft tissue mineral abnormalities and corrected the hyperphosphatemia.

Conclusion

Our study shows CKD rats fed a high phosphate diet and treated with OmniscanTM develop severe NSF like pathology. ASARM infusion prevents OmniscanTM induced subdermal calcification, corrects mineral defects and hyperphosphatemia. In conclusion, ASARM peptides induce release of free Gd3+ from GBCAs but reduce mineralization pathology. These findings have clinical importance for GBCA use in inherited or acquired renal bone-mineral loss disorders with increased circulating ASARM-peptides.

Funding

  • NIDDK Support