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Abstract: FR-PO492

Effect of Advanced Glycation End-Products (AGE) Lowering Drug ALT-711 on a Rat Model of CKD-Mineral Bone Disorder (CKD-MBD)

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Chen, Neal X., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Srinivasan, Shruthi, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Aromeh, Loretta O., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • O'Neill, Kalisha, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Avin, Keith, Indiana University-Indianapolis, Indianapolis, Indiana, United States
  • Allen, Matthew R., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Nickolas, Tom, Columbia University Medical Center, New York, New York, United States
  • Wallace, Joseph M., Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States
  • Moe, Sharon M., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

Reduced bone quality is a key determinant of skeletal fragility in CKD. We hypothesized that the increased formation of AGEs that occur in advanced CKD due to oxidative stress may be responsible for the impaired bone fragility. To test this hypothesis, we evaluated the efficacy of an AGE breaker (ALT-711) on CKD-MBD and bone AGEs in a slowly progressive rat model of CKD, the Cy/+ rat.

Methods

We compared five groups of animals [1: Normal (NL); 2: CKD; 3:CKD+ALT-711; 4: CKD+ 3% calcium in drinking water (Ca, lowering PTH and reducing bone remodeling); and 5: CKD+ALT-711+Ca] . Treatment was started at 25 weeks of age (~50% kidney function) and ended at 35 weeks (~15% function). Blood, kidney weight, and heart weight were examined at sacrifice and aorta calcification determined biochemically. Bone AGE content was determined in demineralized femur shaft using fluorescence plate reader, normalized by collagen (hydroxyproline) content.

Results

As expected, there was progressive decline in kidney function over time in all 4 CKD groups compared to NL. The serum levels of calcium and FGF23 were higher, and phosphorus and PTH lower in CKD animals treated with calcium consistent with resolution of secondary hyperparathyroidism. The administration of ALT did not alter BUN, calcium, PTH or FGF23 levels but did reduce serum phosphorus levels in CKD animals. Heart weight and left ventricular mass index (LVMI) increased in all of the CKD animal groups compared to NL. Treatment with ALT-711, calcium, or ALT+Ca all reduced the heart weight and LVMI in CKD animals. There was increased vascular calcification in all of the CKD animal groups but no effect of ALT-711 treatment. Serum 8-OHdG levels (marker of DNA oxidation) was elevated in CKD compared to NL and not lowered by ALT-711. Bone AGE levels were increased in CKD compared to NL but not reduced by ALT treatment.

Conclusion

In a progressive rat model of CKD, there is increased AGE accumulation in bone. Starting treatment with an AGE breaker early in the course of CKD failed to improve bone AGE levels, but did reduce heart weight. Interestingly, there was also an interaction with secondary hyperparathyroidism in the pathogenesis of AGEs and response to ALT. Bone biomechanical testing is in progress.

Funding

  • Other NIH Support