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Abstract: PO0316

Efficacy of Oxidative Stress Inhibitor Alone or Combined Therapy with a Calcimimetic in a Rat Model of 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
  • O'Neill, Kalisha, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Srinivasan, Shruthi, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Metzger, Corinne E., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Stacy, Alexander James, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Dominguez, James M., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Biruete, Annabel, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Allen, Matthew R., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Avin, Keith G., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Moe, Sharon M., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

We previously demonstrated the role of NADPH oxidase (NOX 1 & 4) and hyperparathyroidism in the pathogenesis of arterial calcification, a component of CKD-MBD. We hypothesized that the combination of reduced NOX activity and lower PTH would have additive benefit on CKD-MBD. To test this hypothesis, we evaluated the efficacy of the NOX 1/4 inhibitor GKT137831(GKT) alone or combination with the PTH-lowering calcimimetic KP-2326 (KP) on CKD-MBD 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+GKT (60mg/kg s.q. daily); 4: CKD+ KP (0.6mg/kg i.p., 3x/wk) and 5: CKD+GKT+KP. Treatment began at 18 weeks of age (~60% NL kidney function) and ended at 28 weeks (~25% NL function). Serum biochemistries, aorta and heart calcification and bone architecture were assessed. One Way ANOVA was used for statistical analysis.

Results

As expected, there was a decline in kidney function in all CKD groups compared to NL. There was no difference in serum phosphorus or calcium levels between NL and any of the CKD groups. PTH and FGF23 serum levels were elevated by 5 and 2.3 fold, respectively, in CKD rats; only KP treatment reduced PTH levels (p<0.003). Interestingly, GKT alone or combined with KP increased FGF23 levels by 2-fold in CKD rats (p<0.002). Serum 8-OHdG (marker of DNA oxidation) was higher in all CKD animals (p<0.01) and unaffected by treatment. There was increased aorta calcification (by 45%) and heart calcification (by 32%) in all of the CKD animal groups (p<0.01) and only GKT treatment reduced aorta calcification (p<0.03). Compared to NL, trabecular bone volume (BV/TV%) and trabecular number were lower and trabecular separation was higher in all CKD rats (p<0.001). GKT also increased trabecular separation in CKD rats (p<0.04).

Conclusion

In a progressive rat model of CKD-MBD, treatment with a NOX1/4 inhibitor (GKT) early in the course of CKD reduced aorta calcification but did not decrease oxidative stress and also increased FGF23 levels in CKD rats. KP treatment decreased serum PTH levels in CKD, but had no effect on aorta calcification or bone architecture. There were no additive beneficial or adverse effects with the combination of KP and GKT.

Funding

  • Veterans Affairs Support