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Kidney Week

Abstract: TH-PO515

INS-3001 Efficiently Inhibits Severe CKD-Induced Cardiovascular Calcifications by Directly Targeting Hydroxyapatite Growth and Deposition

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Verhulst, Anja, University of Antwerp, Antwerp, ANTWERP, Belgium
  • Ivarsson, Mattias E., Inositec Inc., Zurich, Switzerland
  • D'Haese, Patrick, University of Antwerp, Antwerp, ANTWERP, Belgium
Background

Prevention of cardiovascular calcification (CVC) in CKD patients currently is based on controlling CKD-specific risk factors such as hyperphosphatemia. A new therapeutic approach with potential higher efficacy consists in the use of molecules that directly interfere with the calcification process in the vessel wall, such as INS-3001. In this study we evaluated the efficacy of INS-3001, an inositol phosphate analog in a rat model of CKD-induced CVC.

Methods

CVC was induced in 48, 8 weeks old, male Wistar rats by the administration of an adenine (0.75%) and phosphate (0.92%) supplemented diet for 4 weeks, followed by a diet with 1.02% phosphate for 1 week until sacrifice. Rats were randomly assigned to 1 vehicle, and 3 INS-3001 groups (n=12 each) and treated with INS-3001 (5, 15 and 50 mg/kg) or vehicle (distilled water) by subcutaneous administration via osmotic minipumps during the last 4 weeks before sacrifice. CKD development was evaluated by measurement of serum creatinine and phosphate levels. CVC was evaluated on Von Kossa stained thoracic aorta tissue sections and by measurement of the total Ca content of the heart, abdominal aorta and a. carotis by atomic absorption spectrometry. Bone samples were analyzed by quantitative bone histomorphometry.

Results

Mortality rate was limited (≤1 animal/group). CKD developed to a similar extent in all groups. In the thoracic aorta, significantly lower Von Kossa positivity (area%) was measured in the INS-3001 group (50mg/kg) compared to the vehicle group (2.7±6.0 vs 14.5±15.1 %). Total Ca content of the abdominal aorta was also significantly lower in the INS-3001 (50mg/kg) group compared to the vehicle group (1.7±1.8 vs 14.5±13.9 mg/g tissue). Similar reductions in total Ca content were seen in the a. carotis and the heart. Quantitative bone histomorphometric analysis in vehicle treated rats showed a tremendously increased (not quantifiable) bone turnover. INS-3001 treated animals showed a significant increase in the bone area % (of total tissue area) compared to vehicles (42.3±14.6 vs 15.5±7.0 %). Neither osteoclast nor osteoblast morphology was affected.

Conclusion

In conclusion, INS-3001 is a promising molecule for the treatment of CKD induced CVC. Effects on bone have to be further investigated in a model with physiological bone turnover.

Funding

  • Commercial Support