Kidney Week

Abstract: SA-PO248

Inhibitory Dynamics of SBI-425 on Medial Arterial Calcification in Mice with CKD: A Therapeutic Perspective

Session Information

• CKD-MBD: Basic and Translational
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Tani, Takashi, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Takashi Tani, MD, PhD

• Tani, Hitomi, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Hitomi Tani, MD, PhD

• Mii, Akiko, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Akiko Mii, MD, PhD

• Nakazato, Rei, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Rei Nakazato, MD

• Kamijo, Natsumi, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Natsumi Kamijo, MD

• Shimizu, Akira, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Akira Shimizu, MD, PhD

• Sakai, Yukinao, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan

Yukinao Sakai, MD, PhD

Background

Daily oral administration of SBI-425, a TNAP inhibitor, prevents medial arterial calcification (MAC) in CKD mice. This study evaluated the efficacy of continuous TNAP inhibition via mixed feeding in MAC prevention and assessed its therapeutic effect on MAC progression when pre-existing MAC is present.

Methods

The Vehicle group of 10-week-old mice received 0.2% adenine. From 16 weeks, they were subjected to 0.2% adenine and 1.8% phosphorus for 10 weeks. Treatment groups, SBI-10W, SBI-6W, and SBI-4W, were switched to diets containing 0.03% SBI-425 at 16, 20, and 22 weeks, respectively, continuing the adenine and phosphorus load. The Control group was raised under normal conditions for 16 weeks from 10 weeks of age.

Results

Blood urea nitrogen, serum creatinine, serum phosphorus, FGF-23, and intact PTH were significantly elevated in the CKD group compared to the Control group, but there were no significant differences between the CKD groups. Animal CT images showed ectopic calcification in the aorta, heart, and bilateral kidneys in the Vehicle group, and the respective calcification volumes (mm³) worsened over time after the start of the high-phosphorus diet. Control and SBI-10 groups showed almost no ectopic calcification throughout the experimental period. SBI-6 and SBI-4 groups showed ectopic calcification as in the Vehicle group, although ectopic calcification at all sites tended to be suppressed after the start of pharmacological intervention compared to the Vehicle group. In the aortic and renal histopathology, ectopic calcification with positive Von-kossa staining was observed in the CKD model groups. The area ratios (%) of calcified areas in the tissues of both aorta and kidney were in the order of Vehicle > SBI-4 > SBI-6 > SBI-10 group, indicating that the severity of calcification was inversely proportional to the length of treatment period with SBI-425.

Conclusion

Sustained TNAP inhibition with SBI-425 prevented MAC in CKD mice. TNAP inhibitors showed pharmacological effects proportional to the duration of drug administration, suggesting that they are effective in inhibiting the progression of ectopic calcification even in the presence of pre-existing MAC.

Funding

• Government Support – Non-U.S.