Inhibition of tissue‐nonspecific alkaline phosphatase protects against medial arterial calcification and improves survival probability in the CKD‐MBD mouse model

Medial arterial calcification (MAC) is a major complication of chronic kidney disease (CKD) and an indicator of poor prognosis. Aortic overexpression of tissue‐nonspecific alkaline phosphatase (TNAP) accelerates MAC formation. The present study aimed to assess whether a TNAP inhibitor, SBI‐425, protects against MAC and improves survival probability in a CKD‐mineral and bone disorder (MBD) mouse model. CKD‐MBD mice were divided in three groups: vehicle, SBI‐10, and SBI‐30. They were fed a 0.2% adenine and 0.8% phosphorus diet from 14 to 20 weeks of age to induce CKD, followed by a high‐phosphorus (0.2% adenine and 1.8% phosphorus) diet for another 6 weeks. At 14–20 weeks of age, mice in the SBI‐10 and SBI‐30 groups were given 10 and 30 mg/kg SBI‐425 by gavage once a day, respectively, while vehicle‐group mice were given distilled water as vehicle. Control mice were fed a standard chow (0.8% phosphorus) between the ages of 8 and 20 weeks. Computed tomography imaging, histology, and aortic tissue calcium content revealed that, compared to vehicle animals, SBI‐425 nearly halted the formation of MAC. Mice in the control, SBI‐10 and SBI‐30 groups exhibited 100% survival, which was significantly better than vehicle‐treated mice (57.1%). Aortic mRNA expression of Alpl, encoding TNAP, as well as plasma and aortic tissue TNAP activity, were suppressed by SBI‐425 administration, whereas plasma pyrophosphate increased. We conclude that a TNAP inhibitor successfully protected the vasculature from MAC and improved survival rate in a mouse CKD‐MBD model, without causing any adverse effects on normal skeletal formation and residual renal function. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.