Hormonal and mineral dysregulation determine the dynamics of calcification in adenine-induced CKD in male rats.

Abstract

Disturbances in calciotropic hormones: parathyroid hormone (PTH), vitamin D, fibroblast growth factor-23 (FGF-23)/Klotho, and mineral homeostasis are often seen in chronic kidney disease (CKD) and are key factors driving vascular calcification (VC). Importantly, the role of these hormones in VC is poorly understood. Therefore, we investigated how the dysregulation of calciotropic hormones and mineral metabolism determines the dynamics of the VC process in adenine-induced CKD in rats. Male rats were fed a diet containing 0.3% adenine for 4, 6, and 8 weeks to establish CKD. Classical markers of renal function, mineral homeostasis, and progression of VC were determined. In the earlier stages of CKD, in conditions of low 1,25-dihydroxyvitamin-D3 (1,25(OH)2D3) and Klotho deficiency, PTH exhibited an effective phosphaturic effect, and the PTH/FGF-23/Klotho axis seems to have a protective function against VC. In the later stage of the disease, the predominance of PTH led to the activation of 1,25(OH)2D3 synthesis, which resulted in the rebuilding of Klotho resources and allowed FGF-23 to take over a phosphaturic role. As a result, PTH/1,25(OH)2D3/Klotho signaling seems to exert a procalcifying effect. Moreover, VC was directly and inversely associated with the minerals excreted in the urine, and receiver operating characteristic analysis revealed a high diagnostic potential of calcium excretion in VC prediction. The present study shows that measuring serum panel of calciotropic hormones and urine tests assessing the excretion of minerals performed in a laboratory routine may be helpful tools for predicting VC progression at different CKD stages.