Effects of uremic ultrafiltrate on the regulation of the parathyroid cell cycle by calcitriol

Abstract

Calcitriol (CTR) is used in the treatment of hyperparathyroidism secondary to renal failure because it decreases parathyroid hormone (PTH) synthesis and parathyroid cell proliferation. Previous studies in tissues other than parathyroids have demonstrated that uremic factors affect the action of CTR on the target cells. We questioned whether the uremic milieu interferes with the inhibition of parathyroid cell proliferation by CTR. Studies were performed in vitro using freshly excised normal dog parathyroid tissue incubated for 24 hours with and without CTR and in the presence of either total uremic ultrafiltrate (UUF) from uremic patients or high-pressure liquid chromatography (HPLC)-derived fractions (hydrophilic compounds eluting early and hydrophobic compounds eluting late) of this UUF (F1 to F4). Parathyroid cell proliferation was assessed by flow cytometry. The addition of CTR 10-8 and 10-7 mol/L to parathyroid tissue produced an inhibition of the proliferation that was prevented in the presence of UUF. In a medium containing CTR 10-8 mol/L, the addition of F1, F2 and F3, but not F4, prevented the CTR-induced inhibition of parathyroid cell proliferation. With CTR 10-7 mol/L, the inhibition of proliferation was observed even in the presence of F1, F2 and also F4, but was prevented by F3. Uric acid (7 mg/dL), indoxyl sulfate (5 mg/dL) and p-cresol (1.4 mg/dL), which coeluted with F1, F2 and F4, respectively, did not interfere with the inhibitory action of CTR 10-7 mol/L; however, the addition of phenol (0.14 mg/dL), which coeluted with F3, prevented the CTR-induced inhibition of parathyroid cell proliferation. The presence of uremic toxins prevents the inhibition of parathyroid cell proliferation induced by calcitriol.