Effect of Paricalcitol on FGF-23 and Klotho in Kidney Transplant Recipients

Abstract

Background: Paricalcitol decreases intact parathyroid hormone and the frequency of secondary hyperparathyroidism after kidney transplantation. This proof-of-concept study aimed to assess the effect of paricalcitol on fibroblast growth factor-23/KLOTHO axis in renal transplants.

Methods: Twenty-nine subjects with secondary hyperparathyroidism received oral paricalcitol 1 μg/d for 3 months, and 8 patients matched by age, sex, and creatinine clearance, but with intact parathyroid hormone less than 100 pg/mL, were included as controls.

Results: Intact parathyroid hormone decreased in paricalcitol-treated patients (P < 0.0001). Serum fibroblast growth factor-23 enhanced (P < 0.01), whereas KLOTHO concentrations showed a trend to increase (P = 0.067). KLOTHO gene expression in peripheral blood mononuclear cells increased by 45.7% in paricalcitol-treated patients (P < 0.01), without change in controls. Paricalcitol administration resulted in a median percent decrease of 56% in methylated DNA levels of KLOTHO promoter (P < 0.001). The ratio of the unmethylated/methylated KLOTHO promoter DNA did not change in controls, but it increased by 177% in paricalcitol-treated subjects (P < 0.0001). The increase in this ratio was independently associated with the change in serum KLOTHO (r = 0.55, P < 0.01) and messenger RNA expression levels (r = 0.40, P < 0.05).

Conclusions: Paricalcitol administration to renal transplant patients significantly reduced intact parathyroid hormone and increased fibroblast growth factor-23, with a trend to increase in serum KLOTHO. Paricalcitol-treated patients showed a decrease in the methylation of the KLOTHO promoter with an increment in the ratio of un-methyated/methylated DNA, which was associated with an increase of KLOTHO gene expression levels and serum KLOTHO concentrations. Long-term studies are needed to assess whether paricalcitol-induced increase in KLOTHO gene expression and serum concentrations may translate into beneficial clinical effects.