Serum FGF-23 level was found to be the most useful factor in predicting future development of refractory secondary hyperparathyroidism in long-term dialysis patients with mild secondary hyperparathyroidism. The measurement of serum FGF-23 levels is a promising laboratory examination that can be applied in the clinical practice of uremic secondary hyperparathyroidism.

Skeletal resistance to parathyroid hormone (PTH) is well known to the phenomenon in chronic renal failure patient, but the detailed mechanism has not been elucidated. In the process of analyzing an animal model of renal failure with low bone turnover, we demonstrated decreased expression of PTH receptor (PTHR) accompanying renal dysfunction in this model. In the present study, we focused on the accumulation of uremic toxins (UTx) in blood, and examined whether indoxyl sulfate (IS), a UTx, is associated with PTH resistance. We established primary osteoblast cultures from mouse calvariae and cultured the cells in the presence of IS. The intracellular cyclic adenosine 3',5' monophosphate (cAMP) production, PTHR expression, and free radical production in the primary osteoblast culture were studied. We found that the addition of IS suppressed PTH-stimulated intracellular cAMP production and decreased PTHR expression in this culture system. Free radical production in osteoblasts increased depending on the concentration of IS added. Furthermore, expression of organic anion transporter-3 (OAT-3) that is known to mediate cellular uptake of IS was identified in the primary osteoblast culture. These results suggest that IS taken up by osteoblasts via OAT-3 present in these cells augments oxidative stress to impair osteoblast function and downregulate PTHR expression. These finding strongly suggest that IS accumulated in blood due to renal dysfunction is at least one of the factors that induce skeletal resistance to PTH.

Fibroblast growth factor 23 (FGF23) is a member of the fibroblast growth factor superfamily which displays a strong phosphaturic action and an inhibition of vitamin D 1-alpha hydroxylase activity. Fourty-six patients undergoing maintenance hemodialysis therapy participated in the study. They were randomly divided into 2 groups, and treated with either 3 g sevelamer hydrochloride+3 g of calcium bicarbonate (CaCO3), or 3 g of CaCO3 alone. Serum FGF23 levels were determined by a sandwich enzyme-linked immunosorbent assay (ELISA) system that detects the intact form of FGF23 molecules. Although the serum inorganic phosphate (Pi) levels were comparable before treatment, the levels were significantly lower in the patients treated with sevelamer hydrochloride+CaCO3 than those with CaCO3 alone after 4 weeks of treatment (P<0.05). Serum FGF23 levels significantly decreased after 4 weeks of the treatment with sevelamer hydrochloride+CaCO3 from the pretreatment levels (P<0.05), while no changes were found in the patients treated with CaCO3 alone. Thus, the use of sevelamer hydrochloride and CaCO3 reduced serum FGF23 levels in dialysis patients presumably through inhibiting phosphate load into the intestine.

Background/Aims: Fibroblast growth factor-23 (FGF-23) is a recently discovered phosphaturic factor. Although increased levels of serum FGF-23 have been reported in dialysis patients, the role of high FGF-23 levels remains unclear. Since FGF-23 is associated also with vitamin D metabolism, we examined the changes of serum FGF-23 levels in chronic dialysis patients treated with intravenous calcitriol therapy. Methods: Thirty patients with severe secondary hyperparathyroidism were treated with intravenous calcitriol (0.5–1.0 µg) two or three times per week for 6 months. The changes of serum levels of calcium, phosphate, intact PTH, and FGF-23 were evaluated. Results: Baseline serum FGF-23 levels were markedly high. By intravenous calcitriol therapy, intact PTH levels decreased effectively in the first month (p < 0.001). In contrast, FGF-23 levels increased gradually during the study period (p = 0.027). The Δ serum FGF-23 level was significantly correlated with the total doses of calcitriol injected intravenously in 6 months in patients with refractory secondary hyperparathyroidism (R^{2 =} 0.147; p = 0.036). Conclusions: Intravenous calcitriol decreased serum intact PTH level and increased serum FGF-23 levels significantly. Extremely high levels of serum FGF-23 in these patients may be attributed, at least in part, to the cumulative dose of vitamin D.

Background. Adynamic bone disease (ABD), which is characterized by reduced bone formation and resorption, has become an increasingly common manifestation of bone abnormalities in patients with end-stage renal failure. It has been recognized that skeletal resistance to parathyroid hormone (PTH) underlies the pathogenesis of ABD; however, the mechanisms of such resistance remain unclear. Methods. We established a rat model simulating ABD under chronic renal failure conditions by thyroparathyroidectomy and partial nephrectomy (TPTxNx). TPTx-Nx rats were infused subcutaneously with a physiological dose of PTH. We analysed bone histomorphometric parameters and demonstrated gene expression using semi-quantitative reverse transcription-polymerase chain reaction. Results. Reduced bone formation was observed in this model, simulating ABD. The reduction was dependent on the degree of renal dysfunction. Bone formation rate was 6.4±2.7 mm 3 /m 2 /year in TPTx-5/6Nx rats and 22.7±7.2 mm 3 /m 2 /year in TPTx rats (P<0.05). Osteoblast surface was also significantly depressed (P<0.05) in TPTx-5/6Nx (3.8±2.7%) compared with TPTx rats (15.9±8.6). The expression of PTH/parathyroid hormone-related peptide (PTHrP) receptor and alkaline phosphatase genes was reduced significantly in TPTx-Nx compared with TPTx rats (P<0.05). Reduced bone formation in TPTx-Nx rats was ameliorated by intermittent injection of pharmacological doses of PTH. Conclusions. Renal dysfunction without secondary hyperparathyroidism induces osteoblast dysfunction and reduces bone formation. Skeletal resistance to PTH develops in renal failure even at low or normal PTH levels, possibly through downregulation of PTH/PTHrP receptor and dysfunction of osteoblasts.

Administration of the oral charcoal adsorbent AST-120 decreases the osteoblast cytotoxicity of UTx including IS, and suppresses progression of low bone turnover in uraemic rats.

FGF23 is a physiological regulator of phosphate homeostasis. Excessive activity of FGF23 with normal renal function results in hypophosphatemia, low 1,25-dihydroxyvitamin D levels, and rickets/osteomalacia. By contrast, excessive FGF23 activity suppresses 1,25-dihydroxyvitamin D synthesis, but may not be sufficient to excrete the phosphate load appropriately with deteriorating renal function, both of which contribute to the development of hyperparathyroidism.

These findings indicated the significant role of oxidative stress in the development of diabetic nephropathy and a potential inhibition of progression of nephropathy by TRX1.