SummaryBackground and objectives Fibroblast growth factor 23 (FGF23) is an independent risk factor for mortality in patients with ESRD. Before FGF23 testing can be integrated into clinical practice of ESRD, further understanding of its determinants is needed.Design, setting, participants, & measurements In a study of 67 adults undergoing peritoneal dialysis, we tested the hypothesis that longer dialysis vintage and lower residual renal function and renal phosphate clearance are associated with higher FGF23. We also compared the monthly variability of FGF23 versus parathyroid hormone (PTH) and serum phosphate.Results In unadjusted analyses, FGF23 correlated with serum phosphate (r ϭ 0.66, P Ͻ 0.001), residual renal function (r ϭ Ϫ0.37, P ϭ 0.002), dialysis vintage (r ϭ 0.31, P ϭ 0.01), and renal phosphate clearance (r ϭ Ϫ0.38, P ϭ 0.008). In adjusted analyses, absence of residual renal function and greater dialysis vintage associated with higher FGF23, independent of demographics, laboratory values, peritoneal dialysis modality and adequacy, and treatment with vitamin D analogs and phosphate binders. Urinary and dialysate FGF23 clearances were minimal. In three serial monthly measurements, within-subject variability accounted for only 10% of total FGF23 variability compared with 50% for PTH and 60% for serum phosphate.Conclusions Increased serum phosphate, loss of residual renal function, longer dialysis vintage, and lower renal phosphate clearance are associated with elevated FGF23 levels in ESRD patients undergoing peritoneal dialysis. FGF23 may be a more stable marker of phosphate metabolism in ESRD than PTH or serum phosphate.

We report on an adolescent who experienced the onset of linear nevus sebaceous syndrome (LNSS) prior to 1 year of age. At 7 years of age he was diagnosed to have hypophosphatemic rickets. He was suboptimally controlled with phosphate and calcitriol treatment and sustained numerous insufficiency fractures ipsilateral to the linear sebaceous nevus. Fibroblast growth factor-23 (FGF-23), the phosphaturic peptide, was elevated in the plasma. Treamtent with the somatostatin agonist, octreotide, and excision of the nevus were followed by normalization of FGF-23 and clinical improvement. The patient also had hyperimmunoglobulinemia E, which responded to octreotide and surgery. We speculate that in some patients with LNSS there may be more than one mediator of hypophosphatemia and that FGF-23 is the mediator of hyperphosphaturia in this and other hypophosphatemic syndromes.

PTH binds to specific receptors that are coupled to adenylate cyclase and activate cAMP-dependent protein kinase. Since it has been shown that PTH activates phospholipid inositol metabolism, we investigated whether PTH influences protein kinase-C (PKC) activity in rat osteosarcoma (ROS) cells 17/2.8 that contain a large number of PTH receptor. Incubation of ROS cells with PTH or phorbol 12-myristate 13-acetate (PMA) for 1-30 min caused a rapid and transient decrease in PKC activity in the cytosol, which was associated with a transient increase in PKC activity in the membrane fraction. After 1, 5, 15, and 30 min of incubation with PTH, cytosolic PKC activity decreased to 57%, 74%, 84%, and 93% of the control value, whereas membrane PKC activity increased to 156%, 122%, 111%, and 106% of the control value, respectively. After PMA treatment for 1, 5, 15, and 30 min, cytosolic PKC activity decreased by 81%, 74%, 63%, and 44%, whereas membrane-bound PKC activity increased by 83%, 44%, 28%, and 17%, respectively. The effects of PTH and PMA on PKC were dose dependent, with ED50 values of 0.3 nM PTH and 4 nM PMA. Chronic treatment of ROS cells for 3 days with PMA caused depletion of total PKC activity in cytosolic and membrane fractions to less than 10% of that in control cells. Conversely, chronic treatment of ROS cells with PTH did not deplete PKC. In addition, chronic treatment of ROS cells with PTH inhibited the responsiveness of PKC activity to subsequent acute PTH challenge, but not to acute PMA challenge, suggesting specific desensitization of this response by PTH. Activation of cytosolic PKC by diolein, phosphatidylserine, and calcium caused phosphorylation of many cytosolic proteins, including those having apparent mol wt of 39K, 35K, 33K, 25K, 19K, and 16K. Pretreatment of ROS cells with PTH resulted in a transient decrease in the phosphorylation of these cytosolic proteins by PKC. This decrease in cytosolic protein phosphorylation by treatment with PTH is temporally associated with PTH-stimulated translocation of PKC activity from the cytosol to the membranes. These data suggest a potential role for PKC in the mechanism of action of PTH in ROS cells.