Circulating Fibroblast Growth Factor 23 in Patients with End-Stage Renal Disease Treated by Peritoneal Dialysis Is Intact and Biologically Active

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Abstract
Context: Fibroblast growth factor 23 (FGF23) regulates phosphorus homeostasis and vitamin D metabolism. Circulating FGF23 levels are elevated in inherited and acquired hypophosphatemic disorders that can cause rickets or osteomalacia. Particularly increased concentrations of FGF23 are observed in patients with chronic kidney disease (CKD), in which increased FGF23 is associated with more rapid disease progression, improved bone mineralization, the development of left ventricular hypertrophy, and increased mortality. Objective: Our objective was to determine whether the markedly elevated levels of immunoreactive FGF23 in CKD represent accumulation of intact, biologically active hormone, C-terminal cleavage fragments, or both. Design: Biologically active FGF23 in plasma from CKD patients treated by peritoneal dialysis was quantified using a cell-based Egr-1 reporter assay; bioactive FGF23 levels were compared with those measured with immunometric FGF23 assays detecting either intact hormone alone or intact hormone and C-terminal fragments. Setting and Patients: Adult and pediatric patients with end-stage renal disease treated with peritoneal dialysis participated in the study at a tertiary referral center. Results: Serially diluted patient samples revealed levels of bioactive FGF23 that ran in parallel to CHO cell-derived recombinant human FGF23. FGF23 bioactivity was inhibited by an anti-FGF23 antibody. Levels of bioactive and immunoreactive FGF23 were tightly correlated, and Western blot analysis of FGF23 immunoprecipitated with anti-FGF23 antibodies from plasma of dialysis patients revealed only a single prominent protein band, which was indistinguishable from recombinant intact FGF23, without clear evidence for FGF23 fragments. Conclusions: Our results provide strong evidence for the conclusion that virtually all circulating FGF23 in dialysis patients is intact and biologically active.