Fibroblast growth factor-23 in early chronic kidney disease: additional support in favor of a phosphate-centric paradigm for the pathogenesis of secondary hyperparathyroidism

Abstract

Background and objectives: The discovery of fibroblast growth factor-23 (FGF-23) and the elucidation of its function as a phosphaturic and 1,25(OH)2VitD counter-regulatory hormone provides a new conceptual framework for the understanding of the pathogenesis of secondary hyperparathyroidism. This study aims to elucidate the complex associations between FGF-23, parathyroid hormone (PTH), 1,25(OH)2D, and phosphate in patients with early-stage chronic kidney disease (CKD) and to provide clinical evidence in favor of the new phosphate-centric paradigm for the pathogenesis of secondary hyperparathyroidism.

Design, setting, participants, & measurements: Serum biointact PTH and FGF-23, 25(OH)D, 1,25(OH)2D, calcium, phosphate, 24-hour urine excretion of phosphate and calcium, and urinary fractional excretion of phosphate were determined in a cross-sectional study including 125 patients with CKD stages 1 to 3.

Results: Serum phosphate levels showed an inverse association with estimated GFR (eGFR), but were within the normal range in all but one patient. FGF-23 and PTH were inversely associated with eGFR, even in the subgroup of patients with CKD stages 1 and 2. High FGF-23 levels were significantly more prevalent than high PTH levels. The urinary fractional excretion of phosphate was highest in patients with both a high serum FGF-23 and PTH level. Increased FGF-23 and phosphate and decreased 25(OH)D were independently associated with decreased 1,25(OH)2D.

Conclusions: Our data are in favor of the new paradigm for the pathogenesis of secondary hyperparathyroidism according to which a reduced phosphate excretion capacity is the principal abnormality that initiates secondary hyperparathyroidism.

Trial registration: ClinicalTrials.gov NCT00441623.

Figure 1.

Phosphate (A), PTH (B), FGF-23 (C), and calcitriol (D) levels according to eGFR. Dashed line denotes the upper normal limit.

Figure 2.

Fractional excretion of phosphate according to eGFR (A) and categorized according to serum FGF-23 and PTH level (high denotes >40 ng/L for PTH and >50 pg/ml for FGF-23) (B).