FGF23 and Cardiovascular Disease in CKD

Project: Research project

Project Details

Description

FGF23 levels are elevated in patients with CKD, and strongly associated with increased risks of CKD progression, cardiovascular disease (CVD) and death. Designing therapies to lower FGF23 requires further understanding of the factors that stimulate FGF23 production in early CKD. Iron deficiency stimulates FGF23 transcription in osteocytes. In health, increased FGF23 transcription induced by iron deficiency is coupled to a comparable increase in post-translational inactivation of FGF23 by cleavage of the parent molecule into inactive fragments. The result is normal levels of biologically active intact FGF23, but increased levels of inactive FGF23 fragments. The normal intact FGF23 levels account for the lack of change in serum phosphate levels in iron deficiency, while the elevated levels of FGF23 fragments reflect increased production and subsequent cleavage of FGF23.

Current assays allow non-invasive assessment of FGF23 regulation by osteocytes. C-terminal (cFGF23) assays detect both full-length, intact hormone and its C-terminal fragments, whereas intact assays (iFGF23) detect the intact biologically active hormone exclusively. Using both assays enables an assessment of the fraction of total circulating FGF23 that is intact hormone, which can be summarized as the iFGF23:cFGF23 ratio (range: 0 -100%).

We previously demonstrated that the iFGF23:cFGF23 is ~100% in end-stage renal disease (ESRD): meaning, virtually all circulating FGF23 is intact, biologically active hormone in ESRD. Other groups demonstrated far lower iFGF23:cFGF23 ratios (i.e. more fragments) in healthy individuals, and an intermediate ratio in patients with CKD. Collectively, these data indicate that the concentration of fragments gradually decreases as CKD progresses (the opposite of PTH, fragments of which increase as CKD progresses). We hypothesize that the balance between FGF23 transcription and cleavage in osteocytes is a fundamental mechanism of FGF23 regulation. Furthermore, we hypothesize that increased FGF23 transcription and downregulated FGF23 cleavage are basic mechanisms underlying the early increase in FGF23 levels in CKD. Consistent with our hypotheses, we confirmed in mice that FGF23 cleavage is decreased in CKD and, as a result, iron deficiency specifically increases intact FGF23 levels only in mice with CKD.

By performing detailed assessments of iron status, we will also be positioned to perform the most comprehensive analyses of iron status and clinical outcomes in CKD. Small previous studies suggest adverse effects of anemia and iron deficiency, but these were limited to small studies with incomplete biochemical assessments of iron status.
StatusFinished
Effective start/end date12/1/167/31/18

Funding

  • Duke University (2036138//7R01DK081374-11)
  • National Institute of Diabetes and Digestive and Kidney Diseases (2036138//7R01DK081374-11)

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