Fibroblast growth factor 23

FGF-23 is a hormone secreted by osteoblasts and osteocytes that is as a central regulator of phosphorus and vitamin D metabolism (Figure). FGF-23 acts primarily in renal proximal tubules to increase urinary phosphate excretion though down-regulation of sodium-phosphate cotransporters and decrease 1,25-dihydroxyvitamin D (1,25(OH)2D) levels through the inhibition of 25-hydroxyvitamin D-1α-hydroxylase.22 The primary systemic stimuli of FGF-23 secretion appear to be increased dietary phosphorus intake and increased 1,25(OH)2D levels. In kidney disease, FGF-23 concentrations are constitutively elevated and steadily rise with progression of CKD.23 While this likely represents an appropriate physiological response to help maintain normal phosphorus balance by increasing urinary phosphate excretion and decreasing gut phosphorus

absorption via decreased 1,25(OH)2D synthesis, in the long-term, this contributes to a progressive decline in 1,25(OH)2D levels with associated consequences such as the stimulation of PTH secretion.23,24 Thus, elevated FGF-23 levels are thought to play a central role in the initiation and progression of secondary hyperparathyroidism in CKD patients.25 Furthermore, FGF-23 levels have been shown to be inversely correlated with osteoid volume and osteoid thickness in children,26 suggesting that, in addition to promoting secondary hyperparathyroidism, FGF-23 may also directly mediate bone disease by disrupting bone mineralization in patients with CKD.


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A growing body of evidence suggests that elevated FGF-23 levels may also be linked with cardiovascular morbidity and mortality. Increased FGF-23 levels have been associated with increased risks of CVD events and death among hemodialysis patients and among patients with moderate to severe CKD not yet requiring dialysis,27-29 independently of classical risk factors including age, gender, and diabetes. Moreover, similar relationships between FGF-23 with mortality were demonstrated in community-dwelling individuals with largely preserved kidney function,30 suggesting that the relationship between elevated FGF-23 and adverse outcomes is not specific to kidney disease, but may also extend to the general population. While the mechanisms for these associations remain to be elucidated, studies have shown a consistent and independent relationship between increased FGF-23 with markers of CVD, including left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and coronary artery disease,31-36 suggesting that the relationship between increased FGF-23 and mortality may be mediated by a link between FGF-23 and CVD. Taken together, these data suggest that while excess FGF-23 may be important for maintaining normal phosphorus balance in states of phosphate excess (particularly kidney failure), long-term exposure to elevated FGF-23 may become maladaptive by accelerating CVD and mortality. 

Whether FGF-23 exerts a direct toxic effect on end-organ tissues—perhaps by non-selectively activating fibroblast growth factor receptors in non-renal organs25—or whether its link with adverse outcomes is mediated through other factors—remains a critical question with key implications for the management of patients with CKD.  Indeed, FGF-23 levels can be decreased using routine clinical interventions that limit gut phosphorus absorption, including oral phosphorus binders.37,38 Therefore, if FGF-23 has direct toxicity, then it is possible that early implementation of dietary phosphorus restriction, even when serum phosphate levels may still be normal, could help ameliorate the markedly high rates of CVD and mortality in CKD.39

Even if FGF-23 is not shown to have direct toxicity and is “only” a biomarker of phosphorus excess, FGF-23 measurements may still have clinical utility for guiding the management of abnormal phosphorus metabolism in CKD. Indeed, serum phosphate levels represent a dynamic balance between dietary phosphorus intake, urinary and/or dialysis clearance, and exchanges with bone and soft tissue stores.40 As a result, single measurements of serum phosphate provide only a crude assessment of overall phosphorus balance, limiting their utility for identifying those patients who might benefit from early dietary phosphorus reduction (e.g., to mitigate the development of secondary hyperparathyroidism), particularly when serum phosphate levels are within the normal range. Furthermore, given that FGF-23 levels manifest much less diurnal and day-to-day variability than serum phosphate,39,41 FGF-23 may serve as a more stable marker of global phosphorus balance than random serum phosphate measurements, integrating critical information with respect to dietary phosphorus intake and urinary phosphate clearance. Future studies will need to investigate these possibilities, and determine whether measuring and “treating” elevated FGF-23 levels may improve clinical outcomes in patients with CKD.

Summary

Despite their limitations, PTH and alkaline phosphatase will remain central to the diagnosis and treatment of disordered mineral metabolism in CKD. As such, future research initiatives should focus on clarifying the growing uncertainties as to how best to utilize these markers in clinical practice, particularly as it relates to targets of therapy in each stage of CKD. Otherwise, the management of elevated PTH and alkaline phosphatase levels will likely evolve in accordance with changing hemodialysis reimbursement patterns and not, as it should, with emerging scientific evidence. Hopefully, the incorporation of newer biomarkers such FGF-23 into the treatment paradigm of CKD-MBD will eventually help to bolster the available diagnostic armamentarium by providing more refined tools for guiding clinical decision-making, especially with respect to managing abnormalities in phosphorus metabolism. Ultimately,  it is likely that obtaining measurements of all these biomarkers will be needed to navigate the increasingly complex environment of bone and mineral disorders in CKD.    

Dr. Gutiérrez is Assistant Professor of Medicine in the Division of Nephrology, Department of Medicine at the University of Alabama at Birmingham. He completed his internal medicine residency at the Massachusetts General Hospital and his nephrology fellowship at the combined Brigham and Women’s Hospital/Massachusetts General Hospital Joint Nephrology Fellowship Program. 


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