Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis

Abstract

Background: Fibroblast growth factor 23 (FGF-23) is a hormone that increases the rate of urinary excretion of phosphate and inhibits renal production of 1,25-dihydroxyvitamin D, thus helping to mitigate hyperphosphatemia in patients with kidney disease. Hyperphosphatemia and low 1,25-dihydroxyvitamin D levels are associated with mortality among patients with chronic kidney disease, but the effect of the level of FGF-23 on mortality is unknown.

Methods: We examined mortality according to serum phosphate levels in a prospective cohort of 10,044 patients who were beginning hemodialysis treatment and then analyzed FGF-23 levels and mortality in a nested case-control sample of 200 subjects who died and 200 who survived during the first year of hemodialysis treatment. We hypothesized that increased FGF-23 levels at the initiation of hemodialysis would be associated with increased mortality.

Results: Serum phosphate levels in the highest quartile (>5.5 mg per deciliter [1.8 mmol per liter]) were associated with a 20% increase in the multivariable adjusted risk of death, as compared with normal levels (3.5 to 4.5 mg per deciliter [1.1 to 1.4 mmol per liter]) (hazard ratio, 1.2; 95% confidence interval [CI], 1.1 to 1.4). Median C-terminal FGF-23 (cFGF-23) levels were significantly higher in case subjects than in controls (2260 vs. 1406 reference units per milliliter, P<0.001). Multivariable adjusted analyses showed that increasing FGF-23 levels were associated with a monotonically increasing risk of death when examined either on a continuous scale (odds ratio per unit increase in log-transformed cFGF-23 values, 1.8; 95% CI, 1.4 to 2.4) or in quartiles, with quartile 1 as the reference category (odds ratio for quartile 2, 1.6 [95% CI, 0.8 to 3.3]; for quartile 3, 4.5 [95% CI, 2.2 to 9.4]; and for quartile 4, 5.7 [95% CI, 2.6 to 12.6]).

Conclusions: Increased FGF-23 levels appear to be independently associated with mortality among patients who are beginning hemodialysis treatment. Future studies might investigate whether FGF-23 is a potential biomarker that can be used to guide strategies for the management of phosphorus balance in patients with chronic kidney disease.

Figure 1. Odds Ratios (and 95% CIs) for Death According to Quartile of C-Terminal Fibroblast Growth Factor 23 (cFGF-23) Levels

Crude, case-mix adjusted, and multivariable adjusted odds ratios for death are shown according to quartile of cFGF-23 levels (quartile 1, <1090 reference units [RU] per milliliter; quartile 2, 1090 to 1750 RU per milliliter; quartile 3, 1751 to 4010 RU per milliliter; quartile 4, >4010 RU per milliliter). The case-mix adjusted analysis included the following variables: age, sex, race or ethnic group, blood pressure, body-mass index, facility-specific standardized mortality rate, vascular access at initiation of dialysis (fistula, graft, or catheter), cause of renal failure, urea reduction ratio, and coexisting conditions. The multivariable adjusted analysis included the case-mix variables plus phosphate, calcium, log parathyroid hormone, albumin, creatinine, and ferritin levels. Quartile 1 was the reference group in all models. I bars represent 95% confidence intervals. Asterisks indicate P<0.05. R denotes reference.