Fractional excretion of phosphorus modifies the association between fibroblast growth factor-23 and outcomes

Abstract

Fibroblast growth factor-23 (FGF23) induces phosphaturia through its effects on renal tubules. Higher levels of FGF23 associate with cardiovascular disease (CVD) events and all-cause mortality, but it is unknown whether these associations differ by the degree of phosphaturia. Here, we measured serum FGF23 and 24-hour urine fractional excretion of phosphorus (FePi) in 872 outpatients with stable CVD and a mean estimated GFR of 71 ml/min per 1.73 m(2). During an average 7.5 years of follow-up, there were 337 deaths and 199 CVD events. Urinary FePi significantly modified the association of FGF23 with each outcome (P interaction<0.001 for all-cause mortality and P interaction<0.05 for CVD events). In models adjusted for CVD risk factors, kidney function, and PTH, those patients who had FGF23 above the median (≥ 42.3 relative units [RU]/ml) but FePi below the median (<15.7%) had the highest risks of both all-cause mortality (HR=1.98, 95% CI=1.42-2.77) and CVD events (HR=1.92, 95% CI=1.25-2.94) compared with those patients who had low concentrations of FGF23 and low FePi. In summary, associations of FGF23 with mortality and CVD events are stronger in persons with lower FePi independent of PTH and kidney function. In such individuals, the renal tubular response to FGF23 may be suboptimal.

Figure 1.

Adjusted HRs of FGF23 quartiles with mortality and CVD events stratified by urine fractional excretion of phosphorus above versus below the median. The low FGF23 quartile served as the reference category. Models were adjusted for age, sex, estrogen use (women), race, diabetes, systolic BP, BMI, total cholesterol, HDL cholesterol, smoking, CRP, eGFR, ACR, and PTH. Cut points for FGF23 quartiles were quartile 1, FGF23<27.7 RU/ml; quartile 2, FGF23=27.8–42.3 RU/ml; quartile 3, FGF23=42.3–69.5 RU/ml; quartile 4, FGF23>69.5 RU/ml.