Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease

Abstract

Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2-4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100 RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels.

Figure 1. Prevalence of hyperphosphatemia, secondary hyperparathyroidism and elevated FGF23 in relation to eGFR

Hyperphosphatemia was defined as serum phosphate ≥ 4.6 mg/dl, secondary hyperparathyroidism as PTH ≥ 65 pg/ml and FGF23 excess as FGF23 ≥ 100 RU/ml.

Figure 2. Proportions of participants with normal or high FGF23 and PTH levels within each eGFR category

Sections of pie charts indicate proportions of individuals with FGF23 and/or PTH abnormalities by eGFR category: white – normal PTH and FGF23 levels; yellow – high PTH/normal FGF23; gray – high FGF23/high PTH; and blue – high FGF23/normal PTH.

Figure 3. Cubic spline functions of the associations of eGFR with logFGF23 and with logPTH

The shadowed areas represent 95% confidence intervals for the fitted splines. The red dotted lines represents the statistically significantly thresholds of eGFR at which the slopes increased. Tick marks on the x axis indicate individual observations at each level of eGFR. (A) logFGF23 versus eGFR; (B) logPTH versus eGFR.

Figure 4. Cubic spline functions of the associations between serum phosphate and logFEPi with eGFR

The shadowed areas represent 95% confidence intervals for the fitted splines. The red dotted line represents the statistically significantly thresholds of eGFR at which the slope of serum phosphate changed. Based on this change, two phases of the phosphate curve are proposed.