FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis

Abstract

Concentrations of the phosphate-regulating hormone fibroblast growth factor-23 (FGF-23) are elevated in patients with chronic kidney disease (CKD), but whether higher plasma FGF-23 concentrations associate with all-cause mortality, cardiovascular events, or initiation of chronic dialysis is not completely understood. Here, we measured FGF-23 concentration in stored plasma samples from 1099 patients with advanced CKD who participated in The Homocysteine in Kidney and End Stage Renal Disease study. Mean serum phosphorus concentration was 4.3 mg/dl, median FGF-23 concentration was 392 RU/ml, and mean GFR was 18 ml/min/1.73 m(2). During a median follow-up of 2.9 yr, 453 (41%) patients died from any cause, 215 (20%) had a cardiovascular event, and 615 (56%) initiated chronic dialysis. Compared with the lowest quartile of FGF-23, each subsequent quartile associated with a progressively higher risk for death, adjusted for confounders (HR [95% CI] of 1.24 [0.91 to 1.69], 1.76 [1.28 to 2.44], and 2.17 [1.56 to 3.08] for the second through fourth quartiles, respectively). In addition, compared with the lowest quartile, the two highest quartiles of FGF-23 also associated with a significantly elevated risk for cardiovascular events and initiation of chronic dialysis. In conclusion, in advanced CKD, FGF-23 strongly and independently associates with all-cause mortality, cardiovascular events, and initiation of chronic dialysis.

Figure 1.

Kaplan-Meier curve of all-cause mortality according to quartiles of baseline plasma fibroblast growth factor-23 (FGF-23) concentrations.

Figure 2.

Hazard ratio (95% CI) for all-cause mortality according to quartiles of baseline plasma fibroblast growth factor-23 (FGF-23) concentrations. Model 1: adjusted for age, gender, race Model 2: adjusted for covariates in Model 1 plus smoking, alcohol intake, diabetes, hypertension, prevalent cardiovascular disease, Charlson score, body mass index, systolic and diastolic BP, homocysteine, folate, vitamin B₁₂, treatment arm, hemoglobin, estimated GFR, albumin, calcium, phosphorus, 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, intact parathyroid hormone, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides Model 3: adjusted for covariates in Model 2 plus use of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, aldosterone antagonists, lipid-lowering agents, aspirin, anticoagulants, anti-arrhythmic drugs, and sevelamer Quartile 1 is the reference group in all models. R denotes reference and bars represent 95% confidence intervals.

Figure 3.

Kaplan-Meier curve of cardiovascular events according to quartiles of baseline plasma fibroblast growth factor-23 (FGF-23) concentrations.

Figure 4.

Hazard ratio (95% CI) for the composite of cardiovascular events according to quartiles of baseline plasma fibroblast growth factor-23 (FGF-23) concentrations Model 1: adjusted for age, gender, race Model 2: adjusted for covariates in Model 1 plus smoking, alcohol intake, diabetes, hypertension, prevalent cardiovascular disease, Charlson score, body mass index, systolic and diastolic BP, homocysteine, folate, vitamin B₁₂, treatment arm, hemoglobin, estimated GFR, albumin, calcium, phosphorus, 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, intact parathyroid hormone, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides Model 3: adjusted for covariates in Model 2 plus use of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, aldosterone antagonists, lipid-lowering agents, aspirin, anticoagulants, anti-arrhythmic drugs, and sevelamer Quartile 1 is the reference group in all models. R denotes reference and bars represent 95% confidence intervals.

Figure 5.

Association of baseline plasma fibroblast growth factor-23 with the composite of all-cause mortality and cardiovascular events within subgroups. Error bars represent 95% confidence intervals. eGFR = estimated GFR; 1,25D = 1,25-dihydroxyvitamin D.

Figure 6.

Hazard ratio (95% CI) for initiation of chronic dialysis according to quartiles of baseline plasma fibroblast growth factor-23 (FGF-23) concentrations Model 1: adjusted for age, gender, race Model 2: adjusted for covariates in Model 1 plus smoking, alcohol intake, diabetes, hypertension, prevalent cardiovascular disease, Charlson score, body mass index, systolic and diastolic BP, homocysteine, folate, vitamin B₁₂, treatment arm, hemoglobin, estimated GFR, albumin, calcium, phosphorus, 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, intact parathyroid hormone, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides Model 3: adjusted for covariates in Model 2 plus the use of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, aldosterone antagonists, lipid-lowering agents, aspirin, anticoagulants, anti-arrhythmic drugs and sevelamer Quartile 1 is the reference group in all models. R denotes reference and bars represent 95% confidence intervals.