Fibroblast growth factor-23 and cardiovascular events in CKD

Abstract

An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44±15 ml/min per 1.73 m(2)). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4.

Figure 1.

FGF-23 is associated with atherosclerotic and congestive heart failure events. Multivariable-adjusted hazard ratios of cardiovascular events according to levels of FGF-23 on the arithmetic scale. (A) Atherosclerotic events. (B) Congestive heart failure events. Models are adjusted for age, sex, income, eGFR, urinary albumin-to-creatinine ratio; history of hypertension, hypercholesterolemia, atherosclerotic cardiovascular disease, congestive heart failure, and diabetes; control of BP <140/90 mmHg; hemoglobin A1c; smoking status; body mass index; waist circumference; serum triglycerides; LDL cholesterol; use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, β-blockers, statins, and loop diuretics; and the number of prescribed classes of BP medications. The median of the first quartile of FGF-23 (74 RU/ml) serves as the reference. Tick marks on the x axis represent individual participants’ FGF-23 levels.

Figure 2.

FGF-23 is associated with cardiovascular events across strata of cardiovascular risk factors. HRs ratio (diamonds) and 95% CIs (horizontal bars) of cardiovascular events by levels of FGF-23 in selected subgroups. (A) Atherosclerotic events. (B) Congestive heart failure events. Models are adjusted for age, sex, income, eGFR, urinary albumin-to-creatinine ratio; history of hypertension, hypercholesterolemia, atherosclerotic cardiovascular disease, congestive heart failure, and diabetes; control of BP<140/90 mmHg; hemoglobin A1c; smoking status; body mass index; waist circumference; serum triglycerides; LDL cholesterol; use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, β-blockers, statins, and loop diuretics; and the number of prescribed classes of BP medications. History of cardiovascular disease refers to a history of atherosclerotic or congestive heart failure. Anemia is defined as hemoglobin<12 g/dl in women and <13 g/dl in men. Total N does not sum across groups to 3860 because of missing data for individual covariates that were included in the multivariable models.

Figure 2.

FGF-23 is associated with cardiovascular events across strata of cardiovascular risk factors. HRs ratio (diamonds) and 95% CIs (horizontal bars) of cardiovascular events by levels of FGF-23 in selected subgroups. (A) Atherosclerotic events. (B) Congestive heart failure events. Models are adjusted for age, sex, income, eGFR, urinary albumin-to-creatinine ratio; history of hypertension, hypercholesterolemia, atherosclerotic cardiovascular disease, congestive heart failure, and diabetes; control of BP<140/90 mmHg; hemoglobin A1c; smoking status; body mass index; waist circumference; serum triglycerides; LDL cholesterol; use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, β-blockers, statins, and loop diuretics; and the number of prescribed classes of BP medications. History of cardiovascular disease refers to a history of atherosclerotic or congestive heart failure. Anemia is defined as hemoglobin<12 g/dl in women and <13 g/dl in men. Total N does not sum across groups to 3860 because of missing data for individual covariates that were included in the multivariable models.

Figure 3.

FGF-23 is more strongly associated with congestive heart failure compared to atherosclerotic events in overall, incident and definite event analyses. HRs (squares) and 95% CIs (vertical bars) for overall, incident, and definite atherosclerotic (A) and congestive heart failure events (B) by quartiles (Q) of FGF-23. Models are adjusted for demographic variables, kidney function, traditional cardiovascular risk factors, and medications. Q1 served as the reference group for all analyses.