Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease

Abstract

Context: A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease.

Objective: To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease.

Design, setting, and participants: A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008.

Main outcome measures: All-cause mortality and end-stage renal disease.

Results: At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5) mL/min/1.73 m(2), and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239 reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266 participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000 person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a greater risk of death (hazard ratio [HR], per SD of natural log-transformed FGF-23, 1.5; 95% confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3 (95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95% CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently associated with significantly higher risk of end-stage renal disease among participants with an estimated GFR between 30 and 44 mL/min/1.73 m(2) (HR, 1.3 per SD of FGF-23 natural log-transformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m(2) or higher (HR, 1.7; 95% CI, 1.1-2.4), but not less than 30 mL/min/1.73 m(2).

Conclusion: Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with relatively preserved kidney function and for mortality across the spectrum of chronic kidney disease.

Figure 1. Plot of the multivariable-adjusted hazard function for death according to measured (untransformed) levels of FGF23

The median FGF23 level within the lowest FGF23 quartile (74 RU/ml) served as the referent value (hazard = 1). The model was stratified by center and adjusted for age, sex, race, ethnicity, estimated glomerular filtration rate, natural log-transformed urine albumin-to-creatinine ratio, hemoglobin, serum albumin, systolic blood pressure, body mass index, diabetes, smoking, low density lipoprotein, history of coronary artery disease, congestive heart failure, stroke, and peripheral vascular disease, and use of aspirin, beta-blockers, statins, and angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and serum calcium, phosphate and natural log-transformed parathyroid hormone. Tick marks on the × axis indicate individual observations at corresponding levels of FGF23.

Figure 2. Stratified analyses of risk of death according to FGF23 levels

The multivariable-adjusted hazard ratio of death per unit increment in standard deviation (SD) of natural log-transformed (ln) FGF23 is plotted for the entire cohort and according to strata of baseline covariates. Multivariable models were stratified by center and adjusted for age, sex, race, ethnicity, estimated glomerular filtration rate, natural log-transformed urine albumin-to-creatinine ratio, hemoglobin, serum albumin, systolic blood pressure, body mass index, diabetes, smoking, low density lipoprotein, history of coronary artery disease, congestive heart failure, stroke, and peripheral vascular disease, and use of aspirin, beta-blockers, statins, and angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and serum calcium, phosphate and natural log-transformed parathyroid hormone. The number of participants (No.) and total number of deaths are presented for each stratum. Abbreviations: CI, confidence; CVD, cardiovascular disease; ACR, urine albumin-to-creatinine ratio; PTH, parathyroid hormone, LDL, low density lipoprotein.

Figure 3. FGF23 levels and risks of ESRD and death according to baseline kidney function

Multivariable-adjusted risks of ESRD and death per unit increment in standard deviation (SD) of natural log-transformed (ln) FGF23 in all participants and according to categories of baseline estimated glomerular filtration rate (eGFR). Models were stratified by center and adjusted for age, sex, race, ethnicity, natural log-transformed urine albumin-to-creatinine ratio, hemoglobin, serum albumin, systolic blood pressure, body mass index, diabetes, smoking, low density lipoprotein, history of coronary artery disease, congestive heart failure, stroke, and peripheral vascular disease, and use of aspirin, beta-blockers, statins, and angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and serum calcium, phosphate and natural log-transformed parathyroid hormone. Error-bars indicate 95% confidence intervals. The number of participants (No.), their median FGF23 levels, total number of events, and the unadjusted event rate, expressed per 1000 person-years, are presented for the categories of baseline eGFR. Abbreviations: ESRD, end-stage renal disease; HR, hazard ratio; SD, standard deviation.