Fibroblast growth factor 23 and adverse clinical outcomes in chronic kidney disease

Abstract

Purpose of review: The aim is to review data on the epidemiology of fibroblast growth factor 23 (FGF23) and adverse clinical outcomes in chronic kidney disease (CKD) and introduce recent insights into the pathophysiology behind the observed relationships.

Recent findings: End-stage renal disease and cardiovascular disease are frequent events in patients with CKD, in whom cardiovascular disease is the leading cause of death. Elevated levels of FGF23, a phosphate and vitamin D-regulating hormone, have been associated with risks of end-stage renal disease, cardiovascular disease and mortality. FGF23 excess has also been linked with left-ventricular hypertrophy, and innovative translational experiments have recently established direct end-organ toxicity of FGF23, which induced left-ventricular hypertrophy in animals.

Summary: FGF23 is emerging as a novel risk factor in CKD. Future studies should determine whether interventions that lower FGF23 levels improve clinical outcomes in CKD.

Figure 1. Crude, case-mix-adjusted, and multivariable-adjusted odds ratio of mortality according to quartiles of cFGF23

The case-mix-adjusted analysis included the following variables: age, sex, race, ethnicity, blood pressure, body mass index, standardized mortality rate, vascular access, history of diabetes, and congestive heart failure. The multivariable-adjusted analysis included the case-mix variables plus phosphate, calcium, log parathyroid hormone, albumin, creatinine, and ferritin. Quartile 1 is the reference group in all models (Quartile 1, < 1090 RU/ml; Quartile 2, 1090–1750 RU/ml; Quartile 3, 1751–4010 RU/ml; Quartile 4, > 4010 RU/ml). Vertical lines represent 95% confidence intervals. This figure is reproduced from Gutiérrez et al [24], with permission from the Massachusetts Medical Society. Copyright c [2008] Massachusetts Medical Society. All rights reserved.

Figure 2. Multivariable-adjusted hazard function for death according to FGF23 levels

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 x axis indicate individual observations at corresponding levels of FGF23. This figure is reproduced from Isakova et al [25], with permission from the American Medical Association. Copyright c [2011] American Medical Association. All rights reserved.

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. This figure is reproduced from Isakova et al [25], with permission from the American Medical Association. Copyright c [2011] American Medical Association. All rights reserved.