Association of Fibroblast Growth Factor 23 With Atrial Fibrillation in Chronic Kidney Disease, From the Chronic Renal Insufficiency Cohort Study

Abstract

Importance Levels of fibroblast growth factor 23 (FGF23) are elevated in chronic kidney disease (CKD) and strongly associated with left ventricular hypertrophy, heart failure, and death. Whether FGF23 is an independent risk factor for atrial fibrillation in CKD is unknown. Objective To investigate the association of FGF23 with atrial fibrillation in CKD. Design, Setting, and Participants Prospective cohort study of 3876 individuals with mild to severe CKD who enrolled in the Chronic Renal Insufficiency Cohort Study between June 19, 2003, and September 3, 2008, and were followed up through March 31, 2013. Exposures Baseline plasma FGF23 levels. Main Outcomes and Measures Prevalent and incident atrial fibrillation. Results The study cohort comprised 3876 participants. Their mean (SD) age was 57.7 (11.0) years, and 44.8% (1736 of 3876) were female. Elevated FGF23 levels were independently associated with increased odds of prevalent atrial fibrillation (n = 660) after adjustment for cardiovascular and CKD-specific factors (odds ratio of highest vs lowest FGF23 quartile, 2.30; 95% CI, 1.69-3.13; P < .001 for linear trend across quartiles). During a median follow-up of 7.6 years (interquartile range, 6.3-8.6 years), 247 of the 3216 participants who were at risk developed incident atrial fibrillation (11.9 events per 1000 person-years). In fully adjusted models, elevated FGF23 was independently associated with increased risk of incident atrial fibrillation after adjustment for demographic, cardiovascular, and CKD-specific factors, and other markers of mineral metabolism (hazard ratio of highest vs lowest FGF23 quartile, 1.59; 95% CI, 1.00-2.53; P = .02 for linear trend across quartiles). The results were unchanged when further adjusted for ejection fraction, but individual adjustments for left ventricular mass index, left atrial area, and interim heart failure events partially attenuated the association of elevated FGF23 with incident atrial fibrillation. Conclusions and Relevance Elevated FGF23 is independently associated with prevalent and incident atrial fibrillation in patients with mild to severe CKD. The effect may be partially mediated through a diastolic dysfunction pathway that includes left ventricular hypertrophy, atrial enlargement, and heart failure events.

Stability of Fibroblast Growth Factor 23 in Human Plasma

“…Fibroblast growth factor 23 (FGF23) 4 is an osteocyte-derived phosphaturic hormone that plays an important role in vitamin D metabolism (1). Over the past decade, FGF23 has emerged as a powerful biomarker of death (2,3) and other adverse outcomes (4)(5)(6) in patients with chronic kidney disease (CKD). Moreover, recent studies in animal models suggest that increased plasma FGF23 concentrations in CKD patients may be directly implicated in the pathogenesis of left ventricular hypertrophy (7), immune dysfunction (8), and inflammation (9).…”

A Novel Distal Enhancer Mediates Inflammation‐, PTH‐, and Early Onset Murine Kidney Disease‐Induced Expression of the Mouse Fgf23 Gene

“…For example, FGF23 levels increase in early stages of renal failure and become gradually elevated during CKD progression in parallel with increased serum phosphate levels . Elevated FGF23 levels in CKD have also been associated with increased cardiovascular disease and mortality . Although these studies suggest that FGF23 is an important component in CKD, the causes, sources, and the molecular mechanisms through which FGF23 is increased are largely unknown.…”

Randomized Clinical Trial of Sevelamer Carbonate on Serum Klotho and Fibroblast Growth Factor 23 in CKD

“…Elevated FGF23 is an independent risk factor for the progression to ESRD in patients with CKD with relatively preserved residual kidney function (4). Lastly, high serum FGF23 levels are reportedly associated with vascular calcification (5), left ventricular hypertrophy (6), cardiovascular events (7,8), and mortality (9,10).…”