Fibroblast growth factor 23 and cardiovascular mortality after kidney transplantation

Abstract

Background and objectives: Circulating fibroblast growth factor 23 (FGF23) is associated with adverse cardiovascular outcomes in CKD. Whether FGF23 predicts cardiovascular mortality after kidney transplantation, independent of measures of mineral metabolism and cardiovascular risk factors, is unknown.

Design, setting, participants, & measurements: The association between plasma C-terminal FGF23 and cardiovascular mortality was analyzed in a single-center prospective cohort of 593 stable kidney transplant recipients (mean age ± SD, 52 ± 12 years; 54% male; estimated GFR, 47 ± 16 ml/min per 1.73 m(2)), at a median of 6.1 (interquartile range, 2.7-11.7) years after transplantation. Multivariate Cox regression models were built, adjusting for measures of renal function and mineral metabolism; Framingham risk factors; the left ventricular wall strain markers midregional fragment of pro-A-type natriuretic peptide (MR-proANP) and N-terminal-pro brain natriuretic peptide (NT-proBNP); and copeptin, the stable C-terminal portion of the precursor of vasopressin.

Results: In multivariate linear regression analysis, MR-proANP (β=0.20, P<0.001), NT-proBNP (β=0.18, P<0.001), and copeptin (β=0.26, P<0.001) were independently associated with FGF23. During follow-up for 7.0 (interquartile range, 6.2-7.5) years, 128 patients (22%) died, of whom 66 (11%) died due to cardiovascular disease; 54 (9%) had graft failure. FGF23 was associated with an higher risk of cardiovascular mortality in a fully adjusted multivariate Cox regression model (hazard ratio [HR], 1.88 [95% confidence interval (CI), 1.11 to 3.19]; P=0.02). FGF23 was also independently associated with all-cause mortality (full model HR, 1.86 [95% CI, 1.27 to 2.73]; P=0.001). Net reclassification improved for both cardiovascular mortality (HR, 0.07 [95% CI, 0.01 to 0.14]; P<0.05) and all-cause mortality (HR, 0.11 [95% CI, 0.05 to 0.18]; P<0.001).

Conclusions: Plasma FGF23 is independently associated with cardiovascular and all-cause mortality after kidney transplantation. The association remained significant after adjustment for measures of mineral metabolism and cardiovascular risk factors.

Figure 1.

Scatter diagrams illustrating the associations between fibroblast growth factor 23 (FGF23) and (A) N-terminal-pro brain natriuretic peptide (NT-proBNP), (B) pro–A-type natriuretic peptide (MR-proANP), and (C) copeptin.

Figure 2.

Kaplan-Meier survival plots of fibroblast growth factor 23 (FGF23) tertiles and cardiovascular mortality. Higher FGF23 levels are associated with an increased incidence of cardiovascular mortality.

Figure 3.

Comparative analysis of fibroblast growth factor 23 (FGF23), fractional phosphate excretion (FE PO4), parathyroid hormone, phosphate (P), 25(OH)-vitamin D, or 1,25(OH)₂ vitamin D as independent risk factors for cardiovascular (CV) mortality. The model was adjusted for age, sex, cardiovascular history, estimated GFR, proteinuria, and Framingham risk factors. For each exposure, the lowest tertile served as the reference group (R).