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 6 SD, 52612 years; 54% male; estimated GFR, 47616 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 (b=0.20, P,0.001), NT-proBNP (b=0.18, P,0.001), and copeptin (b=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.

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

“…Most studies show a near-linear increase in risk with increasing FGF23 concentrations, with available (but limited) data suggesting comparable results between cFGF23 and iFGF23 (42,45). With respect to renal outcomes, higher FGF23 concentrations have been associated with earlier initiation of chronic dialysis and significant decrements in renal function in patients with nondialysis-dependent CKD (4,5,36,46), again yielding improvements in event reclassification (19%) (47), and have variably predicted graft failure after kidney transplantation (44,45). Moreover, FGF23 predicts progression in disease-specific causes of renal failure, including IgA nephropathy, and those patients with heavy proteinuric diabetic kidney disease (48,49).…”

“…Multiple prospective studies have shown a consistent link between higher FGF23 concentrations and increased risk of both death and cardiovascular events across the entire spectrum of renal disease (4,5,(42)(43)(44)(45). Most studies show a near-linear increase in risk with increasing FGF23 concentrations, with available (but limited) data suggesting comparable results between cFGF23 and iFGF23 (42,45).…”

Calcification Propensity and Survival among Renal Transplant Recipients

“…Finally, we performed mediation analyses to identify potential causal pathways shared among T 50 and two established nontraditional cardiovascular risk factors in RTR: N-terminal-pro brain natriuretic peptide (NT-proBNP) 12 and fibroblast growth factor 23 (FGF23). 13 …”

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“…Although patients with the highest FGF23 levels were characterized by an overall high cardiovascular risk profile, the associations between FGF23 and mortality (cardiovascular and all-cause) remained significant after adjustment for several major cardiovascular risk factors, including Framingham risk factors, suggesting that FGF23 is a strong and independent risk marker. 16 In addition, Dominguez and associates reported associations between FGF23 and mortality, with events related to cardiovascular disease more likely in individuals with lower fractional excretion of phosphate independent of PTH and kidney function. In such individuals, the renal tubular response to FGF23 may be suboptimal.…”