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.

Dysregulated phosphate metabolism is a common consequence of chronic kidney disease, and is characterized by a high circulating level of fibroblast growth factor (FGF)-23, hyperparathyroidism, and hyperphosphataemia. Kidney transplantation can elicit specific alterations to phosphate metabolism that evolve over time, ranging from severe hypophosphataemia (<0.5 mmol/l) to hyperphosphataemia (>1.50 mmol/l) and high FGF-23 levels. The majority of renal transplant recipients develop hypophosphataemia during the first 3 months after transplantation as a consequence of relatively slow adaptation of FGF-23 and parathyroid hormone levels to restored renal function, and the influence of immunosuppressive drugs. By 3-12 months after transplantation, phosphate homeostasis is at least partially restored in the majority of recipients, which is paralleled by a substantially reduced risk of cardiovascular-associated morbidity and mortality compared with the pre-transplantation setting. Many renal transplant recipients, however, exhibit persistent abnormalities in phosphate homeostasis, which is often due to multifactorial causes, and may contribute to adverse outcomes on the cardiovascular system, kidney, and bone. Dietary and pharmacologic interventions might improve phosphate homeostasis in renal transplant recipients, but additional insight into the pathophysiology of transplantation-associated abnormalities in phosphate homeostasis is needed to further optimize disease management and improve prognosis for renal transplant recipients.

A higher intake of fish and dietary n-3 fatty acids (EPA-DHA) is related to lower circulating FGF23 levels in renal transplant recipients. Further research is needed to assess the causality of this association and the clinical implications.