TY - JOUR
T1 - C-terminal fibroblast growth factor 23, iron deficiency, and mortality in renal transplant recipients
AU - Eisenga, Michele F.
AU - Van Londen, Marco
AU - Leaf, David E.
AU - Nolte, Ilja M.
AU - Navis, Gerjan
AU - Bakker, Stephan J.L.
AU - De Borst, Martin H.
AU - Gaillard, Carlo A.J.M.
N1 - Funding Information:
Generation of the TransplantLines Food and Nutrition Biobank and Cohort Study (TxL-FN) was funded by Top Institute Food and Nutrition. M.H.d.B. is supported by a Veni grant (The Netherlands Organization for Scientific Research, grant no 016.146.014).
Funding Information:
C.A.J.M.G. received speaking fees and research funding from Vifor Pharma. The other authors have declared that no conflict of interest exists.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Iron deficiency (ID) is independently associatedwith an increased risk of death in renal transplant recipients (RTRs). IDpromotes production and cleavage of intact fibroblast growth factor 23 (iFGF23) into C-terminal fibroblast growth factor 23 (cFGF23), elevated levels of which are also prospectively associated with adverse outcomes. We hypothesized that in RTRs, the relationship between ID and mortality is mediated by FGF23.Wemeasured plasma iFGF23 and cFGF23 levels in 700 stable RTRs at amedian of 5.4 years after transplant. RTRswith IDhadmedian (interquartile range) cFGF23 concentrations higher than those of RTRs without ID (223 [131-361] versus 124 [88-180] RU/ml; P,0.001), whereas iFGF23 concentrations were similar between groups. In multivariable-adjusted Cox regression analyses, ID associated with increased mortality (81 events; hazard ratio, 1.95; 95% confidence interval, 1.22 to 3.10; P,0.01). However, this association lost significance after additional adjustment for cFGF23 levels (hazard ratio, 1.45; 95% confidence interval, 0.87 to 2.51; P=0.15). In further mediation analysis, cFGF23 explained 46% of the association between ID and mortality, whereas iFGF23 did not mediate this association. In conclusion, we found that cFGF23 levels are increased in iron-deficient RTRs and that the underlying biologic process driving production and cleavage of iFGF23, or alternatively the increased level of cFGF23 fragments, probably is an important mediator of the association between ID and mortality. Our results underline the strong relationship between iron and FGF23 physiology, and provide a potential mechanism explaining the relationship between ID and adverse outcome in RTRs.
AB - Iron deficiency (ID) is independently associatedwith an increased risk of death in renal transplant recipients (RTRs). IDpromotes production and cleavage of intact fibroblast growth factor 23 (iFGF23) into C-terminal fibroblast growth factor 23 (cFGF23), elevated levels of which are also prospectively associated with adverse outcomes. We hypothesized that in RTRs, the relationship between ID and mortality is mediated by FGF23.Wemeasured plasma iFGF23 and cFGF23 levels in 700 stable RTRs at amedian of 5.4 years after transplant. RTRswith IDhadmedian (interquartile range) cFGF23 concentrations higher than those of RTRs without ID (223 [131-361] versus 124 [88-180] RU/ml; P,0.001), whereas iFGF23 concentrations were similar between groups. In multivariable-adjusted Cox regression analyses, ID associated with increased mortality (81 events; hazard ratio, 1.95; 95% confidence interval, 1.22 to 3.10; P,0.01). However, this association lost significance after additional adjustment for cFGF23 levels (hazard ratio, 1.45; 95% confidence interval, 0.87 to 2.51; P=0.15). In further mediation analysis, cFGF23 explained 46% of the association between ID and mortality, whereas iFGF23 did not mediate this association. In conclusion, we found that cFGF23 levels are increased in iron-deficient RTRs and that the underlying biologic process driving production and cleavage of iFGF23, or alternatively the increased level of cFGF23 fragments, probably is an important mediator of the association between ID and mortality. Our results underline the strong relationship between iron and FGF23 physiology, and provide a potential mechanism explaining the relationship between ID and adverse outcome in RTRs.
KW - fibroblast
KW - kidney transplantation
KW - mortality risk
UR - http://www.scopus.com/inward/record.url?scp=85034433338&partnerID=8YFLogxK
U2 - 10.1681/ASN.2016121350
DO - 10.1681/ASN.2016121350
M3 - Article
SN - 1046-6673
VL - 28
SP - 3639
EP - 3646
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 12
ER -