Relation between Red Cell Distribution Width and Fibroblast Growth Factor 23 Cleaving in Patients with Chronic Kidney Disease and Heart Failure

Breda, Fenna van; Emans, Mireille E.; Putten, Karien van der; Braam, Branko; Ittersum, Frans J. van; Kraaijenhagen, Rob J.; Borst, Martin H. de; Vervloet, Marc G.; Gaillard, Carlo A. J. M.

doi:10.1371/journal.pone.0128994

Cited by 19 publications

(11 citation statements)

References 37 publications

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“…9 Observational studies in humans have also demonstrated an inverse relationship between markers of iron status and cFGF23 levels. [10][11][12][13] Moreover, administration of intravenous iron in iron-deficient anemic women resulted in markedly decreased circulating cFGF23 concentrations, 14 consistent with the notion that ID is an important physiologic regulator of increased cFGF23 levels.…”

supporting

confidence: 59%

C-Terminal Fibroblast Growth Factor 23, Iron Deficiency, and Mortality in Renal Transplant Recipients

Eisenga¹,

Londen²,

Leaf

et al. 2017

JASN

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Iron deficiency (ID) is independently associated with an increased risk of death in renal transplant recipients (RTRs). ID promotes 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. We measured plasma iFGF23 and cFGF23 levels in 700 stable RTRs at a median of 5.4 years after transplant. RTRs with ID had median (interquartile range) cFGF23 concentrations higher than those of RTRs without ID (223 [131-361] versus 124 [88-180] RU/ml; <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; <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; =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.

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supporting

confidence: 59%

C-Terminal Fibroblast Growth Factor 23, Iron Deficiency, and Mortality in Renal Transplant Recipients

Eisenga¹,

Londen²,

Leaf

et al. 2017

JASN

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“…Third, we were able to show that cFGF23 numerically outperforms iFGF23 in univariate and partially Cox-adjusted regression models. All previous prospective epidemiological studies among non-dialysis CKD patients focused upon cFGF23, and did not measure iFGF23 [3][4][5][6][7]; iFGF23 measurements are available from cross-sectional CKD cohorts [33][34][35]. Interestingly, the ratio iFGF23 to cFGF23 only marginally correlates with eGFR, which disputes the idea that splicing of iFGF23 into inactive fragments is substantially reduced as renal function deteriorates and that nearly all FGF23 is biologically active in advanced CKD [36].…”

Section: Discussion/conclusionmentioning

confidence: 97%

Strength of Fibroblast Growth Factor 23 as a Cardiovascular Risk Predictor in Chronic Kidney Disease Weaken by ProBNP Adjustment

Emrich¹,

Brandenburg²,

Sellier³

et al. 2019

Am J Nephrol

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Background: Various epidemiological studies linked high fibroblast growth factor 23 (FGF23) levels with cardiovascular events in chronic kidney disease (CKD). It remains enigmatic whether high FGF23 exerts adverse cardiovascular effects, or whether it reflects detrimental effects of residual confounders. Earlier studies adjusted for CKD-mineral bone disease (CKD-MBD) regulators of FGF23 rather than for recently discovered non-CKD-MBD regulators, among which iron deficiency and heart failure are of particular importance. Moreover, they used c-terminal FGF23 (cFGF23) assays rather than more specific intact FGF23 (iFGF23) assays. Methods: The CARE FOR HOMe study analyzed plasma ferritin, iFGF23, cFGF23 and N-terminal proBNP (NT-proBNP) along with conventional risk factors, among 575 CKD G2-G4 patients to determine the interaction between FGF23, its non-CKD-MBD regulators, and incident cardiovascular events in CKD patients. The participants were followed up for 5.1 ± 2.1 years for the occurrence of atherosclerotic events and hospitalization for acute decompensated heart failure. Results: cFGF23 correlated strongly with high iFGF23 (r = 0.607), fairly with high NT-proBNP (r = 0.453) and weakly with low ferritin (r = –0.207); correlation coefficients of iFGF23 with NT-proBNP and ferritin were numerically lower. In Kaplan-Meier analyses, both endpoints were predicted by cFGF23 and iFGF23. In Cox regression models, cFGF23 remained an outcome predictor after adjustment for conventional risk factors and ferritin. This prediction was largely eliminated when further adjusting for NT-proBNP. iFGF23 was less consistently associated with adverse outcome in partly adjusted models, and failed to predict outcome in fully adjusted models. Conclusion: In summary, iron deficiency and heart failure affect plasma FGF23. As adjustment for NT-proBNP virtually eliminates the association between plasma FGF23 and predefined outcome, we speculate that high FGF23, rather than exerting detrimental cardiovascular effects, mirrors prevalent heart disease.

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“…C-terminal FGF23 concentration has been reported to have not only a strong linear correlation with intact FGF23 concentration [ 8 ], but also an association with adverse cardiovascular and renal events [ 37 , 38 ]. On the other hand, recent studies suggested an increase in C-terminal FGF23 may precede an increase in intact FGF23 in the relatively early phase of CKD [ 39 ] and that cleavage of FGF23 might be a major determinant for FGF23 activity in various diseases [ 40 , 41 , 42 ]; therefore, serum levels of intact FGF23 should be assessed, especially among populations including patients without severe renal dysfunction, such as the current study sample.…”

Section: Discussionmentioning

confidence: 99%

Association between FGF23, α-Klotho, and Cardiac Abnormalities among Patients with Various Chronic Kidney Disease Stages

et al. 2016

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BackgroundSeveral experimental studies have demonstrated that fibroblast growth factor 23 (FGF23) may induce myocardial hypertrophy via pathways independent of α-Klotho, its co-factor in the induction of phosphaturia. On the other hand, few studies have clearly demonstrated the relationship between FGF23 level and left ventricular hypertrophy among subjects without chronic kidney disease (CKD; i.e., CKD stage G1 or G2).PurposeTo investigate the data from 903 patients admitted to the cardiology department with various degrees of renal function, including 234 patients with CKD stage G1/G2.Methods and ResultsSerum levels of full-length FGF23 and α-Klotho were determined by enzyme immunoassay. After adjustment for sex, age, and estimated glomerular filtration rate (eGFR), the highest FGF23 tertile was significantly associated with left ventricular hypertrophy among patients with CKD stage G1/G2 and those with CKD stage G3a/G3b/G4 as compared with the lowest FGF23 tertile, and the association retained significance after further adjustment for serum levels of corrected calcium, inorganic phosphate, and C-reactive protein, as well as diuretic use, history of hypertension, and systolic blood pressure. FGF23 was also associated with low left ventricular ejection fraction among patients with CKD stage G1/G2 and those with CKD stage G3a/G3b/G4 after adjusting for age, sex, eGFR, corrected calcium, and inorganic phosphate. On the other hand, compared with the highest α-Klotho tertile, the lowest α-Klotho tertile was associated with left ventricular hypertrophy and systolic dysfunction only among patients with CKD stage G3b and stage G3a, respectively.ConclusionsAn association between FGF23 and cardiac hypertrophy and systolic dysfunction was observed among patients without CKD as well as those with CKD after multivariate adjustment. However, the association between α-Klotho and cardiac hypertrophy and systolic dysfunction was significant only among patients with CKD G3b and G3a, respectively.

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Relation between Red Cell Distribution Width and Fibroblast Growth Factor 23 Cleaving in Patients with Chronic Kidney Disease and Heart Failure

Cited by 19 publications

References 37 publications

C-Terminal Fibroblast Growth Factor 23, Iron Deficiency, and Mortality in Renal Transplant Recipients

C-Terminal Fibroblast Growth Factor 23, Iron Deficiency, and Mortality in Renal Transplant Recipients

Strength of Fibroblast Growth Factor 23 as a Cardiovascular Risk Predictor in Chronic Kidney Disease Weaken by ProBNP Adjustment

Association between FGF23, α-Klotho, and Cardiac Abnormalities among Patients with Various Chronic Kidney Disease Stages

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