Induction of cardiac FGF23/FGFR4 expression is associated with left
          ventricular hypertrophy in patients with chronic kidney disease

Leifheit-Nestler, Maren; Siemer, R. Große; Flasbart, Kathrin; Richter, Beatrice; Kirchhoff, F.; Ziegler, Wolfgang; Klintschar, Michael; Becker, Jan U.; Erbersdobler, Andreas; Aufricht, Christoph; Seeman, Tomáš; Fischer, Dietrich; Faul, Christian; Haffner, Dieter

doi:10.1093/ndt/gfv421

Cited by 181 publications

(171 citation statements)

References 59 publications

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“…In autopsy studies of children with advanced CKD, the upregulation of FGF23 and FGFR4 expression in heart tissue were associated with fibrosis [24], a known precursor of diastolic dysfunction, HF, and arrhythmia. In addition, FGF23 can induce a spike in intracellular calcium in cardiomyoctes and alter contractility, physiology predisposing to SCD [27,28]. Thus, the findings in the present study support the biologic effects of FGF23.…”

Section: Discussion/conclusionsupporting

confidence: 80%

“…In rodent models, FGF23 induces cardiac hypertrophy mediated by FGFR4 [2,25,26]. Genetic ablation of FGFR4 can prevent the induction of LVH by FGF23 in rodent models of CKD and aging [27]. In autopsy studies of children with advanced CKD, the upregulation of FGF23 and FGFR4 expression in heart tissue were associated with fibrosis [24], a known precursor of diastolic dysfunction, HF, and arrhythmia.…”

Section: Discussion/conclusionmentioning

confidence: 99%

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Fibroblast Growth Factor 23 Genotype and Cardiovascular Disease in Patients Undergoing Hemodialysis

Schwantes-An

Liu²,

Stedman³

et al. 2019

Am J Nephrol

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Background: Elevated serum concentrations of fibroblast growth factor 23 (FGF23) are associated with cardiovascular mortality in patients with chronic kidney disease and those undergoing dialysis. Objectives: We tested the hypotheses that polymorphisms in FGF23, its co-receptor alpha-klotho (KL), and/or FGF23 receptors (FGFR) are associated with cardiovascular events and/or mortality. Methods: We used 1,494 DNA samples collected at baseline from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events Trial, in which patients were randomized to the calcimimetic cinacalcet or placebo for the treatment of secondary hyperparathyroidism. We analyzed European and African Ancestry samples separately and then combined summary statistics to perform a meta-analysis. We evaluated single-nucleotide polymorphisms (SNPs) in FGF23, KL, and FGFR4 as the key exposures of interest in proportional hazards (Cox) regression models using adjudicated endpoints (all-cause and cardiovascular mortality, sudden cardiac death, and heart failure [HF]) as the outcomes of interest. Results: rs11063112 in FGF23 was associated with cardiovascular mortality (risk allele = A, hazard ratio [HR] 1.32, meta-p value = 0.004) and HF (HR 1.40, meta-p value = 0.007). No statistically significant associations were observed between FGF23 rs13312789 and SNPs in FGFR4 or KL genes and the outcomes of interest. Conclusions: rs11063112 was associated with HF and cardiovascular mortality in patients receiving dialysis with moderate to severe secondary hyperparathyroidism.

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Section: Discussion/conclusionsupporting

confidence: 80%

Section: Discussion/conclusionmentioning

confidence: 99%

Fibroblast Growth Factor 23 Genotype and Cardiovascular Disease in Patients Undergoing Hemodialysis

Schwantes-An

Liu²,

Stedman³

et al. 2019

Am J Nephrol

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“…FGF23 can play a physiological role through classical Klotho -dependent and non-dependent pathways, which require receptor FGFR1c or FGFR4 involvement [6]. Klotho provides a binding site for the C-terminus of FGF23 and then binds to the receptor FGFR through the N-terminus of FGF23 to activate the classical Klotho-dependent pathway [7]. However, with the progress of CKD, FGF23-Klotho axislose balance.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Yishen Jiangzhuo Granules on Serum IFGF23 and CFGF23 in Patients with Chronic Kidney Disease 3-5 Stage

Wang¹,

Liu²,

Cai³

et al. 2017

Altern Integr Med

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Aim: The objective is to investigate the changes of serum IFGF23 and CFGF23 levels in patients with chronic kidney disease of 3-5 stage before and after treatment by Yishen Jiangzhuo Granules and its clinical significance. Methods:A subset of samples (n=76) from a cohort of patients with CKD of renal function between stage three and five. (Stage 3: n=37; stage 4: n=30; stage 5: n=9). The patients were treated in hospital or in clinic between October 2013 and April 2015 at the nephrology department of Fujian Provincial People's Hospital. Additionally, a total of 30 healthy volunteers were selected in this hospital during the same period as the normal control group. IFGF23, CFGF23 were detected by enzyme-linked immunosorbent assay (ELISA). Calcium (Ca), phosphorus (P), urea nitrogen (BUN), serum creatinine (Scr) was assessed by BECKMAN-C800 automatic biochemical analyzer. Urine creatinine was determined by Reversed Phase High Performance Liquid Chromatography. The endogenous creatinine clearance rate (Ccr) was calculated according to the simplified MDRD formula. Result:The expression levels of serum IFGF23 and CFGF23 did not change significantly before and after drug treatment. But the serum IFGF23 and CFGF23 expression level has been significantly increased in the CKD3 stage, while serum phosphorus levels has not yet increased. Compared with normal group, the expression level of serum IFGF23 and CFGF23 was significantly higher than that of the normal group before and after treatment.Both of them showed a tendency to increase gradually with the decrease of renal function, and the degree of increase of serum IFGF23 expression level was significantly higher than that of CFGF23. Scr and P levels were decreased in CKD 3-5 stage after treatment (P˂0.05). In CKD 4-5 stage, after treatment, the serum calcium level was higher than that before treatment (P˂0.05)In CKD 3-5 stage, after treatment, the Ccr was higher than that before treatment (P˂0.05).Conclusion: IFGF23 increases rapidly with the decrease of Ccr and CFGF23 increases slowly with the decrease of Ccr. In the short term, Yishenjiangzhuo Granules cannot improve serum IFGF23 and CFGF23 levels in CKD 3-5 stage in patients, but it improves the renal function and the metabolism of calcium and phosphorus, and reduces the level of serum creatinine.

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“…In addition, although no differences were observed in FGFR1 expression in myocardial tissue from cases and controls, FGFR4 mRNA expression was higher in cases than controls and higher in LVH(+) cases compared with those without LVH where it was correlated positively with cardiomyocyte cross-sectional area and FGF23 expression. Finally, mRNA FGF-23 as well as myocardial expression of the regulatory subunit of calcineurin and NFAT were higher in cases with LVH as compared with those without LVH (30). Of note, previous studies in experimental CKD have shown that complete inhibition of FGF-23 activity prevents the development of LVH and secondary hyperparathyroidism but it is associated with increased mortality linked to hyperphosphatemia and vascular calcifications [31].…”

mentioning

confidence: 89%

Fibroblast Growth Factor-23: A Novel Biomarker for Cardiovascular Disease in Chronic Kidney Disease Patients

Papagianni

2017

Prilozi

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Fibroblast Growth Factor (FGF)-23 increase is considered one of the earliest biochemical abnormalities in chronic kidney disease-mineral bone disorder (CKD-MBD). Furthermore, accumulating data have provided evidence of a link between increased FGF-23 levels and cardiovascular morbidity and mortality in CKD patients as well as in several other populations including cardiology patients and general population. The cellular and molecular mechanisms underlying the deleterious effect of FGF-23 on the cardiovascular system are not yet completely defined and are the focus of intense research. However, animal and human studies have demonstrated important actions of FGF-23 in the heart and vessels through which could promote the development of cardiovascular complications in uremia. Moreover, significant interactions have been reported between FGF-23 and other well recognized cardiovascular risk factors such as renin-angiotensin system and inflammation which could account, at least in part, for the observed associations between FGF-23 and adverse clinical outcomes. Further studies are needed to clarify the mechanisms responsible for the pleiotropic actions of FGF-23 and moreover to identify whether it is a modifiable risk factor and a potential target of therapeutic interventions which could probably help to reduce the unacceptably high cardiovascular morbidity and mortality of CKD patients.

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Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease

Abstract: Our results indicate a strong association between LVH and enhanced expression levels of FGF23, FGFR4 and calcineurin, activation of NFAT and reduced levels of soluble Klotho in the myocardium of patients with CKD. These alterations are not observed in kidney transplant patients.

Cited by 181 publications

References 59 publications

Fibroblast Growth Factor 23 Genotype and Cardiovascular Disease in Patients Undergoing Hemodialysis

Fibroblast Growth Factor 23 Genotype and Cardiovascular Disease in Patients Undergoing Hemodialysis

The Effect of Yishen Jiangzhuo Granules on Serum IFGF23 and CFGF23 in Patients with Chronic Kidney Disease 3-5 Stage

Fibroblast Growth Factor-23: A Novel Biomarker for Cardiovascular Disease in Chronic Kidney Disease Patients

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