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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 18  |  Issue : 1  |  Page : 17-23

Fibroblast growth factor-23 and vascular calcification in chronic kidney disease and hemodialysis patients


1 Department of Internal Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Cardiology and Angiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
3 Department of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
4 Department of Radiodiagnosis and Intervention, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Date of Submission12-Dec-2017
Date of Acceptance28-Dec-2017
Date of Web Publication02-May-2018

Correspondence Address:
Dr. Marwa R.A El Hameed
Master of Internal Medicine, Department of Internal Medicine, Faculty of Medicine, Alexandria University, Alexandria
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jesnt.jesnt_28_17

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  Abstract 


Context Fibroblast growth factor-23 (FGF-23) is secreted by osteoblasts and regulates phosphate and vitamin D homeostasis. As a potential explanatory mechanism of FGF-23-associated mortality, multiple studies have consistently demonstrated that higher FGF-23 levels are independently associated with greater risk of prevalent and incident left ventricular hypertrophy (LVH). In contrast, observational studies reported conflicting results on the association of FGF-23 with arterial calcification, which is another prominent pattern of cardiovascular injury in chronic kidney disease (CKD).
Aims The aim was to correlate between serum FGF-23 and vascular calcification (VC) in CKD and hemodialysis (HD) patients.
Settings and design A single-center cross-sectional study was conducted on 60 patients who were divided into two groups. Group I included thirty patients with CKD stages 4 and 5, and group II included thirty patients on maintenance HD. Group III included 30 age-matched and sex-matched healthy volunteers.
Materials and methods Estimation of serum calcium, phosphorus, bone-specific alkaline phosphatase, intact parathyroid hormone, and serum FGF-23 level was carried out. Assessment of LVH by echocardiography and VC by multidetector computed tomography was done.
Results There was a statistically significant negative correlation between FGF-23 and serum calcium level in group I and of no statistical significant correlation in group II and III, whereas there were a statistically significant positive correlations between FGF-23 with serum phosphorus, bone-specific alkaline phosphatase and intact parathyroid hormone in groups I and II and of no statistical significant correlations in group III. There were statistically significant positive correlations between FGF-23 and both left ventricular mass index and VC in groups I and II (P<0.001) and of no statistical significant correlation in group III.
Conclusion FGF-23 correlates with LVH and VC in CKD and HD patients.

Keywords: chronic kidney disease, fibroblast growth factor-23, hemodialysis, left ventricular hypertrophy, vascular calcification


How to cite this article:
Zaki SA, El Gohary IE, Elsharkawy EM, Hashad DI, Emara DM, El Hameed MR. Fibroblast growth factor-23 and vascular calcification in chronic kidney disease and hemodialysis patients. J Egypt Soc Nephrol Transplant 2018;18:17-23

How to cite this URL:
Zaki SA, El Gohary IE, Elsharkawy EM, Hashad DI, Emara DM, El Hameed MR. Fibroblast growth factor-23 and vascular calcification in chronic kidney disease and hemodialysis patients. J Egypt Soc Nephrol Transplant [serial online] 2018 [cited 2018 May 26];18:17-23. Available from: http://www.jesnt.eg.net/text.asp?2018/18/1/17/231751




  Introduction Top


Vascular calcification (VC) is considered as an aging-related disease, and it is also a leading factor for cardiovascular morbidity and deaths [1],[2]. The hallmark of VC is calcium–phosphate (Ca×P) deposition, which can occur at anywhere like in the aorta, myocardium, and cardiac valves. Calcification of the tunica media is associated with vascular stiffening, and medial calcification appears to be more common in patients with renal disease [3],[4],[5].

On autopsy, cardiac tissue calcification has been reported in ∼60% of patients on dialysis. These deposits have been found in the myocardium, pericardium, conducting system, valves, and small coronary arteries. Calcification leads to damage of normal cardiac tissues, and it may lead to valvular stenosis, and/or regurgitation, complete heart block, ischemia, chronic constrictive pericarditis, congestive heart failure, and death [6],[7].

Furthermore, the characteristic finding of cardiovascular calcification in chronic kidney disease (CKD) and dialysis patients is rapidly progressive, extensive, and severe when compared with the non-CKD population [8].

Fibroblast growth factor-23 (FGF-23) is a bone-derived hormone with a phosphaturic action that reduces the renal synthesis of 1,25-dihydroxy-vitamin D [9]. In CKD, circulating FGF-23 levels correlate inversely with the glomerular filtration rate (GFR), so the renal capacity for phosphate excretion declines, leading to phosphate retention, vitamine D deficiency, secondary hyperparathyroidism, and potentially Klotho deficiency [10],[11],[12].

Klotho deficiency has been implicated in the development of arterial calcification and the resistance to protective cardiovascular effects of FGF-23 [13].

High serum FGF-23 level was shown to be associated with left ventricular hypertrophy (LVH), heart failure, atherosclerosis, stroke, and different cardiovascular events [14].

In agreement of a causal role for elevated FGF-23 in the pathogenesis of LVH, FGF-23 stimulated pathologic hypertrophy of isolated cardiac myocytes and induced LVH in animals [15]. In contrast, observational studies reported conflicting results on the association of FGF-23 with VC, which is another prominent pattern of cardiovascular injury in CKD [16].

The objective of the present study was to correlate between circulating FGF-23 levels with left ventricular mass index (LVMI) and VCs in patients with CKD and on maintenance hemodialysis (MHD).


  Materials and methods Top


A total of 90 participants (30 CKD with eGFR less than 30 ml/min on conservative treatment as group I, 30 on MHD as group II, and 30 matched healthy controls as group III) were recruited. The approval of the ethics committee of the Faculty of Medicine of the Alexandria University was obtained, and all patients gave a written informed consent. Patients greater than 70 or less than 18 years old, BMI greater than 30 kg/m2, diabetes mellitus, severe hypertension, active autoimmune or infectious disease, malignant diseases with secondary bone metastasis, rheumatic heart disease, or any cardiac history were excluded.

Serum calcium, phosphorus [17], bone-specific alkaline phosphatase (BsALP) [18]), and intact PTH [19] were assessed. Assay of serum FGF-23 level was done by enzyme-linked immunosorbent assay technique [20].

Patients were studied on the morning, post-mid-week HD session in group II, and underwent echocardiographic (ECHO) measurements of left ventricular dimensions.

ECHO was done for all participants (post-mid-week HD session in group II) with a Philips Envisor CHD ultrasound system equipped with a 2.5 MHz broadband transducer. All ECHO measurements were made in accordance with the recommendations of the American Society of Echocardiography guidelines [21]. Measurement of LV size and function with assessment of LVM and LVMI was done.

Patients were categorized as having LVH or not based on accepted cutoff values LVMI for ECHO (men >115 g/m2 and women >95 g/m2). The measured relative wall thickness (RWT) allowed for further classification of LVH as either concentric hypertrophy (RWT>0.42) or eccentric hypertrophy (RWT≤0.42) [21].

All participants underwent noncontrast multidetector computed tomography (MDCT) scan of the abdominal aorta using Philips MX 16 machine. The scanning range was from T12 to L4 vertebral levels. The images were reconstructed to 1 mm thickness. VC scores based on the Hounsfield unit (HU) measurement of the aortic wall calcifications were determined using a dedicated work station. The number and the highest HU of the calcifications in the examined abdominal aorta were recorded [22].

Statistical analysis

The SPSS Version 20.0 (IBM Corp., Armonk, New York, USA) was used for statistical analysis [23]. Data were expressed as mean±SD. Proportions were compared by χ2-analysis. Student’s t-test, analysis of variance, and Mann–Whitney tests were used for group comparison. Correlation analysis was performed using Spearman’s correlation coefficient [24].


  Results Top


The study included 30 patients with CKD from the nephrology outpatients’ clinic of Alexandria University Hospital, 30 patients with end-stage renal disease on MHD from the dialysis unit of Al Mowassat University Hospital, and 30 matched healthy volunteers. The studied variables are summarized in [Table 1].
Table 1 Comparison among the three studied groups regarding demographic data

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Comparison among the three studied groups regarding corrected Ca, P, Ca×P product, BsALP, and intact parathyroid hormone (iPTH) levels is shown in [Table 2].
Table 2 Comparison among the three studied groups according to metabolic bone profile

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Regarding FGF-23 levels, there was a statistically significant difference among the three studied groups (P<0.001) ([Table 3]).
Table 3 Comparison among the three studied groups regarding serum fibroblast growth factor-23 levels

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In the current study, LA diameter, left ventricular end diastolic diameter, left ventricular end systolic diameter, and ejection fraction (EF%) by ECHO all showed no statistical significant difference among the studied groups. However, regarding interventricular septum, PWTd, LVM, and LVMI, there was a statistically significant difference among the three groups, being statistically higher in HD than the CKD group (P=0.025, 0.007, <0.001, <0.001, respectively).

The mean systolic function by EF by ECHO was lower in HD group (58.23±7.14%) in comparison with CKD group (59.13±6.84%) and control group (61.27±4.89), but it was not statistically significant.

Left ventricular geometry was normal in 14 (46.7%) cases in CKD group, four (13.3%) cases in HD, group and 28 (93.3%) participants in the control group. Concentric remodeling was present in five (16.7%) cases in CKD group, single (3.3%) case in HD group, and two (6.7%) participants in the control group. In CKD group, 36.7% of patients met ECHO criteria for LVH (26.7% eccentric LVH and 10.0% concentric LVH), whereas in HD group, LVH was designated by ECHO in 83.3% of patients (33.3% eccentric LVH and 50.0% concentric LVH). None of the participants of the control group showed LVH.

LVH by ECHO was mild in none (0.0%) in CKD group and three (12.0%) cases in HD group, moderate in six (54.5%) cases in CKD group and eight (32%) cases in HD group, and severe in five (45.5%) cases in CKD group and 14 (56.0%) cases in HD group.

Other ECHO findings in CKD group included one case with mild aortic valve calcification and another one with moderate mitral valve regurgitation, whereas in HD group, two cases showed mild to moderate aortic valve calcification, another two showed mild pericardial effusion, and four cases showed different degrees of mitral valve regurgitation.

The mean of total anterior and posterior calcification of the abdominal aorta using MDCT was higher in HD group (747.70±500.58 HU) in comparison with CKD group (345.0±343.47 HU), and it was of a statistically significant difference (P<0.001). Three participants of the control group showed aortic wall calcification with a mean of 18.83±57.95 HU ([Table 4]).
Table 4 Grades of abdominal aortic calcification regarding density in the three studied groups (Hounsfield unit)

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In the current study, in the HD group, the duration of HD was positively correlated with the density of VC regarding patients on HD less (50%) and more (50%) than 5 years (with a mean of 557.8±427.5 and 937.6±509.0 HU, respectively).

The correlations between FGF-23 and serum calcium, phosphorus, Ca×P product, BsALP, and iPTH are shown in [Table 5].
Table 5 Correlation between fibroblast growth factor-23 and different parameters in the three studied groups

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The correlation between FGF-23 and LVMI by ECHO and also between it and calcification of abdominal aorta by MDCT in both CKD and HD groups are demonstrated in [Figure 1] and [Figure 2].
Figure 1 Correlation between fibroblast growth factor-23 and left ventricular mass index in chronic kidney disease and hemodialysis groups.

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Figure 2 Correlation between fibroblast growth factor-23 and aortic wall calcification in chronic kidney disease and hemodialysis groups.

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  Discussion Top


Multiple noninvasive radiological techniques are used for detection of VC: plain radiography for macroscopic calcification of the aorta and peripheral arteries; two-dimensional ultrasound for calcification of the carotid arteries, femoral arteries, and aorta; ECHO for assessment of valvular calcification; and MDCT is considered the gold standard for quantification of coronary and aortic calcifications [25].

In the current study, there was a statistically significant difference regarding Ca levels, being higher in CKD group in comparison with the HD group; this could be explained as most of the patients with CKD were on oral calcium and vitamin D3 analogs, being more compliant than those on HD.

Serum phosphate levels were significantly higher in both CKD and HD groups than in control group, with nonsignificant difference between them.

An interesting study done by Benini et al. [26], who studied the effect of high-dietary intake of phosphorus, reported that it was extremely difficult to keep a normal serum phosphorus concentration even with the use of phosphate binders in dialysis patients. Another two reports conducted by Sullivan et al. [27] and Cupisri et al. [28], studying the effect of high-dietary phosphate on the mortality risk in dialysis patients, concluded that restriction of foods containing phosphorus additives resulted in clinically significant improvements in hyperphosphatemia, which corresponded to a 5–15% reduction in relative mortality risk.

In the present study, the Ca×P product was significantly higher in the CKD and HD patients than controls. Meanwhile, there was no statistical difference between CKD and HD patients. Dhingra et al. [29] prospectively evaluated 3368 patients with CKD with higher level of serum phosphorus, and they reported a strong association with increased CVD. There was an increase of 1.5-fold CVD risk and mortality in patients with higher levels of serum phosphorus and Ca×P product.

In the current work, there was a statistical difference between the three studied groups (P<0.0001) regarding BsALP, being higher in HD patients than in CKD group. This could be explained by the increased incidence of mineral and bone disorder owing to bone resorption in patients on regular HD. Moreover, there was a significant difference among the three groups regarding iPTH levels (P<0.001), being significantly higher in both CKD and HD groups than controls, with no statistical difference between them.

In the current study, serum FGF-23 was significantly higher in HD group than in CKD and control groups (P<0.001). These results were supported by the study conducted by Viaene et al. [30] on the residual renal function and reported a strong, inverse, and independent relationship with serum phosphorus and FGF-23 levels in dialysis patients. As renal function declines, phosphorus homeostasis is maintained through a compensatory decline in renal tubular reabsorption, mediated partly by the phosphaturic hormones PTH and FGF-23. This adaptation allows serum phosphorus levels to remain within the normal range until GFR decreases less than 30 ml/min.

In the current study, there was a statistically significant negative correlation between FGF-23 and corrected serum Ca levels only in CKD group (P=0.002) but not in both HD and control groups (P=0.455, 0.144, respectively), whereas there were statistically significant positive correlations between FGF-23 with serum PO4, Ca×P, BsALP, and iPTH in both CKD and HD groups and of no statistical significance in the control group.

In univariate linear regressions conducted by Jean et al. [31] in long-term HD patients, a significant correlations between FGF-23 and age, serum CRP, iPTH, serum calcium, serum phosphorus, and Ca×P product were reported. In multivariate regressions that included all the aforementioned parameters, only phosphatemia remained significantly correlated with FGF-23. In contrast to our results, Urena et al. [32] reported that in HD patients, FGF-23 was correlated with phosphatemia but not with PTH levels.

In the current study, there was a statistically significant positive correlation between FGF-23 and LVMI in both CKD and HD groups (P<0.001) and of no statistical significance in the control group (P=0.362).

The link between FGF-23 and cardiac injury in CKD was studied by an ECHO study of 3070 Chronic Renal Insufficiency Cohort study participants [15]. In the cross-sectional component of the analysis, higher FGF-23 levels were independently associated with reduced EF, greater LVMI, and greater prevalence of concentric and eccentric LVH. In the first prospective analysis of FGF-23 and risk of LVH, elevated FGF-23 predicted new-onset LVH in Chronic Renal Insufficiency Cohort participants who had normal LV geometry at baseline and underwent repeat ECHO 3 years later. The risk of incident LVH according to baseline FGF-23 was magnified in the subgroup of participants without hypertension. Presumably, eliminating this major confounder allowed the independent effects of FGF-23 to appear clearly.

These data match with those of Tanaka et al. [33], who reported that the mean LVMI seems to increase with FGF-23 value in all CKD stage subgroups. Laddha et al. [34] reported that LVH was detected in 74% of patients with end-stage renal disease on HD.

In the current study, the duration on HD was positively associated with the density of VC among patients on HD less and more than 5 years. These results were in agreement with previous studies that have identified the time spent on dialysis as an important risk factor, not only for the medial but also for the intimal arterial calcifications, particularly in medium sized arteries, in which each year on RRT increased the risk of having VC nearly by 15% [35],[36].

The prevalence of aortic calcifications in the study of Naves et al. [37] was significantly higher in HD patients (79%) than in a random-based general population of the same age, sex, and region (37.5%). Similar results have been reported in another study conducted on long-term HD patients [38].

In the current study, there was a statistically significant positive correlation between FGF-23 and aortic wall calcification in both CKD and HD groups (P<0.001), whereas no significant correlation in the control group (P=0.129).

Van Venrooij et al. [39] reported that the expression of FGF-23 in the coronary arteries of the explanted hearts was found in more than half of the 50 patients who received a heart transplantation. Another important finding of this study was that FGF-23 protein was coexpressed with its main receptors (FGFR-1 and FGFR-3) and its co-receptor Klotho.


  Conclusion Top


MDCT scan may be used to evaluate aortic wall calcification. It is simple, relatively inexpensive, and useful for an initial diagnosis of VC.

FGF-23 predicts cardiovascular outcomes in CKD and HD patients mainly by affecting mineral metabolism and directly by promoting LVH.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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