| Abstract|| |
Fibroblast growth factor 23 (FGF-23) is a recently discovered regulator of phosphate and mineral metabolism and has been associated with both progression of CKD and mortality in dialysis patients. To evaluate the association between serum FGF-23 levels and echocardiographic measurements in long-term HD (HD) patients without cardiac symptoms, we studied 90 consecutive patients treated in a single HD center (51 males, 39 females; mean age 41.5 ± 14.2 years, mean HD duration 71.2 ± 14.2 months). Comprehensive echocardiography was performed after HD and blood samples were obtained before HD. The serum FGF-23 level in dialysis patients was 95.7 ± 88.4 pg/mL. In univariate analysis, serum calcium levels (r = 0.33, P <0.05), serum creatinine (r = 0.34, P <0.05), serum albumin (r = 0.35, P <0.05) and left ventricular mass index (LVMI) (r = 0.33, P <0.001) were correlated weakly with the FGF-23 levels. Neither s. phosphorus nor calcium x phosphorus product correlated with FGF-23. In univariate regression analysis, only LVMI [β = 0.42, P <0.05, confidence interval (CI) 0.3-4.3], serum calcium (β= 0.87, P <0.001, CI 0.8-7.3), serum albumin (β= 0.87, P < 0.001, CI 0.8-7.3) and serum creatinine (β= 0.67, P <0.05, CI 0.5-6.5) significantly correlated with FGF-23. FGF-23 was identified as a factor that is weakly associated with LVMI. Thus, FGF-23 alone may not be a parameter that can be used for evaluation of the cardiac status in HD patients.
|How to cite this article:|
Sany D, Elsawy AE, Aziz A, Elshahawy Y, Ahmed H, Aref H, El Rahman MA. The value of serum FGF-23 as a cardiovascular marker in HD patients. Saudi J Kidney Dis Transpl 2014;25:44-52
|How to cite this URL:|
Sany D, Elsawy AE, Aziz A, Elshahawy Y, Ahmed H, Aref H, El Rahman MA. The value of serum FGF-23 as a cardiovascular marker in HD patients. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2019 Nov 22];25:44-52. Available from: http://www.sjkdt.org/text.asp?2014/25/1/44/124483
| Introduction|| |
Cardiovascular disease is common in end-stage renal disease (ESRD) patients.  The majority of deaths in dialysis patients are cardiovascular deaths, followed by infection and stroke. ,,, Left ventricular hypertrophy (LVH) is one of the most common cardiovascular disorders in dialysis patients. ,, In addition, LVH is an independent risk factor for cardiovascular death in patients who have received maintenance hemodialysis (HD). , The causes of LVH onset and progression in dialysis patients are complicated. Possible pathogenic factors include volume overload, pressure overload, anemia, arteriovenous fistulae as blood accesses, coronary artery disease, hypertension, diabetes and other factors. ,, However, for dialysis patients, aggressive control of blood pressure and anemia does not prevent LVH.  Thus, it seems likely that other factors play a role in the formation of uremia-related LVH.
Hyperphosphatemia is common in many HD patients,  and control of serum phosphate levels in these patients correlates with a reduction in left ventricle mass index (LVMI).  It has been suggested that among HD patients, a novel mechanism may be responsible for the association of elevated serum phosphate and LVH and the subsequent deleterious effect on cardiovascular outcomes. However, the exact mechanism is still unknown. Fibroblast growth factor 23 (FGF-23) is a recently discovered phosphate-regulating hormone largely produced by the bone. Genetic and biochemical evidence indicates that FGF-23 reduces the serum phosphate concentration. The serum concentration of FGF-23 increases as kidney function declines,  and its levels are extremely high in HD patients. , Recent studies demonstrated that increased FGF-23 levels are independently associated with mortality among patients undergoing HD. ,
Given that a major target organ of FGF-23 is the kidney, the association between FGF-23 levels and clinical outcome in HD patients suggests that FGF-23 may play a role in conferring a cardiovascular risk on HD patients, independent of its role in the renal reabsorption of inorganic phosphate. The previous research suggests that elevation of FGF-23 levels may be related to the development of LVH and clinical outcome for dialysis patients. The aim of this study was to evaluate the role of FGF-23 in long-term HD patients by examining the associations between serum FGF-23 levels and LVMI.
| Materials and Methods|| |
We studied 60 healthy volunteers and 90 maintenance HD patients (39 women and 51 men, mean age 41.5 ± 14.2 years, mean HD time 71.2 ± 14.2 months). The patients suffered from ESRD due to diabetic nephropathy (n = 35), hypertensive nephrosclerosis (n = 30), chronic glomerulonephritis (n = 10) or chronic pyelonephritis (n = 5); the renal diagnosis was unknown in ten patients. The patients were prescribed treatments including CaCO 3 (35%), Ca acetate (45%), alfa calcidol (65%) and erythropoietin (50%). All patients were receiving conventional 4-h HD schedule for at least six months with polysulphone dialysers F6HPS and F7HPS (Fresenius AG, Bad Homburg, Germany) thrice a week, with bicarbonate dialysate and unfractionated heparin using a standard regimen, a 2000 unit initial bolus followed by infusion of 1000 U/h for standard anticoagulation. The mean blood flow rate was 300 mL/min during the HD session (range 250-340 mL/min). Dialysate fluid composition included sodium 140 mmol/L, potassium 1-3 mmol/L, calcium 1.5 mmol/L and bicarbonate 33 mmol/L. Dry weight was considered optimal when the patients had no residual symptoms of orthopnea, dyspnea and edema during the interdialytic period. Blood pressure (BP) of the patients was measured with a conventional mercury manometer prior to each HD session.
Hypertension was defined as a systolic BP of 140 mmHg or above and diastolic BP of 90 mmHg or above;  the average values of systolic and diastolic BP obtained in the first three weeks of the study were used in the statistical analysis. The patients were considered diabetic if they met the 1997 American Diabetes Association criteria.
Data on demographic characteristics, medical history, medication (statins, angiotensin-converting enzyme inhibitors, calcium channel-blockers, β-blockers, activated vitamin D) and blood samples were collected in all subjects at the time of enrollment.
The patients were on antihypertensive medications: Angiotensin-converting enzyme inhibitors (n = 20), β-blockers (n = 30) and calcium channel blockers (n = 8); no patient was on statin therapy. All the patients signed informed consents in accordance with the guidelines of the Human Clinical Study Committee of Ain Shams University Hospital before participating in the study.
Venous blood samples were drawn after an overnight fast. The blood samples were obtained directly through an arterio-venous fistula or central catheter on a mid-week dialysis day. Serum total cholesterol and triglycerides were quantified by commercial colorimetrical assay methods (GPO-PAP and CHOD-PAP; Boehringer-Mannheim, Mannheim, Germany). Serum biochemical parameters (creatinine, blood urea nitrogen, glucose, electrolytes, albumin and complete blood count) and intact parathormone levels were studied by means of a computerized auto-analyzer (Hitachi 717; Boehringer-Mannheim) and the HCV antibodies by ELISA. The Human Intact FGF-23 was measured by two-site enzyme-linked immunosorbent assay (ELISA) (DRG® FGF-23; EIA-4737 International Inc., USA) and measurement of the intact FGF-23 concentration was done using EDTA plasma. A morning, 12-h fasting sample was drawn. Samples were assayed immediately or stored frozen at -20°C or below. Intra-assay and inter-assay variations were 5% and 6.4%, respectively. Echocardiographic examination was performed using a Philips medical systems ultrasound Sonos7500 (Koninklijke Philips Electronics N.V., the Netherlands) with a 1.6/3.2-MHz transducer. M-mode and 2-dimensional measurements were performed in accordance with the methods recommended by the American Society of Echocardiography. Echocardiograms were obtained with the patients in semi-recumbent and left lateral positions, with the echocardiographic window located at the third or fourth intercostal space at the left sternal border. The ventricular volume and ejection volume were calculated by the Doppler technique, according to a previously published protocol.  Left ventricular mass was calculated according to a formula derived by Devereux and Reichek  and indexed for body surface area to define the LVMI. The patients were considered to have LVH if the LVMI was greater than 134 g/m 2 for men and greater than 110 g/m 2 for women.  Cardiac mass was calculated from a formula derived by Devereux and Reichek  : Left ventricle mass (g) = 1.04 × [(LVEDD + IVST + LVPWT) 3 - (LVESD) 3 ] -13.6. LVMI (g/m 2 ) = left ventricle mass (LVM)/body surface area, where LVPWT is left ventricular posterior wall thickness, IVST is interventricular septum thickness, LVEDD is left ventricular end-diastolic diameter and LVESD is left ventricular end-systolic diameter.
| Statistical Analysis|| |
Baseline characteristics were assessed with standard descriptive statistics. Whether the distributions of continuous variables were normal or not was determined by using the Shapiro Wilk test. Data were shown as mean, standard deviation, median and interquartile range. Chi-square test was used to compare qualitative variables between groups. The Fisher exact test was used instead of the chi-square test when one expected a value less than or equal to 5. Unpaired t-test was used to compare two groups with regard to quantitative variables in parametric data SD <50% of the mean. The Mann-Whitney test was used instead of the t-test for non-parametric data (SD >50% mean). Degrees of associations between continuous variables were calculated by the Spearman's correlation co-efficient. The associations between FGF-23 levels, LVMI and baseline demographic, clinical and laboratory variables were assessed by the determination of the Pearson product-moment correlation coefficient. Linear regression was used to examine the association between FGF-23, LVMI and laboratory variables. All analyses were conducted using statistical software (SPSS, version 12.0.0; SPSS, Chicago, IL, USA) and P-values less than 0.05 were considered to be statistically significant.
| Results|| |
The serum FGF-23 levels in 90 dialysis patients were significantly higher than those of 60 healthy volunteers (95.7 ± 88.4 pg/mL vs 1.12 ± 44, P <0.001). All the patients received echocardiography and were examined for LVMI. [Table 1] and [Table 2] show the comparison of demographic and biochemical profiles between diabetic and non-diabetic HD patients. Diabetic patients (n = 45) were older than those in the non-DM group (n = 45). There were no significant differences in age, sex, BMI, HD duration, hemoglobin or serum levels of creatinine, BUN, serum albumin, serum Ca, serum P, Ca x P product, iPTH, cholesterol or triglycerides levels between the HD patients with and without DM. In addition, there were no significant differences in plasma FGF-23 levels among diabetic [median 55, interquartile range (25-135) pg/mL] and non-diabetic [median 95, interquartile range (50-125) pg/mL] patients (P >0.05). There was a significant difference in LVMI of the diabetic versus the non-diabetic patients (mean ± SD = 110.4 + 28 g/m 2 vs 89.2 + 29 g/m 2 ) (P <0.001) [Figure 1], [Table 2]. There was a significant difference in the prevalence of HCV infection among the diabetic versus the non-diabetic patients (57.8% vs 35.6%) (P <0.05). Among the biomarkers examined, correlation analysis showed that serum creatinine (r = 0.34, P <0.05), serum calcium (r = 0.33, P <0.05) and serum albumin (r = 0.35, P <0.05) were significantly associated with FGF-23 levels [Table 3]. In addition, only LVMI among the echocardiographic data determined was significantly correlated with FGF-23 levels (r = 0.33, P <0.01) [Figure 2]. In univariate linear regression analysis that included all the aforementioned parameters, serum calcium [β= 0.87, P <0.001, confidence interval (CI) 0.8-7.3], serum albumin (β= 0.87, P <0.001, CI 0.8-7.3) and serum creatinine (β= 0.67, P <0.05, CI 0.5-6.5) correlated with FGF-23 [Table 4], [Figure 3] and [Figure 4].
|Figure 1: Left ventricular mass index in diabetic versus non-diabetic patients.|
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|Table 1: Laboratory characteristics of diabetic and non-diabetic patients.|
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|Table 2: FGF-23 and LV mass index among diabetic and non-diabetic patients.|
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|Table 3: Correlation between FGF-23 versus demographic and laboratory data among the studied group.|
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|Table 4: Correlation between FGF-23 levels versus laboratory data by using linear regression analysis.|
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LVMI only correlated with FGF-23 (r = 0.33, P <0.001) [Table 4]. In univariate linear regression analysis, LVMI was significantly associated with FGF-23 (β= 0.42, P <0.05, CI 0.3-4.3). R  of FGF-23 = 0.78%, every one unit increase in FGF-23 resulted in a 78% increase in LVMI.
| Discussion|| |
A previous study found that ESRD patients maintained on HD had high levels of FGF-23 as well as hyperphosphatemia and hyperparathyroidism.  FGF-23 is primarily produced in bone tissue by osteocytes,  and its principal actions are inhibition of sodium-dependent α- hydroxylase activity in the proximal tubule of the kidney, causing phosphaturia and suppression of circulating 1,25(OH)2D levels.  When renal function declines (which is often associated with phosphate imbalance), the serum FGF-23 level increases along with an increase of phosphate and a decrease of 1,25(OH)2D levels. In ESRD, phosphate excretion does not increase even with high levels of FGF-23,  and this is in agreement with the higher FGF-23 levels in HD patients than that in healthy volunteers in our study (P <0.001). FGF-23 activation of target tissues requires the co-expression of FGF receptors and Klotho (a 130-kDa single-pass β-transmembrane glucuronidase).  Other members of the FGF family, such as FGF1 and FGF2, have been linked to growth and repair of cardiovascular system. Thus, it is reasonable to suppose that FGF-23 plays a role in the pathogenesis of hyperphosphatemia that occurs in HD patients with LVH.
The present study provides two major findings. First, we found that elevated serum FGF-23 levels were weakly correlated with LVMI, serum calcium levels, serum albumin levels and serum creatinine levels; second, FGF-23 was weakly associated with LVMI, irrespective of serum phosphate and calcium levels.
It has been consistently shown that LVH is a powerful predictor for cardiovascular outcomes in dialysis patients including congestive heart failure, cardiac ischemia and arrhythmias, and stroke.  Gutierrez et al have recently reported that FGF-23 is associated with LVMI in asymptomatic patients with chronic kidney disease (CKD).  Unlike our study, the recruited subjects in that study were CKD patients not yet requiring HD. Thus, the link between elevated FGF-23 levels and LVMI appears to be consistent in patients with CKD from moderate stage to end stage. Our finding that FGF-23 levels were weakly associated with LVMI may provide the clue to clarify the pathogenesis of cardiovascular disease in HD patients. Recently, Gutierrez et al demonstrated that elevated FGF-23 concentrations at the initiation of HD are independently associated with increased 1-year mortality in a prospective cohort of 10,055 patients.  Importantly, a linear dose-response relationship was observed between FGF-23 levels and mortality, even after multivariable adjustment including serum phosphate, calcium, log parathyroid hormone and other confounders recorded in a clinical database. In addition, FGF-23 levels were most informative when serum phosphate was relatively normal; thus, FGF-23 may represent a novel risk biomarker for death in HD patients.  Jean et al have recently reported similar findings in long-term HD patients.  Our present study suggests that patients with increased FGF-23 levels are likely to have LVH, which may be a risk factor driving the high rate of cardiovascular mortality in HD patients. In addition, we emphasize that FGF-23 levels were weakly associated with LVMI, irrespective of serum phosphate in our study. This finding is also consistent with the report by Gutierrez et al and Jean et al, who showed that increased mortality in patients with elevated levels of FGF-23 was independent of the serum phosphate levels. ,
It is interesting to note that serum FGF-23 levels were positively associated with serum calcium levels, which is consistent with the report by Jean et al, who showed that the highest FGF-23 quartile was associated with hypercalcemia.  However, no correlation has been observed in patients who are starting HD treatment.  We did not vigorously explore the precise mechanisms underlying the positive relationship between serum FGF-23 and serum calcium. Further studies will be required to understand the mechanism of the association between FGF-23 and calcium in HD patients.
Our study did not show a correlation between FGF-23 and serum phosphorus levels. Animal studies have demonstrated a linear association between FGF-23 and phosphate; however, human trials have reported a variable rise in FGF-23 levels following phosphate loading,  which highlights the complexity of phosphate regulation in humans. It is likely that FGF-23 is not the only mediator of increasing phosphate excretion and that other phosphatonins (frizzled-related protein-4, fibroblast growth factor-7, matrix extracellular phosphoglyco-protein) play a currently poorly understood role.  The stimulation of FGF-23 depends on the dose and the duration of exposure to phosphate and bone-derived co-factors besides the severity and the chronicity of CKD. It is unclear whether serum or local phosphate concentrations provide the primary stimulus for FGF-23 secretion. FGF-23 has an inhibitory effect on PTH secretion; however, FGF-23 secretion may also occur in response to PTH levels. It is not known whether this occurs through a negative feedback loop mechanism or is conferred by the effects of PTH on calcitriol and serum phosphate.  The interaction between FGF-23 and Klotho may be necessary for normal phosphate metabolism. However, it is possible that high levels of FGF-23, as seen in CKD patients, can exert a Klotho-independent effect and bind to FGF-R with low affinity. This is supported by decreased expression of Klotho in renal biopsies from CKD patients.  The expression of Klotho occurs predominantly in the distal tubules, and the signaling sequence that leads to decreased phosphate absorption in the proximal tubules remains unclear. 
In our study, the sample size was relatively small. In addition, there are potential limitations to LVMI measurement using the formula of Deveraux, because echocardiographic measurement of LV mass relies upon geometric assumptions derived from normal hearts and tends to overestimate the volume, although the measurement still correlates well with LVMI by magnetic resonance imaging. This warrants 3-dimensional echocardiographic measurement of LVMI in HD patients in the future.
We conclude that serum FGF-23 is weakly associated with LVMI among HD patients. Thus, FGF-23 is not a good marker for evaluation of the cardiac status in this population. Further studies are needed to confirm the association of elevated FGF-23 and LV mass in HD patients.
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Division of Nephrology, University of Ain-Shams, Cairo
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]