|Year : 2013 | Volume
| Issue : 1 | Page : 7-17
Fibroblast growth factor 23 as a risk factor of left ventricular hypertrophy and vascular calcification in predialysis chronic kidney disease patients
Hassan Abdel-hady1, Said S.A. Khamis1, Yassein S. Yassein1, Hany Elbarbary1, Eman M. Zahir2, Ahmed M. Elmahmoudy1
1 Department of Internal Medicine, Nephrology & Dialysis Unit, Faculty of Medicine, Menoufia University, Menufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menufia, Egypt
|Date of Submission||21-Feb-2013|
|Date of Acceptance||09-Apr-2013|
|Date of Web Publication||26-Jun-2014|
Ahmed M. Elmahmoudy
MSc, Nephrology & Dialysis Unit, Faculty of Medicine, Menoufia University, Menufia
Source of Support: None, Conflict of Interest: None
The objective of this study was to evaluate the possible role of fibroblast growth factor 23 (FGF23) in the occurrence of left ventricular hypertrophy and vascular calcification in predialysis chronic kidney disease (CKD) patients.
FGF23 is a suggested risk factor for poor outcome of CKD. This raises the possibility that FGF23 is a hormone that controls calcium–phosphorus metabolism and is a real risk factor for cardiovascular mortality and morbidity in predialysis CKD patients.
Materials and methods
Thirty predialysis CKD patients with estimated glomerular filtration rate (90≥eGFR>15 ml/min/1.73 m2) by the modification of diet in renal diseases formula were included in this study. Patients were recruited from the Internal Medicine Department, Menoufia University (Egypt). Our controls were 10 individuals with preserved kidney function of more than 90 ml/min/1.73 m2 with normal BUN and creatinine matched by age and sex. Routine and specific investigations (serum FGF23 measurement using ELISA immunoassay, serum intact parathyroid hormone, conventional echocardiography, and lateral abdominal aortic radiograph for calcification) were performed.
The mean log FGF23 level in CKD patients was 2.3±0.6 Ru/ml and was significantly higher than that of control participants, 1.7±0.1 Ru/ml (P<0.001). There was a significant difference between CKD2–3 stage and CKD4 stage in the FGF23 (P<0.05) level but not in serum phosphorus (P>0.05). Left ventricular mass index was correlated positively with log FGF23 (r=0.44, P<0.05) and negatively with eGFR (r=−0.4, P<0.05). Abdominal aortic calcification was correlated positively with age (r=0.55, P<0.001), but had no correlation with FGF23 (r=0.36, P>0.05).
FGF23 could be an early risk factor for the occurrence of left ventricular hypertrophy even before an increase in serum phosphorus in predialysis CKD patients.
Keywords: abdominal aortic calcification, chronic kidney disease, fibroblast growth factor 23, left ventricular hypertrophy, left ventricular mass index
|How to cite this article:|
Abdel-hady H, Khamis SS, Yassein YS, Elbarbary H, Zahir EM, Elmahmoudy AM. Fibroblast growth factor 23 as a risk factor of left ventricular hypertrophy and vascular calcification in predialysis chronic kidney disease patients. Menoufia Med J 2013;26:7-17
|How to cite this URL:|
Abdel-hady H, Khamis SS, Yassein YS, Elbarbary H, Zahir EM, Elmahmoudy AM. Fibroblast growth factor 23 as a risk factor of left ventricular hypertrophy and vascular calcification in predialysis chronic kidney disease patients. Menoufia Med J [serial online] 2013 [cited 2020 Feb 17];26:7-17. Available from: http://www.mmj.eg.net/text.asp?2013/26/1/7/135421
| Introduction|| |
Chronic kidney disease (CKD) is a growing public health epidemic that is associated with a markedly increased risk of cardiovascular disease and mortality 1.
Although CKD populations manifest a high prevalence of traditional risk factors for atherosclerosis such as hypertension and diabetes mellitus, these classic risk factors do not fully account for the burden of cardiovascular disease in patients with CKD 2.
Left ventricular hypertrophy (LVH) and diffuse arterial calcification are common manifestations of cardiovascular disease that are powerful independent risk factors for mortality in patients with CKD 3.
Approximately 40% of patients with predialysis CKD and up to 80% of patients initiating hemodialysis develop LVH 4. Similarly, diffuse arterial calcification begins before patients are initiated on dialysis, and significant disease is present in more than 60% of new dialysis patients. Understanding the early mechanisms of LVH and arterial calcification is essential for the design of novel therapeutic strategies to attenuate cardiovascular disease in CKD 5.
High phosphate concentrations promote nonatherosclerotic arterial calcification by stimulating metaplasia of vascular smooth muscle cells into an osteogenic phenotype 6. These results suggest that disordered phosphorus metabolism is a novel risk factor for cardiovascular disease. However, overt hyperphosphatemia is uncommon in predialysis, and the small absolute increases in serum phosphate concentrations that were associated with poor clinical outcomes in large epidemiological studies limit their utility as a tool to detect which individual patients with CKD are at greatest cardiovascular risk 7.
Fibroblast growth factor 23 (FGF23) is a recently discovered hormone that helps maintain normal serum phosphate concentrations in patients with kidney disease by stimulating urinary phosphate excretion and decreasing dietary phosphorus absorption through the inhibition of 1,25-dihydroxyvitamin D synthesis 8.
Importantly, circulating concentrations of FGF23 increase early in the course of kidney disease, long before the development of hyperphosphatemia; thus, a high FGF23 concentration is among the earliest markers of disordered phosphorus metabolism in CKD 9.
In CKD patients, an independent relationship has been found between FGF23 and LVH (particularly concentric LVH). FGF23 selectively binds to FGF receptors normally activated by other factors, thus inducing enhanced fibrosis 10.
| Materials and methods|| |
This study was carried out at Menoufyia University Hospital (Egypt). All participants provided informed consent and this study was approved by the local ethics committee of Menoufyia University Hospital.
The population studied included 40 patients divided into two groups: group I, 30 predialysis CKD patients with various stages (from CKD2 to CKD4) [90≥glomerular filtration rate (GFR)>15 ml/min/1.73 m2] on the basis of the modification of diet in renal diseases (MDRD) formula 11 and according to the Kidney Disease Outcomes Quality Initiative 12; and group II, 10 healthy individuals with preserved kidney function defined by normal blood urea and serum creatinine and GFR higher than 90 ml/min/1.73 m2.
Patients were eligible for the study if they were at least 30 years of age, had CKD stage 2 to CKD stage 4, and had no previous history of coronary artery disease. All participants recruited in this study underwent a standard procedure consisting of assessment of detailed history and complete physical examination. Blood pressure measurements were performed, and were the mean of measurements on three different occasions in the sitting position. The mean arterial pressure (MAP) was calculated from the formula: MAP=DP+1/3(SP−DP); BMI was calculated using the equation BMI=weight (kg) divided by the square of the height (m).
Exclusion criteria were as follows: patients with stage 5 kidney disease (eGFR<15 ml/min/1.73 m2), those receiving renal replacement therapy (dialysis or kidney transplant), and those with known ischemic heart diseases or heart failure. Patients had to stop their α calcidol or phosphate binder 6 weeks before FGF23 measurement.
Blood samples were obtained from all patients and immediately centrifuged, separated into aliquots for further assays, and stored at −20°C until measurement. Blood urea and serum creatinine were measured using auto-analyzer synchron CX5 Beckman (Diamond Diagnostics, Massachusetts, USA). Serum phosphate, calcium, albumin and liver function tests, serum sodium, and potassium were measured using standard commercial assays. Standard ECG and abdominopelvic ultrasound (Fukuda Fx 2100, Japan) were performed. eGFR was calculated according to the MDRD equation 13:
Serum fibroblast growth factor 23 concentration
Serum FGF23 concentration was measured using a two-site enzyme-linked immunosorbent assay (ELISA) that detects two epitopes in the carboxyl-terminal portion of FGF23 (Immutopics, San Clemente, California, USA). This second-generation Human FGF-23 (carboxyl terminal) ELISA Kit (Immutopics) is a two-site ELISA for the measurement of FGF23 in plasma or cell culture media. Two affinity-purified goat polyclonal antibodies were selected to detect epitopes within the carboxyl-terminal portion of FGF23. One antibody was biotinylated for capture and the other antibody was conjugated with the enzyme horseradish peroxidase for detection.
A sample containing human FGF23 was incubated simultaneously with the biotinylated capture antibody and the horseradish peroxidase-conjugated antibody in a streptavidin-coated microtiter well. FGF23 contained in the sample was immunologically bound by the capture antibody and the detection antibody to form a ‘sandwich’ complex:
Well/avidin-biotin anti-h FGF23-human FGF23-HRP anti-h FGF23:
At the end of this incubation period, the well was washed to remove any unbound antibody and other components. The enzyme bound to the well was incubated with a substrate solution in a timed reaction and then measured in a spectrophotometric microtiter plate reader.
The enzymatic activity of the antibody complex bound to the well is directly proportional to the amount of FGF23 in the sample. A standard curve was generated by plotting the absorbance versus the respective FGF23 concentration for each standard on linear or logarithmic scales.
The concentration of human FGF23 in the samples was determined directly from this curve.
The FGF23 concentrations of the controls and samples were read directly from the standard curve using their respective corrected absorbance.
To assess intra-assay precision, the mean and coefficient of variation were calculated from 20 duplicate determinations of two samples each performed in a single assay.
To assess intra-assay precision, the mean and coefficient of variation were calculated from duplicate determinations of two samples each performed in 10 assays.
Normal value: (33.8–110.2 RU/ml) (Immutopics).
Serum intact parathyroid hormone
Serum intact parathyroid hormone (PTH) was measured using the Elecsys PTH assay (Roche, Germany). The ElectroChemiLuminescence Immunoassay is intended for use on Elecsys and Cobas e immunoassay analyzers (Roche).
Sandwich principle. Total duration of assay: 18 min.
First incubation: 50 µl of sample, a biotinylated monoclonal PTH-specific antibody, and monoclonal PTH-specific antibody labeled with a ruthenium complex form a sandwich complex.
Second incubation: after the addition of streptavidin-coated microparticles, the complex became bound to the solid phase through interaction of biotin and streptavidin.
The reaction mixture was aspirated into the measuring cell, where the microparticles were magnetically captured onto the surface of the electrode. Unbound substances were then removed with ProCell.
Application of a voltage to the electrode then induced chemiluminescent emission, which was measured using a photomultiplier.
Results were determined from the calibration curve, which is an instrument specifically generated by two-point calibration and a master curve provided by the reagent barcode.
Normal serum intact PTH (10–71 pg/ml).
The examinations were performed by one investigator in a blinded manner using a Hewlett Packard 77020A ultra sound system (Hewlett Packard Inc., California, USA) equipped with a 2.5 MHz transducer.
Left ventricular posterior wall endocardium, septal wall endocardium, and posterior wall epicardium were measured from the wave of the subsequent beat left ventricular end-diastolic dimension (LVEDD); the thickness of interventricular septum and posterior wall were measured at the onset of the ECG Q ware. The left ventricular end-systolic dimension (LVESD) was measured at the time of the smallest left ventricular diameter. Left ventricular fractional shortening was defined as (LVEDD−LVESD)×100/LVEDD and the ejection fraction as (LVEDD3−LVESD3)×100/LVEDD3. The M-mode echocardiography measurements were interpreted according to the standards of the American Society of Echocardiography. Left ventricular mass and left ventricular mass indexed to the body surface area estimated by left ventricular cavity dimension and wall thickness at end-diastole.
Relative wall thickness (RWT) allows further classification of left ventricular mass increase as either concentric hypertrophy (RWT>0.42) or eccentric hypertrophy (RWT⩽0.42) 14:
Lateral aortic radiography
Lateral aortic radiography was performed in the standing position using standard radiographic equipment. A minimum of 4 cm anterior to the lumbar spines had to be visible: the film distance was 100 cm and other adjustments were 94 kpV, 33–200 mAs and estimated dose of radiation was ∼15 mGy.
Calcification of the aorta was graded using a previously validated system in which both the location and the severity of calcific deposits at each lumbar vertebral segment (L1–L4) were evaluated (score 1–24) 15.
IBM SPSS statistics (V. 20.0, 2011; IBM Corp., New York, USA) was used for data analysis. Data were expressed as mean±SD for quantitative parametric measures in addition to percentage for categorized data. Routine statistics were calculated after adjustment for age and BMI using analysis of covariance. The following tests were carried out: (a) comparison between two independent mean groups for parametric data using the Student t-test. (b) Comparison between two independent groups for nonparametric data using the Mann–Whitney U-test. (c) Ranked Spearman correlation test to study the possible association between two variables in each group for nonparametric data. (d) Linear regression analysis was used to examine the association of left ventricular mass index (LVMI) with clinical and laboratory data of the studied group (I). (e) χ2-Test to study the association between two variables or comparison between two independent groups in terms of the categorized data. (f) Specificity and sensitivity testing for FGF23. The probability of error was considered significant at 0.05 and highly significant at 0.01 and 0.001.
| Results|| |
The demographic, laboratory, echocardiogram, and radiological data of all 40 patients involved in the study are presented in [Table 1]: results are expressed as mean±SD or percent as appropriate. There was no significant difference in age, sex, and BMI between the controls and the CKD patients.
There was a significant difference between them in estimated GFR, hemoglobin level, serum calcium, serum phosphorus, blood urea, creatinine level, serum intact PTH, log FGF23, LVMI (g/m2), and abdominal aortic calcification (AAC) score [Table 1].
CKD patients (group I) were further subclassified according to estimated GFR (MDRD) into two subgroups: subgroup A: two patients (6%) with GFR higher than 60 ml/min/1.73 m2 (CKD2) and 18 patients (60%) with GFR between 30 and 59 ml/min/1.73 m2 (CKD3) and subgroup B: 10 patients (34%) with GFR between 15 and 29 ml/min/1.73 m2 (CKD4). The two patients with GFR higher than 60 ml/min/1.73 m2 (CKD2) were included with CKD3 patients for statistical significance; there was a significant difference between the two subgroups in age (50.4±12.1 and 59.8±7.1), hemoglobin level (11.23±1.1 and 9.7±1.2), serum calcium (8.99±1.06 and 8.1±1.04), and log FGF23 (2.21±0.6 and 2.6±0.4), respectively, but no significant difference between them in serum phosphorus, which means that serum phosphorus can be normal even in the late CKD stage.
In order to identify the relationships of LVH and vascular calcification, CKD patients (group I) were further subclassified according to the presence or absence of LVH and aortic calcification.
In group I, 73.3% of patients had LVH and 26.7% had no LVH; the concentric pattern was predominant (81.8%). The relationship of LVH and other clinical, laboratory, and radiological features in [Table 2] showed that LVH was detected in 73.3% of patients of group I (n=22) (118.7±17.3). One patient (4.5%) had mild concentric LVH, seven patients (31.8%) had moderate concentric LVH, 10 patients (45.5%) had severe concentric LVH, and four patients (18.2%) had eccentric LVH.
There was a highly significant difference between group I (127.3±21.4) and group II (65.2±11.79) in LVMI (g/m2) (P<0.001) [Table 1].
Group I was further subdivided into two subgroups according to the presence or absence of LVH measured by LVMI (g/m2) (LVMI>115 in men and LVMI>95 in women). There was a significant difference between both subgroups in age (years), sex, estimated GFR (ml/min/1.73 m2), hemoglobin level, serum creatinine, and serum log FGF23 (P<0.05), but no significant difference in BMI, MAP, serum uric acid, serum albumin, serum calcium, serum phosphorus, serum cholesterol, triglyceride, or serum Intact PTH (P>0.05) [Table 2].
Aortic calcification was detected in nine patients (40.9%) who had LVH (1.6±2.9) and one patient (12.5%) who did not have LVH, and there was no significant difference between both groups in the AAC score (P>0.05) [Table 2].
There was a significant correlation between LVH and age (years) (r=0.45), BMI (g/m2) (r=0.39), estimated GFR (MDRD) (ml/min/1.73 m2) (r=−0.4), and hemoglobin level (r=−0.45) in group I (P<0.05) [Table 3].
|Table 1: Demographic, laboratory, and radiological characteristics of all patients|
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There was a significant correlation between LVH measured by LVMI (g/m2) and log FGF23 (Ru/ml) (r=0.44, P<0.05) [Table 3].
Linear regression analysis showed an association between LVH and log FGF23 (Ru/ml) (r2=0.46, P<0.05) and with age (r2=0.63, P<0.001) after multivariable analysis [Table 4].
|Table 2: Clinical, laboratory, and radiological characteristics of the studied group (I) (chronic kidney disease patients) according to the presence or absence of left ventricular hypertrophy measured by left ventricular mass index|
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AAC was detected in 10 patients (33.3%) whereas there was no calcification in the rest of the 20 patients (66.7%) in group I.
There was a significant difference between group I (1.4±2.6) and group II (0±0) in the AAC score (P<0.05) [Table 1].
Group I was subdivided into two subgroups according to the presence or absence of vascular calcification measured by the AAC score.
There was no significant difference in age (years), MAP, sex, estimated GFR, hemoglobin level, serum uric acid, serum calcium, serum phosphorus, serum cholesterol, triglyceride, serum intact PTH, or log FGF23 (Ru/ml) (P>0.05) [Table 5].
|Table 3: Correlation coefficient between left ventricular mass index (g/m2) and clinical, laboratory, and radiological characteristics of the studied group (I) (chronic kidney disease patients)|
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There was no significant difference in LVMI (g/m2) between patients with vascular calcification (119.4±24.6) and patients without vascular calcification (131.2±19.2) (P>0.05) [Table 5].
There was a significant correlation between vascular calcification measured by the AAC score and age (years) in group I (r=0.55, P<0.05) [Table 6].
|Table 4: Linear regression analysis (r2) between left ventricular hypertrophy and clinical and laboratory data of the studied group (I) (chronic kidney disease patients)|
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Age was still a good predictor of vascular calcification measured by (AAC score) after multivariable regression analysis (r2=0.33, P<0.05) [Table 7].
|Table 5: Clinical, laboratory, and radiological characteristics of the studied group (I) (chronic kidney disease patient) according to the presence or absence of vascular calcification measured by abdominal aortic calcification score|
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There was no significant correlation between vascular calcification measured by the AAC score and MAP, estimated GFR, hemoglobin level, serum calcium, serum phosphorus, serum Intact PTH, or log FGF23 (Ru/ml) in group I (P>0.05) [Table 6].
FGF-23 was examined on a continuous scale using natural log FGF23 values to achieve a normal distribution.
Serum log FGF23 (Ru/ml) was 2.3±0.6 in group I and 1.7±0.1 in group II and there was a highly significant difference between both groups (P<0.001) [Table 1].
The mean log FGF23 (Ru/ml) was 2.6±0.4 in patients with LVH and 1.8±0.3 in patients without LVH, with a highly significant difference between them (P<0.001) [Table 2].
The mean log FGF23 (Ru/ml) was 2.4±0.7 in patients with vascular calcification and 2.3±0.3 in patients without vascular calcification, with no significant difference between both groups (P>0.05) [Table 5].
There was a significant correlation between log FGF23 (Ru/ml) and LVMI (g/m2) in group I (r=0.44, P<0.05) [Table 3].
There was no significant correlation in univariate analysis between log FGF23 (Ru/ml) and the AAC Score in the CKD patients in group I (r=0.36, P>0.05) [Table 6].
Log FGF23 showed a significant negative correlation with estimated GFR and hemoglobin level (r=−0.54, −0.62, respectively, P<0.001); however, it showed a positive correlation with serum phosphorus (r=0.46, P<0.05) and no correlation with serum intact PTH in univariable analysis (r=0.31, P>0.05) [Table 8].
|Table 6: Correlation coefficient between aortic vascular calcification and clinical, laboratory, and radiological characteristics of the studied group (I) (chronic kidney disease patients)|
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Hemoglobin level and serum phosphorus were still significantly correlated with log FGF23 after multivariable regression analysis (r2=0.512, P<0.05) [Table 9].
|Table 7: Linear regression analysis (r2) between aortic vascular calcification and clinical data of the studied group (I) (chronic kidney disease patients)|
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log FGF23 (Ru/ml) was still significantly correlated with LVMI (g/m2) in group I after multivariable regression analysis [Table 4].
Serum intact PTH showed a highly significant difference between group I (86.9±47.3) and group II (28.5±12.75) (P<0.001) [Table 1].
There was no significant difference in serum intact PTH (pg/ml) between patients with LVH (93.9±44.15) and patients without LVH (67.5±53.4) in group I (P>0.05) [Table 2].
There was no significant difference in serum intact PTH (pg/ml) between patients with vascular calcification (97.2±50.7) and patients without vascular calcification (81.8±46.03) (P>0.05) [Table 5].
There was a significant correlation between serum intact PTH (pg/ml) and LVMI (g/m2) in group I (r=0.35, P<0.05) [Table 6]; [Figure 1], [Figure 2], [Figure 3] and [Figure 4].
|Figure 1: Classification of group I [chronic kidney disease (CKD) patients] in terms of estimated glomerular filtration rate (MDRD). MDRD, modification of diet in renal diseases.|
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|Figure 2: Correlation coefficient (r) between left ventricular mass index (LVMI) (g/m2) and log FGF23 (r=0.44, P<0.05). FGF23, fibroblast growth factor.|
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|Figure 3: Fibroblast growth factor 23 (FGF23) levels in patients with and without left ventricular hypertrophy (LVH).|
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|Figure 4: Receiver-operating characteristic (ROC) curve for fibroblast growth factor 23 (FGF23). Specificity 0% – sensitivity 83% – cutoff value 1.94 Ru/ml – area under the curve 70%. ROC curve: is a graphical plot of the sensitivity vs. false-positive rate (FPR) (1−specificity). The ROC is also known as a relative-operating characteristic curve because it is a comparison of two operating characteristics [true-positive rate (TPR) and FPR]. Sensitivity or TPR=true positive/(true positive+false negative). Specificity or true-negative rate=true negative/(true negative+false positive)=1−FPR. Accuracy=(true positive)+(true negative)/(positive+negative) (|
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| Discussion|| |
Interest in FGF23 increased tremendously after the publication of two prospective cohort studies in which FGF23 was identified as a risk factor predicting worse outcome in CKD patients. The ArMORR study and the MMKD trial first reported that high FGF23 levels in patients initiated on hemodialysis were an independent predictor of 1-year mortality after adjustment for serum phosphate levels 16.
The first clinical data linking high FGF23 levels to end-organ damage in CKD were presented at the American Society of Nephrology Renal Week in 2008, when Gutiérrez et al. 10 reported an association between LVH and high FGF23 levels.
The aim of the study was to evaluate the possible role of FGF23 in the occurrence of LVH and vascular calcification in predialysis CKD patients in an attempt to identify other nontraditional risk factors and pathophysiological mechanisms that could help decrease the CVS burden of CKD patients and identify new targets of therapy.
This study showed high levels of FGF23 in CKD patients (66.7%) compared with normal individuals and a significant difference between CKD4 and CKD2–3 in serum FGF23 level (2.6±0.4 and 2.21±0.6, respectively).
In contrast, serum phosphorus was not significantly different in CKD4 and CKD2–3 subgroups, which means that serum phosphorus remains within the normal range with advanced kidney stage (CKD4); this can be explained by the fact that high FGF23 attempts to maintain serum phosphorus within this normal range in predialysis CKD.
In agreement with this result, a study of Gutiérrez et al. 9 concluded that FGF23 levels increase early in CKD before the development of serum mineral abnormalities and are independently associated with serum phosphate, FePO4, and calcitriol deficiency. Increased FGF23 may contribute toward maintaining normal serum phosphate levels in the face of advancing CKD, but may worsen calcitriol deficiency, and thus may be a central factor in the early pathogenesis of secondary hyperparathyroidism.
In this study, predialysis CKD patients showed a high prevalence of LVH measured by LVMI (73.3%), mainly a concentric pattern rather than an eccentric pattern.
In the present study, LVH was correlated significantly with age, BMI, and MAP and significantly negatively correlated with estimated GFR and hemoglobin level.
In agreement with our study, a study by Paoletti et al. 17 evaluated the prevalence of LVH in 244 patients with CKD, free of diabetes and coronary artery disease; the prevalence of hypertension was 66%. GFR was estimated using the Cockcroft–Gault equation. An independent association was found between LVM and ambulatory pulse pressure. LVM was indexed by body surface area (LVMI) and LVH was defined as LVMI more than 134 g/m2 in men and more than 110 g/m2 in women. The overall prevalence of LVH was 74%, and was increasingly higher with decreasing renal function: 51% in stage 1–2 CKD, 71% in stage 3, and 80 and 84% in stages 4 and 5, respectively. Further, a higher prevalence of concentric geometry was found in patients with more advanced renal dysfunction 17.
In the African American Study of Kidney Disease, the prevalence and the correlations of LVH were evaluated in 599 nondiabetic hypertensive African Americans. The mean age of the patients was 60 years and the mean GFR was 44 ml/min/1.73 m2. It is noteworthy that in this study, GFR was estimated using a different equation developed from baseline data in the African American Study of Kidney Disease trial. LVM was indexed by height elevated to a power of 2.7 (LVMH 2.7) and LVH was defined as LVMH 2.7>49.2 g/m2.7 in men and>46.7 g/m2.7 in women. The variables associated independently with LVH, the overall prevalence of which was 69.4%, were daytime and nighttime ambulatory blood pressure, GFR, and younger age 18.
This study showed a significant correlation between FGF23 and LVH measured by LVMI, whereas phosphorus did not show any significant correlation at this stage. This could indicate that FGF23 could be an early marker of LVH before serum phosphorus increases.
In agreement with our study, Gutiérrez et al. 10 reported that FGF23 is associated independently with LVMI and LVH in patients with CKD.
A study by Stevens et al. 19 examined the relationship between FGF23 and LVH measured using the gold standard technique, Cardiac MRI, and reported a direct relationship between LVH and FGF23, but they did not prove a causality with elevated FGF23 on LVH.
Also, they had examined in vitro the effect of FGF23 on endothelial cells and showed that FGF23 stimulates the production of the cell adhesion molecules E-selectin and VCAM. Higher levels of E-selectin and VCAM indicate activation of the vascular endothelium, which are also present in patients with essential hypertension, who have endothelial dysfunction 19.
Another study showed that FGF23 levels are associated with left-ventricular function and atrial fibrillation even in the absence of renal function impairment 20.
In the present study, serum log FGF23 showed no significant difference between patients with vascular calcification and patients without vascular calcification and also showed a nonsignificant correlation with vascular calcification.
In the present study, vascular calcification measured by the AAC score showed a highly significant correlation with age (r=0.55, P<0.001).
In terms of FGF23 relation’s with calcification, studies had researched this relation especially with coronary artery calcification (CAC) and reported an association with CAC in hemodialysis patients, but not evident in predialysis CKD patients 10.
Gutiérrez et al. 10 had described an association between CAC and FGF23; however, this association was no longer significant after multivariable adjustment or when examined on a continuous scale.
The relationship between vascular calcification and FGF23 in CKD patients is unclear; one recent study reported an independent positive correlation between FGF23 and peripheral vascular calcification 21, whereas another study reported a negative association; even less clear is the relation of FGF23 with aortic calcification 22.
In another study, aortic calcification was shown to be associated with coronary calcification in CKD 23.
The relationship between aortic calcification and FGF23 was not determined as preceding studies did not account for aortic calcification as a separate entity 21, or could not find a correlation with aortic calcification on lateral lumbar radiographs 22.
Inaba et al. 22 reported that no relationship was present between plasma FGF23 levels and aortic calcification in patients with hemodialysis, but an association with peripheral vascular calcification was present. In that study, aortic vascular calcification was found in 41.1 and 65.6% of hemodialysis patients with and without DM, respectively 22.
In agreement with this study, the study of Inaba et al. 22 had detected aortic vascular calcification in 10 patients (33.3%), but they could not find a significant correlation between aortic calcification and log FGF23. A possible explanation for the absence of correlation may be that aortic and peripheral vessel calcification may reflect different aspects of vascular calcification. ‘Atheromatous’ calcification occurs in the aorta and mainly affects the intimal layer of the vessel wall and is associated with atherosclerosis, whereas calcification of the hand arteries affects the medial layer and is of the type found in Moenckeberg’s sclerosis 24.
In contrast to this study, Desjadins et al. 25 suggested that FGF23 is an independent biomarker of vascular calcification in patients with various stages of CKD including early stages. Pulse wave velocity was used to detect aortic calcification.
| Conclusion|| |
FGF23 could be an early risk factor for the occurrence of LVH even before the increase of serum phosphorus in predialysis CKD patients.
Further studies are required to uncover the possible pathophysiological role of FGF23 in myocardium; furthermore, FGF23 should be considered in future studies for prevention of LVH in CKD patients, and further studies in a large population are required to determine the unclear role of FGF23 in vascular calcification in predialysis CKD [Table 10].
|Table 8: Correlation coefficient (r) between serum log FGF23 and laboratory characteristics of the studied group (I) (chronic kidney disease patients)|
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12]