|Year : 2019 | Volume
| Issue : 5 | Page : 1010-1021
|Serum fibroblast growth factor 23 levels do not correlate with carotid intima-media thickness in patients with chronic kidney disease
Bulent Kaya1, Neslihan Seyrek1, Saime Paydas1, İbrahim Karayaylali1, Mustafa Balal1, Kairgeldy Aikimbaev2
1 Department of Nephrology, Cukurova University Faculty of Medicine, Sarıçam, Adana, Turkey
2 Department of Radiology, Cukurova University Faculty of Medicine, Sarıçam, Adana, Turkey
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|Date of Submission||15-May-2018|
|Date of Decision||05-Aug-2018|
|Date of Acceptance||05-Aug-2018|
|Date of Web Publication||4-Nov-2019|
| Abstract|| |
High levels of fibroblast growth factor 23 (FGF 23) are associated with mortality and cardiovascular events in patients with chronic kidney disease (CKD). Carotid intima-media thickness (CIMT) is a useful marker of subclinical atherosclerosis. This study aimed to investigate the relationship between serum FGF23 levels and CIMT of CKD patients. In this cross-sectional study, CIMT was measured in 162 patients with CKD Stage of 2–5 (age range 18–79 years, 61.7% males). Serum FGF23 levels were determined by enzyme-linked immunosorbent assay. CIMT was measured by ultrasonography. Serum FGF-23 levels were significantly higher (P = 0.046) in advanced CKD patients. CIMT was thicker in patients with advanced CKD patients (P = 0.01). CIMT was correlated with age (r = 0.486, P <0.001), smoking (r = 0.411, P <0.001), and 25-OH Vitamin D (r = −0.195, P= 0.045). There was no correlation between serum FGF23 and CIMT. Multivariate analysis showed that age (β = 0.373, P <0.001), smoking (β = 0.228, P = 0.004), and serum 25-hydroxyvitamin D levels (β = −0.164, P = 0.042) were associated with CIMT. There was no relationship between FGF23 and CIMT. The CIMT was found to be related to increased age, smoking, and 25-hydroxyvitamin D in CKD patients.
|How to cite this article:|
Kaya B, Seyrek N, Paydas S, Karayaylali &, Balal M, Aikimbaev K. Serum fibroblast growth factor 23 levels do not correlate with carotid intima-media thickness in patients with chronic kidney disease. Saudi J Kidney Dis Transpl 2019;30:1010-21
|How to cite this URL:|
Kaya B, Seyrek N, Paydas S, Karayaylali &, Balal M, Aikimbaev K. Serum fibroblast growth factor 23 levels do not correlate with carotid intima-media thickness in patients with chronic kidney disease. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2021 Sep 25];30:1010-21. Available from: https://www.sjkdt.org/text.asp?2019/30/5/1010/270255
| Introduction|| |
Fibroblast growth factor 23 (FGF23) is a recently discovered hormone synthesized mainly from osteocytes which is involved in phosphate regulation and metabolism of Vitamin D. It increases progressively in chronic kidney disease (CKD) to compensate for the persistent phosphate retention. In early CKD, increased FGF23, to maintain neutral phosphate balance, results in suppression of renal 1,25-dihydroxy vitamin D production and thereby triggers the early development of secondary hyperparathyroidism. FGF23 also acts directly on the parathyroid gland to decrease parathormone (PTH) synthesis and secretion, but this effect is blunted in advanced stages of CKD.
Cardiovascular diseases (CVDs) are the major cause of death in patients with end-stage renal disease and their mortality is 20–30 times more when compared with the general population.
The elevated FGF23 level is suggested to be an early biomarker of phosphorus metabolism in the earlier stages of CKD and acts as a strong predictor of mortality in dialysis patients.
Carotid intima-media thickness (CIMT) is a predictor of future cardiovascular events such as myocardial infarction and stroke., In addition to major traditional cardiovascular risk factors, several uremia-related risk factors such as inflammation, oxidative stress, endothelial dysfunction, vascular calcification, hyperhomocysteinemia, and immunosuppressants have been associated with accelerated atherosclerosis (AS). The contribution of increased serum FGF23 levels to AS in CKD patients is unclear. In this study, we evaluated the relationship between serum FGF23 levels and CIMT in patients with Stage 2–5 CKD.
| Methods|| |
This cross-sectional study included 162 patients with Stage 2–5 CKD (age range 18–79 years, 61.7% males). Patients who had NYHA class 3–4 congestive heart failure, active infectious disease, chronic liver disease, documented coronary artery disease, history of renal transplantation, obesity ([body mass index (BMI) ≥35 kg/m2], malignancy and/or history of malignancy, parathyroidectomy or who refused to sign the consent form were excluded from the study.
Sixteen patients were undergoing a standard 4-h hemodialysis (HD) three times a week. Bicarbonate dialysate containing potassium (K)+ 2.0 mmol/L, calcium (Ca2+) 1.25 mmol/L, sodium (Na+) 138 mmol/L, and magnesium (Mg2+) 0.5 mmol/L was used. Standard (conventional) peritoneal dialysis (PD) solutions (Baxter Healthcare, Fresenius Medical Care) were used in patients who received PD treatment.
Height, weight, BMI, blood pressure (BP), and other systemic findings of the patients were recorded. BP was measured in the sitting position in a silent room using a sphygmomanometer. BMI was calculated using the height and weight measurement as weight (kg)/height (m2). Glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease formula.
The study was performed in accordance with the Declaration of Helsinki for Human Research and was approved by the Institutional Review Board. All patients provided written informed consent before inclusion in each study.
Following 8–10 h of fasting patients’ routine blood samples and an additional 8 mL sample of blood were obtained. The sample was put in polystyrene tubes and centrifuged. The obtained serum was put in three different 1.5 mL covered Eppendorf tube and stored in the deep freezer at −80°C. The FGF23 level was measured using ELISA. The FGF23 measorement was done with USCN Life Science Inc., Wuhan, China ELISA kit in the Chromate micro-EL ISA device.
PTH was measured with Roche Elecys -170 devices using the electro chemoluminescence, 25-OH Vitamin D was measured with an Agilent-1100 device with high-pressure liquid chromatography method. Glucose, BUN, creatinine, uric acid, calcium (Ca), phosphate (P), and albumin (alb) were measured with Roche Modular DPP device using the enzymatic calorimetry method. Ferritin was measured with the Roche Modular system device using the immunoturbidimetric method. C-reactive protein (CRP) was measured with Date Behring BN II device using the immuno-turbidimetric method. HbA1c was measured with Roche Integra 800 device with using the immunoturbidimetric method. Whole blood count was analyzed in a Beckman Coulter machine.
Carotid intima-media thickness
CIMT measurements were done with Logiq 8 (General Electric Medical Systems) with high-resolution B-mode ultrasound and linear probe at 12.0 MHz frequency. CIMT was defined in accordance with Pignoli et al as the distance between the echogenic line representing the intimal inner surface of the lumen and the outer echogenic line representing the collagenous media-adventitia layer. The same experienced radiologist measured all parameters by using carotid Doppler ultrasound.
The measurements were obtained with the patient in the supine position with the head tilted 45° to the opposite side of the measurement. In all of the patients, three different measurements were made bilaterally from the posterior wall of the main carotid artery (2 cm proximal of the bulbus), and CIMT was evaluated separately for the left and right sides. No measurement was taken when an atheroma plaque was seen.
| Statistical Analysis|| |
Kolmogorov–Smirnov test was used to see if the quantitative measurements showed normal distribution. A t-test was used between independent groups when the hypothesis was fulfilled; Mann–Whitney U-test was used when the hypothesis was not fulfilled. Some of the ordinal measurements did not show normal distribution; thus, the correlations between these continuous measurements were done by using the Spearman Correlation coefficient. Correlations between two variables were examined by linear regression analysis. Independent associations between variables were evaluated by multiple regression analysis. Statistical probability was used as 0.05 in all the tests. The categorical measurement was done using number and percentage, numerical measurements were done using average and standard deviation (when appropriate median and minimum-maximum). The data were analyzed using the Statistical Package for the Social Sciences version 19.0 (IBM Corp., Armonk, NY, USA).
| Results|| |
Demographic and clinical characteristics of the patients are shown in [Table 1]. CKD patients in the early stages (Stage 2–3) were older than those in advanced stage (Stage 4–5).
|Table 1: Demographic and clinical characteristics of the patients (n=162).|
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The patients were classified according to their CKD stages as follows: 18 patients in Stage 2, 38 patients in Stage 3, 39 patients in Stage 4, and 67 patients in Stage 5 (16 HD, 28 PD) and 23 nondialysis Stage 5.
The etiology of CKD in patients were diabetic nephropathy (n = 57), chronic glomerulonephritis (n = 14), polycystic kidney disease (n = 13), nephrolithiasis (n = 10), hypertensive nephrosclerosis (n = 9), other (n = 20), and unknown (n = 39)
Eighty-one patients were active smokers and 22 patients were consuming alcohol. The drugs used by the patients were: angiotensin-converting enzyme inhibitor (n = 30), angiotensin II receptor blocker (n = 28), calcium channel blocker (n = 74), beta-blocker (n = 58), diuretic (n = 51), alfa blocker (n = 35), calcitriol (n = 42), phosphate-binding drugs (n = 38), lipid-lowering drug (LLD) (n = 10), allopurinol (n = 20).
CKD stages were re-classified into two groups; Stage 2 and Stage 3 gathered into one group and called the early-stage group, and Stage 4 and Stage 5 gathered into other group and called advanced stage groups [Table 2]. FGF23, age, smoking, HbA1C, systolic BP (SBP), diastolic BP (DBP), 25-hydroxyvitamin D, and CIMT levels were compared between these two groups. Early-stage patients (58.5 ± 10.8 year) were older than advanced stage patients (48.7 ± 13.9 years) (P <0.001). DBP was higher in advanced stage (83.3 ± 10.5 mm Hg) patients compared with early-stage patients (78.4 ±10.1 mm Hg) (P = 0.005). Mean HbA1C levels were significantly higher in early-stage CKD (6.8% ± 1.7%); when compared advanced stage CKD (5.9% ± 1.3%) (P = 0.001). FGF-23 levels were significantly higher in advanced stage (17.1 pg/mL) when compared with the early stage (9.7 pg/mL) (P = 0.046). Right CIMT was thicker in patients with early CKD (0.077 mm) than in patients with advanced stage CKD (0.069 mm) (P = 0.010).
|Table 2: The relationship between fibroblast growth factor 23 levels, carotid intima-media thickness and other parameters in patients with early and advanced-stage chronic kidney disease.|
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The relationship of FGF23 and CIMT levels between the other related variables are shown in [Table 3] and [Table 4]. In the early stages of CKD, serum FGF23 levels correlated with serum ferritin (r= 0.420, P = 0.001), phosphorus (r = 0.307, P= 0.021), and Ca × P production (r = 0.296, P = 0.027). In the advanced stages CKD, FGF23 levels correlated with serum 25-hydroxyvitamin D (r = 0.198, P = 0.041), phosphorus (r= −0.206, P= 0.035), Ca × P (r = −0.209, P= 0.031), and SBP (r = 0.253, P = 0.009). In the advanced stages CKD, CIMT correlated with age (r = 0.486, P <0.001), smoking (r = 0.411, P <0.001) and 25-hydroxyvitamin D (r = −0.195, P = 0.045). There was no correlation between serum FGF-23 and CIMT.
|Table 3: Spearman rank correlation between fibroblast growth factor 23 levels and the other variables in early and advanced chronic kidney disease patients.|
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|Table 4: Spearman rank correlation between carotid intima-media thickness levels and the other variables in early and advanced chronic kidney disease patients.|
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Patients were divided into tertiles according to CIMT and FGF23 levels and characteristics of the study population in the three tertiles [Table 5] and [Table 6]. Patients in the highest FGF23 tertile had higher SBP and serum levels of creatinine, PTH, ferritin. Patients in the highest CIMT tertile had a higher age.
|Table 5: Characteristics of the study population, according to fibroblast growth factor 23 tertiles.|
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|Table 6: Characteristics of the study population according to carotid intima-media thickness tertiles.|
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Independent risk factors associated with CIMT in multiple linear regression analysis were age (β = 0.373 P = ≤0.001), smoking (β = 0.228, P = 0.004), and serum 25-hydroxy-vitamin D levels (β = -0.164, P= 0.042) [Table 7].
|Table 7: Multiple regression analysis of factors associated with carotid intima-media thickness (n=162 patients).|
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| Discussion|| |
In this study, we observed that serum FGF23 levels increased with the progression of CKD. This finding was compatible with other studies showing the increase in serum FGF23 levels with the progression of CKD.,
We found only a slight increase in FGF-23 levels in patients with different CKD stages. This may be the result of normal serum phosphate level seen in most of the patients even among Stage 5 CKD patients and renal residual function (RRF). Our patients were treated with phosphate binder drugs (if necessary) and were on phosphorus restricted diet.
FGF23 is an important hormone that shows bone and mineral metabolism early in patients with CKD. Increasing FGF23 levels during the early stages of CKD increases renal excretion of phosphate and decreases 1,25-dihydroxy vitamin D production. At the same time, FGF23 directly decreases PTH secretion and release from parathyroid glands. The progression of CKD, leading to decreased expression of Klotho and FGFR1, resistance develops to FGF23. Serum phosphorus levels are normal in patients with early stages of CKD and begin to rise when GFR drop <60 mL/min/1.73 m2. Vitamin D deficiency increases progressively in the course of CKD.,, In this study, the early stages of CKD serum FGF23 levels correlated with serum phosphorus, and Ca × p production. In the advanced stages CKD, FGF23 levels correlated with serum 25 hydroxy D vitamin, phosphorus, Ca × p production. In our results, the inverse relationship between serum FGF23 level and serum phosphorus level in advanced-stage patients may suggest that the phosphaturia effect of FGF23 still persists. In addition, we could not measure serum 1,25-dihydroxy vitamin D and Klotho levels, although there was a positive relationship between FGF23 and 25-hydroxyvitamin D levels. Several studies have shown a similar relationship between serum levels of FGF23 and P, Ca χ P product, 25-hydroxyvitamin D.,,,
According to our results, there was a positive correlation between FGF23 level, and SBP in the advanced stages of CKD, and patients in the high FGF23 tertile had higher SBP. This positive correlation was shown in previous studies in incident HT and hypertensive individuals. In addition, FGF23 gene polymorphisms are associated with the risk of developing essential HT. This positive assodation between SBP and serum FGF23 levels may be mediated by renal Na-uptake, increased arterial stiffness and RAS activation.,,
We found a significant positive relationship between ferritin with FGF23 in the early stages of CKD. İn addition, patients of the high FGF23 tertile had higher serum ferritin levels. This positive relationship has been reported in various studies., The mechanism of FGF increase due to parenteral iron therapy is unknown. It may stimulate the production of FGF23 in the osteocytes or osteoblasts either directly or indirectly. Unfortunately, we did not record parenteral iron preparations used by patients. The positive relationship may be due to the treatment of parenteral iron. Inflammation increases FGF23 level through suppression FGF23 degradation. High level of ferritin and FGF23 can be secondary to inflammation but CRP levels of our patients within normal levels. Further studies are needed to elucidate the mechanism of FGF-23 regulation by iron.
In our results, right CIMT was found to be thicker in early-stage CKD than in advanced stage CKD. This result can be attributed to the fact that the mean age of patients with CKD in early-stage patients is higher (58.5 ± 10.8) than the mean age of advanced-stage patients (48.7 ± 13.9). Interestingly, there was no difference between the early and advanced CKD stages of left CIMT. We cannot explain the reason for this difference between right and left CIMT measurements. Although atherosclerosis is a systemic disease, its distribution in the vascular system may change. Various factors such as vessel geometry may contribute to this situation. This situation should be clarified through comprehensive studies.
The traditionally known risk factors of AS are advanced age, HT, DM, smoking, and HL., In addition to these, several uremia-related risk factors contribute to AS. In our study, CIMT had a positive correlation with age and smoking, and negative correlation with serum 25 hydroxy D vitamin. In addition, the patients in the highest CIMT tertile had a higher age and male gender.
AS begins with the development of fatty streaks in childhood and progression of lesions with age progression. Smoking is a significant atherosclerotic risk factor. It impairs endothelium-dependent vasodilation and associated increased inflammation and increases oxidative modification of LDL. The results of our study also support the importance of age and smoking in AS formation in CKD patients.
In our study, we found a negative correlation between CIMT and 25-hydroxyvitamin D. Yadav et al found an inverse relationship between serum 25-hydroxyvitamin D level and CIMT in 101 patients with Stage 4–5 CKD. Other CIMT determinants were age, diabetic status. Ng et al Stage 3–4 in 100 patients with CKD, there was no relationship between serum 25-hydroxyvitamin D level and CIMT.
In our results, CIMT was only associated with lower 25-hydroxyvitamin D levels than nontraditional risk factors. This relationship has also been reported in previous large studies., Interestingly, the lowest 25-hydroxyvitamin D levels were detected in the CKD Stage 5 group. At the same time, these patients were the most treated group with active D vitamin. Unfortunately, serum 1,25-dihydroxyvitamin D levels were not measured in patients. Therefore, our results do not fully reflect the level of functional D vitamins. Vitamin D deficiency is a pro-inflammatory condition., Vitamin D deficiency is also associated with various atherosclerotic risk factors such as obesity, diabetes, blood pressure elevation, and dyslipidemia. Several studies have reported that Vitamin D deficiency is associated with a variety of pathways involved in the pathogenesis of AS, such as oxidative stress, inflammation, endothelial dysfunction, and vascular smooth muscle cell proliferation, migration, and apoptosis.
In our study, there was no correlation between serum FGF23 and CIMT. Figurek et al have shown that CIMT increased from with CKD Stage 1 until Stage 3, but did not show further increase until Stage 5. This situation has been associated with stable lipid values under the treatment of LLDs. There are many studies addressing the relationship between FGF23 and CIMT, but the results are controversial. There was a positive relationship between FGF23 and CIMT in 91 CKD patients and 137 HD patients. On the other hand, in a study of 87 patients with CKD Stage 3–4 and 67 PD patients, this relationship could not be shown. This study suggest that age, smoking, and 25-hydroxyvitamin D are more important risk factors for AS formation in CKD patients than FGF23.
| Study Limitations|| |
There are some limitations to the current study. There is no healthy control group. There are different and only a few patients in the different CKD stages. Our study was limited by its monocentric nature; hence, the findings cannot be generalized to the overall population of patients with CKD. İn addition, our study was a cross-sectional one, which may have led to masking a possible relationship between FGF23 and CIMT. Prospective studies with larger number of patients are warranted.
| Conclusion|| |
In our study, a significant association was found between CIMT and age, smoking, and 25-hydroxy D vitamin levels. There was no correlation between FGF23 and CIMT.
Interestingly, FGF23 correlated positively with ferritin in early-stage (2–3) CKD and SBP in advanced stage (4–5) CKD, in addition to 25–hydroxy D vitamin, p, and Ca X p. Atherosclerotic CVD is very common in patients with CKD. In our study, this difference was detected in the right CIMT in patients with early and advanced CKD. Traditional and nontraditional factors in CKD have an active role in AS, but the relationship between FGF23 and AS has not been shown in our study.
Conflict of interest: None declared.
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Department of Nephrology, Cukurova University, Faculty of Medicine, Sarıçam, Adana
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]
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