|Year : 2017 | Volume
| Issue : 3 | Page : 87-92
Associations between serum fibroblast growth factor 23 level and intradialytic hypotension in hemodialysis patients
Huan Zhang1, Xueli Lai1, Xiaoxi Wang2, Hongtao Lu2, You Zhang1, Hao Wu1, Zhiyong Guo1
1 Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, China
2 Cadet Brigade, Second Military Medical University, Shanghai, China
|Date of Web Publication||28-Sep-2017|
Department of Nephrology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433
Source of Support: None, Conflict of Interest: None
Objectives: To explore possible link between intradialytic hypotension (IDH) with serum fibroblast growth factor 23 (FGF23) and serum soluble klotho (sKl) in maintenance hemodialysis (MHD) patients in a single dialysis center. Materials and Methods: Cross-sectional data were collected from MHD patients. Intradialytic blood pressure was recorded continuously in a 1-month period. According to the dialysis records, MHD patients were divided into IDH group and non-IDH group. Fast sera of the MHD patients were obtained for FGF23 and sKl assay at the end of IDH record month, and other routing laboratory results were analyzed statistically for comparison between the two groups. Results: A total of eighty MHD patients with complete laboratory data were enrolled into the study. The occurrence rate of IDH was 77.5%. The significant differences in serum ferritin (P = 0.046), serum triglyceride (P = 0.045), parathyroid hormone (P = 0.042), calcium-phosphorus product (P = 0.047), and serum FGF23 (P < 0.001) were found between the two groups, but the difference in sKl between the two groups was marginal (P = 0.747). Furthermore, the serum FGF23 was positively correlated with the occurrence of IDH (r = 0.807, P< 0.001). Conclusions: The present study indicated a positive correlation between serum FGF23 and IDH in MHD patients, which suggested the FGF23 could be a potential biomarker for incidence of IDH in the hemodialysis population.
Keywords: Calcification, fibroblast growth factor 23, hemodialysis, intradialytic hypotension, soluble klotho
|How to cite this article:|
Zhang H, Lai X, Wang X, Lu H, Zhang Y, Wu H, Guo Z. Associations between serum fibroblast growth factor 23 level and intradialytic hypotension in hemodialysis patients. J Integr Nephrol Androl 2017;4:87-92
|How to cite this URL:|
Zhang H, Lai X, Wang X, Lu H, Zhang Y, Wu H, Guo Z. Associations between serum fibroblast growth factor 23 level and intradialytic hypotension in hemodialysis patients. J Integr Nephrol Androl [serial online] 2017 [cited 2022 Aug 15];4:87-92. Available from: http://www.journal-ina.com/text.asp?2017/4/3/87/215741
| Introduction|| |
Intradialytic hypotension (IDH) is a common complication in hemodialysis (HD) patients, with an incidence of 20%–30%, or even more than 40% as reported in some studies in the literature. With accompanying symptoms of anxiety, restlessness, nausea and vomiting, abdominal pain and muscular spasm, IDH seriously affects the patient's quality of life. Studies have shown that the number of various HD patients with IDH symptoms is increasing gradually in recent years  and that IDH is also closely associated with the occurrence of cardiovascular events and death in HD patients., Previous studies reported that decreases in circulating blood volume, cardiac output and peripheral resistance, and vascular dysfunction were the main causes of IDH. Reported risk factors contributing to IDH include age, hypocalcemia, low blood phosphorus and magnesium, high blood parathyroid hormone (PTH), low plasma albumin, high serum NT-proBNP, and dysautonomia.,,, More recent studies found that serum fibroblast growth factor 23 (FGF23) is an important molecule in regulating balance of calcium and phosphorus metabolism and maintaining vitamin D metabolism.,,, Likewise, soluble klotho (sKl) protein also plays an important role in regulating calcium and phosphorus metabolism by increasing the affinity of FGFs with their receptors through binding with its receptor. The aim of the present study was to explore the association of FGF23 and sKl, two important upstream molecules in calcium and phosphorus metabolism, with IDH.
| Material and Methods|| |
Included in this study were patients who received maintenance HD (MHD) at a frequency of three times weekly and 3.5–4 h at a time in Shanghai Changhai Hospital of the Second Military Medical University (Shanghai, China) between December 2013 and January 2014, with a previous history of HD for more than 6 months. Patients with acute cardio- or cerebro-vascular events, histories of surgery within 3 months, severe liver and kidney function impairment, and unstable conditions were excluded. The study protocol was approved by the Local Ethics Committee, and written informed consent was obtained from each participant. Fast sera before dialysis session for tests beyond routine biochemistry were taken together and stored in condition of −80°C.
Blood pressure (BP) measurement: BP measurements of the MHD patients were recorded continuously throughout the whole month of December 2013. According to European Best Practice Guideline, IDH in dialysis session was defined as a decline in systolic BP ≥20 mmHg or a decline in mean arterial BP ≥10 mmHg accompanied with abdominal discomfort, yawning, sighing, nausea and vomiting, muscular spasm, restlessness, dizziness, syncope, or anxiety. When the incidence of IDH rate (ratio of times of sessions with IDH and all times of dialysis session during the month) was higher than 0.25, the case would be defined into the group of IDH, and the rest of the participants could be classed into non-IDH (N-IDH) group.
HD protocols: All patients received HD three times weekly with 3.5–4 h at a time at a blood flow rate of 200–300 mL/min. Bicarbonate was used as the dialysate at a flow rate of 500 mL/min at 35.5–36.5°C, with Na + 138 mmol/L, Ca 2+ 1.50 mmol/L, and K + 2.0 mmol/L.
Clinical information included the baseline data including BP, body weight, and HD duration of the MHD patients before, during, and after HD. Laboratory data included blood routine, liver and kidney functions, blood electrolytes, and intact PTH (iPTH) were detected by routine laboratory methods (Hitachi 7600). Serum sKl and FGF23 were determined with commercially available enzyme-linked immune sorbent assays (Uscn Life Sci. Inc) according to the manufacturers' instructions.
Data were recorded and analyzed by SPSS statistical software for Windows (Version 17.0, SPSS Inc., Chicago, IL, USA). Data with normal distribution are expressed as mean ± standard deviation. Intergroup comparison was performed using independent samples t-test. Measurement data of nonnormal distribution were described by medians (p25–p75). Intergroup differences were compared by rank sum test. Enumeration data are described by percentage (%), and intergroup differences were tested by Chi-square test. Variable correlation test was performed using Spearman or Pearson correlation analysis. Factors reaching statistical significance and the risk factors were then included in a multivariable linear regression analysis with stepwise model. The inspection level was set at α = 0.05, and P< 0.05 was considered statistically significant.
| Results|| |
IDH occurred in 62 (77.5%) of the 80 MHD patients with complete clinical data and serum specimens. Univariate analysis on risk factors contributing to IDH showed that serum ferritin (SF) and triglyceride (TG) levels in IDH group were significantly higher than those in N-IDH group (P = 0.046, P= 0.045), while calcium-phosphorus product (CPP) and serum iPTH in IDH group were significantly lower than those in N-IDH group (P = 0.042, P= 0.047), suggesting that high TG and SF and low CPP and iPTH were risk factors of IDH [Table 1]. There was no significant difference in sKl between the two groups (P = 0.747). FGF23 level in IDH group was significantly higher than that in N-IDH group (P < 0.001), suggesting that high FGF23 level may be a risk factor of IDH [Figure 1]a and [Figure 1]b.
|Table 1: Differences in biochemical parameters between intradialytic hypotension and nonintradialytic hypotension patients|
Click here to view
|Figure 1: Significant elevated serum fibroblast growth factor 23 levels in intradialytic hypotension group than that in nonintradialytic hypotension (a), while similar levels of serum soluble klotho between nonintradialytic hypotension and intradialytic hypotension groups (b)|
Click here to view
Correlation analysis of the above IDH risk factors showed that there was a negative correlation between CPP and TG (r = −0.368, P< 0.001), while there was a positive correlation between CPP and iPTH (r = 0.370, P< 0.001) [Figure 2]a and [Figure 2]b.
|Figure 2: Negative correlation between calcium-phosphorus product and triglycerides (a) and positive correlation between calcium-phosphorus product and intact parathyroid hormone in eighty hemodialysis patients (b)|
Click here to view
Using FGF23 = 55.50 pg/mL as the boundary value, the MHD patients were divided into low-FGF23 (<55.50 pg/mL) group and high-FGF23 (>55.50 pg/mL) group for comparison. The result showed that the mean TG level was higher in high-FGF23 group than that in low-FGF23 group (P = 0.037), and the occurrence of IDH was significantly higher in high-FGF23 group than that in low-FGF23 group (P < 0.001) [Table 2].
|Table 2: Differences in biochemical parameters between maintenance hemodialysis patients with different fibroblast growth factor 23 levels|
Click here to view
There was a strong positive correlation between serum FGF23 and the frequency of IDH in 80 patients (r = 0.807, P< 0.001) [Figure 3]. Further, multivariable linear regression analysis in [Table 3] showed that the IDH frequency was predicted by levels of FGF 23 (β =0.773, P< 0.001).
|Figure 3: Significant positive correlation between the frequency of intradialytic hypotension occurrence and serum fibroblast growth factor 23 in eighty hemodialysis patients|
Click here to view
|Table 3: Linear regression showing variables associated with Intradialytic hypotension occurrence|
Click here to view
| Discussion|| |
The results of the present study showed that the occurrence of IDH in MHD patients was as high as 77.5%, which is higher than the reported rate of 40%. It might be resulted from a high proportion of long dialysis duration patients, just like the previous study. IDH patients usually present with symptoms of dizziness, convulsion, and fatigue due to insufficient cardio perfusion and cerebral perfusion, but the therapeutic efficacy of currently available drugs is unsatisfactory for these symptoms., Moreover, the approach of dialysate sodium concentration modification might be helpful to reduce the incidence of IDH. The generally accepted risk factors of IDH are mainly concerned with blood vessels, including vascular elasticity, endothelial dysfunction, and calcification in particular. Thus, the present study focused on molecules discovered recently, related to calcium and phosphorus metabolism.
We use the definition of IDH according to European Best Practice Guideline which has become a standard of acceptance.,, Univariate analysis of this study showed that there were significant differences in SF, TG, CPP, iPTH, and FGF23 between IDH and N-IDH groups. It was found in our study that serum iPTH level in IDH group was lower than that in N-IDH group, which is different from the previous finding that high calcium and iPTH levels were risk factors of IDH. In addition, the occurrence of IDH was decreased in MHD patients who had undergone parathyroidectomy. This may be due to the high FGF23 level in IDH patients as compared with that in N-IDH patients, knowing that FGF23 has a significant inhibitory effect on PTH expression. This may be the reason why serum iPTH level in IDH group was lower than that in N-IDH group. In addition, increased serum FGF23 can reduce the serum phosphorus level through multiple pathways. Knowing that CPP is related to serum phosphorus, CPP in IDH group was lower than that in N-IDH group. Although correlation analysis suggested a positive correlation between CPP and iPTH, it cannot compensate for CPP, because iPTH is affected by multiple factors. Therefore, iPTH cannot accurately reflect the status of calcium-phosphorus metabolism of the body or be used as a sensitive biomarker for predicting the occurrence of IDH. Knowing that FGF23 is a key factor in regulating calcium and phosphorus, it has aroused increasing attention and interest of nephrologists in recent years. As FGF23 is a peptide hormone secreted from osteocytes or osteoblasts, it needs klotho as a cofactor to work together in regulating the metabolism of inorganic phosphorus. It was found in our study that the mean FGF23 level in IDH group was significantly higher than that in N-IDH group, while no significant difference in sKl was observed between the two groups. This does not mean that sKl is not related to IDH. Previous studies  showed that sKl was associated with vascular calcification, knowing that vascular calcification is a risk factor of IDH in MHD patients. Therefore, more studies are needed to further clarify the association between sKl and IDH.
The result of the present study showed that the degree and frequency of IDH occurrence in IDH group were positively correlated with serum FGF23 level (r = 0.722, P< 0.001). Chen et al. found that the concentration of serum FGF23 was positively correlated with the degree of vascular calcification. Knap et al. reported that elevation of serum FGF23 would increase the risk of left ventricular hypertrophy. Cseprekal and Marton  showed that serum FGF23 was associated with vascular dilation in patients with chronic renal disease. In the present study, we divided all serum FGF23 levels into high- and low-FGF23 groups and found that the mean TG level in high-FGF23 group was higher than that in low-FGF23 group. Knowing that high TG level is a factor contributing to atherosclerosis and calcification, we postulate that FGF23 affects the occurrence of IDH by calcifying blood vessels. Although the exact mechanism underlying this effect needs to be further investigated, high serum FGF23 level may prove to be a potential biomarker for predicting and assessing the occurrence of IDH and the efficacy of pharmaceutical intervention.
| Conclusion|| |
This study has some limitations. The sample size was relatively small, and the patients included were relatively old with a relatively long history of HD. Other than FGF-23 and sKl, we did not describe influences of osteoblast- and osteoclast-related serum parameters on calcium-phosphorus metabolism of the body, which may induce bias of the study results. Larger sample studies are needed to verify the conclusion that we have drawn from the present study.
This study was partly supported by the Creativity and Innovation Training Program of Second Military Medical University for (MS2014015) and Research Program from Health and Family Planning Commission of Shanghai (20134Y035).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Noble VE, Murray AF, Capp R, Sylvia-Reardon MH, Steele DJ, Liteplo A, et al.
Ultrasound assessment for extravascular lung water in patients undergoing hemodialysis. Time course for resolution. Chest 2009;135:1433-9.
Koremoto M, Takahara N, Takahashi M, Okada Y, Satoh K, Kimura T, et al.
Improvement of intradialytic hypotension in diabetic hemodialysis patients using Vitamin E-bonded polysulfone membrane dialyzers. Artif Organs 2012;36:901-10.
Shoji T, Tsubakihara Y, Fujii M, Imai E. Hemodialysis-associated hypotension as an independent risk factor for two-year mortality in hemodialysis patients. Kidney Int 2004;66:1212-20.
Stefánsson BV, Brunelli SM, Cabrera C, Rosenbaum D, Anum E, Ramakrishnan K, et al.
Intradialytic hypotension and risk of cardiovascular disease. Clin J Am Soc Nephrol 2014;9:2124-32.
Pakfetrat M, Roozbeh Shahroodi J, Malekmakan L, Zare N, Hashemi Nasab M, Hossein Nikoo M, et al.
Is there an association between intradialytic hypotension and serum magnesium changes? Hemodial Int 2010;14:492-7.
Lei G, Li X, Tu W, Xu C, Duan Z, Wu X, et al.
Risk of intradialytic hypotension in patients on thrice-weekly versus twice-weekly hemodialysis. Int J Cardiol 2014;174:821-3.
Shih CJ, Tarng DC, Yang WC, Yang CY. Parathyroidectomy reduces intradialytic hypotension in hemodialysis patients with secondary hyperparathyroidism. Kidney Blood Press Res 2013;37:323-31.
Bossola M, Laudisio A, Antocicco M, Panocchia N, Tazza L, Colloca G, et al.
Intradialytic hypotension is associated with dialytic age in patients on chronic hemodialysis. Ren Fail 2013;35:1260-3.
Quarles LD. FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab 2003;285:E1-9.
Schiavi SC, Kumar R. The phosphatonin pathway: New insights in phosphate homeostasis. Kidney Int 2004;65:1-14.
Dërmaku-Sopjani M, Sopjani M, Saxena A, Shojaiefard M, Bogatikov E, Alesutan I, et al.
Downregulation of naPi-IIa and naPi-IIb na-coupled phosphate transporters by coexpression of klotho. Cell Physiol Biochem 2011;28:251-8.
Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, et al.
Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006;281:6120-3.
Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al.
Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006;444:770-4.
Kooman J, Basci A, Pizzarelli F, Canaud B, Haage P, Fouque D, et al.
EBPG guideline on haemodynamic instability. Nephrol Dial Transplant 2007;22 Suppl 2:ii22-44.
Sands JJ, Usvyat LA, Sullivan T, Segal JH, Zabetakis P, Kotanko P, et al.
Intradialytic hypotension: Frequency, sources of variation and correlation with clinical outcome. Hemodial Int 2014;18:415-22.
Schreiber MJ Jr. Clinical case-based approach to understanding intradialytic hypotension. Am J Kidney Dis 2001;38:S37-47.
Prakash S, Garg AX, Heidenheim AP, House AA. Midodrine appears to be safe and effective for dialysis-induced hypotension: A systematic review. Nephrol Dial Transplant 2004;19:2553-8.
Kim DY, Kim B, Moon KH, Lee S, Lee DY. Effect of gradually lowering dialysate sodium concentration on the interdialytic weight gain, blood pressure, and extracellular water in anuric hemodialysis patients. Ren Fail 2014;36:23-7.
Akhmouch I, Bahadi A, Zajjari Y, Bouzerda A, Asserraji M, Alayoud A, et al.
Characteristics of intradialytic hypotension: Experience of Agadir Center-Morocco. Saudi J Kidney Dis Transpl 2010;21:756-61.
] [Full text]
Kuipers J, Oosterhuis JK, Krijnen WP, Dasselaar JJ, Gaillard CA, Westerhuis R, et al.
Prevalence of intradialytic hypotension, clinical symptoms and nursing interventions – A three-months, prospective study of 3818 haemodialysis sessions. BMC Nephrol 2016;17:21.
Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, et al.
The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007;117:4003-8.
Ersoy FF. A short story of klotho and FGF23: A deuce of dark side or the savior? Int Urol Nephrol 2014;46:577-81.
Chen Z, Chen X, Xie J, Ma X, Zhong F, Hou L, et al.
Fibroblast growth factor 23 is a predictor of aortic artery calcification in maintenance hemodialysis patients. Ren Fail 2013;35:660-6.
Knap B, Večerić-Haler Ž, Benedik M, Buturović-Ponikvar J, Ponikvar R, Bren AF, et al.
Fibroblast growth factor 23 and left ventricular mass index in maintenance hemodialysis patients: Standard versus long nocturnal hemodialysis. Ther Apher Dial 2013;17:407-11.
Cseprekal NZ, Marton EV. Associations between FGF23-level and arterial distensibility in chronic kidney disease. Curr Opin Nephrol Hypertens 2013;7:142-3.
Labreuche J, Deplanque D, Touboul PJ, Bruckert E, Amarenco P. Association between change in plasma triglyceride levels and risk of stroke and carotid atherosclerosis: Systematic review and meta-regression analysis. Atherosclerosis 2010;212:9-15.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]