|Year : 2019 | Volume
| Issue : 3 | Page : 967-971
Fibroblast growth factor 23: a novel biomarker of phosphate retention in patients with chronic kidney disease
Seham Ahmed Zaky Khodair1, Yassin S Yassin2, Rasha I Noor El-Din1, Asmaa A. A. Sabik3
1 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Clinical Pathology, El-Shohadaa Hospital, Menoufia, Egypt
|Date of Submission||05-Dec-2017|
|Date of Acceptance||01-Feb-2018|
|Date of Web Publication||17-Oct-2019|
Asmaa A. A. Sabik
Department of Clinical Pathology, El-Shohadaa Hospital, Shebin El-Kom, Menoufia
Source of Support: None, Conflict of Interest: None
The objective of this study was to evaluate fibroblast growth factor 23 (FGF23) expression in patients with chronic kidney disease (CKD) and its effect on diagnosis, grading, and prognosis of patients.
CKD is recognized as a major public health problem in which there is progressive loss in renal function over a period of months or years. FGF23 is a protein that in humans is encoded by the FGF23 gene. FGF23 is a member of the FGF family which is responsible for phosphate metabolism.
Patients and methods
This study was conducted on 73 patients with CKD (with its five stages) and 15 age-matched and sex-matched healthy individuals as a control group. All patients were subjected to full history taking, clinical examination, and laboratory investigations. FGF23 was measured for all the study participants using enzyme-linked immunosorbent assay technique.
FGF23 expression increased gradually with increased degree of CKD than in controls.
There is increased expression of FGF23 in the serum of patients with CKD with its 5°.
Keywords: chronic kidney disease, fibroblast growth factor, phosphate, renal failure, tubular phosphate reabsorption
|How to cite this article:|
Zaky Khodair SA, Yassin YS, Noor El-Din RI, Sabik AA. Fibroblast growth factor 23: a novel biomarker of phosphate retention in patients with chronic kidney disease. Menoufia Med J 2019;32:967-71
|How to cite this URL:|
Zaky Khodair SA, Yassin YS, Noor El-Din RI, Sabik AA. Fibroblast growth factor 23: a novel biomarker of phosphate retention in patients with chronic kidney disease. Menoufia Med J [serial online] 2019 [cited 2019 Nov 19];32:967-71. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/967/268851
| Introduction|| |
Chronic kidney disease (CKD) is prevalent worldwide in the middle-aged and old aged population; it has been recognized as an important disease, threatening human health .
Serum phosphate level is normal in most patients at the early and intermediate stages of CKD (stages 1–3) owing to compensatory increases in fibroblast growth factor (FGF23) and parathyroid hormone (PTH) .
Serum phosphate is therefore of restricted use as an early marker of disordered phosphate metabolism in patients with CKD. Thus, other markers for mineral and bone abnormalities are needed as markers for treatment to adjust serum phosphate in early stage CKD, before the appearance of hyperphosphatemia. FGF23 has been used as a new and good biomarker of early phosphate retention .
Tubular reabsorption of phosphate (TRP) is a simple and effective method that has been commonly used to assess renal tubular phosphate transport. As renal function decreases, escalations in FGF23 increase phosphaturia by reducing reabsorption of filtered phosphate. When TRP decreases below normal, it may be important to start interventions to limit phosphate retention and to avoid the increase of serum phosphate. TRP can be easily determined by calculating the ratio of phosphate clearance to creatinine clearance and can also be used to monitor the response to intervention .
We conducted a cross-sectional observational study of predialysis patients with CKD to evaluate the complex associations among TRP, FGF23, and phosphate in patients with CKD and to provide clinical evidence of TRP as a new surrogate biomarker for FGF23 in management of CKD-mineral bone disease.
| Patients and Methods|| |
Study population and selection of patients
This study was approved by the Ethical Committee of Faculty of Medicine, Menoufia University. Informed consent was obtained from every patients and controls. The study involved 73 patients with CKD and 15 age-matched and sex-matched healthy individuals as a control group.
The following were the exclusion criteria: malignancy, infection, anuria, acute kidney injury, PTH dysfunction, and kidney transplant.
Patients were divided into five grades from grade 1 to grade 5 according to estimated glomerular filtration rate (eGFR).
All participants were submitted to clinical history taking and full physical examination.
Routine laboratory tests
Complete blood count was performed using XT-1800i hematology analyzer (Sysmex, Kobe, Japan), which is based on fluorescent flow technology and hydrodynamic focusing.
Serum urea, serum creatinine, serum uric acid, serum albumin, serum calcium, and serum phosphorus levels were estimated by Cobas Integra 400 autoanalyzer (Roche Diagnostics, Mannheim, Germany).
Estimated glomerular filtration rate
Special laboratory investigations
Serum FGF23 was estimated by enzyme-linked immunosorbent assay, which was supplied by Wkea Med Supplies Corp. (WKEA Med Supplies Corp. Inc., Changchun, Jilin, China). The assay kit measures human FGF23 level in serum samples. It uses purified human FGF23 antibody that is coated in microtiter plate wells, making solid-phase antibody. Then, addition of FGF23 to wells is done, which combines with FGF23 antibody, which with enzyme-labeled antibody becomes antibody-antigen–enzyme-antibody complex. After complete washing, substrate is added, and the substrate becomes blue in color through horseradish peroxidase enzyme-catalyzed reaction. This reaction is terminated by addition of sulfuric acid solution, and the color changes to yellow and its intensity is measured spectrophotometrically at a wavelength of 450 nm. The concentration of Monocyte Chemoattractant Protein-1 (MCP-1) in the samples is then determined by comparing the Optical Density (OD) of the samples to the standard curve. Assay range is from 4 to 100 ng/l.
Data collected were tabulated and analyzed by statistical package for the social sciences (SPSS, version 20; SPSS Inc., Chicago, Illinois, USA) on IBM personal computer. The following statistics were applied: descriptive statistics, for example, percentage, mean, and SD, and analytic statistics, for example, χ2-test, Student's t-test, Mann–Whitney test, paired t-test, and Wilcoxon's test. P value of less than 0.05 was considered to be significant.
| Results|| |
There were significant statistical differences regarding urea, uric acid, creatinine, eGFR, hemoglobin, and phosphorus tests in comparison between cases and controls. No significant statistical differences were detected regarding age, weight, height, BMI, albumin, and calcium.
Comparison between cases and control showed that there were significant statistical differences regarding FGF23 [Figure 1].
|Figure 1: Fibroblast growth factor 23 (ng/l) level among the cases and control.|
Click here to view
Comparison between case subgroups (stages 1–5 CKD) and control showed significant statistical differences regarding FGF23 ([Table 1] and [Figure 2].
|Table 1: Fibroblast growth factor 23 (ng/l) among cases subgroups and control|
Click here to view
|Figure 2: Fibroblast growth factor 23 (ng/l) among cases subgroups and control.|
Click here to view
At the cut-off 32.5 ng/l, FGF23 can discriminate between CKD cases and normal controls with a sensitivity of 100% and specificity of 100% [Table 2] and [Figure 3].
|Table 2: Sensitivity and specificity of fibroblast growth factor 23 to differentiate between cases and control|
Click here to view
|Figure 3: Receiver operating characteristic curve of fibroblast growth factor 23 to differentiate between cases and control.|
Click here to view
A positive predictive value of 100% and a negative predictive value of 100% discriminate stage 1 CKD from control.
At the cut-off 72.5 ng/l, FGF23 can discriminate between stage 1 CKD from stage 2 with a sensitivity of 90% and specificity of 100%.
At the cut-off 88.7 ng/l, FGF23 can discriminate between stage 2 CKD from stage 3 with a sensitivity of 90% and specificity of 75%.
At the cut-off 120 ng/l, FGF23 can discriminate between stage 3 CKD from stage 4 with a sensitivity of 100% and specificity of 95%.
At the cut-off 180 ng/l, FGF23 can discriminate between stage 4 CKD from stage 5 with a sensitivity of 100% and specificity of 100%.
| Discussion|| |
In this study of 73 patients with CKD stages 1–5, we found that serum phosphate and FGF23 concentrations increased whereas serum calcium and TRP decreased with decreasing eGFR. The increase in FGF23 level and decrease in TRP began as early as CKD stage 2 and before increased serum phosphate levels. Recent studies recommended a phosphate binder or dietary phosphate restriction in the early stages of CKD when phosphate retention has begun, as indicated by elevation of FGF23 levels but before the start of increase in phosphate to prevent CKD-mineral bone diseases .
Early control of serum FGF23 level may prevent the decrease in serum 1,25-dihydroxyvitamin D and consequent increase in serum PTH .
In our study, FGF23 excess became clear at an eGFR of 75–89 ml/min/1.73 m 2. The changes in TRP began at an eGFR of 75–89 ml/min/1.73 m 2 and became clear at an eGFR of 45–59 ml/min/1.73 m 2. Both the increase in FGF23 and the decrease in TRP began while serum phosphate was still within the normal range. Although FGF23 level was an earlier marker of physiologic renal phosphate excretion than TRP, the distribution of FGF23 varied widely in different patients during progress to advanced stages of CKD. FGF23 level in CKD stage 5 varied from 185 to 310 ng/l in our study. Therefore, FGF23 is an early and sensitive biomarker at the early stage of CKD but does not appear to serve as a stable marker in the advanced stages of CKD. Moreover, a cut-off value of FGF23 has not clearly detected the need for phosphate binder in clinical practice. TRP is a physiological biomarker for phosphate metabolism. Regulation and pathophysiological changes of renal proximal reabsorption of inorganic phosphate can be attributed to the final amount of type IINa-Pi co-transporters, localized in the brush border membrane of the renal proximal tubule .
Minerals such as sodium and phosphate are mainly handled by tubular reabsorption, and their levels remain normal in serum till late deterioration of renal function. As the number of functioning nephrons decrease, each remaining nephron performs a greater fraction of total renal excretion of phosphate .
We found a good positive relation between TRP and eGFR, and the changes of TRP during CKD progress were agreed with the 'intact nephron hypothesis'. Although changes in TRP begin later than those in FGF23, TRP was insensitive in very early stages of CKD (eGFR: 90 ml/min/1.73 m 2). Decreased TRP level was found to be a compensatory mechanism that leads to phosphaturia and maintains normal serum phosphate level in mild to moderate CKD. In addition, the strong relation between TRP, serum phosphate, and FGF23 was in agreement with renal phosphate homeostasis. The regular measurement of FGF23 is unlikely in clinical practice because of high measurement costs and insufficient standardization. Therefore, measurement of TRP may be particularly useful to assess phosphate regulation in at least normophosphatemic early stages of CKD in patients, instead of FGF23. Another noteworthy finding was that factors influencing iPTH were independently associated with decreased TRP, 25-hydroxyvitamin D, and corrected calcium but not with FGF23 in multivariable regression analysis. FGF23 principally functions as a hormone, regulating phosphaturia and renal 1,25-dihydroxyvitamin D production, suggesting that it also regulates secretion of PTH, at least indirectly, by regulating serum phosphate and 1,25-dihydroxyvitamin D levels .
FGF23 decreases both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D owing to Cyp24-mediated catabolism, and the resulting decrease of 1,25-dihydroxyvitamin D leads to secondary changes in PTH owing to impaired calcium absorption by the intestine and loss of direct effects of 1,25-dihydroxyvitaminD on parathyroid gland and bone. Consequently, PTH acts to restore the calcium balance by stimulating bone remodeling, leading to both increased bone calcium and phosphate efflux. PTH also acts in kidneys to increase Cyp27b1 and decrease renal calcium excretion .
In our study, FGF23 elevation as the important pathophysiological action did not show a direct association with increased PTH or decreased 25-hydroxyvitamin D, which appeared to be consistent with its conventional physiologic function as indirect effect for PTH. Recently, Kuro-O proposed a new paradigm for phosphate restriction, in which dietary phosphate restriction should be started when serum FGF23 level starts to rise while serum phosphate level is within normal ranges .
He suggested that the therapeutic goal should be to delay progression of CKD and to decrease or delay tubular damage by decreasing the serum FGF23 level at the early stage of CKD. Serum FGF23 should thus be measured on regular basis, and if increased, 24 h urinary phosphate level should be estimated, and phosphate restriction should be made through dietary consultation and the use of phosphate binder. Serum phosphate is known to indirectly regulate FGF23 by affecting bone mineralization .
The effects of phosphate on FGF23 are also affected by vitamin D levels as increasing dietary phosphorus intake does not increase FGF23 in the absence of the vitamin D receptor .
Thus, dietary phosphate restriction and phosphate binder therapy immediately reduce 24 h urinary phosphate excretion but not serum FGF23 .
Because TRP is calculated from plasma and urine creatinine and phosphate measurements, it may be good biomarker to asses current phosphate regulation and monitor the response to interventions such as dietary phosphate restriction or phosphate binder therapy .
In conclusion, we propose that serial monitoring of TRP in patients with mild to moderate CKD may help to diagnose abnormal phosphorus metabolism and maintain normal serum phosphate level without additional serologic markers or biomarkers related to secondary hyperparapthyroidism. TRP is a simple, useful, and cost-saving method as a surrogate marker for the assessment of altered mineral levels.
Metabolism instead of serum FGF23 can be used in patients with CKD, especially in patients with mild to moderate CKD.
| Conclusion|| |
From this study, we can conclude that FGF23 has been advocated as a novel and potentially useful biomarker of early phosphate retention. Its expression increased significantly in patients with CKD predicting an important role in the diagnosis, staging and progression of the disease; thus, FGF23 may be considered a therapeutic target through its positive correlation with progress of CKD.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zeng J, Liu M, Wu L, Ang S, Wang Y. The association of hypertriglyceridemic waist phenotype with CKD and its sex difference: a cross-sectional study in Urban Chinese eldery population. Int J Environ Res Public Health 2016; 13
Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, et al
. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005; 16
Martin KJ, Gonzalez EA. Prevention and control of phosphate retention/hyperphosphatemia in CKD-MBD: what is normal, when to start, and how to treat? Clin J Am Soc Nephrol 2011; 6
Payne RB. Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation. Ann Clin Biochem 1998; 35
Isakova T, Gutierrez OM, Smith K, Epstein M, Keating LK, Juppner H, et al
. Pilot study of dietary phosphorus restriction and phosphorus binders to target fibroblast growth factor 23 inpatients with chronic kidney disease. Nephrol Dial Transplant 2011; 26
Oliveira RB, Cancela AL, Graciolli FG, Dos Reis LM, Draibe SA, Cuppari L, et al
. Early control of PTH and FGF23
in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am SocNephrol 2010; 5
Forster IC, Hernando N, Biber J, Murer H. Proximal tubular handling of phosphate: a molecular perspective. Kidney Int 2006; 70
Slatopolsky E, Robson AM, Elkan I, Bricker NS. Control of phosphate excretion in uremic man. J Clin Invest 1968; 47
Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 2008; 118
Quarles LD. Role of FGF23
in vitamin D and phosphate metabolism: implications in chronic kidney disease. Exp Cell Res 2012; 318
Kuro OM. Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism. Nat Rev Nephrol 2013; 9
Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, et al
. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 2006; 17
Shimada T, Yamazaki Y, Takahashi M, Hasegawa H, Urakawa I, Oshima T, et al
. Vitamin D receptor-independent FGF23
actionsin regulating phosphate and vitamin D metabolism. Am J Physiol Renal Physiol 2005; 289
Komaba H, Koizumi M, Tanaka H, Takahashi H, Sawada K, Kakuta T, et al
. Effects of cinacalcet treatment on serum soluble eKlotho levels in haemodialysis patients with secondary hyperparathyroidism. Nephrol Dial Transplant 2012; 27
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]