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Fibroblast growth factor-23 rs7955866 polymorphism and risk of chronic kidney disease

Abstract

Background

A missense gain-of-function fibroblast growth factor-23 (FGF23) gene single nucleotide polymorphism (SNP) (rs7955866) has been associated with FGF23 hypersecretion, phosphaturia, and bone disease. Excess circulating FGF23 was linked with atherosclerosis, hypertension, initiation, and progression of chronic kidney disease (CKD).

Methods

The study included 72 CKD stage 2/3 Egyptian patients (27–71 years old, 37 females) and 26 healthy controls matching in age and sex. Repeated measures of blood pressure were used to quantify hypertension on a semiquantitative scale (grades 0 to 5). Fasting serum urea, creatinine, uric acid, total proteins, albumin, calcium, phosphorus, vitamin D3, intact parathyroid hormone (iPTH), and intact FGF23 (iFGF23) were measured. DNA extracted from peripheral blood leucocytes was used for genotyping of FGF23 rs7955866 SNP using the TaqMan SNP genotyping allelic discrimination method.

Results

Major causes of CKD were hypertension, diabetic kidney disease, and CKD of unknown etiology. There was no significant difference in minor allele (A) frequency between the studied groups (0.333 in GI and 0.308 in GII). Median (IQR) serum iFGF23 was significantly higher in GI [729.2 (531.9–972.3)] than in GII [126.1 (88.5–152.4)] pg/mL, P < 0.001. Within GI, the minor allele (A) frequency load, coded for codominant inheritance, had a significant positive correlation with both hypertension grade (r = 0.385, P = 0.001) and serum iFGF23 (r = 0.259, P = 0.028). Hypertension grade had a significant positive correlation with serum phosphorus and iFGF23.

Conclusions

For the first time in an Egyptian cohort, we report a relatively high frequency of the rs7955866 SNP. It may remain dormant or become upregulated in response to some environmental triggers, notably dietary phosphorus excess, leading to increased circulating iFGF23 with ensuing hypertension and/or renal impairment. Subjects with this SNP, particularly in the homozygous form, are at increased risk for CKD of presumably “unknown” etiology, with a tendency for early onset hypertension and increased circulating iFGF23 out of proportion with the degree of renal impairment. Large-scale population studies are needed to confirm these findings and explore the role of blockers of the renin–angiotensin–aldosterone system and sodium chloride cotransporters in mitigating hypertension associated with FGF23 excess.

Background

Chronic kidney disease (CKD), defined as kidney damage or glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 for ≥ 3 months [1], is a major clinical and public health problem, afflicting about one-tenth of the population worldwide [2]. It is a complex, inherently progressive condition that drastically reduces a person`s productivity, impairs quality of life, and increases rates of hospitalizations and mortality, particularly in low- and middle-income countries [3]. Parallel with renal dysfunction, these patients typically develop CKD-mineral bone disorder (CKD-MBD); which is a complex syndrome encompassing abnormal bone histology, perturbed calcium and phosphorus metabolism, and progressive extra-skeletal (predominantly vascular) calcification (VC) and accelerated atherosclerotic cardiovascular disease [4]. In a significant proportion of patients, CKD cannot be attributed to an identifiable cause, the so-called CKD of unknown etiology (UKN). In these cases, trying to identify the as yet unknown, possibly genetic, underlying factors is tempting and might open avenues for earlier recognition and more specific management [5].

Fibroblast growth factor 23 (FGF23), the master regulator of phosphorus homeostasis, is a 251 amino acid polypeptide, primarily secreted by osteocytes and osteoblasts in response to phosphorus loading. In the renal tubules, it forms a trimeric signaling complex with FGF23 receptor (FGFR) and α-klotho coreceptor [6] that efficiently promotes phosphaturia, both directly (by suppressing apical epithelial expression of type 2 sodium phosphate cotransporters responsible for proximal tubular phosphate reabsorption), and indirectly (by inhibiting one α-hydroxylase activation of vitamin D and promoting its inactivation by 24-hydroxylase) [7, 8]. Cleavage of the intact FGF23 (iFGF23) between Arg179 and Ser180 generates two (n- and c-terminal) inactive fragments. Excess cFGF23 competitively inhibits the biologically active, full-length iFGF23. Therefore, cleavage of iFGF23 is an important post-translational regulatory event [9]. Missense gain-of-function mutations affecting the cleavage site might result in iFGF23 molecules becoming more resistant to proteolytic cleavage, increasing their circulating level [10, 11]. In fact, the FGF23 gene was first identified by positional cloning on chromosome 12p13.3 as being responsible for autosomal dominant hypophosphatemic rickets (ADHR), a rare hereditary disorder, characterized by increased circulating FGF23, hypophosphatemia, hypovitaminosis D, and impaired skeletal development [12].

By direct sequencing of the three coding exons and the two flanking introns, screening for FGF23 gene variation in 183 Finnish children and adolescents identified nine variants. A relatively common exon 3 variant (rs7955866) occurred in a heterozygote form in 37 (one-fifth) of these subjects [13]. In this variant, the normal ACG triplet (encoding threonine) at codon 239 changes to an ATG triplet (encoding methionine), with a corresponding change from guanine to adenine on the opposite DNA strand [14]. This variant was designated c.716C > T, g.4370383G > A, or p.T239M [15]. In vitro, FGF23 levels were significantly higher in conditioned media containing human embryonic kidney (HEK293) cells transfected with FGF23-239M plasmids, compared with media of cells expressing the wild FGF23-239T protein [16]. However, in instrumental analysis, FGF23 gene variance was a weak determinant of circulating FGF23 and phosphate concentrations [13]. ADHR mutations have variable penetrance and age at clinical presentation, with spontaneous resolution of the renal phosphate wasting in some cases [17]. Among 42 subjects with ADHR mutations, only 24% and 9% had increased c-terminal and iFGF23 levels, respectively. The iFGF23 increments and ADHR features tended to wax and wane over time [18].

FGF23 is a pleotropic hormone with a host of klotho-dependent and klotho-independent functions [19, 20]. Early in CKD, an adaptive increase of circulating FGF23 precedes alterations of other CKD-MBD markers and guards against hyperphosphatemia [21]. With CKD progression, serum iFGF23 continues to increase due to progressive hyperphosphatemia [22], hyperparathyroidism [23], klotho deficiency [24], as well as decreased renal clearance [25]. The highest ever reported serum iFGF23 values (> 10,000 pg/mL) occur in patients with advanced CKD and constitute a significant harbinger of end-stage renal disease (ESRD) and mortality [26, 27]. Several recent reports have linked circulating FGF23 excess with an expanding spectrum of disease conditions including CKD initiation [28] and progression [29, 30], renal allograft loss [31, 32], chronic inflammation [33], immune deficiency [34], insulin resistance [35], dyslipidemia [36], early [37, 38] and advanced atherosclerosis [39, 40], VC [41], hypertension [42,43,44], left ventricular hypertrophy [45], heart failure [46], as well as cardiovascular and all-cause mortality [47, 48], particularly in CKD [49] and ESRD [50,51,52,53] patients. The adverse consequences of circulating FGF23 excess remained significant after adjustment for serum calcium, phosphorus, parathyroid hormone (PTH) [29], and vitamin D levels [52].

In Egypt, the prevalence of ESRD has been steadily increasing. Although this trend may reflect increased surveillance, more availability of dialysis centers, and increased longevity on treatment, a true surge of incident cases is evident and compatible with the increased prevalence of non-communicable diseases closely linked with CKD development and progression, particularly hypertension and diabetes mellitus [54]. Hypertension is highly prevalent in Egypt, with apparently suboptimal management [55,56,57]. It has been repeatedly recognized as the major cause of ESRD [58,59,60]. About one-fifth of ESRD cases are not attributable to a known factor (UKN) and may represent the tip of a large iceberg of poorly identified CKD cases [61]. There is now ample evidence for the role of circulating FGF23 excess in occurrence and progression of hypertension [42,43,44] and CKD [28,29,30] that may be more prominent in genetically predisposed individuals [10, 11]. Therefore, we hypothesized that gain-of-function variants of FGF23 gene might represent unforeseen contributors to the recognizable burden of hypertensive CKD in Egypt. Accordingly, we studied the occurrence and correlates of the rs7955866 FGF23 gene single nucleotide polymorphism (SNP) among Egyptian subjects with or without CKD.

Methods

Study design and participants

This was a cross-sectional, case–control study that involved two comparative groups (Fig. 1, Table 1):

Fig. 1
figure 1

Study flowchart. Main causes of CKD were hypertension (HTN), diabetic kidney disease (DKD), unknown cause (UKN), lupus nephritis (LN), primary glomerulonephritis (1ry GN), chronic pyelonephritis (CPN), obstructive uropathy (ObUro), gouty nephropathy (GoN), and autosomal dominant polycystic kidney disease (ADPKD). Hypertension load in CKD patients ranged from G0 (normal BP without any treatment) to G5 (stage 2 hypertension despite multiple antihypertensive therapies). Number of patients within each category is shown as absolute numbers followed by (percent)

Table 1 Characteristics of the study subjects

Group 1 (G I): 72 CKD patients (27–71 years old, 37 females).

  • Inclusion Criteria:

    • Adult age.

    • Having CKD stage 2 or 3, as defined by an estimated glomerular filtration rate (eGFR) of 30–89 mL/min/1.73 m2 as per K/DOQI guidelines[62].

    • Providing a written informed consent to participate.

  • Exclusion criteria: secondary hypertension, (such as patients with endocrinopathies and renovascular hypertension), urologic abnormalities potentially impacting urinary protein excretion or renal functions (such as vesicoureteric reflux), malignancies, and paraproteinemias.

Group 2 (G II): 26 healthy control subjects matching in age and sex.

The main causes of CKD were identified by thorough history, clinical examination, and medical record review. Blood pressure (BP) was measured by a standard technique in the upper arm while sitting comfortably. Three measures were made, one minute apart; and the average of the last two was recorded. Measurements were repeated at 2–3 visits, 2–3 weeks apart. Further office and/or home measurements were made, if required. The BP was ultimately given a score of either 0 (normal), 1 (elevated), 2 (stage 1 HTN), or 3 (stage 2 HTN), according to the 2017 ACC/AHA guidelines [63]. To account for the effect of therapy, one extra point was added if the patient achieved this level of BP with interrupted or single-agent therapy; and two points were added for patients on regular treatment with ≥ 2 agents. Patients with inconsistent findings were checked at more occasions until they were ultimately placed on a semiquantitative scale to express hypertension burden extending from 0 (normal without treatment) to 5 (stage 2 hypertension despite regular multiple antihypertensive medications).

Laboratory studies [64]

After an overnight fast, blood samples were drawn into EDTA tubes (for complete blood count and DNA extraction) and serum separator tubes that were immediately transported and centrifuged. The separated serum was kept at – 80 °C until batch analysis was made for urea, creatinine, uric acid, total proteins, albumin, calcium, phosphorus, intact parathyroid hormone (iPTH) (third-generation assay), vitamin D3, and intact FGF23 (iFGF23). The latter was tested by Kainos ELISA kit that targets the iFGF23 molecule by utilizing two monoclonal antibodies which simultaneously capture two epitopes flanking the cleavage site of the c-terminal fragment (Kainos Laboratories, Tokyo, Japan) [65]. Estimated GFR was calculated by the CKD epidemiology collaboration (CKD-EPI) equation [66]. A 24-h urine collection was used to assess total daily urinary protein excretion.

Study of FGF23 Gene rs7955866 SNP

DNA extraction

DNA was extracted from whole blood EDTA samples using a spin column protocol [QIAamp DNA Blood Mini Kit] provided by QIAGEN Inc. (Qiagen, Hilden, Germany) according to manufacturer’s instructions. Extracted DNA was kept at – 80 °C till analysis.

Determination of the DNA concentration and quality

NanoDrop 2000/2000c (Thermoscientific, USA) was used to check DNA quality and quantity. Samples having poor DNA-purity or extensively fragmented DNA were excluded from the analysis [67].

Genotyping

This was performed using 40 × TaqMan® predesigned SNP genotyping assay provided by Thermo Fisher Scientific, Waltham, Massachusetts, USA (Assay ID: C_25605491_10). The context sequence of the rs7955866 FGF23 SNP was:

  • AGCCTTCCGGGCCC[G/A]TTCCCCCAGCGTGTTCACT.

The A allele was detected with VIC® dye and the G allele with FAM® dye.

The reaction mix was composed of 40X TaqMan® genotyping assay, TaqMan® universal PCR master mix, and nuclease-free water. The 40X predesigned SNP assay was diluted to a 20X working solution with nuclease-free water. The recommended final reaction volume per well was 20 μL for a 48-well plate (17 μL reaction mix + 3 μL DNA sample). For reaction mix preparation, 10μL of 2X TaqMan® Genotyping Master Mix, 1 µL of 20X Assay Working Solution (0.5 µL 40X TaqMan assay + 0.5 µL Nuclease free water), and 6 µL of nuclease-free water were added in each well. The total reaction volume uses 20 ng of genomic DNA. Real-time PCR was performed using Applied Biosystems StepOne™ Real-Time PCR System.

In the real-time PCR system software, an experiment or plate document was using the following thermal cycling conditions; first AmpliTaq Gold® Enzyme Activation step at 95 °C for 10 min then 40 cycles; each consisted of 15 s at 95 °C for denaturation and 1 min at 60 °C for annealing/extension. No template controls (NTC) were performed by adding 3 µl of DNase-free water into each well instead of DNA.

Post-PCR plate read and analysis

Life Technologies real-time instrument software plotted the results of the allelic discrimination data as a scatter plot of allele 1 (VIC® dye) versus allele 2 (FAM™ dye). Each well of the 48-well reaction plate was represented as an individual point on the plot. Applied Biosystems Step One™ Software was the software application used to analyze raw data from genotyping experiments created on a Life Technologies real-time PCR system.

Statistical methods

Data were analyzed using SPSS software package version 20 (SPSS Inc., Chicago, Illinois, USA). Categorical data were expressed as absolute numbers (percentages) and compared by Chi-square or Fisher exact test. Continuous data were tested for normality using Shapiro–Wilk test. Parametric data were presented as mean ± SD and compared by independent t-test or analysis of variance (ANOVA). Nonparametric data were presented as median (interquartile range) and compared by Mann–Whitney U or Kruskal–Wallis H test. Correlations were tested by the Spearman’s rank correlation coefficient. Significance was judged at the 5% level.

Results

Among CKD patients, 15.3% had normal BP without any treatment (G0), whereas 18%, 20.8%, 26.4%, 12.5%, and 7% had hypertension grades 1 through 5, respectively (Fig. 1). Compared with controls, CKD patients had significantly higher S. creatinine, urea, uric acid, phosphorus, iPTH, iFGF23, WBCs, and proteinuria, and significantly lower eGFR, serum total proteins, albumin, vitamin D3, hemoglobin, and platelets (Table 1).

There was no significant difference in the minor allele frequency (MAF) of the rs7955866 FGF23 SNP (A allele) between CKD patients (0.333) and controls (0.308) with any mode of inheritance (all P > 0.7). (Table 2, Fig. 2).

Table 2 Comparison between CKD patients and controls regarding FGF23 RS7955866 polymorphism genotypes
Fig. 2
figure 2

Distribution of the 3 genotypes of FGF23 gene rs7955866 SNP in the two study groups

CKD patients with the homozygote variant “AA” were compared with the other two genotypes, either separately (Table 3, Figs. 3, 4), or considering these two genotypes as one group “GG/GA” (not shown). In both instances, “AA” CKD patients had significantly higher hypertension grade, significantly higher serum iFGF23, and significantly lower serum albumin. The “A” allele load had a significant positive correlation with hypertension grade, which was consistent across the 3 inheritance modes (Table 4). Coded for some inheritance modes only, the “A” allele load had a significant but weak positive correlation with serum iFGF23, and a significant but weak negative correlation with serum albumin and WBCs. In the codominant and recessive modes, correlations of the “A” allele load with serum iFGF23 persisted, after controlling for GFR, serum phosphorus, and iPTH. Hypertension grade had a significant but weak positive correlation with serum phosphorus and iFGF23 (Table 5). Having “AA” genotype modestly increased the risk for having hypertension (OR: 1.73, CI 0.2–15.21, P = 0.621) and for being in the highest serum iFGF23 tertile (OR: 2.26, CI 0.59–8.75, P = 0.236).

Table 3 Comparison between CKD patients regarding FGF23 RS7955866 polymorphism genotypes
Fig. 3
figure 3

Comparison of different genotypes of FGF23 gene rs7955866 SNP in CKD patients according to hypertension grade, showing the P value for the difference between GG and AA phenotypes in post hoc pairwise comparison

Fig. 4
figure 4

Comparison of different genotypes of FGF23 gene rs7955866 SNP in CKD patients according to serum iFGF23, showing the P value for the difference between GG and AA phenotypes in post hoc pairwise comparison

Table 4 Statistical correlations of "A" allele load of FGF23 RS7955866 polymorphism in CKD patients
Table 5 Other correlations of hypertension grade in CKD patients

Discussion

Genetic variants affecting circulating FGF23 level may occur within the FGF23 gene itself or within loci controlling vitamin D and phosphate metabolism [68]. Most previous studies of the rs7955866 SNP (c.716C > T, g.4370383G > A, p.T239M) have reported a MAF < 0.2 [14, 69, 70]. For the first time in an Egyptian cohort, we report a remarkably higher MAF (0.327), which was insignificantly higher among CKD subjects compared with controls (0.333 versus 0.308, respectively). Both experimental [16] and clinical [14, 71] studies have established that the missense, gain-of-function ADHR mutations may result in increased tissue or circulating FGF23 levels that are attributed to the resistance of the variant molecule to proteolytic cleavage [10, 11]. However, complex translational and post-translational FGF23 regulatory mechanisms tend to maintain its circulating levels within normal, unless the expression of the variant FGF23 gene is stimulated by some acquired triggering factors, notably anemia, iron deficiency or hyperphosphatemia, which typically accompany renal function impairment [18, 72,73,74]. The differential expression of the variant FGF23 gene was evident in the present study. Within controls, serum iFGF23 showed neither a significant difference between different genotypes (Additional file 1: Supplemental Sheet 1), nor a significant correlation with the “A” allele load, employing different inheritance modes (Additional file 1: Supplemental Sheet 2). On the other hand, CKD patients, with their significantly lower eGFR, hemoglobin, and significantly higher serum phosphorus, displayed a significant elevation of serum iFGF23 in “AA” compared with “GG” patients. Moreover, the “A” allele load, coded for codominant and recessive modes, had significant positive correlations with serum iFGF23, which persisted after controlling for serum phosphorus, iPTH and eGFR (Table 4). The rs7955866 FGF23 SNP may therefore be relatively dormant in healthy subjects. Once subjects with this variant develop impaired kidney function, the variant becomes actively expressed, leading to increased circulating FGF23 with its potential multi-system morbid sequelae, including further progression of CKD, thus creating a vicious cycle. Indeed, CKD is the protype and most common disorder of secondary increased circulating iFGF23 [72]. These patients typically have a constellation of the key FGF23 secretion triggers (hyperphosphatemia, hyperparathyroidism, and klotho deficiency), in addition to the frequent occurrence of hypoxia, anemia, iron deficiency, and chronic inflammation, which are all known to upregulate FGF23 gene expression [75, 76].

The global burden of hypertension is increasing [77], with comparatively higher prevalence but lower recognition and control rates in lower- and middle-income countries [78]. In the present study, hypertension was the most common cause of CKD, accounting for 23.6% of cases, which was matching with the role of hypertension as the leading cause of ESRD in Egypt [58,59,60]. Hypertension is a salient feature of CKD of whatever etiology; both conditions have a well-recognized bidirectional relation in which the kidney behaves as both a culprit and a victim [79]. Some degree of hypertension occurred in 84.7% of CKD patients in the present study, emphasizing the importance of hypertension control as a feasible approach to delay CKD progression [80, 81]. Hypertension is a highly heritable trait, with genetic factors significantly determining the rates of its prevalence and response to therapy among different ancestral groups [82]. In the present study, “AA” CKD patients had significantly higher hypertension grade and significantly higher serum iFGF23, compared with the other genotypes. Hypertension grade had a significant positive correlation with both the “A” allele load (coded for different inheritance modes) and serum iFGF23. Therefore, harboring the “A” genotype, in a homo- or a heterozygote state, stood out as a significant risk factor for hypertension, which is mediated through circulating iFGF23 excess.

The association between increased circulating iFGF23 and hypertension has been described both in community dwellers [42, 43] and CKD patients [44]. Urinary FGF23/creatinine ratio was found to be significantly higher in 42 hypertensive children and adolescents, compared with controls; and it had a significant direct correlation with systolic BP in all study participants [83]. Circulating iFGF23 excess may be related to hypertension through its stimulant effect on the renin–angiotensin–aldosterone system (RAAS) [84]. RAAS activation may be mediated by FGF23 either by suppressing the angiotensin converting enzyme-2 (ACE2) expression in the kidney, independent of other CKD-MBD abnormalities [85], or by inducing active vitamin D (calcitriol) deficiency. FGF23 is a strong independent predictor of low calcitriol levels, even after adjustment for renal function, serum phosphorus, and calcidiol levels [86]. Calcitriol behaves as a negative RAAS regulator [87, 88], probably by reducing renin gene expression [89]. More recently, further pathogenetic associations between FGF23 and hypertension were established when its ability to augment distal renal tubular sodium reabsorption was disclosed [90]. Mice treated with an intraperitoneal injection of recombinant FGF23 developed a klotho-dependent 40% upregulation of the distal tubular sodium chloride cotransporter (NCC), reduced urinary sodium and water excretion coupled with circulatory sodium and water retention, and ensuing hypertension. Therefore, FGF23 was assigned a significant role as a sodium-retaining hormone involved in volume and BP regulation [91]. Further studies should explore whether RAAS blockers (as ACE inhibitors) and NCC blockers (as thiazide diuretics) are particularly effective in treating hypertension in the context of FGF23 excess. The hypertensive effects of iFGF23 may also stem from induction of endothelial dysfunction [37, 38] and VC [41].

The relationship between circulating iFGF23 levels and serum phosphorus is largely influenced by renal function [92]. The markedly increased circulating iFGF23 levels in patients with hereditary hypophosphatemic disorders and normal renal function are closely correlated with increased urinary fractional excretion of phosphate and hypophosphatemia [93,94,95]. A similar situation occurs in the early few months following renal transplantation, when increased serum iFGF23 is the primary factor responsible for post-transplant hypophosphatemia [96,97,98]. In patients with less striking iFGF23 elevations and normal to moderately decreased renal function (like the current study cohort, Additional file 1: Supplemental Sheet 3), serum iFGF23 has no significant correlation with serum phosphorus [99, 100]. However, as CKD progresses to ESRD, serum iFGF23 increases in a strong direct correlation with serum phosphorus [52, 53, 101]; hyperphosphatemia may then partly explain the association of iFGF23 with adverse cardiovascular outcomes [102,103,104]; and control of hyperphosphatemia may be a feasible approach to mitigate FGF23 excess and its morbid sequelae [105].

Hyperphosphatemia is a common finding and a major risk factor for cardiovascular events and mortality in CKD patients [106,107,108]. A graded association between serum phosphorus and cardiovascular disease extends to the normal serum phosphorus range and to people with normal renal function [109,110,111]. In the present study, serum phosphorus had a significant positive correlation with hypertension grade in the CKD patients. Previously, hyperphosphatemia has been strongly and independently associated with hypertension in hemodialysis patients [112], and with increased BP variability in patients with earlier stages of CKD [113]. It was also associated with poor response to antihypertensive therapy, irrespective of renal function status [114]. Several mechanisms explain the association between hyperphosphatemia and hypertension. Phosphorus exposure decreased endothelium-dependent vasodilatation of the brachial artery in healthy men; a similar in vitro effect was documented in rat aortic rings [115]. Similar results were recently reproduced by a study involving two counterparts of humans and rat mesenteric vessels [116]. Hyperphosphatemia may also increase endothelial production of the vasoconstrictor endotelin-1 [117], increase renin expression [118], and activate the sympathetic nervous system [119], besides playing a key role in CKD progression [120], VC and arterial stiffness [121,122,123]. High phosphorus diet may also stimulate FGF23 secretion, leading to RAAS activation, sodium and water retention, and consequently hypertension, in subjects with or without CKD [90]. Therefore, phosphorus overconsumption may be a dietary factor augmenting the pressor effect of the rs7955866 SNP, particularly in less-privileged communities, habitually consuming relatively low-cost processed foods having high inorganic phosphate content, that is almost totally absorbed [124,125,126,127].

We report also an association between the “A” allele load and lower serum albumin in the studied CKD patients (Tables 3, 4). This effect could not be explained by variations in total proteinuria, which had no relation with the occurrence of the SNP or the serum iFGF23 level. Circulating FGF23 has been correlated with the extent of proteinuria in CKD patients in some [128, 129], but not all studies [130]. It is possible that patients with the FGF23 SNP had lower serum albumin due to higher albuminuria. Increased circulating FGF23 increases the risk of albuminuria in patients with normal kidney function to moderate CKD [30, 131]. However, urinary albumin excretion rate was not specifically assayed in the present study.

Previous studies have described an association between circulating FGF23 excess and both CKD initiation [28] and progression [29, 30]. Increased circulating iFGF23 may directly affect the glomerular endothelial function or glomerular hemodynamics, through klotho-independent signaling [38, 131]. Alternatively, FGF23 may exert its detrimental effects on renal function through its association with hypertension, atherosclerosis, and VC. The present study did not reveal a clear association between the rs7955866 SNP and all-cause CKD, although, more specifically, this SNP seemed to increase the risk of hypertension and hypertensive CKD, an association mediated by circulating FGF23 excess. In 18% of the patients, CKD could not be attributed to a definitive cause (UKN). When CKD develops in relation to a gain-of-function FGF23 gene mutation, it is conceivable that the insidiously occurring hypertension and renal impairment would be largely asymptomatic and difficult to recognize, at least initially, unless the condition is specifically looked for. The considerable frequency of this SNP in the studied Egyptian cohort, and the prevalence of environmental triggers that tend to over-express it as iron deficiency [76, 132] and dietary phosphate overconsumption [126], should generate an impetus to develop nationwide gene studies to further explore the role of genetic factors in such significant health problems. Increased serum iFGF23 has emerged as an early biochemical marker of increased risk for hypertension and hypertensive CKD in genetically predisposed individuals. Further research should determine its practical utility as a diagnostic parameter, and possibly as a therapeutic target, and should try to define its recommended target range that provides the best balance between its adaptive and maladaptive effects in patients with different stages of CKD.

To the best of our knowledge, this is the first study to address the rs7955866 FGF23 SNP in the Arab region. Studies of this SNP are generally scarce. We acknowledge the limitations imposed by the limited number of included subjects and the cross-sectional nature of the study, which undermine its power to draw firm conclusions about cause–effect relationships, particularly regarding very complex and multi-factorial traits like hypertension and CKD. Hypertension load may have been better assessed by ambulatory BP monitoring [133]. The study did not include other FGF23 genetic variants or other related biochemical measures like urinary albumin and phosphate excretion, active vitamin D, and markers of iron profile.

Conclusions

For the first time in an Egyptian cohort, we report a relatively high frequency of the rs7955866 SNP. It may remain dormant or become upregulated in response to some environmental triggers, notably dietary phosphorus excess, leading to increased circulating iFGF23 with ensuing hypertension and/or renal impairment. Subjects with this SNP, particularly in the homozygous form, are at increased risk for CKD of presumably “unknown” etiology, with a tendency for early onset hypertension and increased circulating iFGF23 out of proportion with the degree of renal impairment.

Large-scale population studies are needed to confirm these findings and explore the role of blockers of the renin–angiotensin–aldosterone system and sodium chloride cotransporters in mitigating hypertension associated with FGF23 excess.

Availability of data and material

The data that support the findings of this study are available from the corresponding author upon request.

Abbreviations

ACE2:

Angiotensin converting enzyme-2

ADHR:

Autosomal dominant hypophosphatemic rickets

BP:

Blood pressure

CKD:

Chronic kidney disease

eGFR:

Estimated glomerular filtration rate

iFGF23:

Intact fibroblast growth factor 23

iPTH:

Intact parathyroid hormone

MAF:

Minor allele frequency

MBD:

Mineral bone disorder

NCC:

Sodium chloride cotransporter

RAAS:

Renin–angiotensin–aldosterone system

SNP:

Single nucleotide polymorphism

VC:

Vascular calcification

References

  1. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW et al (2003) National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 139(2):137–147

    PubMed  Google Scholar 

  2. Bikbov B, Purcell CA, Levey AS, Smith M, Abdoli A, Abebe M et al (2020) Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 395(10225):709–733

    Google Scholar 

  3. Ameh OI, Ekrikpo UE, Kengne A-P (2020) Preventing CKD in low-and middle-income countries: a call for urgent action. Kidney Int Rep 5(3):255–262

    PubMed  Google Scholar 

  4. Wheeler DC, Winkelmayer WC (2017) KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) foreword. Kidney Int Suppl 7(1):1–59

    Google Scholar 

  5. Witasp A, Ekström TJ, Schalling M, Lindholm B, Stenvinkel P, Nordfors L (2014) How can genetics and epigenetics help the nephrologist improve the diagnosis and treatment of chronic kidney disease patients? Nephrol Dial Transplant 29(5):972–980

    CAS  PubMed  Google Scholar 

  6. Wöhrle S, Bonny O, Beluch N, Gaulis S, Stamm C, Scheibler M et al (2011) FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. J Bone Miner Res 26(10):2486–2497

    PubMed  Google Scholar 

  7. Kocełak P, Olszanecka-Glinianowicz M, Chudek J (2012) Fibroblast growth factor 23–structure, function and role in kidney diseases. Adv Clin Exp Med 21(3):391–401

    PubMed  Google Scholar 

  8. Liu S, Quarles LD (2007) How fibroblast growth factor 23 works. J Am Soc Nephrol 18(6):1637–1647

    CAS  PubMed  Google Scholar 

  9. Goetz R, Nakada Y, Hu MC, Kurosu H, Wang L, Nakatani T et al (2010) Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci 107(1):407–412

    CAS  PubMed  Google Scholar 

  10. Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K et al (2002) Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinol 143(8):3179–3182

    CAS  Google Scholar 

  11. White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ (2001) Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int 60(6):2079–2086

    CAS  PubMed  Google Scholar 

  12. White KE, Evans WE, O’Riordan JL, Speer MC, Econs MJ, Lorenz-Depiereux B et al (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26(3):345–348

    CAS  Google Scholar 

  13. Pekkinen M, Laine CM, Mäkitie R, Leinonen E, Lamberg-Allardt C, Viljakainen H et al (2015) FGF23 gene variation and its association with phosphate homeostasis and bone mineral density in Finnish children and adolescents. Bone 71:124–130

    CAS  PubMed  Google Scholar 

  14. Rendina D, Esposito T, Mossetti G, De Filippo G, Gianfrancesco F, Perfetti A et al (2012) A functional allelic variant of the FGF23 gene is associated with renal phosphate leak in calcium nephrolithiasis. J Clin Endocrinol 97(5):E840–E844

    CAS  Google Scholar 

  15. den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J et al (2016) HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat 37(6):564–569

    Google Scholar 

  16. De Filippo G, Rendina D, Esposito T, Gianfrancesco F, Mossetti G, Magliocca et al (2010) A common variant of FGF23 gene significantly influences phosphate homeostasis. Horm Res Paediatr 74(Suppl 3):34

    Google Scholar 

  17. Econs MJ, McEnery PT (1997) Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab 82(2):674–681

    CAS  PubMed  Google Scholar 

  18. Imel EA, Hui SL, Ecibs MJ (2007) FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res 22(4):520–526

    CAS  PubMed  Google Scholar 

  19. Quarles LD (2019) FGF-23 and α-Klotho co-dependent and independent functions. Curr Opin Nephrol Hypertens 28(1):16

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Erben RG (2017) Pleiotropic actions of FGF23. Toxicol Pathol 45(7):904–910

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Isakova T, Wahl P, Vargas GS, Gutiérrez OM, Scialla J, Xie H et al (2011) Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 79(12):1370–1378

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Burnett SAM, Gunawardene SC, Bringhurst FR, Jüppner H, Lee H, Finkelstein JS (2006) Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res 21(8):1187–1196

    CAS  PubMed  Google Scholar 

  23. Rhee Y, Bivi N, Farrow E, Lezcano V, Plotkin LI, White KE et al (2011) Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone 49(4):636–643

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Lu X, Hu MC (2017) Klotho/FGF23 axis in chronic kidney disease and cardiovascular disease. Kidney Dis 3(1):15–23

    Google Scholar 

  25. van Ballegooijen AJ, Rhee EP, Elmariah S, de Boer IH, Kestenbaum B (2016) Renal clearance of mineral metabolism biomarkers. J Am Soc Nephrol 27(2):392–397

    PubMed  Google Scholar 

  26. Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J et al (2011) Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. J Am Med Assoc 305(23):2432–2439

    CAS  Google Scholar 

  27. Lima F, El-Husseini A, Monier-Faugere M-C, David V, Mawad H, Quarles D et al (2014) FGF-23 serum levels and bone histomorphometric results in adult patients with chronic kidney disease on dialysis. Clin Nephrol 82(5):287

    CAS  PubMed  PubMed Central  Google Scholar 

  28. De Jong MA, Eisenga MF, van Ballegooijen AJ, Beulens JW, Vervloet MG, Navis G et al (2021) Fibroblast growth factor 23 and new-onset chronic kidney disease in the general population: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study. Nephrol dial Transplant 36(1):121–128

    PubMed  Google Scholar 

  29. Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel A et al (2007) Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 18(9):2600–2608

    CAS  PubMed  Google Scholar 

  30. Lundberg S, Qureshi AR, Olivecrona S, Gunnarsson I, Jacobson SH, Larsson TE (2012) FGF23, albuminuria, and disease progression in patients with chronic IgA nephropathy. Clin J Am Soc Nephrol 7(5):727–734

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Wolf M, Molnar MZ, Amaral AP, Czira ME, Rudas A, Ujszaszi A et al (2011) Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol 22(5):956–966

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Sezer S, Bal Z, Uyar EM, Ozdemir H, Guliyev O, Yildirim S et al (2014) Fibroblast growth factor 23/Klotho axis is a risk factor for kidney transplant loss. Abstract A261. Transplantation 98:473–474

    Google Scholar 

  33. David V, Francis C, Babitt JL (2017) Ironing out the cross talk between FGF23 and inflammation. Am J Physiol Renal Physiol 312(1):F1–F8

    CAS  PubMed  Google Scholar 

  34. Abdullah Z, Kurts C (2016) More trouble with FGF23: a novel role in systemic immunosuppression. Kidney Int 89(6):1176–1177

    CAS  PubMed  Google Scholar 

  35. Hanks LJ, Casazza K, Judd SE, Jenny NS, Gutiérrez OM (2015) Associations of fibroblast growth factor-23 with markers of inflammation, insulin resistance and obesity in adults. PLoS ONE 10(3):e0122885

    PubMed  PubMed Central  Google Scholar 

  36. Yan J, Zhang M, Ni Z, Jin S, Zhu M, Pang H (2017) Associations of serum fibroblast growth factor 23 with dyslipidemia and carotid atherosclerosis in chronic kidney disease stages 3–5D. Clin Exp Med 10:13588–13597

    Google Scholar 

  37. Mirza MA, Larsson A, Lind L, Larsson TE (2009) Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis 205(2):385–390

    CAS  PubMed  Google Scholar 

  38. Yilmaz MI, Sonmez A, Saglam M, Yaman H, Kilic S, Demirkaya E et al (2010) FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease. Kidney Int 78(7):679–685

    CAS  PubMed  Google Scholar 

  39. Shah NH, Dong C, Elkind MS, Sacco RL, Mendez AJ, Hudson BI et al (2015) Fibroblast growth factor 23 is associated with carotid plaque presence and area: the Northern Manhattan Study. Arterioscler Thromb Vasc Biol 35(9):2048–2053

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Mirza MA, Hansen T, Johansson L, Ahlström H, Larsson A, Lind L et al (2009) Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrol Dial Transplant 24(10):3125–3131

    CAS  PubMed  Google Scholar 

  41. Donate-Correa J, Martín-Núñez E, Hernández-Carballo C, Ferri C, Tagua VG, Delgado-Molinos A et al (2019) Fibroblast growth factor 23 expression in human calcified vascular tissues. Aging (Albany NY) 11(18):7899

    CAS  Google Scholar 

  42. Fyfe-Johnson AL, Alonso A, Selvin E, Bower JK, Pankow JS, Agarwal SK et al (2016) Serum fibroblast growth factor-23 and incident hypertension: the Atherosclerosis Risk in Communities (ARIC) Study. J Hypertens 34(7):1266–1272

    CAS  PubMed  Google Scholar 

  43. Akhabue E, Montag S, Reis JP, Pool LR, Mehta R, Yancy CW et al (2018) FGF23 (fibroblast growth factor-23) and incident hypertension in young and middle-aged adults: the CARDIA study. Hypertension 72(1):70–76

    CAS  PubMed  Google Scholar 

  44. Li J, Yu G, Zhuang Y (2018) Impact of serum FGF23 levels on blood pressure of patients with chronic kidney disease. Eur Rev Med Pharmacol Sci 22(3):721–725

    PubMed  Google Scholar 

  45. Stevens KK, McQuarrie EP, Sands W, Hillyard DZ, Patel RK, Mark PB et al (2011) Fibroblast growth factor 23 predicts left ventricular mass and induces cell adhesion molecule formation. Int J Nephrol 2011:1–6

    Google Scholar 

  46. Poelzl G, Trenkler C, Kliebhan J, Wuertinger P, Seger C, Kaser S et al (2014) FGF 23 is associated with disease severity and prognosis in chronic heart failure. Eur J Clin Invest 44(12):1150–1158

    CAS  PubMed  Google Scholar 

  47. Ärnlöv J, Carlsson AC, Sundström J, Ingelsson E, Larsson A, Lind L et al (2013) Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Kidney Int 83(1):160–166

    PubMed  Google Scholar 

  48. Ix JH, Katz R, Kestenbaum BR, de Boer IH, Chonchol M, Mukamal KJ et al (2012) Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol 60(3):200–207

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Xue C, Yang B, Zhou C, Dai B, Liu Y, Mao Z et al (2017) Fibroblast growth factor 23 predicts all-cause mortality in a dose-response fashion in pre-dialysis patients with chronic kidney disease. Am J Nephrol 45(2):149–159

    CAS  PubMed  Google Scholar 

  50. Bouma-de Krijger A, de Roij van Zuijdewijn CL, Nubé MJ, Grooteman MP, Vervloet MG (2021) Change in FGF23 concentration over time and its association with all-cause mortality in patients treated with haemodialysis or haemodiafiltration. Clin Kidney J 14(3):891–897

    CAS  PubMed  Google Scholar 

  51. Komaba H, Fuller DS, Taniguchi M, Yamamoto S, Nomura T, Zhao J et al (2020) Fibroblast growth factor 23 and mortality among prevalent hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study. Kidney Int Rep 5(11):1956–1964

    PubMed  PubMed Central  Google Scholar 

  52. Gutiérrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A et al (2008) Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. New Engl J Med 359(6):584–592

    PubMed  Google Scholar 

  53. Jean G, Terrat J-C, Vanel T, Hurot J-M, Lorriaux C, Mayor B et al (2009) High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant 24(9):2792–2796

    CAS  PubMed  Google Scholar 

  54. Soliman AR, Fathy A, Roshd D (2012) The growing burden of end-stage renal disease in Egypt. Ren Fail 34(4):425–428

    PubMed  Google Scholar 

  55. Ibrahim MM, Rizk H, Appel LJ, Aroussy WE, Helmy S, Sharaf Y et al (1995) Hypertension prevalence, awareness, treatment, and control in Egypt: results from the Egyptian National Hypertension Project (NHP). Hypertension 26(6):886–890

    CAS  PubMed  Google Scholar 

  56. Elbaz WF, Eissa SS, Mohamed RA, Aly NK, Reda TM (2018) Essential hypertension among Egyptian adults. Egypt J Hosp Med 61(1):643–652

    Google Scholar 

  57. Ibrahim MM (2013) Problem of hypertension in Egypt. Egypt Heart J 65(3):233–234

    Google Scholar 

  58. Ghonemy TA, Farag SE, Soliman SA, El-Okely A, El-Hendy Y (2016) Epidemiology and risk factors of chronic kidney disease in the El-Sharkia Governorate, Egypt. Saudi J Kidney Dis Transplant 27(1):111

    Google Scholar 

  59. El-Ballat MA-F, El-Sayed MA, Emam HK (2019) Epidemiology of end stage renal disease patients on regular hemodialysis in El-Beheira governorate. Egypt Egypt J Hosp Med 76(3):3618–3625

    Google Scholar 

  60. Ahmed HA, Zahran AM, Issawi RA (2020) Prevalence and etiology of end-stage renal disease patients on maintenance hemodialysis. Menoufia Medical J 33(3):766–771

    Google Scholar 

  61. Wijerathne BT, Meier RJ, Salgado LS, Rathnayake GK, Kumara SS, Agampodi SB (2018) Chronic kidney disease of unknown etiology: the tip of the iceberg? Ceylon J Med Sci 55(2):55–57

    Google Scholar 

  62. Levey AS, Coresh J, Bolton K, Culleton B, Harvey KS, Ikizler TA et al (2002) K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kid Dis 39(2 Suppl. 1):S1–S266

    Google Scholar 

  63. Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C et al (2018) 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 71(19):e127–e248

    PubMed  Google Scholar 

  64. Burtis CA, Ashwood ER, Bruns DE (2012) Tietz textbook of clinical chemistry and molecular diagnostics-e-book. Elsevier Health Sciences, Amsterdam

    Google Scholar 

  65. Heijboer AC, Levitus M, Vervloet MG, Lips P, ter Wee PM, Dijstelbloem HM et al (2009) Determination of fibroblast growth factor 23. Ann Clin Biochem 46(Pt 4):338–340

    CAS  PubMed  Google Scholar 

  66. Levey AS, Stevens LA (2010) Estimating GFR using the CKD epidemiology collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions. Am J Kid Dis 55(4):622–627

    PubMed  Google Scholar 

  67. Alharbi KK, Abudawood M, Khan IA (2021) Amino-acid amendment of arginine-325-tryptophan in rs13266634 genetic polymorphism studies of the SLC30A8 gene with type 2 diabetes-mellitus patients featuring a positive family history in the Saudi population. J King Saud Univ-Sci 33(1):101258

    Google Scholar 

  68. Robinson-Cohen C, Bartz TM, Lai D, Ikizler TA, Peacock M, Imel EA et al (2018) Genetic variants associated with circulating fibroblast growth factor 23. J Am Soc Nephrol 29(10):2583–2592

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Ishii T, Gemma A, Kida K (2015) Senescence is involved in the pathogenesis of chronic obstructive pulmonary disease through effects on telomeres and the anti-aging molecule fibroblast growth factor 23. Geriatr Gerontol Int 15(7):827–833

    PubMed  Google Scholar 

  70. Kim HJ, Kim K-H, Lee J, Oh JJ, Cheong HS, Wong EL et al (2013) Single nucleotide polymorphisms in fibroblast growth factor 23 gene, FGF23, are associated with prostate cancer risk. BJU Int 114(2):303–310

    PubMed  Google Scholar 

  71. Merlotti D, Rendina D, Gennari L, Esposito T, Magliocca S, De FG et al (2013) Interaction between FGF23 R176W mutation and C716T nonsynonymous change (T239M, rs7955866) in FGF23 on the clinical phenotype in a family with autosomal dominant hypophosphatemic rickets. Bone Abstracts 1

  72. Wolf M, White KE (2014) Coupling FGF23 production and cleavage: iron deficiency, rickets and kidney disease. Curr Opin Nephrol Hypertens 23(4):411–419

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Liu C, Li X, Zhao Z, Chi Y, Cui L, Zhang Q et al (2021) Iron deficiency plays essential roles in the trigger, treatment, and prognosis of autosomal dominant hypophosphatemic rickets. Osteoporos Int 32(4):737–745

    CAS  PubMed  Google Scholar 

  74. Larsson T, Nisbeth U, Ljunggren Ö, Jüppner H, Jonsson KB (2003) Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 64(6):2272–2279

    CAS  PubMed  Google Scholar 

  75. David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V et al (2016) Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 89(1):135–146

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Wheeler JA, Clinkenbeard EL (2019) Regulation of fibroblast growth factor 23 by iron, EPO, and HIF. Curr Mol Biol Rep 5(1):8–17

    PubMed  PubMed Central  Google Scholar 

  77. Zhou B, Bentham J, Di Cesare M, Bixby H, Danaei G, Cowan MJ et al (2017) Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants. Lancet 389(10064):37–55

    Google Scholar 

  78. Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K et al (2016) Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation 134(6):441–450

    PubMed  PubMed Central  Google Scholar 

  79. Ritz E (2009) The kidney: both culprit and victim. Hypertension 54(1):25–26

    CAS  PubMed  Google Scholar 

  80. Ravera M, Re M, Deferrari L, Vettoretti S, Deferrari G (2006) Importance of blood pressure control in chronic kidney disease. J Am Soc Nephrol 17(4 suppl 2):S98–S103

    PubMed  Google Scholar 

  81. Sarafidis PA, Li S, Chen S-C, Collins AJ, Brown WW, Klag MJ et al (2008) Hypertension awareness, treatment, and control in chronic kidney disease. Am J Med 121(4):332–340

    PubMed  Google Scholar 

  82. Bress AP, Irvin R, Muntner P (2017) Genetics of blood pressure: new insights into a complex trait. Am J kid Dis 69(6):723–725

    PubMed  Google Scholar 

  83. Zając M, Rybi-Szumińska A, Wasilewska A (2015) Urine fibroblast growth factor 23 levels in hypertensive children and adolescents. Croat Med J 56(4):344–350

    PubMed  PubMed Central  Google Scholar 

  84. Böckmann I, Lischka J, Richter B, Deppe J, Rahn A, Fischer D-C et al (2019) FGF23-mediated activation of local RAAS promotes cardiac hypertrophy and fibrosis. Int J Mol Sci 20(18):4634

    PubMed Central  Google Scholar 

  85. Dai B, David V, Martin A, Huang J, Li H, Jiao Y et al (2012) A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model. PLoS ONE 7(9):e44161

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G et al (2005) Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16(7):2205–2215

    CAS  PubMed  Google Scholar 

  87. de Borst MH, Vervloet MG, ter Wee PM, Navis G (2011) Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease. J Am Soc Nephrol 22(9):1603–1609

    PubMed  PubMed Central  Google Scholar 

  88. Li YC, Kong J, Wei M, Chen Z-F, Liu SQ, Cao L-P (2002) 1, 25-Dihydroxyvitamin D 3 is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110(2):229–238

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Li YC (2003) Vitamin D regulation of the renin–angiotensin system. J Cell Biochem 88(2):327–331

    CAS  PubMed  Google Scholar 

  90. Erben RG, Andrukhova O (2015) FGF23 regulation of renal tubular solute transport. Curr Opin Nephrol Hypertens 24(5):450–456

    CAS  PubMed  Google Scholar 

  91. Andrukhova O, Slavic S, Smorodchenko A, Zeitz U, Shalhoub V, Lanske B et al (2014) FGF 23 regulates renal sodium handling and blood pressure. EMBO Mol Med 6(6):744–759

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Weber TJ, Liu S, Indridason OS, Quarles LD (2003) Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res 18(7):1227–1234

    CAS  PubMed  Google Scholar 

  93. Yu X, White KE (2005) FGF23 and disorders of phosphate homeostasis. Cytokine Growth Factor Rev 16(2):221–232

    CAS  PubMed  Google Scholar 

  94. Huang X, Jiang Y, Xia W (2013) FGF23 and phosphate wasting disorders. Bone Res 1(1):120–132

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Kobayashi K, Imanishi Y, Koshiyama H, Miyauchi A, Wakasa K, Kawata T et al (2006) Expression of FGF23 is correlated with serum phosphate level in isolated fibrous dysplasia. Life Sci 78(20):2295–2301

    CAS  PubMed  Google Scholar 

  96. Tony EA, Sobh MA, Abdou MAA, Ali MF (2018) Serum changes in fibroblast growth factor-23 and in parameters of phosphorus metabolism after renal transplantation. J Egypt Soc Nephrol Transplant 18(2):46–56

    Google Scholar 

  97. Kawarazaki H, Shibagaki Y, Fukumoto S, Kido R, Nakajima I, Fuchinoue S et al (2011) The relative role of fibroblast growth factor 23 and parathyroid hormone in predicting future hypophosphatemia and hypercalcemia after living donor kidney transplantation: a 1-year prospective observational study. Nephrol Dial Transplant 26(8):2691–2695

    CAS  PubMed  Google Scholar 

  98. Bhan I, Shah A, Holmes J, Isakova T, Gutierrez O, Burnett S-A et al (2006) Post-transplant hypophosphatemia: tertiary ‘hyper-phosphatoninism’? Kidney Int 70(8):1486–1494

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Marsell R, Grundberg E, Krajisnik T, Mallmin H, Karlsson M, Mellstrom D et al (2008) Fibroblast growth factor-23 is associated with parathyroid hormone and renal function in a population-based cohort of elderly men. Eur J Endocrinol 158(1):125–130

    CAS  PubMed  Google Scholar 

  100. Roos M, Lutz J, Salmhofer H, Luppa P, Knauss A, Braun S et al (2008) Relation between plasma fibroblast growth factor-23, serum fetuin-A levels and coronary artery calcification evaluated by multislice computed tomography in patients with normal kidney function. Clin Endocrinol 68(4):660–665

    CAS  Google Scholar 

  101. Kritmetapak K, Losbanos L, Berent TE, Ashrafzadeh-Kian SL, Algeciras-Schimnich A, Hines JM et al (2021) Hyperphosphatemia with elevated serum PTH and FGF23, reduced 1, 25 (OH) 2 D and normal FGF7 concentrations characterize patients with CKD. BMC Nephrol 22(1):1–8

    Google Scholar 

  102. Tentori F, Blayney MJ, Albert JM, Gillespie BW, Kerr PG, Bommer J et al (2008) Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J kid Dis 52(3):519–530

    CAS  PubMed  Google Scholar 

  103. Slinin Y, Foley RN, Collins AJ (2005) Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J Am Soc Nephrol 16(6):1788–1793

    CAS  PubMed  Google Scholar 

  104. Seiler S, Heine GH, Fliser D (2009) Clinical relevance of FGF-23 in chronic kidney disease. Kidney Int 76:S34–S42

    Google Scholar 

  105. Rodelo-Haad C, Rodríguez-Ortiz ME, Martin-Malo A, Pendon-Ruiz de Mier MV, Agüera ML, Muñoz-Castañeda JR et al (2018) Phosphate control in reducing FGF23 levels in hemodialysis patients. PLoS ONE 13(8):e0201537

    PubMed  PubMed Central  Google Scholar 

  106. McGovern AP, de Lusignan S, van Vlymen J, Liyanage H, Tomson CR, Gallagher H et al (2013) Serum phosphate as a risk factor for cardiovascular events in people with and without chronic kidney disease: a large community based cohort study. PLoS ONE 8(9):e74996

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Gross P, Six I, Kamel S, Massy ZA (2014) Vascular toxicity of phosphate in chronic kidney disease. Circulation J 78(10):2339–2346

    CAS  Google Scholar 

  108. Disthabanchong S (2018) Phosphate and cardiovascular disease beyond chronic kidney disease and vascular calcification. Int J Nephrol 2018:3162806

    PubMed  PubMed Central  Google Scholar 

  109. Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G (2005) Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 112(17):2627–2633

    CAS  PubMed  Google Scholar 

  110. Dhingra R, Sullivan LM, Fox CS, Wang TJ, D’Agostino RB, Gaziano JM et al (2007) Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Int Med 167(9):879–885

    CAS  Google Scholar 

  111. Zhou C, Shi Z, Ouyang N, Ruan X (2021) Hyperphosphatemia and cardiovascular disease. Front Cell Dev Biol 9:644363

    PubMed  PubMed Central  Google Scholar 

  112. Huang CX, Plantinga LC, Fink NE, Melamed ML, Coresh J, Powe NR (2008) Phosphate levels and blood pressure in incident hemodialysis patients: a longitudinal study. Adv Chronic Kidney Dis 15(3):321–331

    PubMed  Google Scholar 

  113. Wang Q, Cui Y, Yogendranath P, Wang N (2018) Blood pressure and heart rate variability are linked with hyperphosphatemia in chronic kidney disease patients. Chronobiol Int 35(10):1329–1334

    CAS  PubMed  Google Scholar 

  114. Patel RK, Jeemon P, Stevens KK, Mccallum L, Hastie CE, Schneider A et al (2015) Association between serum phosphate and calcium, long-term blood pressure, and mortality in treated hypertensive adults. J Hypertens 33(10):2046–2053

    CAS  PubMed  Google Scholar 

  115. Shuto E, Taketani Y, Tanaka R, Harada N, Isshiki M, Sato M et al (2009) Dietary phosphorus acutely impairs endothelial function. J Am Soc Nephrol 20(7):1504–1512

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Stevens KK, Denby L, Patel RK, Mark PB, Kettlewell S, Smith GL et al (2017) Deleterious effects of phosphate on vascular and endothelial function via disruption to the nitric oxide pathway. Nephrol Dial Transplant 32(10):1617–1627

    CAS  PubMed  Google Scholar 

  117. Olmos G, Martínez-Miguel P, Alcalde-Estevez E, Medrano D, Sosa P, Rodríguez-Mañas L et al (2017) Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin-1 production. Aging Cell 16(6):1300–1312

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Bozic M, Panizo S, Sevilla MA, Riera M, Soler MJ, Pascual J et al (2014) High phosphate diet increases arterial blood pressure via a parathyroid hormone mediated increase of renin. J Hypertens 32(9):1822–1832

    CAS  PubMed  Google Scholar 

  119. Mizuno M, Mitchell JH, Crawford S, Huang C-L, Maalouf N, Hu M-C et al (2016) High dietary phosphate intake induces hypertension and augments exercise pressor reflex function in rats. Am J Physiol Regul Integr Comp Physiol 311(1):R39–R48

    PubMed  PubMed Central  Google Scholar 

  120. Da J, Xie X, Wolf M, Disthabanchong S, Wang J, Zha Y et al (2015) Serum phosphorus and progression of CKD and mortality: a meta-analysis of cohort studies. Am J Kid Dis 66(2):258–265

    CAS  PubMed  Google Scholar 

  121. Giachelli CM (2009) The emerging role of phosphate in vascular calcification. Kidney Int 75(9):890–897

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Cozzolino M, Gallieni M, Brancaccio D (2008) The mechanisms of hyperphosphatemia-induced vascular calcification. Int J Artif Organs 31(12):1002–1003

    CAS  PubMed  Google Scholar 

  123. Cozzolino M, Ciceri P, Galassi A, Mangano M, Carugo S, Capelli I et al (2019) The key role of phosphate on vascular calcification. Toxins 11(4):213

    CAS  PubMed Central  Google Scholar 

  124. Gutiérrez OM, Anderson C, Isakova T, Scialla J, Negrea L, Anderson AH et al (2010) Low socioeconomic status associates with higher serum phosphate irrespective of race. J Am Soc Nephrol 21(11):1953–1960

    PubMed  PubMed Central  Google Scholar 

  125. Gutiérrez OM, Isakova T, Enfield G, Wolf M (2011) Impact of poverty on serum phosphate concentrations in the Third National Health and Nutrition Examination Survey. J Ren Nutr 21(2):140–148

    PubMed  Google Scholar 

  126. Erem S, Razzaque MS (2018) Dietary phosphate toxicity: An emerging global health concern. Histochem Cell Biol 150(6):711–719

    CAS  PubMed  Google Scholar 

  127. Kim H-K, Mizuno M, Vongpatanasin W (2019) Phosphate, the forgotten mineral in hypertension. Curr Opin Nephrol Hypertens 28(4):345–351

    PubMed  PubMed Central  Google Scholar 

  128. Vervloet MG, van Zuilen AD, Heijboer AC, ter Wee PM, Bots ML, Blankestijn PJ et al (2012) Fibroblast growth factor 23 is associated with proteinuria and smoking in chronic kidney disease: an analysis of the MASTERPLAN cohort. BMC Nephrol 13(1):1–8

    Google Scholar 

  129. Kim H, Park J, Nam KH, Jhee JH, Yun H-R, Park JT et al (2020) The effect of interactions between proteinuria, activity of fibroblast growth factor 23 and serum phosphate on renal progression in patients with chronic kidney disease: a result from the Korean cohort study for outcome in patients with chronic kidney disease study. Nephrol Dial Transplant 35(3):438–446

    PubMed  Google Scholar 

  130. Ozeki M, Fujita S-i, Kizawa S, Morita H, Sohmiya K, Hoshiga M et al (2014) Association of serum levels of FGF23 and α-Klotho with glomerular filtration rate and proteinuria among cardiac patients. BMC Nephrol 15(1):1–8

    Google Scholar 

  131. Ix JH, Shlipak MG, Wassel CL, Whooley MA (2010) Fibroblast growth factor-23 and early decrements in kidney function: the Heart and Soul Study. Nephrol Dial Transplant 25(3):993–997

    CAS  PubMed  Google Scholar 

  132. Tawfik AA, Hanna ET, Abdel-Maksoud AM (2015) Anemia and iron deficiency anemia in Egypt. IOSR J Pharm 5(4):30–34

    Google Scholar 

  133. Velasquez MT, Beddhu S, Nobakht E, Rahman M, Raj DS (2016) Ambulatory blood pressure in chronic kidney disease: ready for prime time? Kidney Int Rep 1(2):94–104

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors and was completely funded by the authors.

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YA designed the study, searched the literature, interpreted the results, and prepared the manuscript. DM and AH selected and examined the participants and compiled the results. GK performed the hematological and biochemical studies. AS and FD performed DNA extraction and polymorphism testing. All authors reviewed the manuscript and approved its final version.

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Correspondence to Yaser Aly Ammar.

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This study was carried out in accordance with the tenets of the Declaration of Helsinki and its later amendments for experiments involving humans. It was approved by the Medical Research Ethics Committee of the Medical Research Institute, Alexandria University. Written informed consents were obtained from all participants; and their identification information was kept confidential.

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Supplementary Information

Additional file 1.

Three excel sheets displaying further results analysis.

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Ammar, Y.A., Maharem, D.A., Mohamed, A.H. et al. Fibroblast growth factor-23 rs7955866 polymorphism and risk of chronic kidney disease. Egypt J Med Hum Genet 23, 76 (2022). https://doi.org/10.1186/s43042-022-00289-7

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  • DOI: https://doi.org/10.1186/s43042-022-00289-7

Keywords

  • Chronic kidney disease
  • Fibroblast growth factor-23
  • Gene polymorphism
  • Hypertension
  • Phosphorus