Crosstalk of fibroblast growth factor 23 and anemia‑related factors during the development and progression of CKD (Review)
- Authors:
- Published online on: August 11, 2021 https://doi.org/10.3892/etm.2021.10593
- Article Number: 1159
Abstract
1. Introduction
Fibroblast growth factor 23 (FGF23) expression is elevated in early-stage chronic kidney disease (CKD), and continues to increase as the glomerular filtration rate decreases (1-4). FGF23 is a hormone derived from osteocytes that regulates the metabolism of phosphorus and 1,25-dihydroxyvitamin D (1,25[OH]2D). 1,25(OH)2D and high dietary phosphate intake upregulate FGF23 expression, resulting in increased renal excretion of phosphate and decreased synthesis of 1,25(OH)2D, which decreases FGF23 expression, thus completing a negative feedback loop (5). Recent studies have reported that iron deficiency (6-9) and erythropoietin (EPO) (10-13) also affect FGF23 production. In addition, a study on mice reported that applying hypoxia inducible factor-proline hydroxylase inhibitors (HIF-PHIs) increases the serum level of FGF23(8). Several clinical studies on patients with kidney disease have demonstrated that increased FGF23 expression is associated with poor patient outcomes (14-17). High-dose EPO treatment also contributes to the high mortality and morbidity rates of patients diagnosed with CKD (18,19). Thus, it is important to determine the associations among FGF23, 1,25(OH)2D, EPO and HIFs to identify novel therapeutic targets for the treatment of CKD-mineral bone disorder (MBD) and renal anemia, and improve the prognosis of these patients. The present review aimed to discuss the associations among FGF23, iron, EPO and HIFs in CKD-MBD.
2. Clinical perspective
Iron deficiency, induced by overproduction of EPO or activation of HIFs, upregulates FGF23 expression and is associated with adverse events in patients with CKD (8). Thus, it is important to identify interventions that downregulate FGF23 expression to correct iron deficiency and improve patient outcomes.
A total of 79 single nucleotide polymorphisms (SNPs) in 29 genes are associated with CKD-MBD (20). Among these, five SNPs (rs1126616, rs35068180, rs1800247, rs4236 and rs2248359) are in proteins involved in mineral metabolism (osteocalcin, osteopontin, Gla protein matrix metalloprotease 3, and 24 hydroxylase), which may be responsible for upregulating FGF23 expression (20). A Previous study has demonstrated that FGF23 expression closely parallels plasma EPO expression, either from administration of exogenous EPO or increased production of endogenous EPO, induced by HIF-PHIs (12).
The present review compares the induction of FGF23 expression by EPO administration and HIF-PHIs, and discusses optimal therapeutic regimens for CKD-related anemia and MBD. EPO is associated with an increase in the inactive form of FGS23, C-terminal (c)FGF23, which can result in adverse events (21). Thus, the biological activity of cFGF23 requires further investigation.
3. FGF23 and iron deficiency
Regulation of FGF23 by iron deficiency
Iron functions as a cofactor in several enzymatic reactions and a critical component of hemoglobin, which is required for normal oxygen transport (22). Several factors can cause iron deficiency and anemia, including pregnancy (23), poor diet (24-26), inflammation (27,28), iron malabsorption (29,30) and CKD (31,32). A study on patients with CKD reported an association between low iron levels and high cFGF23 expression levels (33). Recently, Eisenga et al (34) confirmed that iron deficiency is associated with high serum FGF23 levels in patients with CKD and kidney transplant recipients (9,34). Molecular studies have reported that iron deficiency upregulates furin by stabilizing HIF1-α, which subsequently cleaves FGF23 into cFGF23 fragments (6,35,36). Furthermore, Eisenga et al (37) demonstrated that increased FGF23 levels mediate the association between iron deficiency and mortality. Iron deficiency, as a crucial determinant of FGF23 expression, can also occur during blood loss from trauma, surgery and bowel dysfunction (38,39). Rabadi et al (11) observed that acute bleeding elevated cFGF23 expression in healthy mice, and that the number of transfusions was positively associated with cFGF23 expression in patients in intensive care. It has also been demonstrated that GalNac-transferase 3 bone marrow mRNA expression decreases in mice following acute blood loss, which protects intact (i)FGF23 from proteolysis by furin, and thus enhances FGF23 cleavage (40). These findings regarding the regulation of FGF23 via iron deficiency are consistent with previous studies (35,36). However, a recent study reported that iFGF23 expression has a significantly negative association with serum iron parameters in elderly men (41). Presumably, certain age-related factors may affect the cleavage of FGF23 in individuals with iron deficiency.
Previous studies have demonstrated that iron deficiency increases cFGF23 expression, and that iFGF23 expression may remain normal due to FGF23 cleavage (42). However, the factors that affect FGF23 cleavage remain unclear. In particular, the functions of cleaved fragments in patients with CKD, such as cFGF23, remain largely unknown.
Impact of iron supplementation on FGF23
The physiological mechanisms underlying the association between increased FGF23 expression and mortality are presented in Fig. 1. FGF23 can directly induce left ventricular hypertrophy and eventually lead to heart failure, during which time oxidative stress enhances, the level of nitric oxide decreases and vasodilatation is impaired. FGF23 can increase the extent of vascular calcification and risk of cardiovascular disease. Vascular calcification may promote dysregulation of bone mineral metabolism, aggravate anemia and inflammatory response, and contribute to the progression of CKD. In addition, FGF23 increases the likelihood of cancer and mortality risk, and these factors may interact with one another. For example, inflammation may affect vasodilatation by promoting vascular calcification directly or indirectly through bone and mineral metabolism disorder. Anemia aggravates heart failure by increasing left ventricular hypertrophy, and aggravates mineral metabolism disorder. Conversely, bone mineral metabolism disorder and inflammation further promote the occurrence of anemia (43). Given the effect of elevated FGF23 expression on mortality and other pathophysiological outcomes (44-51), it is important to understand the pathways and molecular mechanisms underlying elevated FGF23 expression. As a major determinant of FGF23, iron deficiency can be easily modified to decrease FGF23 expression. Thus, the potential therapeutic benefits of iron supplementation should be considered. A previous study reported the effect of iron supplementation on elevated iFGF23 expression in two patients with osteomalacia (52). Currently, two major iron formulations are used as supplements, oral iron and intravenous (IV) iron. Patients with early-stage (non-dialysis) CKD often receive oral iron supplementation as treatment for iron deficiency and mild anemia. Clinicians administer IV iron to circumvent gastrointestinal intolerance and improve treatment efficacy, particularly in patients with late-stage CKD who are receiving hemodialysis (53).
A prospective randomized study assessed the use of oral iron and IV iron for 10 weeks as treatment for patients with CKD who were receiving hemodialysis and had iron-deficiency anemia. Serum cFGF23 levels decreased in both groups, while serum iFGF23 levels increased in the IV iron group (54). These findings suggest that oral iron is superior to IV iron in preventing high iFGF23 expression levels. However, the majority of patients with CKD also received EPO or EPO-stimulating agents, the effects of which were not compared between both groups. Thus, whether EPO administration affects the iFGF23/cFGF23 ratio remains unclear.
Hyperphosphatemia, due to decreased phosphate secretion, is significantly associated with CKD progression. Thus, researchers have developed several novel phosphate binders as treatment (55). Sucroferric oxyhydroxide effectively decreases serum phosphorus levels (56) and simultaneously improves iron parameters (57). Notably, serum FGF23 levels markedly decrease following treatment with sucroferric oxyhydroxide in patients with CKD undergoing hemodialysis (58). Ferric citrate, another iron-based phosphate binder, efficiently decreases serum phosphorus levels (59) and notably improves iron parameters (60), while simultaneously decreasing serum FGF23 levels in patients with CKD undergoing hemodialysis (61). Thus, concurrent reduction of serum phosphorus levels and correction of iron deficiency may be used to effectively decrease iFGF23 expression.
Taken together, these findings suggest that elevated serum FGF23 levels contribute to high mortality in patients with CKD. The correction of iron deficiency, a major determinant of elevated FGF23 expression, can reverse high FGF23 expression levels. Clinical studies have indicated that oral iron is superior to IV iron. Iron-based phosphate treatment, which simultaneously decreases phosphorus levels and corrects iron deficiency, may be used to decrease serum FGF23 levels and improve the long-term outcomes of these patients.
4. FGF23 and EPO
FGF23 and recombinant (rh)EPO administration
EPO is a hematopoietic hormone that is primarily produced by the kidneys as a physiological response to iron deficiency (62). Iron deficiency and anemia are co-morbidities in CKD (63) that promote renal function decline (64). There are several causes of iron deficiency in CKD, but reduced EPO synthesis is the main factor (65). Thus, clinicians often administer rhEPO to correct iron deficiency and anemia in these patients (66). However, the effect of rhEPO administration on serum FGF23 levels remains unclear. Previous studies have reported that acute injections of rhEPO significantly increase the expression levels of cFGF23(11) and iFGF23 (10,67) in mice. Conversely, it has been demonstrated that rhEPO injections only increase cFGF23 expression in mice with CKD (68). Notably, these observed effects were independent of iron status. Studies on patients with chronic heart failure and CKD have reported that exogenous EPO injections markedly increase cFGF23 expression (69,70). The potential reasons for these differences may be attributed to the differences in renal functions of patients and/or the dose of rhEPO used. A previous study demonstrated that high cFGF23 expression competes with iFGF23 by binding to the FGF receptor, thereby decreasing iFGF23 expression (71). Another study on adult rats reported that in vitro treatment with cFGF23 increases the surface area of ventricular myocytes (72). Thus, it is important to identify which specific fragments of FGF23 are responsible for its effect on mortality. Prospective studies are required to assess the biological activity of different FGF23 fragments, and the effects of rhEPO replacement treatment on FGF23 expression in patients with CKD.
FGF23 and HIFs
HIFs are proteins that regulate transcription in response to low cellular oxygen levels. HIF prolyl-hydroxylase (PHD) regulates HIFs in an oxygen-dependent manner (73). HIFs are heterodimers composed of an α subunit and β subunit; HIF-α is oxygen-sensitive and stabilized due to decreased PHD-dependent hydroxylation during hypoxia (74-76). HIF-PHI stabilizes HIFs by stimulating hypoxia, thereby activating HIF signaling, inducing the transcription of endogenous EPO (77), promoting iron uptake and availability (78), and further influencing FGF23 expression (8,79,80). The HIF-PH inhibitor, roxadustat, has been used as an oral drug for the treatment of anemia (81). This drug increases FGF23 production, suggesting that HIF-PHI may affect FGF23 expression and cleavage by inducing the transcription of endogenous EPO (80). Generally, FGF23 produced by osteocytes is affected by the level of phosphate, parathyroid hormone and 1,25(OH)2D (82). However, a recent study reported that other factors may regulate FGF23 production and cleavage, including iron, HIF and EPO signaling (83). Recent data have demonstrated that FGF23 expression may be directly regulated by HIF signaling in osteogenic cells, or indirectly regulated by EPO (12,82). Another study reported that treatment with HIF-PHI increases FGF23 expression (8). Examinations of the underlying molecular mechanism have demonstrated that inflammation or iron deficiency induce HIF-1α (8), and that binding of HIF-1α to the FGF23 promoter increases its synthesis in osteogenic cells (84). In addition, HIF-1α may also indirectly increase FGF23 expression by inducing EPO, thus promoting FGF23 transcription and cleavage (10-12,68,85). It has been reported that interleukin-6 and tumor necrosis factor-α levels are induced during CKD, indicating a general microinflammatory state in patients with CKD (86). FGF23 bioactivity and anti-inflammatory cytokine expression are abnormal in patients with CKD, which may be associated with the widespread microinflammatory state (87).
Low 1,25(OH)2D expression is associated with nutritional deficiency or endogenous resistance of EPO in patients with CKD, and often contributes to anemia (88). However, these associations are not affected by inflammatory status or secondary hyperparathyroidism (89). 1,25(OH)2D3 upregulates HIF in PMA-differentiated U937 cells, which is inhibited by rapamycin, suggesting that mTOR signaling is also involved in this process (90).
Administrating an anti-EPO antibody abrogates the effect of EPO on upregulation of FGF23(91). This confirms that HIF-PHI increases FGF23 expression by induction of EPO (8). Notably, the majority of FGF23 induced via endogenous EPO following treatment with HIF-PHI is cFGF23, instead of iFGF23 (8,12). However, the pathological significance of increased expression levels of cFGF23 fragments remains unclear. Normal plasma iFGF23 levels are maintained in spite of increased FGF23 expression due to increased cleavage of iFGF23(35). HIF-PHI efficiently induces erythropoiesis due to upregulation of endogenous EPO, but because the EPO level remains near the normal physiological range this treatment is superior to traditional rhEPO administration for treatment of renal anemia (92). Thus, clinicians should consider the use of HIF-PHI as a novel treatment strategy for renal anemia. A recent study reported that iFGF23 expression is not associated with rhEPO dose in hemodialysis patients (93). However, some unrecognized confounders may affect the measurement of FGF23 during CKD, which require further investigation in future studies.
5. Conclusions
In conclusion, iron deficiency, mediated by HIF1α and EPO, independently increases FGF23 expression and promotes the cleavage of FGF23, which is dependent on age and renal function. HIF-PHI induces the transcription of endogenous EPO, although EPO remains within its normal physiological range, and it also affects FGF23 expression and cleavage (12). Further studies are required to determine how endogenous or exogenous EPO increases FGF23 expression and affects FGF23 cleavage. Generally, endogenous EPO levels are elevated during early-stage CKD (94), exogenous EPO is typically administered to patients with late-stage CKD due to the presence of renal anemia, and FGF23 cleavage may decrease as renal function declines (95,96). iFGF23 is considered the bioactive form, and high cFGF23 expression is associated with poor prognosis in patients with CKD (17,69). Future studies are required to determine the biological activities of the C-terminal fragments of FGF23. The compensatory increase in FGF23 expression during the early stages of CKD may enhance urinary phosphate excretion, which may be beneficial to patients with CKD. The induction of FGF23 expression by EPO administration or HIF-PHIs may provide therapeutic regimens for the treatment of patients with CKD. In addition, the potential therapeutic benefits of iron supplementation should be considered, particularly in early-stage CKD with iron deficiency and mild anemia. However, the continuous increase in FGF23 expression during late stages of CKD may aggravate CKD-MBD and promote CKD-related anemia (97). A recent study suggested that blockade of FGF23 signaling prevents renal anemia in a murine model of CKD (21). Future studies must consider the complex molecular and physiological interactions that occur during renal anemia and CKD-MBD to develop novel therapeutic interventions.
Acknowledgements
Not applicable.
Funding
Funding: The present review was supported by Jilin Province Technology and Science Department (grant no. 20200201366JC).
Availability of data and materials
Not applicable.
Authors' contributions
JBZ designed the present study and performed the literature review. RZ drafted the initial manuscript. SYW and FY analyzed the physiopathological mechanisms . SM, XL and CK contributed to the interpretation of the molecular mechanisms. All authors have read and approved the final manuscript. Data sharing is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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