Introduction

Arterial thickness and calcification are a sequential process of arterial remodeling that occurs in response to chronic diseases, injuries, or aging, and leads to arterial stiffness1,2. Several mechanisms were involved in this sequential process, such as the following: (1) First, fibrosis and hyperplasia take place in arterial intima and media layers along with vascular smooth muscle cell (VSMC) migration and proliferation, which contributed to arterial thickness1; after that, (2) nucleation of calcium phosphate, extracellular matrix calcification, and increase arterial tone arise due to VSMC differentiation from the contractile to the secretory phenotype, which contributed to arterial calcification1,3,4, and then (3) loss of arterial wall elasticity occurs due to both previous processes that lead to arterial stiffness2,5. This sequential process may lead to various cardiovascular events, including myocardial infarction6, myocardial remodeling7, hypertension8, atherosclerosis8, stroke6, and chronic kidney disease9, which will eventually increase cardiovascular morbidity and mortality rates10,11,12. Moreover, this complex pathophysiology that started from arterial remodeling involves several proteins13. These proteins may become potential biomarkers and early prevention tools for cardiovascular events. Two of the most extensively studied proteins are Klotho and fibrovascular growth factor-23 (FGF-23), and both proteins were lately known to form the FGF-23/Klotho axis in arterial remodeling14,15.

FGFs compose a large family of proteins that affect development, organogenesis, and metabolism16. FGF-23 has been established as a novel biomarker involved in the development of cardiovascular diseases17. It is an endocrine hormone primarily released by osteocytes and plays a role in phosphate and vitamin D metabolism. FGF-23 regulates serum phosphate levels by downregulating sodium-phosphate cotransporter expression in the lumen of the proximal kidney tubules, further stimulating phosphaturia. FGF-23 also reduces the systemic levels of 1,25-dihydroxyvitamin D by inhibiting 1-α hydroxylase in the kidneys and stimulating the catabolic effects of 24-hydroxylase. Other actions include inhibiting the synthesis and secretion of parathyroid hormones17,18. The integrated effects of FGFs are mediated by their binding to FGF receptors (FGFRs), and recent studies have reported that this signaling requires Klotho proteins18,19.

Klotho proteins are a group of transmembrane proteins consisting of the following: α-Klotho, β-Klotho, and γ-Klotho protein16. They directly bind to multiple FGFRs to form Klotho-FGFR-complex, that are essentially required for the high-affinity binding of FGFs to their receptors20. Before the discovery of its homolog protein (β-Klotho), α-Klotho was also known as Klotho (which will be referred to hereinafter), and it serves as the obligate co-receptor for FGF-23. The expression of Klotho is downregulated by FGF-2319. Klotho is also present in the blood and urine in a soluble circulating form, which has been implicated in regulating endothelial integrity, permeability, and nitric oxide (NO) production21.

FGF-23 is expressed and secreted directly to the blood plasma by the bone, which then downregulates Klotho expression and followed by a reduction in Klotho soluble form generated by the proteolytic cleavage on the cell surface22,23. In an animal study, the deficiency of either FGF-23 or Klotho exhibited an impairment in the calcium phosphate metabolism and contributed to FGF-23/Klotho-mediated vascular calcification11, along with arterial thickness and stiffness22. However, the involvement of the FGF-23/Klotho axis in arterial calcification, thickness, or stiffness still needs to be elucidated whether or not it acts directly on human arteries and VSMCs. Although many studies focused on the connection between FGF-23 and Klotho on arterial calcification, thickness, and stiffness, but these studies are still controversial. Some studies showed significant correlation between FGF-23 or Klotho and arterial calcification/thickness/stiffness24,25,26, while some others did not27,28,29. Intriguingly, some other studies showed results different with theories, in which FGF-23 was inversely correlated with arterial pathologies30, but Klotho was positively correlated31. To the best of our knowledge, no meta-analyses have investigated the role of Klotho and FGF-23 in arterial remodeling, which prompted us to conduct a meta-analysis to establish their roles and prove their involvement in arterial calcification, thickness, and stiffness.

Methods

This review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines32. The systematic review had been registered on PROSPERO (Registration no. CRD42021269744).

Searching strategy

An electronic search was conducted on PubMed, Web of Science, EBSCO/CINAHL, Scopus, and Science Direct for articles up to December 2023. To limit the effect of publication bias, the gray literature was also searched for related articles, as database search alone is insufficiently rigorous. A mixture of Medical Subject Heading terms and free text were used to construct search terms using the following concepts: “Klotho,” “FGF-23,” “vascular calcification,” and “vascular stiffness.” The full search strategies are presented in Supplemental Table 1.

Eligibility criteria

A PECO framework was employed to determine the study’s eligibility criteria, as shown below:

  • Patients: Patients with arterial calcification, thickness, or stiffness. Arterial calcification was validated using a calcification score, arterial thickness was measured by the carotid intima–media thickness (CIMT), and arterial stiffness was assessed by the pulse wave velocity (PWV).

  • Exposure: Klotho or FGF-23 levels.

  • Comparison: None.

  • Outcomes: Calcification score, CIMT, or PWV.

The inclusion criteria were as follows: (1) studies reporting the association of Klotho or FGF-23 level with arterial calcification, thickness, or stiffness; (2) measurement of arterial calcification, thickness, or stiffness used standard quantitative score; (3) English language; (4) observational study design; (5) human participants; and (6) reporting data in numerical values. The exclusion criteria were as follows: (1) review articles, cross-sectional studies, case reports, case series, and meta-analysis; (2) duplicated studies; (3) studies with incomplete or insufficient data; (4) abstract only or conference paper; and (5) insufficient data.

Study selection and data extraction

Mendeley Desktop version 1.19.8 (Elsevier, Mendeley Ltd.) was used to remove duplicates and filter the studies. The extracted data were as follows: first author, publication year, country, sample size, age, study design, affected artery, diagnostic method, specified population, correlation coefficient (r), beta coefficient, odds ratio (OR) with 95% confidence intervals (CIs), and Klotho, or FGF-23 levels in groups with or without arterial calcification. Continuous data in the form of median and range were converted to mean and standard deviation by the method of Hozo et al.33. Beta coefficients were converted to ORs using exp(beta)34. In the case that data required for meta-analysis were not sufficient or not clearly reported in the paper, we contacted the authors.

Searching, study selection, and data extractions were independently conducted by two researchers (CDKW and CP) using a pre-specified form tabulated within the spreadsheet, and all data extraction tables were validated by two other researchers (HS and MYA). Quality assessments were performed independently by two researchers (BSW and APW) who used the Newcastle–Ottawa scale (NOS) for observational studies (cohort, case–control, and cross-sectional studies) to assess information bias, selection bias, and confounding. Studies with scores of 7–9, 4–6, and 0–3 were considered to have high, moderate, and low quality, respectively. Any conflicts or disagreements were resolved by discussion to achieve consensus.

Statistical analysis

Each Spearman or Pearson correlation coefficient (r) was converted to a Z-value via Fisher’s transformation, which was approximately normally distributed35,36. The standard error of Z was calculated, and Z-values were converted via inverse Fisher’s transformation to generate r and 95% CI. The extracted ORs with 95% CIs were pooled to generate the overall adjusted ORs. Pooled standardized mean difference (SMD) and 95% CI were generated to analyze the difference in the Klotho or FGF-23 level between groups with and without arterial calcification.

The chi-squared test and I2 statistics was used to determine heterogeneity across studies. All analyses were pooled using a random-effects model. Sensitivity analysis was performed to guarantee the consistency of the results by omitting several factors that could influence the results (e.g., children and population aside from chronic kidney disease [CKD]). A one-leave-out sensitivity analysis was also performed by removing individual studies. If substantial heterogeneity occurred, subgroup analysis was employed to find the sources of heterogeneity. Publication bias was assessed visually through funnel plot asymmetry. In all analyses, a p-value of < 0.05 was considered statistically significant. Review Manager 5.4 (Cochrane Collaboration, London, UK) was used for this meta-analysis.

Results

Study characteristics

The PRISMA flow diagram of the study selection process is shown in Fig. 1. In total, 51,534 eligible studies were documented from the searched electronic databases. Of the total articles, 31,039 were removed using automation filter tools from each database. Then, 2369 were removed for being duplicates, leaving 18,126 articles for further evaluation. Subsequently, 17,872 articles were excluded based on their titles and abstracts, whereas 254 papers were sought for retrieval. Another 22 articles were rejected for being conference abstracts and posters or having unavailable full-texts, leaving 232 articles for full-text article review. After full-text evaluation, 176 studies were further excluded because of irrelevant outcomes, incomplete data, non-English language, irrelevant study design, and similar study/sample. In addition, 22 extra records were identified from the website and reference list search. After judging the eligibility of the reports, 16 articles were excluded due to irrelevant outcomes, incomplete data, and similar study/sample. Ultimately, 62 articles were included in this meta-analysis.

Figure 1
figure 1

PRISMA flow diagram of the literature search.

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Sixty-two publications, involving 27,459 participants, were eligible according to the inclusion and exclusion criteria. The primary features of the included studies are shown in Table 1. All included studies had an observational study design. In terms of continental regions, the majority of these 62 studies are from Asia (n = 29), including China (n = 12), followed by Europe (n = 16), America (n = 8), Africa (n = 8), and Australia (n = 1). Most studies have adult participants (aged ≥ 18 years), except for three studies involving children and adolescents. The majority of the participants had CKD (n = 46). Most of the studies had cross-sectional designs (n = 50), whereas the rest were cohort and case–control studies (n = 11 and n = 1, respectively). The measured arteries varied, with mostly focused on coronary, aorta, and carotid arteries. The arterial calcification score was measured either with computed tomography (CT) or X-ray imaging, except for the studies by Milovanova37 and Di Lullo38 which used echocardiography. On the contrary, CIMT, and PWV were mostly measured by ultrasonography. According to the sample for FGF-23/Klotho measurement, all studies used blood sample, either in the form of plasma or serum. Forty-eight studies used serum sample, while the rest used plasma. Most FGF-23/Klotho used enzyme-linked immunoassay (ELISA) method, except for one study which used Luminex and one study did not mention the method used. Four studies did not mention the ELISA kit used. Among ELISA kit used for FGF-23 analysis, Immunotopics were used the most (36%), followed by Kainos (30%), Elabscience (8%), and Millipore (6%). As for Klotho analysis ELISA kit, Immuno-Biological Laboratories were mostly used (50%), followed by Cusabio (27.78%).

Table 1 Characteristics of the included studies.
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Among the studies, sixteen24,25,30,31,39,40,41,42,43,44,45,46,47,48,49,50 reported correlations between the FGF-23 level and the calcification score, eight29,51,52,53,54,55,56,57 reported correlations between the FGF-23 level and the CIMT, and five29,47,51,58,59 reported correlations between the FGF-23 level and the PWV. Regarding Klotho, eight studies26,31,37,38,47,60,61,62 reported correlations between the Klotho level and the calcification score and five studies63,64,65,66,67 reported correlations between the Klotho level and the CIMT. For the regression analysis, seven studies30,38,39,47,48,49,68 reported an association between the FGF-23 level and arterial calcification in the linear regression model and ten studies24,27,31,69,70,71,72,73,74,75 reported an association between the FGF-23 level and arterial calcification in the logistic regression model. For continuous data, twenty studies25,30,45,48,68,70,72,74,75,76,77,78,79,80,81,82,83,84,85,86 reported a difference in FGF-23 levels between the group with and without arterial calcification, four87,88,89,90 reported a difference in FGF-23 levels between groups with arterial thickness, and three63,88,89 reported a difference in Klotho levels between groups with arterial thickness.

Quality assessment

The quality of the 62 included studies was assessed using the NOS, which was suitable for each study design. Among those studies, only one study46 was considered to have low quality, 33 as moderate quality, and 28 as high quality. The quality assessment of each study using the NOS critical appraisal checklist is listed in Tables S3–S5.

Correlations between FGF-23 levels and arterial calcification

In sixteen studies, a moderate correlation was found between the FGF-23 level and arterial calcification [pooled r = 0.446 (0.254–0.611), p < 0.0001] (Fig. 2A). After sensitivity analysis by including CKD-only population (all in severe stage), cross-sectional study design, diagnosis of arterial calcification by CT, and high-quality studies, the results did not change much. However, when we perform sensitivity analysis for suspected coronary artery disease (CAD) only and diagnosis of arterial calcification by X-rays, the pooled correlations were given by r = 0.207 (CI = 0.1–0.31, n = 2, p-value 0.0002) and r = 0.282 (CI = 0.02–0.508, n = 5, p-value = 0.03), respectively. The correlation remains statistically significant at the 5% significance level, but the pooled r is lower than the correlation in the previous pooled analysis. In addition, we did not conduct sensitivity analysis for adults only since all studies regarding correlations between FGF-23 levels and arterial calcification score took adults patients only.

Figure 2
figure 2

Forest plot of the pooled r for the correlation between: (A) FGF-23 level and arterial calcification; (B) FGF-23 level and CIMT; (C) FGF-23 level and PWV; (D) Klotho level and arterial calcification; (E) Klotho level and CIMT. All analyses are pooled using a random-effects model.

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Correlation between the FGF-23 level and the CIMT or PWV

Eight studies reported a weak correlation between the FGF-23 level and CIMT. In the pooled analysis, the FGF-23 level positively correlated with CIMT [pooled r = 0.188 (0.02–0.354), p = 0.03] (Fig. 2B). Analysis of the correlation between the FGF-23 level and PWV also showed a significant positive correlation [pooled r = 0.235 (0.159–0.310), p < 0.00001] (Fig. 2C), in which all included studies involved CKD patients. The sensitivity analysis excluded children and included studies with severe CKD-only; however, the results were still consistent.

Correlation between the Klotho level and arterial calcification or CIMT

In contrast to FGF-23, an inverse correlation was found between the Klotho level and arterial calcification [pooled r = − 0.388 (− 0.578 to − 0.159), p = 0.001] (Fig. 2D). However, after including high-quality studies in the analysis, the pooled r changed [− 0.159 (− 0.264 to − 0.05), p = 0.005] along with reduced heterogeneity (47%). A significant negative correlation was also found between the Klotho level and CIMT [pooled r = − 0.38 (− 0.53 to − 0.207), p < 0.00001] (Fig. 2E). After including studies with the CKD-only population and high-quality studies only, the results remained stable. A meta-analysis for the correlation between the Klotho level and PWV was not performed as there was not enough number of studies that reported the correlation.

Association between the FGF-23 and arterial calcification

Seven studies have reported ORs/beta and CIs for the association between the FGF-23 level and arterial calcification generated using multivariate linear regression, and nine reported using a logistic regression model. The extracted effectors in the original studies were generated after adjustment for important confounders including age, sex, estimated glomerular filtration rate, minerals (Ca/P), smoking, dialysis vintage, albumin, sclerostin, parathyroid hormone, vitamin D, and comorbidities. The pooled aOR was 1.36 (1.09–1.69) (p = 0.006) (Fig. 3A). For the logistic regression for the association between the FGF-23 level and arterial calcification, the pooled aOR was 1.22 (1.07–1.39) (p = 0.003) (Fig. 3B). In the sensitivity analysis that included CKD-only population and high-quality studies only, the results remained stable for both linear and logistic regression models. We did not perform pooled aOR analysis for Klotho due to limited data and varied concept of analysis between studies.

Figure 3
figure 3

Forest plot of the pooled OR for the association between: (A) FGF-23 level and arterial calcification in linear regression model and (B) FGF-23 level and arterial calcification in logistic regression model. All analyses are pooled using a random-effects model.

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FGF-23 level in groups with arterial calcification and arterial thickness

An analysis of pooled SMD was also performed by comparing FGF-23 and Klotho levels between groups with and without arterial calcification. The group with arterial calcification had significantly higher FGF-23 levels than the group without arterial calcification [pooled SMD = 0.6 (0.36–0.84), p < 0.00001] (Fig. 4A). After conducting sensitivity analysis by including CKD-only population, measurement of calcification by the Agatston score or Kauppila index only, coronary artery only, and high-quality studies only, the results remained consistent. In subgroup analysis, the results of studies involving mild to moderate CKD only and severe CKD only also yielded consistent results. By comparing FGF-23 level difference between the groups with and without arterial thickness, the FGF-23 level was also significantly higher in the group with arterial thickness [pooled SMD = 1.26 (0.36–2.17), p = 0.006] (Fig. 4B).

Figure 4
figure 4

Forest plot of the pooled SMD for: (A) FGF-23 level in calcification/no calcification groups; (B) FGF-23 level in high CIMT/low CIMT groups; (C) Klotho level in calcification/no calcification groups; (D) Klotho level in high CIMT/low CIMT group. All analyses are pooled using a random-effects model.

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Klotho level in groups with arterial calcification and arterial thickness

Two studies68,84 have reported Klotho level differences between the groups with and without arterial calcification. However, a significant difference in Klotho levels was not found between the two groups [pooled SMD = − 0.04 (− 0.33 to 0.24), p = 0.76] (Fig. 4C). Meanwhile, a significantly lower Klotho level was found in the group with arterial thickness [pooled SMD = − 1.63 (− 3.11 to − 0.15), p = 0.03] (Fig. 4D). Sensitivity analysis revealed that the study by Castelblanco et al.88 had a significant effect on heterogeneity. After removing this study, the pooled SMD was − 2.27 (− 2.82 to − 1.72) (p < 0.00001), and the I2 was 49%. All analyses are summarized along with their sensitivity analyses in Table 2 for FGF-23 and Table 3 for Klotho.

Table 2 Summary of meta-analysis of FGF-23 with each sensitivity analysis.
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Table 3 Summary of meta-analysis of Klotho with each sensitivity analysis.
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Publication bias

Publication bias analysis using Funnel plot (Supplementary materials) indicates no publication bias for most analyses, except for pooled aOR of association between FGF-23 and arterial calcification in the linear regression model. However, after the study by Lee et al.48 was removed as an outlier, the funnel plot yielded a more symmetrical distribution without changing the pooled analysis. For analyses with a small number of included studies, publication bias analysis was not performed since the funnel plot and Egger’s test are not recommended for less than 10 studies91.

Discussion

To the best of our knowledge, this study is the first meta-analysis that establishes the association of protein FGF-23 and Klotho with arterial calcification, thickness, and stiffness, and includes thorough sensitivity analyses. Our study indicates a significant positive correlation between FGF-23 and arterial calcification, CIMT, and PWV, and significant negative correlation between Klotho and arterial calcification and CIMT. FGF-23 and Klotho were also associated with arterial calcification. FGF-23 level was significantly higher in the groups with arterial calcification or thickness than in the group without arterial calcification or thickening. Furthermore, a significantly lower Klotho level was found in the arterial thickness group, not in the arterial calcification group, because only two studies were analyzed in the latter group.

As stated before, arterial thickness, calcification, and stiffness is a sequential process of arterial remodeling1,2,3,4,5. This sequential process is affected by the FGF-23/Klotho axis14,15. Although Klotho itself mainly acts as the cofactor of FGF-23, its expression is downregulated by FGF-2319,92. In the case of vascular Klotho deficiency, FGF-23 may induce the phenotype switching of contractile VSMCs to synthetic VSMCs mediated by FGF receptor-1 (FGFR-1) and Erk1/2 phosphorylation along with an increase in proliferation, which further induces thickening, and stiffening of the arterial wall93. This was confirmed in our study, which showed higher FGF-23, and lower Klotho levels in the arterial remodeling process. FGF-23 and Klotho also have contradictory effects on NO production. Klotho may revert the FGF-23-induced vasoconstriction by increasing NO production to dilate the arteries93,94. Furthermore, atherosclerotic plaques that reside in the arterial wall show a stronger FGFR signaling in response to FGF-23 and a lower expression of contractile VSMC phenotype95. The stronger FGFR signaling can cause further Klotho deficiency caused by FGF-23-induced Klotho downregulation. Interestingly, FGF-23, and Klotho have a unique or special affinity to FGFR-194,96. The binding of Klotho to the principal effector site of FGFR-1 may induce the phosphaturic effects of FGF-23 on the kidney. Thus, the Klotho/FGFR-1/FGF-23 complex in the kidney is an important signaling pathway, either in generating, or counteracting hyperphosphatemia94. Hyperphosphatemia is avoided in this process because of its strong effect on inducing vascular calcification97. Therefore, all of these processes induce arterial remodeling, including vascular calcification, thickening, and stiffening.

Interestingly, the positive effect sizes of FGF-23 in vascular calcification and CIMT were stronger in the CKD-only subgroup analyses than in the overall analyses. Additionally, the pooled correlation between FGF-23 level and CIMT was also stronger in severe CKD only group than in all CKD group, albeit the number of studies was lower. This was further supported by a stronger negative correlation of Klotho to vascular calcification of the CKD-only study population; however, this was not seen in CIMT because only two studies analyzed Klotho in CKD. Despite these findings, we acknowledged that most of our included studies involved CKD patients. One could argue that there might be a tendency toward a significant finding, where higher FGF-23 and lower Klotho levels were associated with the conditions, due to the populations being predominantly CKD. Nevertheless, we observed that this is not utterly the case. For example, in the forest plot of the pooled correlation between FGF-23 and arterial calcification (Fig. 2A), studies with CKD and non-CKD-only populations presented with varying directions of effect sizes. Studies by Cianciolo45 and Nitta30 that included only CKD patients showed a negative direction of effect sizes. Meanwhile, studies by Masai49 and Morita31 showed a positive direction of effect sizes despite including non-CKD populations (suspected CAD patients). This finding was confirmed by our sensitivity analysis including only these two studies which still showed a significant positive effect size, although it was lower than that of the analysis with only CKD patients. In Klotho analyses, we could observe such similar cases, in which studies with non-CKD populations showed a negative direction of effect sizes, i.e., Koga61 and Morita31 in Fig. 2D and Jeong63, Keles64, and Keles65 in Fig. 2E. These findings indicated that FGF-23 and Klotho play important roles as a promoter and inhibitor, respectively98, in both CKD and non-CKD patients, and are not being entirely affected by kidney function status.

We also found a stronger FGF-23–CIMT correlation when two studies including children with CKD were excluded from the analysis. Two reasons could explain this interesting finding. First, despite having CKD, the pediatric populations were still in the growth and development phase, including their vascular thickness. The development of vascular thickness is ongoing throughout life; therefore, the vascular thickness might not be early seen99. Second, the number of children with CKD in the two studies was very limited compared with the number of adult patients in another five studies. Furthermore, the FGF-23–PWV correlation did not change much in the subgroup analyses excluding children and CKD-only participants. An interesting fact was stated by London100; i.e., the result of PWV measurement was age- and blood pressure-dependent. This might not change the correlation strength of FGF-23 and PWV because children and patients with CKD had an individual range of blood pressure.

Despite our findings, this study has four main limitations. First, the definitions, and parameters used for assessing arterial calcification, thickness, and stiffness vary. For example, several studies inappropriately analyzed arterial calcification using CIMT or PWV. CIMT was only designed for measuring the extent of the intimal and medial layers of the carotid arterial wall101, whereas PWV was only designed for measuring velocity and distensibility through the transmitted pulse wave in the arterial system102. Based on the latter statement, both CIMT and PWV did not measure the degree of calcification in the arterial wall, only the extent, and distensibility of the arterial wall, respectively. However, we overcame this limitation by classifying the analyses of calcification, thickness, and stiffness based on the assessment method used in each study: (1) calcification score to determine arterial calcification, (2) CIMT to determine arterial thickness, and (3) PWV to determine arterial stiffness. Second, the heterogeneities among the included studies were appreciable because of several factors, including study design, type of the analyzed artery, assessment process, sample size, age, and population type. We have also performed subgroup analyses to minimize the bias that might be caused by this limitation. We also have tried to explore the cause of the heterogeneity, i.e., measurement method used. However, all sample used blood specimen and almost all study used ELISA method. Hence, the heterogeneity might not likely be caused by the measurement method. Third, there was no detailed data regarding FGF-23 and Klotho levels in each CKD stage. There were limited studies which recruited participants from mild to moderate CKD only, since most included studies used HD or advanced stage CKD as their participants. Nevertheless, we have tried to do subgroup analysis for the available data to minimize this limitation, in which we proved that FGF-23 levels were significantly increased in arterial calcification, either in mild-to-moderate or severe CKD group. Lastly, considering that all included studies had an observational design investigating only associations, the true causality between FGF-23/Klotho and arterial calcification, thickness, and stiffness still cannot be discerned. Moreover, despite of the limitations, this meta-analysis could provide a useful insight on the role of FGF-23 and Klotho in arterial remodeling, since the underlying remodeling process is relatively complex and a unified conclusion is needed. Further research is warranted to establish the role of FGF23 and Klotho in clinical practice. We also suggest preclinical studies to explore further about the exact mechanism of FGF23 and Klotho on arterial remodeling process.

Conclusion

The results of this meta-analysis confirmed the important roles of FGF-23 and Klotho in human arterial calcification, thickness, and stiffness, supporting their use as novel biomarkers for the early detection of arterial remodeling processes. Our study confirms that high FGF-23 levels and low Klotho levels are associated with arterial calcification, thickness, and stiffness, especially in patients with CKD. Despite the current findings, it is important to note that our included studies are mostly involved CKD patients. Hence, we encourage conducting further clinical studies to confirm diagnostic and prognostic roles of FGF-23 and Klotho in various populations, along with preclinical studies to establish the exact mechanism of both markers on arterial remodeling process.