European Journal of Cardiovascular Medicine

“Chronic kidney disease (CKD)” is a global public health crisis impacting millions of individuals. People with CKD are at heightened risk for emerging “end- stage renal disease (ESRD)”, cardiovascular complications, and early mortality.^[1] CKD affects approximately 10% of the population globally and is associated with increased cardiovascular morbidity and mortality.^[2] CKD is defined by kidney damage or an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m², lasting for three months or longer, regardless of the underlying cause.^[3] One of the critical biomarkers in the context of CKD is fibroblast growth factor 23 (FGF23), the bone-derived hormone that plays a crucial role in regulating phosphate balance by acting on the kidneys to enhance urinary phosphate excretion and suppress vitamin D activation. In subjects with CKD, “serum FGF23” levels are markedly elevated and closely correlate with serum creatinine and phosphate levels. Notably, serum FGF23 levels begin to rise early in CKD progression, before increases in serum phosphate levels, making elevated serum FGF23 a potential early indicator of mineral metabolism disturbances in CKD patients. ^[4] FGF23 plays a pivotal role in phosphate metabolism and vitamin D regulation, and raised levels of FGF23 have been associated to adverse cardiovascular outcomes, including arterial stiffness and mortality in CKD patients. ^{[5, 6]}

Arterial stiffness, commonly assessed by measuring pulse wave velocity (PWV), is an independent predictor of cardiovascular events and is often exacerbated in patients with CKD. ^[7] The relationship between elevated FGF23 levels, decreased eGFR, and increased arterial stiffness has garnered significant research interest. Several studies have indicated that higher serum FGF23 levels correlate with

declining kidney function and increased arterial stiffness, signifying that FGF23 may serve as a potential biomarker for cardiovascular risk in CKD patients. ^{[8, 9]} Despite these findings, the precise mechanisms by which FGF23 influences arterial stiffness and its interplay with eGFR remain poorly understood. Therefore, this study aims to examine the correlation of serum FGF23 levels with eGFR and arterial stiffness in CKD patients.

An Observational cross-sectional study was conducted at OPD and IPD of the DR. D.Y Patil Medical College Hospital and Research Institute, Kolhapur for 2 years after institutional ethical committee approval. A total of 56 patients satisfying the below-mentioned inclusion and exclusion criteria were involved in the study.

Inclusion criteria: Age > 18 years, both genders, CKD stages 3, 4 and 5.

Exclusion criteria: Known case of ischemic heart disease, Acute Kidney injury on CKD, Malignancy, known cases of Peripheral vascular disease- Buerger’s disease, Raynaud's disease, Sepsis, known case of any Allergic inflammation, Patients on drugs that can increase blood pressure (Amphetamines, MAO inhibitors, SNRI, TCA, Sympathomimetic, OCPs, Systemic Corticosteroids) Extreme old age (age > 85 years).

Patients who met the inclusion and exclusion criteria were recruited for the study, and written informed consent was obtained from each participant. The eGFR was calculated using the Cockcroft-Gault formula: {((140–age) x weight) / (72 x SCr)} x 0.85 for females. Arterial stiffness was assessed through parameters provided by a diabetes risk profiler, with all findings documented in the case record form (CRF). To further evaluate arterial stiffness, measurements were taken for the Ankle Brachial Index (ABI), Augmentation Index (AIX), and PWV.

PWV Measurement using SphygmoCor Tonometry Carotid to femoral PWV measurements, measured in the supine position after at least 5 minutes of rest.

Pulse waveforms from the Right Carotid & Right Femoral arteries are captured for 10 seconds. The mechanism by which high PWV leads to CKD progression is likely attributable to an increment in the propagation of energy in pulsatile flow wave into the low resistance kidneys. Loss of autoregulation on blood flow, which results in exacerbation of pulsatile energy transmission, damage to glomerular vasculature as progressive loss of kidney function.

ABI Measurement using standard Mercury Sphygmomamometer-

ABI = Highest SBP Posterior tibial artery or Dorsalis pedis artery Highest Brachial SBP

ABI Interpretation

> 1.4- Calcification/ Vessel hardening 1.0-1.4- Normal

0.9-1.0- Acceptable

0.8-0.9- Some Arterial Disease

0.5-0.8- Moderate Arterial Disease

<0.5- Severe Arterial Disease

FGF 23 was estimated using an ELISA test kit

Age

The mean age of the study subjects was 62.39±5.54 years. The majority of the study participants were in the age group of 66 to 70 years, accounting for 39.29% of the total population. This was followed by 21.43% of participants in the age group of 61 to 65 years. The 51–55 years and 56–60years age groups each comprised 19.64% of the participants

Sex

Among the 56 patients included in the study, 39 (69.64%) were male and 17 (30.36%) were female.

Patient characteristics

The mean weight of the patients was 72.09 ± 6.38 kg, and the mean height was 166.00

± 7.72 cm, indicating a relatively uniform body habitus across the cohort. The average duration of diabetes mellitus (DM) was 10.38 ± 3.45 years, while the average duration of hypertension (HTN) was 12.79 ± 3.31 years, suggesting a long-standing history of comorbid conditions that are known contributors to CKD progression. The mean serum creatinine level was 3.59 ± 1.51 mg/dL, reflecting moderate to advanced renal impairment in the study group. In terms of blood pressure, the mean systolic blood pressure (SBP) was 132.93 ± 16.59 mmHg and the mean diastolic blood pressure (DBP) was 77.70 ± 13.38 mmHg (Table 1).

Table 1: Patient characteristics

Stages of CKD

The eGFR among study subjects was found to be 27.42±11.75 mL/min/1.73m2. Out of 56 patients, the majority were in Stage IV CKD, comprising 24 patients (42.86%), followed closely by 22 patients (39.29%) in Stage III CKD. A smaller proportion, 10 patients (17.86%), were in Stage V CKD (Table 4 and Graph 5).

Table 2: Distribution of stages of CKD

Study variables

The mean serum FGF-23 level was 368.98 ± 295.75 pg/mL, indicating considerable variability among the patients. The mean PWV, a marker of arterial stiffness, was

10.70 ± 2.38 m/s, suggesting increased vascular stiffness in the study population. The ABI had a mean value of 0.99 ± 0.19. The AIx, another measure of arterial stiffness and wave reflection, had a mean value of 25.53 ± 10.48% (Table 3).

Table 3: Distribution of study variables

ABI interpretation

In the present study, ABI was found to be <0.90 in 66.07% (n = 37) of the patients, which is diagnostic of peripheral arterial disease (PAD), indicating a high prevalence of peripheral vascular involvement. Borderline ABI values (0.90–0.99) were observed in 5.36% (n = 3) of the participants, suggesting the presence of early or subclinical arterial disease. Only 28.57% (n = 16) of the patients exhibited normal ABI values (1.0–1.4), reflecting intact peripheral perfusion (Table 4).

Table 4: Distribution of ABI interpretation.

Comparison of FGF 23 according to CKD stages

In patients with Stage III CKD, the mean FGF-23 level was 70.29 ± 14.41 pg/mL. This value rose sharply to 433.82 ± 93.52 pg/mL in Stage IV, and further escalated to

870.59 ± 53.34 pg/mL in Stage V CKD. There was significant association between EGF 23 and CKD stages (P<0.001) (Table 5).

Table 5: Comparison of EGF 23 according to CKD stages

Correlation between eGFR and FGF 23

A statistically significant strong negative correlation was observed between eGFR and serum FGF-23 levels (r = -0.811, P < 0.001). This indicates that as eGFR decreases, FGF-23 levels increase substantially (Table 6 and Graph 1).

Table 6: Correlation between eGFR and FGF 23

Graph 1: Correlation between eGFR and EGF 23

Comparison of PWV according to CKD stages

The mean PWV, a validated marker of arterial stiffness, showed a progressive increase across advancing stages of CKD, with the association being statistically significant (P < 0.001). Patients in Stage III CKD demonstrated a mean PWV of 9.62 ± 1.38 m/s, which increased to 10.68 ± 2.25 m/s in Stage IV, and further to 13.15 ± 2.80 m/s in Stage V CKD (Table 7).

Table 7: Comparison of PWV according to CKD stages

Correlation between eGFR and PWV

A statistically significant moderate negative correlation was observed between eGFR and PWV in patients with CKD (r = -0.450, P < 0.001). This indicates that as renal function declines, arterial stiffness—as measured by PWV—increases (Table 8 and Graph 2).

Table 8: Correlation between eGFR and PWV

Graph 2: Correlation between eGFR and PWV

Comparison of ABI according to CKD stages

Patients in Stage III CKD had a mean ABI of 1.03 ± 0.22, while those in Stage IV and Stage V had mean ABI values of 0.95 ± 0.95 and 1.05 ± 1.05, respectively. Although there were numerical differences across CKD stages, the variation was not statistically significant (P = 0.270) (Table 9).

Table 9: Comparison of ABI according to CKD stages

Correlation between eGFR and ABI

In the present study, the correlation between eGFR and ABI was found to be very weak and statistically non-significant (r = 0.065, P = 0.632). This suggests that there is no meaningful linear association between renal function and ABI values in the studied CKD population (Table 10 and Graph 3).

Table 10: Correlation between eGFR and ABI

Graph 3: Correlation between eGFR and ABI

Comparison of Alx according to CKD stages

The AIx, a surrogate marker of arterial stiffness and wave reflection, showed a statistically significant increase across the stages of CKD (P = 0.011). Patients in Stage III CKD had a mean AIx of 22.26 ± 8.62%, which increased to 26.42 ± 9.94% in Stage IV, and further to 32.84 ± 11.82% in Stage V CKD (Table 11)

Table 11: Comparison of Alx according to CKD stages

Correlation between eGFR and Alx

A statistically significant negative correlation was observed between eGFR and AIx in patients with CKD, with a correlation coefficient of r = -0.302 (P = 0.024). This indicates that as renal function declines, there is a corresponding increase in AIx, reflecting greater arterial stiffness and wave reflection (Table 14 and Graph 4).

Table 12: Correlation between eGFR and Alx

Graph 4: Correlation between eGFR and Alx

CKD is a progressive clinical condition characterized by gradual loss of renal function, often accompanied by cardiovascular complications including arterial stiffness and vascular calcification. In this study, we explored the relationship between serum FGF-23, arterial stiffness (as measured by PWV and AIx), and eGFR in patients with CKD.

The average age of participants in this study was 62.39 ± 5.54 years, aligning with prior research that highlights CKD as more prevalent among older adults. This trend is likely due to age-associated nephron loss and the cumulative impact of comorbidities such as diabetes and hypertension. ^[10] A majority of the study population were male (69.64%), reflecting patterns commonly reported in CKD epidemiology worldwide. ^[11]

The mean eGFR was 27.42 ± 11.75 mL/min/1.73 m², indicating that most subjects had moderate to advanced kidney impairment. Stage IV CKD accounted for the largest proportion of patients (42.86%), followed by Stage III (39.29%) and Stage V (17.86%). Mean serum fibroblast growth factor-23 (FGF-23) concentrations rose markedly with progressive CKD severity, ranging from 70.29 pg/mL in Stage III to

870.59 pg/mL in Stage V. This pronounced escalation of FGF-23 levels in parallel with declining kidney function is consistent with earlier findings by Isakova et al. ^[12] and Faul et al. ^[6], who demonstrated that FGF-23 elevations occur early in CKD and show a strong inverse association with eGFR. In the current study, this relationship was statistically robust (r = –0.811, P < 0.001), confirming a significant negative correlation.

Arterial stiffness, as measured by PWV, also showed a progressive increase across CKD stages. The mean PWV rose from 9.62 m/s in Stage III to 13.15 m/s in Stage V, with a statistically significant trend (P < 0.001). This is consistent with the findings of London et al. ^[103] and Townsend RR et al. ^[14] who have demonstrated that arterial stiffness is exacerbated by CKD-related mineral bone disorders and systemic inflammation. The moderate negative correlation between eGFR and PWV (r = - 0.450, P < 0.001) observed in our study further substantiates this association.

The ABI, used to detect PAD, was below 0.90 in 66.07% of participants, pointing to a substantial prevalence of subclinical PAD among individuals with CKD. Although ABI values differed across CKD stages, these differences were not statistically significant (P = 0.270). Additionally, the correlation between ABI and eGFR was weak and did not reach statistical significance (r = 0.065, P = 0.632), suggesting that ABI may have limited sensitivity for identifying vascular changes directly linked to declining renal function. These observations are partly consistent with work by Ix et al. ^[15], who documented ABI abnormalities in CKD but also emphasized its limited role in early detection of vascular pathology in this group.

The AIx, which reflects arterial stiffness and wave reflections, demonstrated a significant upward trend with advancing CKD (P = 0.011). AIx values rose from 22.26% in Stage III to 32.84% in Stage V CKD and showed a modest inverse correlation with eGFR (r = –0.302, P = 0.024). This pattern supports the idea that progressive kidney dysfunction is associated with increased arterial wave reflections, likely attributable to greater vascular calcification and hemodynamic alterations. These findings align with previous studies by Liu JJ et al. ^[16] and Liew Y et al. ^[17], which also identified AIx as a valuable non-invasive measure of arterial stiffness and vascular aging in CKD patients.

Taken together, the data indicate a triad of declining kidney function (as shown by lower eGFR), rising serum FGF-23 concentrations, and worsening arterial stiffness (both PWV and AIx) as CKD progresses. This underscores the mechanistic link between disturbances in mineral metabolism, exemplified by elevated FGF-23, vascular dysfunction, and renal impairment. Elevated FGF-23 emerges not only as a marker of worsening kidney function but also as a possible contributor to vascular calcification and increased arterial stiffness, thereby heightening cardiovascular risk in this population. ^[18]

Despite these insights, certain limitations—such as the modest sample size, cross-sectional study design, and lack of longitudinal follow-up—limit the ability to draw causal inferences. Nonetheless, the strong statistical associations observed here offer persuasive evidence of the interconnections among FGF-23, eGFR, and arterial stiffness in CKD.

This study demonstrates a significant inverse relationship between serum FGF-23 levels and eGFR in patients with CKD, indicating that FGF-23 levels rise markedly as renal function declines. Furthermore, measures of arterial stiffness, including PWV and AIx, were found to increase significantly with advancing stages of CKD, and both showed a negative correlation with eGFR. Although a high prevalence of peripheral artery disease was observed through ABI, its correlation with eGFR was not statistically significant. Overall, the study highlights FGF-23 as a potential early biomarker for both kidney function deterioration and vascular dysfunction, underscoring its clinical utility in risk stratification and early intervention in CKD patients.

1. Wolf Update on fibroblast growth factor 23 in chronic kidney disease. Kidney international. 2012 Oct 1;82(7):737-47.
2. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R, Wang AY, Yang CW. Chronic kidney disease: global dimension and perspectives. The Lancet. 2013 Jul 20;382(9888):260-72.
3. Vaidya SR, Aeddula NR. Chronic kidney disease. InStatPearls [Internet] 2022 Oct StatPearl Publishing. Accessed from: https://www.ncbi.nlm.nih.gov/books/NBK535404/. Accessed on: 19/10/2024.

4. Natsuki Y, Morioka T, Kakutani Y, Yamazaki Y, Ochi A, Kurajoh M, Mori K, Imanishi Y, Shoji T, Inaba M, Emoto M. Serum Fibroblast Growth Factor 23 Levels are Associated with Vascular Smooth Muscle Dysfunction in Type 2 Diabetes. Journal of Atherosclerosis and Thrombosis. 2023 Dec 1;30(12):1838-48.
5. Gutiérrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Jüppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. New England Journal of Medicine. 2008 Aug 7;359(6):584-92.
6. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutiérrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P. FGF23 induces left ventricular hypertrophy. The Journal of clinical investigation. 2011 Oct 10;121(11).
7. Pickup L, Radhakrishnan A, Townend JN, Ferro CJ. Arterial stiffness in chronic kidney disease: a modifiable cardiovascular risk factor?. Current opinion in nephrology and hypertension. 2019 Nov 1;28(6):527-36.
8. Papagianni A. Fibroblast Growth Factor-23: a novel biomarker for cardiovascular disease in chronic kidney disease patients. prilozi. 2017 Sep 1;38(2):19-27.
9. Coban M, Inci A, Yılmaz U, Asilturk E. The association of fibroblast growth factor 23 with arterial stiffness and atherosclerosis in patients with autosomal dominant polycystic kidney disease. Kidney and Blood Pressure Research. 2018 Jul 31;43(4):1160-73.
10. Hsu JJ, Katz R, Ix JH, de Boer IH, Kestenbaum B, Shlipak MG. Association of fibroblast growth factor-23 with arterial stiffness in the Multi-Ethnic Study of Atherosclerosis. Nephrology Dialysis Transplantation. 2014 Nov 1;29(11):2099-105.
11. Alderson HV, Chinnadurai R, Ibrahim ST, Asar O, Ritchie JP, Middleton R, Larsson A, Diggle PJ, Larsson TE, Kalra PA. Longitudinal change in c- terminal fibroblast growth factor 23 and outcomes in patients with advanced chronic kidney disease. BMC nephrology. 2021 Dec;22:1-7.
12. Isakova T, Wahl P, Vargas GS, Gutiérrez OM, Scialla J, Xie H, Appleby D, Nessel L, Bellovich K, Chen J, Hamm L. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney international. 2011 Jun 2;79(12):1370-8.
13. London GM, Marchais SJ, Guerin AP, Pannier B. Arterial stiffness: pathophysiology and clinical impact. Clinical & Experimental Hypertension. 2004 Oct 1;26.
14. Townsend RR, Anderson AH, Chirinos JA, Feldman HI, Grunwald JE, Nessel L, Roy J, Weir MR, Wright Jr JT, Bansal N, Hsu CY. Association of pulse wave velocity with chronic kidney disease progression and mortality: findings from the CRIC Study (Chronic Renal Insufficiency Cohort). Hypertension. 2018 Jun;71(6):1101-7.
15. Ix JH, Katz R, De Boer IH, Kestenbaum BR, Allison MA, Siscovick DS, Newman AB, Sarnak MJ, Shlipak MG, Criqui MH. Association of chronic kidney disease with the spectrum of ankle brachial index: the CHS (Cardiovascular Health Study). Journal of the American College of Cardiology. 2009 Sep 22;54(13):1176-84.
16. Liu JJ, Liu S, Lee J, Gurung RL, Yiamunaa M, Ang K, Shao YM, Choo RW, Tavintharan S, Tang WE, Sum CF. Aortic pulse wave velocity, central pulse pressure, augmentation index and chronic kidney disease progression in individuals with type 2 diabetes: a 3-year prospective BMC nephrology. 2020 Dec;21:1-9.
17. Liew Y, Rafey MA, Allam S, Arrigain S, Butler R, Schreiber M. Blood pressure goals and arterial stiffness in chronic kidney disease. The Journal of Clinical Hypertension. 2009 Apr;11(4):201-6.
18. Heine GH, Seiler S, Fliser D. FGF-23: the rise of a novel cardiovascular risk marker in CKD. Nephrology Dialysis Transplantation. 2012 Aug 1;27(8):3072-81.