Abstract
Fibroblast growth factor 23 (FGF-23) regulates phosphorus and vitamin D. Elevated FGF-23 is associated with incident hypertension in young and middle-aged adults but there is limited data in older adults. Serum FGF-23 was measured using an intact ELISA assay in 2,496 participants of the Healthy Aging and Body Composition Study. The association between FGF-23 and prevalent hypertension (self-reported and confirmed by use of anti-hypertensive medications) and number of anti-hypertensive medications was determined. The associations between FGF-23 and incident hypertension, and diastolic and systolic blood pressure trajectories were evaluated over 10 years. Models were adjusted for demographics, eGFR and albuminuria, cardiovascular disease risk factors, and measures of mineral metabolism. The mean(SD) age was 75(3) years, with 51% women, and 40% black participants. The prevalence of hypertension at baseline was 75% and the mean systolic and diastolic blood pressures were 134(21) mmHg and 70(12) mmHg, respectively. The majority of participants without hypertension at baseline developed incident hypertension (576 of 1109 or 52%). In adjusted models, each two-fold higher FGF-23 was associated with prevalent baseline hypertension (OR=1.46[1.24,1.73]) and greater number of blood pressure medications (IRR=1.14[1.08,1.21]) but not with baseline diastolic or systolic blood pressure. In fully adjusted longitudinal analyses, a two-fold higher FGF-23 was associated with incident hypertension (HR=1.18[1.03,1.36]) and worsening systolic blood pressures (beta=0.24[0.08,0.40] mmHg per year increase), but not with diastolic blood pressures (beta=0.04[−0.04,0.12] mmHg per year increase). Higher FGF-23 concentrations are associated with prevalent and incident hypertension as well as rising systolic blood pressures in community-living older adults.
Keywords: FGF-23, Hypertension, Systolic Blood Pressure, Diastolic Blood Pressure, Biomarker
Graphical Abstract
Introduction
Fibroblast growth factor 23 (FGF-23), a hormone secreted by bone, regulates both phosphorus balance1 and vitamin D metabolism.2 A rise in FGF-23 is observed very early in the development of chronic kidney disease, presumably to maintain phosphorus homeostasis. Elevated FGF-23 is associated with an increased risk for all-cause and cardiovascular mortality3,4, left ventricular hypertrophy, and end-stage renal disease.5 The pathophysiological mechanisms explaining the link between FGF-23 and excess cardiovascular disease remain unclear.
There is pre-clinical evidence that FGF-23 may influence renal sodium handling, with higher FGF-23 levels resulting in sodium retention and hypertension.6 Fibroblast growth factor 23 may also promote hypertension via a decrease in calcitriol, enhancing activation of the renin-angiotensin system.7 Two previous studies demonstrated an association between FGF-23 and incident hypertension, but these studies included only younger and middle-aged participants.8,9 Given the significant burden of hypertension in older adults, and the observation that FGF-23 concentrations increase with aging10, we sought to determine if elevated FGF-23 appears to contribute to hypertension within this population.
The Health Aging and Body Composition Study (Health ABC), is a large diverse cohort of older-aged well-functioning adults with a decade of longitudinal follow-up. We hypothesized that elevated FGF-23 would be associated with baseline hypertension, incident hypertension, and increasing blood pressure trajectories, independent of kidney function and other measures of mineral metabolism.
Materials and Methods
The data used in this manuscript is publicly available through the National Institute of Aging and can be accessed via the following website: https://healthabc.nia.nih.gov/
Study population
Health ABC is a prospective cohort first assembled in 1997 with a goal of assessing how weight and weight-related health conditions impact age-related physiologic and functional status. The study population consists of 3,075 participants aged 70–79 years at baseline with a balanced number of men and women and was pre-specified to include a significant proportion of black participants (38%). All persons included were determined to be free of disability in activities of daily living and free of functional limitation at baseline. All participants who had measures of FGF-23 at year two (stored samples were not available for testing from the baseline visit) and measures of diastolic and systolic blood pressure (n = 2785) were included in the current study. All participants provided written consent for the study. The study was approved by institutional review boards at each participating institution and meets the requirements of the declaration of Helsinki.
Exposure
FGF-23 was measured using a commercial ELISA that detects the full-length intact peptide (Kainos Laboratories, Japan). Serum samples from the year 2 visit were stored at −70°C and were not thawed until time of analysis. The Kainos FGF-23 assay has a limit of detection of 3 pg/mL. Samples were assayed in batches over two months and the between-batch coefficient of variation was 10.7%.
Outcomes
Systolic and diastolic blood pressures were obtained by trained and certified clinical staff from the right arm using a conventional mercury sphygmomanometer with the participant in a seated position. Prevalent hypertension was defined by study protocol as a participant self-report of a previous physician’s diagnosis of hypertension and was confirmed by documentation of current use of antihypertensive medications (e.g. diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium-channel blockers, and β-blockers). Blood pressure measures were obtained at visit years 2–6, 8, 10 and 11. The type, dose and total number of anti-hypertensive medications was also recorded at each visit. Incident hypertension was defined as a new classification of hypertension in any participant who was not classified with hypertension at baseline using the same hypertension definition defined above.
Covariates
All covariates were obtained at the year two visit since this is the visit that mineral metabolism markers were measured, unless otherwise indicated. Cardiovascular disease (CVD) status was defined as a prior history of coronary artery disease, stroke, or heart failure. Diabetes was defined as use of hypoglycemic agents, self-reported history, fasting plasma glucose level ≥ 126 mg/dL, or 2-hour oral glucose tolerance test result ≥ 200 mg/dL. Urine albumin to creatinine ratio (UACR) was measured at baseline. Smoking was classified as current, past (≥100 lifetime cigarettes), or never. Body mass index (BMI) was determined from height and weight obtained at study enrollment. Urine albumin was measured using a particle-enhanced turbidimetric inhibition immunoassay allowing for direct albumin quantification (Siemens), while urine creatinine was measured by a modified Jaffé method on a clinical chemistry analyzer (Siemens). Cystatin C was measured at baseline, as well as years three and ten from stored frozen serum samples at the Health ABC core laboratory (University of Vermont, Burlington, VT) using a BNII nephelometer (Dade Behring Inc., Deerfield, IL) using a particle-enhanced immunonepholometric assay (N Latex Cystatin C)11. As in prior Health ABC studies12,13, serum cystatin C was used as the primary measure of kidney function rather than serum creatinine as cystatin C measures were calibrated across all samples, whereas there was a shift in the creatinine assay from non-IDMS traceable (baseline) to IDMS traceable during the study (years 3 and 10). Estimated glomerular filtration rate (eGFR) was calculated using a validated cystatin C based estimating equation.14,15 Measures of mineral metabolism including calcium, phosphorus, parathyroid hormone (PTH), 25(OH) Vitamin D and soluble klotho were measured at year two, concurrent with FGF-23 measurement, from frozen stored samples. Intact PTH was measured in EDTA plasma using a two-site immunoradiometric assay kit (N-tact PTHSP; DiaSorin). Serum calcium and phosphorus levels were measured using direct quantitative colorimetric determination (Stanbio Laboratory, Boerne, TX, USA). Serum 25(OH) Vitamin D was measured using a two-step radioimmunoassay (25-Hydroxyvitamin D 125I RIA Kit, DiaSorin, Stillwater, MN, USA) in a laboratory participating in the Vitamin D External Quality Assessment Scheme. Soluble klotho was assayed using a commercially available sandwich ELISA test (IBL-International, Japan) from never-thawed frozen serum.
Statistical Analysis
We examined baseline characteristics of participants across quartiles of FGF-23. These were summarized with means and standard deviations, or medians and interquartile ranges (IQR) for highly skewed variables or proportions for categorical variables. For eGFR and UACR, we also included the proportion of participants in each quartile below or above clinically relevant cut points (eGFR < 60 ml/min/1.73m2, UACR > 30 mg/g).
FGF-23 and cross-sectional outcomes
Multivariable linear regression models were used to assess the relationships between FGF-23 and baseline continuous diastolic and systolic blood pressure. For all subsequent analyses, FGF-23 was examined as both a continuous variable (log base 2, so that interpretation would be “per two-fold higher” of the exposure) and categorized by quartiles. Multivariable models were then sequentially constructed through a series of nested models using pre-specified variables as follows: Model 1: unadjusted; Model 2: adjusted for age, sex, and race; Model 3: additionally adjusted for diabetes, CVD, smoking status, BMI, estimated GFR and urine ACR; Model 4: additionally adjusted for calcium, phosphorus, 25(OH) Vitamin D, and PTH. For prevalent hypertension at baseline, logistic regression models with the same pre-specified covariate structures were constructed. We also examined the relationship between FGF-23 and the number of baseline blood pressure medications using Poisson regression (expressed as incident rate ratios), also using the same model structure.
FGF-23 and longitudinal outcomes
Multivariable Cox proportional hazards models following the same covariate structure as described above were used to assess the relationship between FGF-23 and incident hypertension. Notably, participants with hypertension at baseline were excluded from these analyses. To examine the association between FGF-23 and blood pressure trajectories over time, random effects mixed models were used. For these models, the reported beta coefficient reflects the mean difference in blood pressure each year per two-fold higher FGF-23.
Interactions
Based on a priori hypotheses that a synergistic relationship could potentially exist between FGF-23 and age, race (black vs white), diabetes, and CKD status (baseline eGFR < 60 ml/min/1.73m2) we evaluated if the association between FGF-23 and blood pressure was modified by each of these factors by including interaction terms in the final multivariable models. Post-analysis, we also subsequently evaluated sex as a potential modifier of the association between FGF-23 and each outcome by including an interaction term.
Sensitivity Analyses
As blood pressure measures were also available to determine the presence of hypertension, we also defined hypertension using an expanded definition which included in the following: systolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90 mm Hg, and/or self-reported physician’s diagnosis of hypertension and current use of antihypertensive medications.
Additionally, with the publication of the results from the Systolic Blood Pressure Intervention Trial16, there is now greater uncertainty as to the exact blood pressure cutoffs that constitute a diagnosis of hypertension. As such, we performed a sensitivity analysis in which incident hypertension was defined as a systolic blood pressure ≥ 130 mm Hg, diastolic blood pressure ≥ 80 mm Hg, or current use of antihypertensive medications and a self-reported physician’s diagnosis of hypertension. Finally, as there is some preliminary evidence that soluble klotho may influence blood pressure17,18 and that soluble klotho concentrations are inversely related to FGF-23 concentrations19, we re-ran the fully adjusted models with the addition of soluble klotho as a covariate.
Analyses were conducted using SPSS (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp.) and Stata (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP). A two sided p value of < 0.05 was considered statistically significant for all analyses including interaction terms.
Results
Baseline Characteristics
Among 3,075 persons, 288 participants did not have sample available for FGF-23 measurements, while 2 were missing values for systolic blood pressure at baseline, leaving 2785 with complete data available for analysis. At baseline, 2102 (75%) participants had a diagnosis of hypertension, leaving 683 individuals for analyses of incident hypertension. The mean (SD) age was 75 (3) years, with 51% female, and 40% black (Table 1). The median FGF-23 level was 46 pg/mL (37 – 60 (25th – 75th percentile)). The mean (SD) systolic blood pressure was 134 mmHg (21) and the mean diastolic blood pressure was 70 (12). The mean baseline eGFR was 72 (18) ml/min/1.73m2 and 25% of participants had a baseline eGFR of less than 60 ml/min/1.73m2.
Table 1.
Baseline Demographics and Clinical Characteristics by Quartiles of FGF-23
| Variable | Full cohort | Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 |
|---|---|---|---|---|---|
| N | 2785 | 697 | 696 | 696 | 696 |
| FGF-23 Range (pg/mL) | 1.4–1615.8 | 1.4 – 36.7 | 36.8 – 46.6 | 46.7 – 60.1 | 60.2 – 1615.8 |
| Age (years) | 75 ± 3 | 75 ± 3 | 75 ± 3 | 75 ± 3 | 75 ± 3 |
| Female | 1424 (51%) | 387 (56%) | 359 (52%) | 327 (47%) | 351 (50%) |
| Black | 1106 (40%) | 305 (44%) | 261 (38%) | 259 (37%) | 281 (40%) |
| Diabetes | 1027 (37%) | 229 (33%) | 250 (36%) | 261 (38%) | 287 (41%) |
| Hypertension | 2102 (75%) | 459 (66%) | 503 (72%) | 543 (78%) | 597 (86%) |
| Anti-hypertensive medication use | |||||
| ARB | 97 (4%) | 18 (3%) | 19 (3%) | 21 (3%) | 39 (6) |
| Calcium channel blockers | 661 (24%) | 146 (21%) | 152 (22%) | 177 (26%) | 186 (24%) |
| Thiazide diuretic | 545 (20%) | 107 (15%) | 117 (17%) | 139 (20%) | 182 (26%) |
| Coronary Artery Disease | 497 (18%) | 95 (14%) | 107 (16%) | 133 (19%) | 162 (24%) |
| Heart Failure | 33 (1%) | 3 (0.4%) | 3 (0.4%) | 3 (0.4%) | 24 (4%) |
| Cerebrovascular Disease | 193 (7%) | 54 (8%) | 36 (5%) | 48 (7%) | 55 (8%) |
| SBP (mmHg) | 134 ± 21 | 133 ± 20 | 133 ± 20 | 133 ± 21 | 135 ± 23 |
| DBP (mmHg) | 70 ± 12 | 70 ± 12 | 70 ± 12 | 71 ± 12 | 71 ± 12 |
| BMI (kg/m2) | 27.2 ± 4.8 | 26.6 ± 4.6 | 26.8 ± 4.7 | 27.4 ± 4.7 | 28.0 ± 5.1 |
| Smoking | |||||
| Former | 1282 (46%) | 293 (42%) | 339 (49%) | 318 (46%) | 332 (48%) |
| Total cholesterol (mg/dL) | 206 ± 39 | 206 ± 38 | 208 ± 40 | 203 ± 38 | 205 ± 40 |
| C-reactive protein (mg/L) | 2.97 [1.25, 6.44] | 2.89 [1.22, 6.04] | 2.73 [1.12, 6.08] | 2.81 [1.24, 6.13] | 3.50 [1.46, 8.02] |
| eGFR (ml/min/1.73m2) | 72 ± 18 | 77 ±17 | 77 ± 17 | 72 ± 17 | 64 ± 20 |
| eGFR < 60 ml/min/1.73m2 | 682 (25%) | 108 (16%) | 121 (17%) | 170 (25%) | 283 (41%) |
| UACR (mg/g) | 8 [4, 19] | 7 [4, 16] | 7 [4, 16] | 7 [3, 18] | 10 [5, 31] |
| UACR ≥ 30 mg/g | 482 (18%) | 91 (13%) | 99 (14%) | 118 (17%) | 174 (26%) |
| Calcium (mg/dL) | 8.9 ± 0.4 | 8.8 ± 0.4 | 8.8 ± 0.4 | 8.9 ± 0.4 | 8.9 ± 0.5 |
| Phosphorus (mg/dL) | 3.6 ± 0.5 | 3.5 ± 0.4 | 3.5 ± 0.5 | 3.5 ± 0.5 | 3.6 ± 0.5 |
| Parathyroid hormone (pg/ml) | 34 [25, 46] | 32 [24, 42] | 31 [24, 41] | 34 [26, 46] | 39 [28, 56] |
| 25(OH) Vitamin D (ng/mL) | 26 ± 11 | 24 ± 12 | 26 ± 10 | 27 ± 11 | 27 ± 12 |
| klotho (pg/mL) | 683.1 (325.7) | 710.0 (352.2) | 700.8 (354.4) | 679.6 (307.1) | 642.0 (279.3) |
Presented as mean (SD), median [25th-75th percentile], or % as appropriate.
FGF-23 = Fibroblast Growth Factor 23, SBP = systolic blood pressure, DBP = diastolic blood pressure, BMI = body mass index, UACR = urine albumin to creatinine ratio, eGFR = estimated glomerular filtration rate based on cystatin C
Across quartiles of FGF-23, participants in the highest quartile were more likely to have comorbid conditions such as diabetes, coronary artery disease, and heart failure. In addition, those in the highest quartile had lower baseline eGFR, were more likely to have a spot urine ACR > 30 mg/g and had higher serum calcium, phosphorus, and PTH concentrations. There were no observed differences in age, sex, smoking status, or prevalence of black race by quartile of FGF-23.
FGF-23 and cross-sectional outcomes
Higher FGF-23 was not associated with baseline systolic or diastolic blood pressure across all models (Table 2). Higher FGF-23 was associated with greater odds of prevalent hypertension, which was only slightly attenuated after adjustment for demographics, comorbidity, kidney function, and other mineral metabolism markers (fully adjusted OR = 1.46 [1.24, 1.73] per two-fold higher FGF-23). Similarly, in quartile analyses, as compared to the lowest quartile, the highest quartile of FGF-23 was associated with the greatest odds of prevalent hypertension (fully adjusted OR = 2.33 [1.73, 3.14]) (Table 3). Higher FGF-23 was also associated with a greater number of blood pressure medications (fully adjusted IRR = 1.14 [1.08, 1.21] per two-fold higher and IRR = 1.37 [1.22, 1.54] for the highest quartile vs. the lowest quartile). (Table 3)
Table 2.
Association of FGF-23 with systolic and diastolic blood pressure
| FGF-23 | N | Model 1 | Model 2 | Model 3 | Model 4 |
|---|---|---|---|---|---|
| β (95% CI) | β (95% CI) | β (95% CI) | β (95% CI) | ||
| Systolic BP | |||||
| FGF-23 (per 2 fold higher) | 2785 | 0.75 (−0.41, 1.92) | 0.90 (−0.25, 2.04) | −0.22 (−1.41, 0.98) | −0.23 (−1.46, 1.01) |
| FGF-23 Quartiles | |||||
| < 36 | 697 | 0 (ref) | 0 (ref) | 0 (ref) | 0 (ref) |
| 36 -- 46 | 696 | −0.23 (−2.48, 2.02) | 0.15 (−2.07, 2.37) | 0.06 (−2.19, 2.20) | −0.03 (−2.22, 2.16) |
| 47 -- 60 | 696 | −0.13 (−2.37, 2.12) | 0.36 (−1.86, 2.59) | −0.32 (−2.53, 1.89) | −0.45 (−2.68, 1.79) |
| > 60 | 696 | 1.64 (−0.61, 3.89) | 1.82 (−0.41, 4.04) | 0.04 (−2.24, 2.32) | −0.02 (−2.37, 2.33) |
| Diastolic BP | |||||
| FGF-23 (per 2 fold higher) | 2785 | 0.21 (−0.44, 0.87) | 0.30 (−0.34, 0.94) | −0.01 (−0.68, 0.66) | −0.41 (−1.10, 0.29) |
| FGF-23 Quartiles | |||||
| < 36 | 697 | 0 (ref) | 0 (ref) | 0 (ref) | 0 (ref) |
| 36 -- 46 | 696 | −0.32 (−1.58, 0.95) | −0.10 (−1.34, 1.14) | −0.19 (−1.43, 1.04) | −0.38 (−1.61, 0.84) |
| 47 -- 60 | 696 | 0.25 (−1.02, 1.52) | 0.48 (−0.76, 1.73) | 0.22 (−1.02, 1.47) | −0.28 (−1.52, 0.97) |
| > 60 | 696 | 0.23 (−1.04, 1.50) | 0.41 (−0.83, 1.66) | −0.08 (−1.37, 1.20) | −0.85 (−2.17, 0.46) |
Model 1 = unadjusted analysis.
Model 2 = adjusted for age, sex, and race
Model 3 = M2 + diabetes, cardiovascular disease, eGFR, UACR, BMI and smoking.
Model 4 = M3 + calcium, phosphorus, 25(OH) Vitamin D and PTH
Table 3.
Association of FGF-23 with prevalent hypertension and number of BP medications(N = 2785)
| Prevalent HTN | Model 1 | Model 2 | Model 3 | Model 4 | |
|---|---|---|---|---|---|
| # with Prevalent HTN | OR (95% CI) | OR (95% CI) | OR (95% CI) | OR (95% CI) | |
| FGF-23 (per 2 fold higher) | 2102 | 1.67 (1.45, 1.94) | 1.74 (1.50, 2.03) | 1.52 (1.29, 1.79) | 1.46 (1.24, 1.73) |
| FGF-23 Quartiles | |||||
| < 36 | 459 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| 36 -- 46 | 503 | 1.34 (1.06, 1.68) | 1.40 (1.11, 1.77) | 1.45 (1.13, 1.85) | 1.43 (1.12, 1.83) |
| 47 -- 60 | 543 | 1.80 (1.42, 2.30) | 1.92 (1.50, 2.45) | 1.76 (1.36, 2.28) | 1.67 (1.28, 2.17) |
| > 60 | 597 | 3.13 (2.39, 4.10) | 3.26 (2.48, 4.28) | 2.49 (1.87, 3.33) | 2.33 (1.73, 3.14) |
| Baseline BP meds | % with 3 or more meds | IRR (95% CI) | IRR (95% CI) | IRR (95% CI) | IRR (95% CI) |
| FGF-23 (per 2 fold higher) | 8% | 1.26 (1.20, 1.33) | 1.27 (1.21, 1.32) | 1.17 (1.11, 1.23) | 1.14 (1.08, 1.21) |
| FGF-23 Quartiles | |||||
| < 36 | 6% | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| 36 -- 46 | 6% | 1.03 (0.91, 1.17) | 1.05 (0.93, 1.18) | 1.04 (0.92, 1.17) | 1.02 (0.91, 1.16) |
| 47 -- 60 | 8% | 1.25 (1.11, 1.41) | 1.29 (1.15, 1.45) | 1.22 (1.08, 1.36) | 1.19 (1.06, 1.33) |
| > 60 | 14% | 1.60 (1.43, 1.78) | 1.63 (1.46, 1.82) | 1.42 (1.27, 1.59) | 1.37 (1.22, 1.54) |
Model 1 = unadjusted analysis.
Model 2 = adjusted for age, sex, and race
Model 3 = M2 + diabetes, cardiovascular disease, eGFR, UACR, BMI, and smoking
Model 4 = M3 + calcium, phosphorus, 25(OH) Vitamin D and PTH
FGF-23 and longitudinal outcomes
Fifty-two percent of individuals (576 of 1109) without hypertension at baseline developed hypertension during follow-up for an incident rate of 8% per year (Table 4). There was a significant association between FGF-23 and incident hypertension that remained similar across all models (fully adjusted HR = 1.18 [1.03, 1.36]). When examining the change in blood pressure over time, higher FGF-23 was associated with higher systolic blood pressure (0.24 [0.08, 0.40] mmHg higher systolic blood pressure per year for each two-fold higher of FGF-23) but not with change in diastolic blood pressure. (Table 5) When analyses were restricted to those without hypertension at baseline, similar results were seen (0.30 [0.02, 0.58] mmHg higher systolic blood pressure per year for each two-fold higher of FGF-23).
Table 4.
Association FGF-23 with Incident Hypertension
| N | # with incident HTN | incidence rate | Model 1 | Model 2 | Model 3 | Model 4 | |
|---|---|---|---|---|---|---|---|
| (%/yr) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | |||
| FGF-23 (per 2 fold higher) | 1109 | 576 | 7.82 | 1.23 (1.08, 1.39) | 1.21 (1.07, 1.38) | 1.18 (1.03, 1.35) | 1.18 (1.03, 1.36) |
| FGF-23 Quartiles | |||||||
| < 36 | 350 | 166 | 6.62 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| 36 -- 46 | 313 | 152 | 6.98 | 1.08 (0.86, 1.35) | 1.05 (0.84, 1.32) | 1.04 (0.83, 1.30) | 1.04 (0.83, 1.31) |
| 47 -- 60 | 259 | 138 | 8.38 | 1.23 (0.97, 1.54) | 1.20 (0.95, 1.52) | 1.17 (0.92, 1.48) | 1.17 (0.92, 1.49) |
| > 60 | 187 | 120 | 11.61 | 1.80 (1.42, 2.29) | 1.78 (1.40, 2.26) | 1.67 (1.31, 2.14) | 1.69 (1.31, 2.18) |
Model 1 = unadjusted analysis.
Model 2 = adjusted for age, sex, and race
Model 3 = M2 + diabetes, cardiovascular disease, eGFR UACR, BMI, and smoking.
Model 4 = M3 + calcium, phosphorus, 25(OH) Vitamin D and PTH
Table 5.
Association of FGF-23 with systolic and diastolic blood pressure trajectories
| Annualized absolute change in SBP | |||||
|---|---|---|---|---|---|
| Model 1 | Model 2 | Model 3 | Model 4 | ||
| N | β (95% CI) | β (95% CI) | β (95% CI) | β (95% CI) | |
| FGF-23 (per 2 fold higher) | 2785 | 0.14 (−0.01, 0.29) | 0.16 (0.01, 0.31) | 0.20 (0.05, 0.35) | 0.24 (0.08, 0.40) |
| FGF-23 Quartiles | |||||
| < 36 | 697 | 0 (ref) | 0 (ref) | 0 (ref) | 0 (ref) |
| 36 -- 46 | 696 | −0.10 (−0.35, 0.15) | −0.09 (−0.34, 0.16) | −0.09 (−0.34, 0.16) | −0.07 (−0.32, 0.19) |
| 47 -- 60 | 696 | 0.05 (−0.20, 0.31) | 0.10 (−0.15, 0.36) | 0.10 (−0.16, 0.36) | 0.16 (−0.10, 0.42) |
| > 60 | 696 | 0.11 (−0.15, 0.37) | 0.14 (−0.12, 0.40) | 0.21 (−0.06, 0.48) | 0.30 (0.02, 0.58) |
| Annualized absolute change in DBP | |||||
| Model 1 | Model 2 | Model 3 | Model 4 | ||
| FGF-23 (per 2 fold higher) | 2785 | 0.00 (−0.08, 0.08) | 0.00 (−0.07, 0.08) | 0.02 (−0.06, 0.10) | 0.04 (−0.04, 0.12) |
| FGF-23 Quartiles | |||||
| < 36 | 697 | 0 (ref) | 0 (ref) | 0 (ref) | 0 (ref) |
| 36 -- 46 | 696 | −0.06 (−0.19, 0.08) | −0.06 (−0.19, 0.07) | −0.07 (−0.20, 0.06) | −0.06 (−0.19, 0.07) |
| 47 -- 60 | 696 | −0.06 (−0.19, 0.07) | −0.05 (−0.19, 0.08) | −0.05 (−0.19, 0.08) | −0.01 (−0.15, 0.12) |
| > 60 | 696 | −0.01 (−0.14, 0.13) | −0.01 (−0.14, 0.13) | 0.04 (−0.10, 0.18) | 0.09 (−0.06, 0.23) |
Model 1 = unadjusted analysis.
Model 2 = adjusted for age, sex, and race
Model 3 = M2 + diabetes, cardiovascular disease, eGFR, UACR, BMI, and smoking
Model 4 = M3 + calcium, phosphorus, 25(OH) Vitamin D and PTH
Interactions
No significant interactions were noted between FGF-23 and age, diabetes, and CKD status with each cross-sectional outcome (all p values > 0.05). Similarly, no interactions were found between FGF-23, age, diabetes, and CKD with incident hypertension (all p values > 0.05). We observed an interaction between FGF-23, race, and the outcomes of prevalent hypertension and number of BP meds at baseline (p value = 0.03 for prevalent hypertension and p value = 0.04 for number of BP meds). Subsequent stratified analyses by race demonstrated a stronger relationship between FGF-23 and both outcomes (Prevalent hypertension OR = 1.90 [1.42, 2.54] for black participants vs OR = 1.33 [1.09, 1.62] for white participants and Number of BP meds IRR = 1.19 [1.09, 1.31] in black participants vs IRR = 1.11 [1.03, 1.19] for white participants). We also observed a significant interaction between FGF-23, sex, and diastolic blood pressure trajectory, but not for any of the other outcomes (p value = 0.03 for diastolic BP trajectories; p > 0.05 for all other outcomes). Stratified analyses by sex showed that in men, two-fold higher FGF-23 was associated with rising diastolic BP over time (0.17 mmHg higher DBP per year [0.04, 0.30]) but in women there was no relationship between FGF-23 and change in diastolic BP (−0.05 mmHg change in DBP per year [−0.16, 0.06]).
Sensitivity Analyses
Using the expanded hypertension definition including BP measures, there was no association between two-fold higher FGF-23 and incident hypertension (HR = 1.00 [0.84, 1.19]). When incident hypertension was re-defined by a blood pressure of ≥ 130/80 mmHg, FGF-23 was similarly not associated with incident hypertension (OR = 0.91 [0.70, 1.18]) (Supplement Tables S1 & S2). Finally, the addition of soluble klotho to all models resulted in no change to either the point estimates or confidence intervals of each model.
Discussion
In this cohort of community dwelling older adults, higher FGF-23 was associated with some but not all measures of hypertension. Participants with higher FGF-23 were more likely to have prevalent hypertension, a greater number of blood pressure medications at baseline, incident hypertension and rising systolic blood pressure trajectories over time. These associations were independent of cardiovascular and kidney disease risk factors as well as other markers of mineral metabolism. In contrast, there were no associations seen between FGF-23 and incident hypertension when including BP measures or with diastolic blood pressure trajectories. However, we do note that when examining for sex differences, there was an observed interaction between FGF-23 and diastolic BP trajectory such that for men only, higher FGF-23 was associated with rising diastolic BP. Overall, our study provides evidence that FGF-23 is related to hypertension in older adults. These findings are consistent with two previous studies of FGF-23 and hypertension in young and middle aged adults, each of which found independent associations of FGF-23 and incident hypertension.8,9
There are at least two pathophysiologic reasons why elevations in FGF-23 may be associated with hypertension. First, high FGF-23 concentrations suppress 1-alpha hydroxylase activity, resulting in lower production of calcitriol, the activated form of vitamin D.20 Low calcitriol increases kidney renin production and thus activates the renin-angiotensin-aldosterone system leading to hypertension.21 Ultimately, such activation can potentially lead to progression of kidney disease, further increases in FGF-23 levels, and continued activation of this feedback loop. FGF-23 may also influence sodium handling in the kidney independent of the renin-angiotensin-aldosterone system. Experimental studies in rodents indicate that FGF-23 directly regulates sodium reabsorption via the distal tubule sodium/chloride co-transporter NCC.22 Multiple experimental methods to raise FGF-23 levels all similarly led to increased distal sodium reabsorption, volume expansion, and hypertension. Unfortunately, given the observational nature of this study, and due to the lack of availability of intermediary biomarkers such as renin or aldosterone, we are unable to provide additional insight as to the possible mechanism of action by which FGF-23 may promote hypertension. We also note that FGF-23 was associated with rising systolic BP but not diastolic BP. We hypothesize that this finding may in part be due to the older age of the Health ABC cohort. Isolated systolic hypertension is more common in older individuals and may reflect increased vascular stiffness. Interestingly, both FGF-23 and isolated systolic hypertension are associated with left ventricular hypertrophy, hinting at a potential pathophysiologic link between the conditions. Additionally, we found that higher FGF-23 was associated with rising diastolic BPs, but only among men. We are not aware of prior data showing that there are differential effects of FGF-23 by sex, but this is a potential area that may deserve additional research.
Two prior studies have evaluated the association of FGF-23 with hypertension. Fyfe-Johnson et al. examined this association in the Atherosclerosis Risk in Communities (ARIC) study, a longitudinal cohort of middle aged adults.8 Higher intact FGF-23 was associated with both objective and self-reported incident hypertension, independent of CVD risk factors and eGFR. Blood pressure trajectories were not examined in this study. In the second, Akhabue et al. evaluated the association of FGF-23 with incident hypertension in the Coronary Artery Risk Development in Young Adults (CARDIA) study.9 Notably, in this study, FGF-23 was measured using both a c-terminal assay, which includes fragments of FGF-23, and an assay that measures solely intact FGF-23 assay. Higher c-terminal FGF-23 was associated with increasing systolic and diastolic blood pressures over time and with incident hypertension, even when adjusting for CVD risk factors, eGFR and UACR. In contrast, intact FGF-23 was not associated with any of the blood pressure outcomes. Recent data have suggested that the cleavage of FGF-23 to fragments is influenced by inflammation, hypoxia and iron-status23; so all of these factors may bias the relationship of the c-terminal assay to circulating FGF23 activity. This raises the possibility that associations observed with the c-terminal assay of FGF23 may reflect other physiological processes beyond mineral metabolism.
Our study adds to the existing literature in several ways. First, this study included older adults, who are at much higher risk of having prevalent hypertension as well as developing incident hypertension, and for consequences of hypertension including stroke and CVD. Second, we were able to adjust for all key measures of mineral metabolism including calcium, phosphorus, PTH, and vitamin D. We were also able to perform a sensitivity analysis in which we adjusted for soluble klotho concentrations. Klotho is a protein that exists in both transmembrane and circulating or soluble form.24 The transmembrane form serves as a co-factor for FGF-23 and fibroblast growth factor receptors.25 The transmembrane form is cleaved to the smaller soluble fragment, which has multiple systemic effects including beneficial effects on blood pressure and the renin-angiotensin-aldosterone system.17,18 By adjusting for klotho, we are at least partially addressing the potential for confounding by klotho. In addition, our findings are strengthened by the use of a large and diverse prospective cohort
This study also has some important limitations. First, FGF-23 concentrations are influenced by kidney function and the presence of kidney disease may be an important confounder with blood pressure. Though we have adjusted for estimated GFR and the urine albumin to creatinine ratio, this may not capture both the duration and full severity of CKD. Additionally, we acknowledge that the high prevalence of hypertension in this cohort of older adults may make it difficult to evaluate both the severity of hypertension as well as incident cases of hypertension. We also note that the use of a definition of hypertension including blood pressure readings may result in misclassification of incident hypertension due to visit-to-visit variation in blood pressure readings. The labile nature of blood pressure readings themselves may be a potential explanation for the discrepancy between the two definitions of incident hypertension. We note that the primary analyses examining confirmed self-reported hypertension as well as those examining blood pressure trajectories (i.e. avoiding use of a cut-off value) should not be impacted by this bias. Finally, we did not find any association between FGF-23 and baseline blood pressure measures; we believe this finding may be explained by the possibility that the relationship between FGF-23 and actual blood pressure may be attenuated as many of the individuals with normal blood pressure measures were being treated with medications and thus continue to have hypertension.
Perspectives
In summary, we found that higher intact FGF-23 was associated with prevalent and incident hypertension, number of blood pressure medications at baseline, and with rising systolic blood pressure trajectories in a cohort of well-functioning community-living older adults. No association was seen between FGF-23 and baseline systolic or diastolic blood pressure or when incident hypertension was defined using blood pressure measures. Taken together, these data indicate that high FGF-23 may be a modifiable risk factor for hypertension. Additional research is required to investigate the pathophysiologic mechanism by which FGF-23 may influence blood pressure, to determine if modification of FGF-23 concentrations directly influences blood pressure, and to determine whether a rise in FGF-23 is a significant contributor to the high prevalence of hypertension in patients with CKD.
Supplementary Material
Novelty and Significance.
“What Is New?”
First study to show that Fibroblast growth factor 23 is associated with hypertension in older adults
First study to demonstrate that this relationship is independent of soluble klotho
“What Is Relevant?”
Fibroblast growth factor 23 may be a contributing factor to the development of hypertension
This data may provide a novel pathophysiologic pathway to both understand as well as treat high blood pressure
“Summary”
Fibroblast growth factor 23, a hormone involved in regulating Vitamin D and phosphorus, is associated with hypertension, number of blood pressure medications, and rising systolic blood pressures in community dwelling older adults
Acknowledgements & Sources of Funding
This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH) and the National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. Dr. Drew was supported by NIDDK grant K23DK105327. Drs Shlipak, Sarnak, Ix, and Katz were supported by NIA grant 5R01AG027002-07. Dr. Ix was supported by an American Heart Association Established Investigator Award (14EIA18560026). Dr. Gutierrez was supported by grant K24DK116180 and an American Heart Association Strategically Focused Research Network in Disparities grant. Dr. Hoofnagle was supported by NORC grant P30 DK035816. The study sponsors had no role in study design; collection, analysis, and interpretation of the data; writing the report; and the decision to submit the report for publication; however the NIA did approve the manuscript for submission.
Footnotes
Conflicts of Interest: Dr. Gutierrez reports receiving grant support and consulting fees from Akebia, grant support and consulting fees from Amgen, grant support from GSK and consulting feeds from QED. There are no other conflicts of interest to declare. The results presented in this paper have not been published previously, in whole or part.
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