Higher levels of serum phosphorus that remain within the reference range are associated with increased risk of cardiovascular disease (CVD). However, the mechanisms by which higher serum phosphorus concentrations may contribute to the development of CVD remain unclear. Cross-sectional association between serum phosphorus levels and arterial stiffness as estimated by an ankle brachial pressure index (ABPI) >1.3 was examined in 581 participants in the Third National Health and Nutrition Examination Survey. Logistic regression analysis was performed to evaluate whether higher serum phosphorus levels were associated with high ABPI, independently of several potential confounders. Of 581 participants, 38% and 10% had a serum phosphorus levels >3.5 and >4.0 mg/dl, respectively. An ABPI >1.3 was present in 7.3% of participants. Higher quartiles of serum phosphorus levels were associated with a greater prevalence of high ABPI: 5.4%, 3.7%, 7.8%, and 12.9% for quartiles 1 (<3.1 mg/dl), 2 (3.1 to 3.4 mg/dl), 3 (3.4 to 3.7 mg/dl), and 4 (3.7 to 5.0 mg/dl), respectively. There was a strong, positive association between the highest quartile of serum phosphorus (3.7 to 5.0 mg/dl) and high ABPI compared to the reference group (3.1 to 3.4 mg/dl) after adjustment for demographics, traditional CVD risk factors, kidney function, C-reactive protein, serum calcium, and 25-hydroxyvitamin D levels (adjusted odds ratio 4.78, 95% confidence interval 1.73 to 13.2, p = 0.003). In conclusion, serum phosphorus levels, even within the reference range, are independently associated with high ABPI, a marker of arterial stiffness, in the US adult population.
The ankle brachial pressure index (ABPI) is a noninvasive tool used to evaluate vascular stiffness and is a strong predictor of cardiovascular disease (CVD) morbidity and mortality. Noncompressible calcified arteries result in abnormally high ABPI values (i.e., ABPI >1.3), whereas peripheral arterial disease is defined as an ABPI <0.9. The relation between serum phosphorus concentrations and peripheral arterial disease has been evaluated, but the association between serum phosphorus and vascular stiffness (as estimated by ABPI >1.3) has not been thoroughly examined in the US general population. The purpose of the present analysis was to investigate the relation between serum phosphorus concentrations and ABPI >1.3 in US adults. We tested the hypothesis that higher serum phosphorus levels are associated with high ABPI values in the general US adult population.
Methods
The Third National Health and Nutrition Examination Survey (NHANES III) is a national probability survey of Americans conducted from 1988 to 1994 by the National Center for Health Statistics of the Centers for Disease Control and Prevention. The survey was designed to obtain information on health and nutritional status of the noninstitutionalized US population. A stratified, multistage sampling design was used, with oversampling of non-Hispanic blacks, Mexican-Americans, and subjects >60 years of age. Standardized questionnaires were administered in the home, followed by a detailed physical examination and blood specimens at a mobile examination center.
This analysis was restricted to the 581 participants ≥40 years old who had complete data for serum phosphorus, ABPI measurements, and calculation of estimated glomerular filtration rate by the abbreviated Modification of Diet in Renal Disease formula.
Serum phosphorus level was the main predictor for all analyses. Serum phosphorus concentrations were measured using a Hitachi 737 automated analyzer (Boehringer Mannheim Diagnostics, Indianapolis, Indiana) with a reportable range of 0.5 to 20 mg/dl and a coefficient of variation from 0.52% to 2.43% for pooled controls. For this analysis, serum phosphorus levels were divided into quartiles—quartile 1, <3.1 mg/dl; quartile 2, 3.1 to 3.4 mg/dl; quartile 3, 3.4 to 3.7 mg/dl; and quartile 4, 3.7 to 5.0 mg/dl. A serum phosphorus level of 3.1 to 3.4 mg/dl was chosen as the reference range based on previous data showing a higher risk of CVD with phosphorus levels >3.5 mg/dl.
The primary outcome of interest was peripheral arterial stiffness as estimated by ABPI. Systolic blood pressure was measured in a supine position in the right arm (brachial artery) and in the posterior tibial artery of the 2 ankles with an 8-MHz Doppler. Each pressure was measured 2 times in participants 40 to 59 years of age and 1 time in participants >60 years of age to decrease the time for this component in that age group. All blood pressure measurements were performed in a standardized fashion at the mobile examination centers. The ABPI was calculated by dividing the mean systolic blood pressure in the ankle by the mean systolic blood pressure in the arm. The normal range for ABPI is from 1.0 to 1.3. A high ABPI was defined as >1.3 in either leg based on previous studies showing that an ABPI >1.3 is a reliable marker of peripheral vascular stiffness. Data on incompressible arteries were not available.
Questionnaire data included self-reported age, gender, and race/ethnicity. Race/ethnicity was divided into 4 categories: non-Hispanic white, non-Hispanic black, Mexican-American, and other. Participants were defined as having hypertension if they were taking antihypertensive medications, reported being told by a physician that they have high blood pressure, or an average of 3 blood pressure readings of systolic blood pressure ≥140 mm Hg, or a diastolic blood pressure ≥90 mm Hg. Diabetes was diagnosed if participants were taking medication for diabetes, had a fasting plasma glucose concentration ≥126 g/dl, or when a physician had ever told them that they had diabetes mellitus. Body mass index was calculated as weight in kilograms divided by the square of height in meters. Smoking status was classified as never, former, or current. Glomerular filtration rate was estimated from the abbreviated Modification of Diet in Renal Disease equation as follows: estimated glomerular filtration rate = 186.3 × (serum creatinine in milligrams per deciliter) −1.154 × age −0.203 × (0.742 if a woman) × (1.21 if black). Serum creatinine measurements (measured on a Hitachi 704 analyzer using a kinetic rate Jaffé method) were recalibrated to the Cleveland Clinic “standard” assay used in the development of the Modification of Diet in Renal Disease glomerular filtration rate prediction equation to ensure validity of results. Serum concentrations of 25-hydroxyvitamin D (25[OH]D) were measured using an Incstar (Stillwater, Minnesota) 25(OH)D 2-step assay procedure with a coefficient of variation <10%. C-reactive protein was measured by latex-enhanced nephelometry (Behring Diagnostics, Inc., Somerville, New Jersey) with the lower limit of detection of 0.21 mg/dl, and pooled controls had a coefficient of variation from 3.3% to 16.1%. Fasting levels of total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were measured by a Hitachi 704 analyzer. Low-density lipoprotein (LDL) cholesterol concentration was calculated using the equation of Friedewald et al.
Univariate modeling was first performed to determine if a relation existed between variables and quartiles of serum phosphorus. Categorical variables were examined with a Cochran-Armitage trend test and continuous variables were examined with 1-way analysis of variance. Observations were weighted to reflect the general US population as of the early 1990s using weights calculated for that purpose by the National Health Statistics. The independent effect of serum phosphorus levels on high ABPI (defined as ABPI > 1.3) was studied using logistic regression models, adjusting simultaneously for several covariates. We chose covariates as candidate confounding factors based on their biological plausibility or based on previous studies. The following covariates were included: age, gender, race/ethnicity, body mass index, smoking status, hypertension, diabetes, estimated glomerular filtration rate, LDL cholesterol, HDL cholesterol, C-reactive protein, calcium, and 25(OH)D.
In our analysis, serum phosphorus was evaluated as an ordinal (quartiles of serum phosphorus) and as a continuous variable. Of note, we examined age, body mass index, estimated glomerular filtration rate, LDL cholesterol, and HDL cholesterol as continuous and categorical variables, but present results using the categorical treatment because results were similar. Analyses were conducted using SAS 9.1.3 (SAS Institute, Cary, North Carolina). A p value<0.05 was considered statistically significant.
Results
Of the 581 participants, 38% and 10% had serum phosphorus levels >3.5 and >4.0 mg/dl, respectively; only 1.5% of them had a serum phosphorus concentration above the normal laboratory range of 4.5 mg/dl. Baseline characteristics of the entire population stratified according to quartiles of serum phosphorus levels are listed in Table 1 .
| Characteristics | Serum Phosphorus Level (mg/dl) | p Value for Trend | |||
|---|---|---|---|---|---|
| <3.1 | 3.1–3.4 | 3.4–3.7 | 3.7–5.0 | ||
| (n = 143) | (n = 159) | (n = 125) | (n = 154) | ||
| Age (years) | 56 ± 14 | 58 ± 13 | 57 ± 14 | 59 ± 12 | 0.38 |
| Men | 62.0% | 49.0% | 43.0% | 32.0% | |
| Women | 38.0% | 51.0% | 57.0% | 68.0% | <0.0001 |
| Non-Hispanic white | 84.0% | 81.0% | 80.0% | 77.0% | |
| Non-Hispanic black | 7.0% | 10.0% | 10.0% | 9.0% | |
| Mexican-American | 2.5% | 3.0% | 4.0% | 5.0% | 0.84 |
| Other | 6.5% | 6.0% | 6.0% | 9.0% | |
| Body mass index (kg/m 2 ) | |||||
| <25 | 43.0% | 37.0% | 46.0% | 39.0% | |
| 25–29 | 33.0% | 40.0% | 28.0% | 33.0% | 0.41 |
| ≥30 | 24.0% | 23.0% | 26.0% | 28.0% | |
| Smoking | |||||
| Never | 40.0% | 34.0% | 32.0% | 50.0% | |
| Former | 31.0% | 39.0% | 40.0% | 34.0% | 0.02 |
| Current | 29.0% | 27.0% | 28.0% | 16.0% | |
| Diabetes mellitus | 9.5% | 8.6% | 8.9% | 12.3% | 0.41 |
| Hypertension | 29.0% | 37.0% | 33.0% | 36.0% | 0.35 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | |||||
| ≥90 | 40.0% | 54.0% | 47.0% | 44.0% | |
| 60–89 | 50.0% | 42.0% | 46.0% | 51.0% | |
| <60 | 10.0% | 4.0% | 7.0% | 5.0% | 0.13 |
| 25-Hydroxyvitamin D (ng/ml) | 29.0 ± 10.5 | 24.8 ± 8.9 | 27.4 ± 9.4 | 27.6 ± 9.6 | 0.001 |
| Calcium (mg/dl) | 9.2 ± 0.4 | 9.3 ± 0.5 | 9.3 ± 0.4 | 9.3 ± 0.5 | 0.02 |
| Phosphorus (mg/dl) | 2.8 ± 0.2 | 3.3 ± 0.9 | 3.6 ± 0.1 | 4.1 ± 0.3 | ND |
| C-reactive protein (mg/dl) | 0.38 ± 0.6 | 0.46 ± 0.7 | 0.38 ± 0.4 | 0.58 ± 0.8 | 0.03 |
| Low-density lipoprotein cholesterol (mg/dl) | 129 ± 44 | 134 ± 41 | 135 ± 35 | 137 ± 35 | 0.34 |
| High-density lipoprotein cholesterol (mg/dl) | 48 ± 16 | 51 ± 16 | 57 ± 24 | 54 ± 15 | 0.0003 |
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