This prospective cohort study in incident hemodialysis patients showed that serum phosphorus at the beginning of dialysis was strongly and independently associated with SBP, DBP and PP. This association was seen both cross-sectionally and over time. In addition, it showed that the average serum phosphate from baseline to 3 months was associated with a subsequently higher SBP, DBP and PP. The magnitude of these associations was greater for SBP and PP than for DBP. We adjusted for all potential confounders in this study, including anti-hypertensive medication use (beta-blocker, Calcium channel blocker or angiotensin converting enzyme (ACE) inhibitor), patient demographics (age, sex, race), medical history (ICED score, DM, baseline CVD), laboratory values (albumin, log(CRP)) and dialysis non-adherence. Our analyses with calcium and CaP product data indicated that serum phosphate rather than calcium was associated with blood pressure at baseline and over time. A likely mechanism is that hyperphosphatemia leads to mineral deposition in the vascular wall (i.e., metastatic calcification) and this leads to arterial wall stiffness and vessel non-distensability (18
The effect of phosphate concentration on vascular calcification is supported by Raggi and co-workers. (20
), who found that the extent of arterial calcification in adult HD patients was associated with age, male sex, white race, diabetes, dialysis therapy, higher serum calcium and higher serum phosphate concentration. In another study, serum phosphate concentration was higher in young HD patients with coronary calcification than in those without (21
The vascular calcification process in hyperphosphatemia is similar to that of normal skeletal mineralization (22
). Increasing phosphate concentration in vascular smooth muscle cell culture results in a dose-dependent increase in intracellular phosphate via a type III sodium-phosphate cotransporter (6
). This ultimately increases bone-related protein expression of markers such as core-binding factor alpha-1 (cbfa-1) and osteocalcin. Animal models confirm this phenotypic change in vascular smooth muscle cells and human pathologic studies in ESRD substantiate the expression of bone-related proteins in areas of vascular calcification (24
). Hyperphosphatemia is also an independent predictor of left ventricular hypertrophy (LVH)(26
), likely due to the decreased vascular compliance and increased afterload. Short daily hemodialysis significantly decreased serum phosphate level at the end of six months, compared to conventional hemodialysis, and SBP, PP, and LVH were all found to be significantly reduced in patients receiving short daily hemodialysis (27
Our study is one of the first to address the associations of elevated serum phosphate level and higher blood pressures over time. The association of elevated phosphate and high blood pressure persisted even after 2 years. This suggests the persistence of arterial wall stiffness as the result of baseline hyperphosphatemia. Klassen and colleagues (28
) reported that phosphate concentration was directly associated with pulse pressure, which was a strong predictor of 1-year mortality. Melamed et al. (29
) found that patients whose phosphate levels were high at baseline but subsequently decreased significantly by 6 months had a higher mortality relative to those whose levels were low at both time points. The National Kidney Foundation recommends maintaining a serum phosphate concentration between 3.5 and 5.5 mg/dl in stage 5 chronic kidney disease patients (HD patients) (30
). Our results suggest that even if serum phosphate level can be lowered in a short period of time, the vascular calcification from hyperphosphatemia may require a longer time to correct.
Pulse pressure is the difference between systolic and diastolic blood pressure. The rise in aortic pressure from its diastolic to systolic value is determined by the compliance of the aorta as well as the ventricular stroke volume. In the arterial system, the aorta has the highest compliance, due in part to a relatively greater proportion of elastin fibers versus smooth muscle and collagen. Therefore, aortic compliance is a major determinant, along with stroke volume, of the pulse pressure. Guerin et al. (31
) reported aortic pulse velocity has the highest sensitivity and specificity in predicting cardiovascular death in ESRD patients. Klassen et al. (28
) reported that an increment of 10 mmHg in PP was associated with 12% increase in mortality in HD patients.
Our results suggested that baseline serum phosphate is an independent predictor of all-cause mortality, even adjusted for baseline blood pressure. Higher mortality could be mediated not by subsequent vascular calcification from hyperphosphatemia but through other mechanisms (e.g. fibroblast growth factor-23 levels in hyperphosphatemia) (32
). Our study did not show that baseline blood pressure is a significant predictor for mortality, although Klassen and co-workers demonstrated this relationship in hemodialysis patients (28
). Our results reinforce the importance of serum phosphate control in reducing all-cause mortality in hemodialysis patients.
One potential confounding factor for hyperphosphatemia is non-adherence to HD. Patients who are non-adherent to HD may also be non-adherent to their anti-hypertensives. Leggat and colleagues (33
) suggested that skipping HD sessions could be considered with other non-adherent behaviors, such as high interdialytic weight gain, greater serum potassium and phosphate levels. Unruh and colleagues. (17
) reported that skipping 3% of HD sessions is associated with 69% increase in risk of death. We tried to eliminate non-adherence as a cause of hyperphosphatemia by adjusting for non-adherence to HD and for serum potassium in our study.
One strength of our study is repetitive blood pressure measurements. There was an average of 35 pre- and post-dialysis BP measurements in each patient during each follow-up period. The average BP value in this study is a good reflection of the BP in these HD patients although there is generally a big variation of BP in this population. We also used the average of pre- and post-dialysis BP to eliminate potential inter-individual differences in changes of extracellular volume. A similar but even stronger association was found.
This study has several limitations. First, this is an observational study. We cannot establish causality although several features of our study design and results are suggestive of a causal relation, including temporality, strength of the association, the graded nature of the association and biologic plausibility. Second, we did not have data on arterial wall stiffness to examine the mechanism for the observed associations. Although pulse pressure may be a surrogate measure of the arterial wall stiffness, Doppler measurement would have provided more accurate information about arterial wall compliance. Third, there may be residual confounding. For example, we only had information on baseline vitamin D use for 346 patients in the cohort and these data did not include dose or frequency of administration. The association between blood pressure (SBP & PP) and serum phosphate level was present at baseline when we adjusted for vitamin D use, but disappeared at follow-up intervals. We suspect the lack of association in follow-up is due to the smaller sample size over time. Finally, we did not have complete data on calcium-containing and non-calcium-containing phosphate binder use.
In summary, this study found that serum phosphorus is strongly and independently associated with systolic blood pressure and pulse pressure in the early months of dialysis therapy and up to 27 months later. The role of hyperphosphatemia in vascular calcification and arterial stiffness still needs to be further clarified. Studies relating phosphate level to direct measurements of arterial wall stiffness and examining whether lowering serum phosphate will decrease vascular calcification and blood pressure would be very useful.