Discussion
Despite the widespread use of phosphate binders in patients with
end-stage renal disease, relatively few studies have compared calcium
acetate and sevelamer carbonate with respect to their biomarkers of
vascular calcification, inflammation, and endothelial dysfunction in
non-dialysis patients.
The beneficial effects of sevelamer carbonate on serum lipids were
expected from earlier studies in CKD patients.13Significant decrease in total cholesterol and increase in
HDL-cholesterol was seen with sevelamer carbonate but not with calcium
acetate. In another study performed for one year in 200 hemodialysis
patients, sevelamer improved the progression of coronary aortic
calcification compared to calcium based binders.14
In the present study, sevelamer carbonate treatment demonstrated
reductions in biomarkers related to endothelial function and
inflammation. As expected from earlier studies, elevated levels of
calcium were more common in calcium acetate-treated
patients.15 As shown in previous studies, sevelamer
effects on vascular calcification might be secondary to its lower
calcium load versus lipid-lowering properties. Further and consistent
with earlier studies, sevelamer significantly decreased the uric acid
not observed with calcium acetate.16 Johnson et al.
showed that hyperuricemia is associated with insulin resistance,
dyslipidemia, hypertension, and cardiovascular diseases in patients with
CKD.17
In patients with CKD, FGF-23 concentrations constitutively elevate and
increase progressively as kidney function worsens.18FGF-23 is released in the face of phosphate overload in non-CKD and CKD
patients. With reduced nephron mass, excessive FGF-23 concentrations
increase phosphorous elimination per nephron maintaining normal serum
phosphorous concentrations.19 This normalization is
not without consequence; FGF-23 is an inhibitor of 1,25-dihydroxyvitamin
D [1,25(OH)2D] synthesis and further aggravates the prevalent
vitamin D deficiency seen in CKD.20 Excessive levels
of phosphorous and calcium are endogenous minerals capable of
stimulating the phenotypic transformation of vascular smooth muscle
cells into osteoblast-like cells.21 Despite normal
values of calcium and phosphorous in CKD patients, 40% of CKD patients
not receiving dialysis display evidence of calcification on
imaging.22 In the present study, sevelamer carbonate
significantly reduced the FGF-23 levels at the end of 12 weeks of study.
Experimental CKD models in animals showed that reducing intestinal
phosphate absorption with sevelamer HCl lowered serum FGF-23 and
phosphorous concentrations.23 Thus FGF-23 is
considered to be a logical target in early stages of CKD to slow the
progression of calcification with phosphate binders. In a 6-week period,
Oliveria et al. targeted serum FGF-23 in stages 3 and 4 CKD patients
with sevelamer and calcium acetate, and at 6 weeks both phosphorous
binders lowered FGF-23 levels.24 However, this
short-term study did not provide any evidence of reduction or
progression of vascular calcification in response to FGF-23 reduction.
Furthermore, vascular calcification causes hemodynamic alterations such
as reduced compliance of large conductance arteries and autonomic
dysfunction.25 Stiffening of the arterial media layer
as a result of calcification manifests clinically via increased elevated
pulse pressure. Moreover, higher FGF-23 concentrations have been
associated with increased arterial stiffness in CKD
patients.26, 27 Evidence suggests these homeostatic
vascular protective mechanisms are deficient or nonfunctional in CKD
patients resulting in increased amounts of calcification in the CKD
patient population.28, 29 A specific biomarker of
interest is osteroprotegrin. Currently, there are few published clinical
trials on the effect of sevelamer treatment on levels of calcification
biomarkers, specifically feutin-A in the non-dialysis
population.30, 31 However, this short-term study did
not provide any evidence of reduction or progression of vascular
calcification in response to FGF-23 reduction.
Additionally, inflammatory cytokines have been associated with the
process of vascular calcification. Studies have demonstrated that
treatment with sevelamer may have anti-inflammatory effects in
hemodialysis patients.9, 32 In the current study,
sevelamer carbonate significantly reduced the inflammatory markers IL-6,
IL-8, IL-10, CRP, TNFα, and IFN-γ. All these inflammatory markers have
been associated with adverse outcomes and complications in CKD patients.
Inflammatory cytokines also activate and upregulate the expression of
adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), vascular
cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin, which
play a fundamental role in endothelial dysfunction. Markers of
endothelial function are associated with cardiovascular events. In the
present study, there was a significant increase in circulating levels of
ICAM-1 and VCAM-1 with sevelamer compared with calcium acetate and these
results are comparable with those reported in previous
studies.33, 34 In accordance with the above
speculation, chronic uremia is known to be associated with elevated
pro-inflammatory cytokine levels that can upregulate the expression and
release of different adhesion molecules.
Systemic inflammation has been regarded as a cardiovascular risk factor.
Our study demonstrated a negative correlation between serum VCAM-1 and
HDL levels and a highly significant correlation between both ICAM-1 and
VCAM-1 and CRP levels; this is the first report of such a relationship
in chronic hemodialysis patients. Moreover, compared with patients with
normal CRP, patients with elevated CRP had significantly increased serum
ICAM-1. The above findings are particularly important because CRP is an
accepted index of overall inflammatory activity and a surrogate of
underlying cytokine stimulus. Based on the above results, an association
between inflammation, adhesion molecule release, dyslipidemia, and
atherosclerosis could be postulated.
Author contributions: D.M., D.N., and S.A.M. designed the
study; K.G. carried out experiments, analyzed the data, made the
figures; K.G. and S.A.M. drafted and revised the paper; all authors
approved the final version of the manuscript.
Acknowledgment: This investigation would not have been possible
without funding from Sanofi/Genzyme. The authors have no conflicts of
interest to declare.
Disclosures: The authors
have no conflicts of interest to declare.
Data Availability Statement: Research data are not shared. All
data in the figures and tables are derived from the individual data
measurement.