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.