Sevelamer revisited: pleiotropic effects on endothelial and cardiovascular risk factors in chronic kidney disease and end-stage renal disease

Anjay Rastogi, Anjay Rastogi

Abstract

Endothelial dysfunction underlies multiple cardiovascular consequences of chronic kidney disease (CKD) and antecedent diabetes or hypertension. Endothelial insults in CKD or end-stage renal disease (ESRD) patients include uremic toxins, serum uric acid, hyperphosphatemia, reactive oxygen species, and advanced glycation endproducts (AGEs). Sevelamer carbonate, a calcium-free intestinally nonabsorbed polymer, is approved for hyperphosphatemic dialysis patients in the US and hyperphosphatemic stage 3-5 CKD patients in many other countries. Sevelamer has been observed investigationally to reduce absorption of AGEs, bacterial toxins, and bile acids, suggesting that it may reduce inflammatory, oxidative, and atherogenic stimuli in addition to its on-label action of lowering serum phosphate. Some studies also suggest that noncalcium binders may contribute less to vascular calcification than calcium-based binders. Exploratory sevelamer carbonate use in patients with stages 2-4 diabetic CKD significantly reduced HbA1c, AGEs, fibroblast growth factor (FGF)-23, and total and low-density lipoprotein (LDL) cholesterol versus calcium carbonate; inflammatory markers decreased and defenses against AGEs increased. Sevelamer has also been observed to reduce circulating FGF-23, potentially reducing risk of left ventricular hypertrophy. Sevelamer but not calcium-based binders in exploratory studies increases flow-mediated vasodilation, a marker of improved endothelial function, in patients with CKD. In contrast, lanthanum carbonate and calcium carbonate effects on FMV did not differ in hemodialysis recipients. The recent independent-CKD randomized trial compared sevelamer versus calcium carbonate in predialysis CKD patients (investigational in the US, on-label in European participants); sevelamer reduced 36-month mortality and the composite endpoint of mortality or dialysis inception. Similarly, independent-HD in incident dialysis patients showed improved survival with 24 months of sevelamer versus calcium-based binders. This review discusses recent exploratory evidence for pleiotropic effects of sevelamer on endothelial function in CKD or ESRD. Endothelial effects of sevelamer may contribute mechanistically to the improved survival observed in some studies of CKD and ESRD patients.

Keywords: advanced glycation endproducts; atherosclerosis; fetuin-A; fibroblast growth factor-23; sevelamer; vascular dysfunction.

Conflict of interest statement

Conflict of interest statement: The author discloses speakers’ bureau membership for Cubist, Questcor, Sanofi (formerly Genzyme), and ViiV Healthcare Systems, and advisory board membership for Vifor.

Figures

Figure 1.
Figure 1.
Increased cardiovascular mortality risk associated with Stage 5 CKD versus the general population. Reproduced with kind permission from Elsevier (Foley et al. 1998).
Figure 2.
Figure 2.
Structure of sevelamer. a, b = number of primary amine groups, a + b = 9 c = number of crosslinking groups, c = 1 m = large number to indicate extended polymer network
Figure 3.
Figure 3.
Summary of proposed phosphate-reducing and phosphate-independent effects of sevelamer.
Figure 4.
Figure 4.
Effects of sevelamer versus calcium on mortality in patients new to hemodialysis. Adapted with kind permission from Macmillan Publishers Ltd. (Block et al. 2007).
Figure 5.
Figure 5.
Potential pleiotropic effects of sevelamer affecting parameters involved in the inflammatory, metabolic, or developmental modulation of vascular calcification. Factors that have been shown to respond to sevelamer are shown in yellow ovals. Adapted with kind permission from Macmillan Publishers Ltd. (Sage et al. 2010). ALP, alkaline phosphatase; BMP, bone morphogenetic protein; FGF-23, fibroblast growth factor-23; HDL, high-density lipoprotein; IFN-γ, interferon gamma; IGF-1, insulin-like growth factor-1; IL-6, interleukin-6; MGP, matrix GLA protein; MMP, matrix metalloproteinase; Pi, inorganic phosphate; PTH, parathyroid hormone; TNF, tumor necrosis factor.

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