Short-Term Treatment with Sevelamer Increases Serum Fetuin-A Concentration and Improves Endothelial Dysfunction in Chronic Kidney Disease Stage 4 Patients

Background and objectives: Vascular calcification and endothelial dysfunction contribute to the development of cardiovascular disease in patients with chronic kidney disease (CKD). Sevelamer, a non–calcium-based phosphate binder, has been shown to attenuate cardiovascular calcification in CKD patients, although the exact mechanism has not been clarified. This study was designed to investigate the effect of short-term sevelamer treatment on both serum fetuin-A concentrations and endothelial dysfunction seen in CKD patients.Design, setting, participants, & measurements: Fifty nondiabetic stage 4 CKD patients whose phosphate levels were ≥5.5 mg/dl were enrolled in this 8-wk randomized prospective study. Thirty-six healthy volunteers served as matched controls. Patients were treated with either sevelamer (n = 25, 12 males) or calcium acetate (n = 25, 13 males). Fetuin-A, high-sensitivity C-reactive protein, Ca × PO₄ product, flow-mediated dilation (FMD), insulin, and homeostasis model assessment (HOMA) were obtained at baseline and after the treatment period.Results: As expected, CKD patients had significantly lower levels of fetuin-A and FMD, and significantly higher levels of intact parathyroid hormone, Ca × PO₄ product, and high-sensitivity C-reactive protein than controls (P < 0.001 for all). The use of sevelamer led to a significant increase in the fetuin-A concentration with improvement in FMD, whereas no significant difference was observed in the calcium acetate group. In a multiple regression analysis, FMD levels were independently related to fetuin-A both before (β = 0.63, P < 0.001) and after (β = 0.38, P = 0.004) treatment.Conclusions: This small, randomized, prospective study shows that short-term sevelamer treatment significantly increases fetuin-A levels and improves FMD in nondiabetic stage 4 CKD patients.Cardiovascular disease (CVD) is prevalent in patients with chronic kidney disease (CKD) (1). Strong correlation between the derangement in mineral metabolism, such as hyperphosphatemia, hyperparathyroidism, as well as elevated calcium × phosphorus product (Ca × PO₄) and mortality has been reported in hemodialysis (HD) patients (2). These derangements have also been shown to result in vascular calcification, an independent risk factor for cardiovascular mortality (3,4). Elevated Ca × PO₄ product and higher doses of oral calcium ingestion significantly predicted coronary artery calcification (CAC) in patients with end-stage kidney disease (5). Moreover, London et al. (4) have shown significant association between the uses of calcium-based phosphate binders and arterial medial calcification in HD patients. Based on the deleterious effect of high calcium intake on vascular calcification, a calcium-free nonabsorbed phosphate binder, sevelamer hydrochloride, has been developed for the treatment of hyperphosphatemia in CKD patients (6). Studies have shown that sevelamer provides effective control in serum PO₄ levels without inducing hypercalcemia (6,7). Additionally, these studies have also shown beneficial effects of sevelamer on the progression of vascular calcification, although the underlying mechanisms were not clarified (8). Recent studies on vascular calcification have evaluated a number of circulating systemic calcification inhibitors, such as fetuin-A, matrix-Gla protein, osteoprotegrin, etc. (9). Fetuin-A, the major circulating inhibitor of vascular calcification, has been shown to be lower in dialysis patients and to be associated with cardiovascular mortality (10).Recent data have shown a relationship between vascular calcification and endothelial dysfunction (ED) in vascular disease. Nigam et al. (11) showed that there was a significant correlation between ED and large conduit vessel stiffness in patients with coronary artery disease (CAD). Additionally, in 201 healthy subjects, Budoff et al. (12) evaluated the relation between arterial distensibility, arterial reactivity, and CAC scores (electron beam computed tomography). They showed a significant relationship between brachial artery reactivity and CAC. In accordance, Huang et al. (13) have also reported a significant relationship between CAC and ED in patients with suspected CAD.This study was designed to investigate whether the suggested beneficial effects of sevelamer on vascular calcification are related to changes in serum fetuin-A concentration in patients with CKD. On the basis of the recent evidence linking vascular calcification and ED, we also evaluated the effect of sevelamer treatment on ED.