Abstract
A favorable survival effect of phosphate binders (PBs) on incident hemodialysis (HD) patients was recently reported, but no definitive advantages of calcium-based or noncalcium-based PBs have been demonstrated. The aim of this study was to assess the impact of the prescription of PBs using calcium carbonate (CaCO3) or sevelamer HCl (SV) on survival. Baseline PB prescription was recorded using a cross-sectional analysis of prevalent HD patients from the regional Association Régionale des Néphrologues OStéodystrophie French cohort. A prospective 42-month survival analysis study was performed. In July 2005, 1347 HD patients were included. CaCO3, SV, and mixed PBs were prescribed in 55%, 42%, and 24% of cases, respectively, and 26% were not prescribed PBs. Using a Cox proportional model adjusted for several parameters, CaCO3 use was found to be associated with less mortality (HR, 0.64 [0.4–0.78]), but not in the case of SV use (HR, 1.13 [0.92–1.3]). SV prescription was associated with higher mortality than CaCO3 (HR, 1.46 [1.1–1.9]). CaCO3, but not sevelamer prescription, is associated with a favorable effect on survival in a French HD population. This novel result can be partly accounted for by the differences in mineral metabolism disorder management that exist between randomized controlled trials and “real life” conditions.

Most patients with chronic kidney disease experience abnormalities in serum calcium, phosphorus, parathyroid hormone, and vitamin D metabolism. These can lead to vascular calcification (VC), which has been associated with increased risk for cardiovascular disease and mortality. Although hyperphosphatemia is believed to be a risk factor for mortality and VC, no randomized trial was ever designed to demonstrate that lowering phosphate reduces mortality. Nonetheless, binders have been used extensively, and the preponderance of evidence shows that sevelamer slows the development of VC whereas calcium salts do not. Four studies have demonstrated a slower progression of VC with sevelamer than with calcium-containing binders, although a fifth study showed nonsuperiority. Conversely, the results on mortality with sevelamer have been variable, and data on calcium-based binders are nonexistent. Improved survival with sevelamer was demonstrated in a small randomized clinical trial, whereas a larger randomized trial failed to show a benefit. In addition, preclinical models of renal failure and preliminary clinical data on hemodialysis patients suggest a potential benefit for bone with sevelamer. Meanwhile, several randomized and observational studies suggested no improvement in bone density and fracture rate, and a few noted an increase in total and cardiovascular mortality in the general population given calcium supplements. Although additional studies are needed, there are at least indications that sevelamer may improve vascular and bone health and, perhaps, mortality in hemodialysis patients, whereas data on calcium-based binders are lacking.

Most patients with chronic kidney disease (CKD) experience abnormalities in calcium, phosphorus, parathyroid hormone (PTH), and vitamin D metabolism. Hyperphosphatemia that results from declining kidney function is a hallmark of advanced CKD and is associated with abnormal mineral and bone metabolism. In cross-sectional studies, each 1-mg/dl rise in serum phosphorus was associated with a 23% increased risk of death (1). Hyperphosphatemia is also correlated with increased risk of soft tissue and vascular calcification (VC), which may contribute to higher morbidity and mortality (2). Despite the absence of prospective studies to confirm these cross-sectional data, reducing serum phosphorus levels has been at the center of nephrologists' efforts for treatment of dialysis patients for several decades and is now being considered for patients with earlier stage CKD (3).

In randomized clinical trials, calcium-based phosphate binders and sevelamer have shown the same phosphorus-reducing ability (4–7). Laboratory experiments, however, have raised some concern regarding the risk of hypercalcemia as an inducer of VC (8,9). Similarly, in clinical studies that demonstrated progression of VC, episodes of hypercalcemia were significantly more frequent among users of calcium-based binders (4,6). In addition to controlling hyperphosphatemia, potentially beneficial effects of sevelamer include its influence on biomarkers such as C-reactive protein (CRP), uric acid, and LDL cholesterol (10–12), as well as bone density (13), structure (14), and remodeling (15,16).

This review summarizes studies of calcium salts and sevelamer for treatment of hyperphosphatemia as it may affect CKD and mineral and bone disorders (CKD-MBD). CKD-MBD describes a clinical syndrome that is characterized by a systemic disorder manifested by one or more abnormalities in laboratory parameters, bone histomorphometry, and/or VC or other soft tissue calcification (17). The effects of calcium phosphate binders and sevelamer are discussed in four areas: Biomarkers, VC, bone homeostasis, and mortality.