Effect of Sevelamer on Calciprotein Particles in Hemodialysis Patients: The Sevelamer Versus Calcium to Reduce Fetuin-A-Containing Calciprotein Particles in Dialysis (SCaRF) Randomized Controlled Trial

Abstract

Introduction: Calciprotein particles (CPPs) are potentially modifiable mediators of phosphate toxicity in patients with kidney disease. We compared the effects of calcium carbonate (CC) and the non-calcium-based phosphate binder sevelamer on CPP levels in patients undergoing hemodialysis (HD). We hypothesized that treatment with sevelamer would achieve greater reductions in amorphous calcium phosphate-containing CPP (CPP-1) and hydroxyapatite-containing CPP (CPP-2) owing to reduced calcium loading and anti-inflammatory pleiotropic effects.

Methods: We conducted an open-label, randomized controlled trial (RCT) in which 31 stable prevalent HD patients were allocated to receive either sevelamer hydrochloride (SH), sevelamer carbonate (SC), or CC for 24 weeks. Dual primary endpoints were the between groups differences in serum CPP-1 and CPP-2 levels at 24 weeks in SH + SC-treated versus CC-treated patients. Effects on aortic pulse wave velocity (aPWV), inflammatory cytokines (interleukin-6 and -8), and effects across individual treatment arms were also assessed.

Results: Serum CPP-1, but not CPP-2, levels were lower in those randomly assigned to the sevelamer (SH + SC) group compared with the CC group at 24 weeks (-70%, 95% confidence interval [CI] -90% to -15%, P = 0.02). In subgroup analysis, this effect was confined to those receiving SC (-83.4%, 95% CI -95.7% to -36.8%, P = 0.01). aPWV and interleukin-8 levels were also lower in those who received sevelamer compared with CC at 24 weeks (-2.0 m/s, 95% CI -2.9 to -1.1; -57%, 95% CI -73% to -30%, respectively, both P = 0.01). Conventional markers of mineral metabolism remained stable across all treatment groups.

Discussion: Compared with treatment with CC, use of sevelamer for 24 weeks was associated with lower serum CPP-1 levels and a reduction in aPWV and systemic inflammation.

Keywords: calciprotein particles; calcium carbonate; hemodialysis; inflammation; phosphate; phosphate binder; sevelamer.

Graphical abstract

Figure 1

CONSORT diagram showing patient disposition through consent, randomization, and dropout in the Sevelamer Versus Calcium to Reduce Fetuin-A-containing Calciprotein Particles in Dialysis (SCaRF) trial. Primary analyses were conducted on a modified intention-to-treat basis in which randomized patients with at least 1 postrandomization follow-up visit were included. AE, adverse events; CC, calcium carbonate; SC, sevelamer carbonate; SH, sevelamer hydrochloride.

Figure 2

Changes in serum calciprotein particle (CPP)-1 and CPP-2 levels over 24 weeks in response to treatment with calcium carbonate or sevelamer. (a) Changes in serum CPP-1 levels in calcium carbonate (CC) and sevelamer hydrochloride (SH) + sevelamer carbonate (SC) treatment arms. (b) Changes in serum CPP-1 levels by individual SH and SC treatment arms. (c) Changes in serum CPP-2 in CC and SH + SC treatment arms. (d) Changes in serum CPP-2 levels by individual SH CPP and SC treatment arms. Data are presented as median values with error bars depicting interquartile ranges. Data series were offset to aid visualization. Mixed-effects models with repeated measures were used to test for between-group differences: ∗P < 0.02 for CC versus SH + SC; ^†P < 0.01 for CC versus SC, and ^#P < 0.02 for SH versus CC.

Figure 3

Changes in serum interleukin (IL)-6 and IL-8 over 24 weeks in response to treatment with calcium carbonate or sevelamer. (a) Changes in serum IL-6 in calcium carbonate (CC) and sevelamer hydrochloride (SH) + sevelamer carbonate (SC) treatment arms. (b) Changes in serum IL-6 by individual SH and SC treatment arms. (c) Changes in serum IL-8 in CC and SH + SC treatment arms. (d) Changes in serum IL-8 by individual SH and SC treatment arms. Data are presented as median values with error bars depicting interquartile ranges. Data series were offset to aid visualization. Mixed-effects models with repeated measures were used to test for between-group differences: ∗P < 0.02 for CC versus SH + SC.

Figure 4

Changes in aortic pulse wave velocity (aPWV) over 24 weeks in response to treatment with calcium carbonate or sevelamer. (a) Changes in aPWV in calcium carbonate (CC) and sevelamer hydrochloride (SH) + sevelamer carbonate (SC) treatment arms. (b) Changes in aPWV by individual SH and SC treatment arms. Data are presented as mean values with error bars depicting standard deviation. Data series were offset to aid visualization. Mixed-effects models with repeated measures were used to test for between-group differences: ∗P < 0.01 for CC versus SH + SC.