Long-Term Effects of Sevelamer on Vascular Calcification, Arterial Stiffness, and Calcification Propensity in Patients Receiving Peritoneal Dialysis: The Randomized Pilot SERENE (Sevelamer on Vascular Calcification, Arterial Stiffness) Trial

Abstract

Rationale & objective: There is a concern regarding increased risk of vascular calcification with the use of calcium-based phosphorus binders. This study aimed to compare the effects of sevelamer used as a second-line, low-dose therapy with calcium-based phosphorus binders with those of sevelamer used as a first-line, high-dose therapy on coronary artery and heart valve calcification, aortic pulse wave velocity (PWV), and calcification propensity over 2 years in patients with hyperphosphatemia receiving peritoneal dialysis (PD).

Study design: A 2-year-long prospective, multicenter, open-label, randomized pilot study.

Setting & participants: Prevalent patients with hyperphosphatemia receiving PD from 2 university-affiliated hospitals in Hong Kong.

Interventions: The patients were randomized to receive sevelamer either as a first-line therapy at a high dose of 800 mg thrice daily (can titrate up to 1,200 mg thrice daily as required) or a second-line therapy at a low dose of 400 mg thrice daily with calcium carbonate to achieve a serum phosphorus target of ≤5.5 mg/dL.

Outcomes: The primary endpoints were changes in coronary artery calcium score and aortic PWV over 104 weeks. The secondary endpoints were changes in heart valve calcium scores, calcification propensity measure, and biochemical parameters of chronic kidney disease-mineral bone disease over 104 weeks.

Results: Among 60 prevalent patients receiving PD, with a mean age of 53 ± 10 years and with 57% men, changes in the coronary artery calcium score (median [interquartile range], 225 [79-525] vs 223 [56-1,212], respectively; P = 0.21), aortic PWV (mean ± standard error, 0.3 ± 0.1 vs 0.8 ± 0.2 m/s, respectively; P = 0.31), heart valve calcium score, maturation or transformation time, serum calcium levels, and phosphorus levels over 104 weeks were similar for the second-line, low-dose and first-line, high-dose sevelamer groups. Alkaline phosphatase and intact parathyroid hormone levels increased and low-density lipoprotein cholesterol decreased in both the groups, with no significant between-group differences.

Limitations: The sample size was small, and the dropout rates were relatively high.

Conclusions: Low-dose sevelamer used as a second-line therapy for hyperphosphatemia in combination with a calcium-based phosphorus binder had similar effects on vascular calcification, valvular calcification, and arterial stiffness compared with high-dose sevelamer used as a first-line therapy. This approach may be considered in resource-constrained countries to minimize calcium loading.

Funding: The study was supported by a competitive grant from SK Yee Medical Foundation. T50 assays and other biochemical assays were funded by a research grant from Sanofi Renal Corporation.

Trial registration: NCT00745589.

Keywords: Aortic stiffness; calcification propensity; heart valve calcification; hyperphosphatemia; lipid lowering; non–calcium-containing; phosphorus binder; pulse wave velocity; sevelamer; vascular calcification.

Graphical abstract

Figure 1

Study consort diagram. Abbreviations: PD, peritoneal dialysis; PTH, parathyroid hormone; PTx, parathyroidectomy.

Figure 2

(A) CACS, (B) AVCS, and (C) MACS at the baseline, week 48, and week 104 in the low-dose and high-dose sevelamer treatment groups (median [interquartile range] in box plots) and within-group changes calculated using the Wilcoxon signed-rank test. Changes in (D) CACS, (E) AVCS, and (F) MACS over 104 weeks in the low-dose and high-dose sevelamer treatment groups (median [interquartile range] in box plots) and between-group differences calculated using the Mann-Whitney U test. (G) Proportion (%) of rapid progressors of coronary artery calcification in the low-dose and high-dose treatment groups. (H) Proportion (%) of rapid progressors of coronary artery calcification among those with a CACS of ≥100 at the time of study entry. (I) Serial aortic PWV (mean ± standard error) over 104 weeks in the 2 treatment groups. Abbreviations: AVCS, aortic valve calcium score; CACS, coronary artery calcium score; MACS, mitral annulus calcium score; PWV, pulse wave velocity.

Figure 2

(A) CACS, (B) AVCS, and (C) MACS at the baseline, week 48, and week 104 in the low-dose and high-dose sevelamer treatment groups (median [interquartile range] in box plots) and within-group changes calculated using the Wilcoxon signed-rank test. Changes in (D) CACS, (E) AVCS, and (F) MACS over 104 weeks in the low-dose and high-dose sevelamer treatment groups (median [interquartile range] in box plots) and between-group differences calculated using the Mann-Whitney U test. (G) Proportion (%) of rapid progressors of coronary artery calcification in the low-dose and high-dose treatment groups. (H) Proportion (%) of rapid progressors of coronary artery calcification among those with a CACS of ≥100 at the time of study entry. (I) Serial aortic PWV (mean ± standard error) over 104 weeks in the 2 treatment groups. Abbreviations: AVCS, aortic valve calcium score; CACS, coronary artery calcium score; MACS, mitral annulus calcium score; PWV, pulse wave velocity.

Figure 3

Serial (A) mean serum calcium and phosphorus, (B) alkaline phosphatase, (C) iPTH, (D) low-density lipoprotein cholesterol, and (E) serum T50 over 104 weeks in the low-dose and high-dose sevelamer treatment groups. Data are presented as mean ± standard error, except alkaline phosphatase, which is presented as median (interquartile range) in box plots. Abbreviations: iPTH; intact parathyroid hormone; PO4, phosphorus; T50, calcification propensity test.