Effects of sevelamer carbonate on advanced glycation end products and antioxidant/pro-oxidant status in patients with diabetic kidney disease

Abstract

Background and objectives: The primary goals were to re-examine whether sevelamer carbonate (SC) reduces advanced glycation end products (AGEs) (methylglyoxal and carboxymethyllysine [CML]), increases antioxidant defenses, reduces pro-oxidants, and improves hemoglobin A1c (HbA1c) in patients with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD). Secondary goals examined albuminuria, age, race, sex, and metformin prescription.

Design, setting, participants, & measurements: This two-center, randomized, intention-to-treat, open-label study evaluated 117 patients with T2DM (HbA1c >6.5%) and stages 2-4 DKD (urinary albumin/creatinine ratio ≥200 mg/g) treated with SC (1600 mg) or calcium carbonate (1200 mg), three times a day, without changing medications or diet. Statistical analyses used linear mixed models adjusted for randomization levels. Preselected subgroup analyses of sex, race, age, and metformin were conducted.

Results: SC lowered serum methylglyoxal (95% confidence interval [CI], -0.72 to -0.29; P<0.001), serum CML (95% CI, -5.08 to -1.35; P≤0.001), and intracellular CML (95% CI, -1.63 to -0.28; P=0.01). SC increased anti-inflammatory defenses, including nuclear factor like-2 (95% CI, 0.58 to 1.29; P=0.001), AGE receptor 1 (95% CI, 0.23 to 0.96; P=0.001), NAD-dependent deacetylase sirtuin-1 (95% CI, 0.20 to 0.86; P=0.002), and estrogen receptor α (95% CI, 1.38 to 2.73; P ≤0.001). SC also decreased proinflammatory factors such as TNF receptor 1 (95% CI, -1.56 to -0.72; P≤0.001) and the receptor for AGEs (95% CI, -0.58 to 1.53; P≤0.001). There were no differences in HbA1c, GFR, or albuminuria in the overall group. Subanalyses showed that SC lowered HbA1c in women (95% CI, -1.71 to -0.27; P=0.01, interaction P=0.002), and reduced albuminuria in those aged <65 years (95% CI, -1.15 to -0.07; P=0.03, interaction P=0.02) and non-Caucasians (95% CI, -1.11 to -0.22; P=0.003, interaction P≤0.001), whereas albuminuria increased after SC and calcium carbonate in Caucasians.

Conclusions: SC reduced circulating and cellular AGEs, increased antioxidants, and decreased pro-oxidants, but did not change HbA1c or the albumin/creatinine ratio overall in patients with T2DM and DKD. Because subanalyses revealed that SC may reduce HbA1c and albuminuria in some patients with T2DM with DKD, further studies may be warranted.

Keywords: advanced glycation end product; albuminuria; diabetic nephropathy; ethnicity; oxidative stress.

Copyright © 2015 by the American Society of Nephrology.

Figures

Figure 1.

Study design. MI, myocardial infraction.

Figure 2.

Effect of sevelamer carbonate and calcium carbonate on circulating and intracellular AGEs and pro-oxidant and inflammatory factors and antioxidant/anti-inflammatory factors in type 2 diabetes mellitus with diabetic kidney disease. After 6 months on sevelamer carbonate (closed bars) or calcium carbonate (open bars), changes are shown as the percentage from randomization levels (mean±SD). *P≤0.05, statistical significance in percent changes between sevelamer carbonate (SC) and calcium carbonate (CC) groups; **P≤0.05, significance between randomization and mean of the 3- and 6-month values within each group. s, serum; CML, carboxymethyllysine; MG, methylglyoxal; i, intracellular; 8-iso, 8-isoprostane; TNFR1, TNF receptor 1; RAGE, receptor for advanced glycation end products; AGE, advanced glycation end product; SIRT1, NAD-dependent deacetylase sirtuin-1; AGER1, advanced glycation end product receptor 1; ERα, estrogen receptor α; Nrf2, nuclear factor (erythroid-derived 2)-like 2.