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], 20.72 to 20.29; P,0.001), serum CML (95% CI, 25.08 to 21.35; P#0.001), and intracellular CML (95% CI, 21.63 to 20.28; 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 a (95% CI, 1.38 to 2.73; P #0.001). SC also decreased proinflammatory factors such as TNF receptor 1 (95% CI, 21.56 to 20.72; P#0.001) and the receptor for AGEs (95% CI, 20.58 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, 21.71 to 20.27; P=0.01, interaction P=0.002), and reduced albuminuria in those aged ,65 years (95% CI, 21.15 to 20.07; P=0.03, interaction P=0.02) and non-Caucasians (95% CI, 21.11 to 20.22; 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.

Uremic Toxicity of Advanced Glycation End Products in CKD

“…150 Sirtuin1, an NAD + -dependent histone deacetylase that has anti-inflammatory, antiapoptotic, and antioxidant properties 155 and prevents calcification 156 and endothelial senescence, 157 is decreased by AGEs, such as MG. 158 In a recent clinical study in patients with type 2 diabetes mellitus and stages 2-4 diabetic kidney disease, sevelamer significantly increased antioxidant molecules, such as AGER1, Nrf2, and Sirtuin1, while decreasing prooxidant molecules, such as RAGE and AGEs. 159 Decreasing Endogenous Sources of AGEs Dialysis Several dialysis techniques are currently used, such as HD, hemofiltration (HF), hemodiafiltration, and peritoneal dialysis (PD).…”

The Low AGE Diet: A Neglected Aspect of Clinical Nephrology Practice?

“…A larger randomized study comparing sevelamer carbonate with calcium carbonate as parallel groups in 117 patients with type 2 diabetes and stages 2-4 CKD has essentially reproduced all the findings described in the previous crossover study [36]. Of interest, although the urinary albumin/creatinine ratio did not change in the overall group on sevelamer, subgroup analyses showed that the ratio was significantly decreased in subjects less than 65 years of age and in non-Caucasians [36].…”

Roles of microRNA-221/222 in type 2 diabetic patients with post-menopausal breast cancer

“…Binding of estrogen can stimulate proliferation of mammary glandular cells and gene expression; it can also cause DNA damage by formation of oxidative products, and participate in the initiation and progression of breast cancer (Yubero-Serrano et al, 2015). High expression of miR-221/222 in breast cancer tissues causes insulin resistance and increases the metabolic load on pancreatic β cells.…”