title: Effects of sevelamer carbonate on advanced glycation end products and antioxidant/pro-oxidant status in patients with diabetic kidney disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Lipid and Atherosclerosis Unit/IMIBIC/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain and CIBER Fisiopatholigia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain;
authors.forename: Elena M
authors.initials: EM
authors.lastname: Yubero-Serrano
authors.affiliation: The George Institute for Global Health, University of Oxford, Oxford, United Kingdom; University of Sydney, Sydney, New South Wales, Australia;
authors.forename: Mark
authors.initials: M
authors.lastname: Woodward
authors.affiliation: Divisions of Endocrinology and Nephrology, Department of Medicine, and.
authors.forename: Leonid
authors.initials: L
authors.lastname: Poretsky
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics, Divisions of Icahn School of Medicine at Mount Sinai, New York, New York; and Divisions of Endocrinology and.
authors.forename: Helen
authors.initials: H
authors.lastname: Vlassara
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics, Divisions of Icahn School of Medicine at Mount Sinai, New York, New York; and Nephrology, Department of Medicine, and Mount Sinai Health System, New York, New York gary.striker@mssm.edu.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Striker
mesh_terms: D052242:Adiponectin / Q000097:blood; D000367:Age Factors; D000368:Aged; D000419:Albuminuria / Q000188:drug therapy; D002614:Chelating Agents / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000097:blood* / Q000188:drug therapy*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D047628:Estrogen Receptor alpha / Q000097:blood; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D057194:Intention to Treat Analysis; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000097:blood / Q000235:genetics; D011765:Pyruvaldehyde / Q000097:blood; D012333:RNA, Messenger / Q000097:blood; D000067759:Receptor for Advanced Glycation End Products / Q000097:blood / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood / Q000235:genetics; D000069603:Sevelamer / Q000627:therapeutic use*; D012737:Sex Factors; D016037:Single-Blind Method; D056564:Sirtuin 1 / Q000097:blood / Q000235:genetics; D044465:White People
chemical_list: D052242:Adiponectin; D002614:Chelating Agents; D015237:Dinoprost; D047628:Estrogen Receptor alpha; D006442:Glycated Hemoglobin; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D008239:Lysine; D008687:Metformin; D051267:NF-E2-Related Factor 2; D011765:Pyruvaldehyde; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D047888:Receptors, Tumor Necrosis Factor, Type I; D000069603:Sevelamer; D056564:Sirtuin 1; C495635:NFE2L2 protein, human; C517652:hemoglobin A1c protein, human; C075750:8-epi-prostaglandin F2alpha; C048496:N(6)-carboxymethyllysine
keywords: advanced glycation end product; albuminuria; diabetic nephropathy; ethnicity; oxidative stress