Effect of Sevelamer Carbonate on Oxidative Stress in Patients With Diabetic Nephropathy

Diabetic Nephropathy

Diabetic nephropathy, CKD progression, AGEs, oxidative stress, dietary AGEs

The purpose of this study is to determine whether oral sevelamer carbonate binds advanced glycation end products (AGEs) in the gastrointestinal (GI) tract of patients with diabetic nephropathy leading to decrease body AGE load and therefore decreases the inflammation and oxidative stress in these patients.

Traditional vascular risk factors alone cannot account for the elevated cardiovascular risk in patients with chronic kidney disease (CKD). In addition to a high prevalence of hypertension and diabetes, patients with CKD have elevated levels of inflammatory markers and OS, which are emerging as important risk factors for cardiovascular disease (CVD). Patients with CKD are also known to have elevated levels of circulating advanced glycation end products (AGE's), which have been shown to induce OS and to play a central role in the development of diabetic microvascular and macrovascular complications. In CKD patients, AGE's accumulate secondary to decreased renal clearance and increased endogenous production in the setting of high levels of OS. Efforts to understand relationships between the multiple vascular risk factors in chronic kidney disease may lead to reduced morbidity and mortality in this population of patients. Sevelamer Hydrochloride is an anion exchange resin composed of multiple positively charged amine groups indicated for the treatment of hyperphosphatemia in patients with stage V CKD. The positively charged amine groups bind negatively charged dietary phosphate preventing systemic absorption. Sevelamer Hydrochloride has been shown to have the added benefits of lowering LDL levels, lowering highly sensitive C-reactive protein (hsCRP) levels, and improving insulin resistance. Patients treated with Sevelamer Hydrochloride have also been shown to have improved vascular compliance and reduced progression of coronary vascular calcification. Since AGE's are mostly negatively charged compounds, Sevelamer Carbonate by analogy, may have anti-AGE effects which could reduce inflammation and oxidative stress. Sevelamer Carbonate would have a major advantage over Calcium Carbonate-based phosphate binders, based on the fact that it would have the added advantage of reducing the levels of AGEs. The resultant reduction of both OS and inflammation would be expected to have an independent beneficial effect on the rate of progression of CKD and CVD. We have shown in CKD patients and in animal models that AGE's correlate with levels of OS, LDL, hsCRP, and insulin resistance. Additionally, these factors can be remediated in CKD and non-CKD diabetics by decreasing overall AGE load, particularly in the diet. To date, the effect of Sevelamer Hydrochloride or Sevelamer Carbonate on OS and circulating AGE levels has not been studied. The anti-inflammatory and lipid-lowering effects of Sevelamer Hydrochloride may occur through lowering serum AGE levels and OS. Sevelamer Carbonate is an improved form of Sevelamer Hydrochloride that has been shown to be a safe and effective alternative to calcium carbonate in the treatment of hyperphosphatemia in the earlier sta'ges of CKD without causing metabolic acidosis. The development of Sevelamer Carbonate provides an opportunity to study patients with earlier stages of CKD, and to determine if it prevents or slows the progression of CKD. We propose a study designed to compare the effects of calcium carbonate and of Sevelamer Carbonate on serum AGE levels and OS in patients with stage II-IV diabetic nephropathy. Hypothesis: Sevelamer Carbonate administration in persons with stage II-IV CKD, compared with calcium carbonate administration, will result in at least a: 1. 20% decrease in serum levels of AGE's; 2. 10% decease in inflammatory markers of CRP and VCAM-1, or of OS (AGER1/RAGE) in circulating mononuclear cells.

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