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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: 20% decrease in serum levels of AGE's; 10% decease in inflammatory markers of CRP and VCAM-1, or of OS (AGER1/RAGE) in circulating mononuclear cells.

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

Conditions
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Diabetic Nephropathy

Intervention / Treatment
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* Drug: Sevelamer Carbonate
* Drug: Calcium Carbonate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old Evidence of CKD II, III or IV Stage II CKD: eGFR 60-89 cc/min Stage III CKD: eGFR 30-59 cc/min Stage IV CKD: eGFR 15-20 cc/min Proteinuria on urinalysis on two occasions within 18 months of recruitment Diagnosis of diabetes and receiving at least one medication for diabetes mellitus. Exclusion Criteria: Age < 18 years old Stage I and V CKD Patients receiving active treatment for hyperphosphatemia. Biopsy proven renal disease other than diabetic nephropathy Hypophosphatemia Hypercalcemia any history of significant gastrointestinal disorders any history of significant gastrointestinal surgery such as ileostomy, colostomy and colectomy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Sevelamer Carbonate crossover<br>Participants will be patients with stage II-IV CKD due to diabetic nephropathy randomized to start either with sevelamer carbonate or calcium carbonate | Drug: Sevelamer Carbonate<br>* This is a 4 month, prospective, comparative, crossover study. The study will be conducted in 20 patients with stage II, III or stage IV diabetic nephropathy. Patients will be randomized 1:1 to receive either 1,250 mg of calcium carbonate TID with meals (control arm) or Sevelamer Carbonate 1,600 mg (two 800 mg tablets) with meals. Each group of 10 subjects will take the assigned drug for 8 weeks. Following the 8 week treatment period, subjects will discontinue the assigned drug for a one week washout period. Following the washout period, those who were taking calcium carbonate will be crossed over to Sevelamer Carbonate therapy and those who were receiving Sevelamer Carbonate will be crossed over to calcium carbonate for a final 8 week treatment phase.<br>|
| Other: Calcium Carbonate crossover<br>Participants will be patients with stage II-IV CKD due to diabetic nephropathy randomized to start either with sevelamer carbonate or calcium carbonate | Drug: Calcium Carbonate<br>* This is a 4 month, prospective, comparative, crossover study. The study will be conducted in 20 patients with stage II, III or stage IV diabetic nephropathy. Patients will be randomized 1:1 to receive either 1,250 mg of calcium carbonate TID with meals (control arm) or Sevelamer Carbonate 1,600 mg (two 800 mg tablets) with meals. Each group of 10 subjects will take the assigned drug for 8 weeks. Following the 8 week treatment period, subjects will discontinue the assigned drug for a one week washout period. Following the washout period, those who were taking calcium carbonate will be crossed over to Sevelamer Carbonate therapy and those who were receiving Sevelamer Carbonate will be crossed over to calcium carbonate for a final 8 week treatment phase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| serum AGE levels | To compare the effect of Sevelamer Carbonate versus calcium carbonate on serum AGE levels in patients with stage II-IV chronic kidney disease resulting from diabetic nephropathy from baseline to 2 months and to 4 months later. | baseline | 
| serum AGE levels | To compare the effect of Sevelamer Carbonate versus calcium carbonate on serum AGE levels in patients with stage II-IV chronic kidney disease resulting from diabetic nephropathy from baseline to 2 months and to 4 months later. | at 2 months | 
| serum AGE levels | To compare the effect of Sevelamer Carbonate versus calcium carbonate on serum AGE levels in patients with stage II-IV chronic kidney disease resulting from diabetic nephropathy from baseline to 2 months and to 4 months later. | at 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| inflammatory markers | To compare the effect of sevelamer carbonate versus calcium carbonate on markers of inflammation, oxidative stress, and serum lipid levels in patients with stage II-IV CKD resulting from diabetic nephropathy. | baseline | 
| inflammatory markers | To compare the effect of sevelamer carbonate versus calcium carbonate on markers of inflammation, oxidative stress, and serum lipid levels in patients with stage II-IV CKD resulting from diabetic nephropathy. | at 2 months | 
| inflammatory markers | To compare the effect of sevelamer carbonate versus calcium carbonate on markers of inflammation, oxidative stress, and serum lipid levels in patients with stage II-IV CKD resulting from diabetic nephropathy. | at 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic nephropathy, CKD progression, AGEs, oxidative stress, dietary AGEs