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

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.