The Effects of Sevelamer Carbonate on Diabetic Nephropathy
The Effects of Sevelamer Carbonate on Diabetic Nephropathy
The purpose of this study is to see if taking a medication can lower the amount of oxidants
 from food that go into our body. Previous research shows that if the investigators lower the
 oxidants from food in people with diabetes, this simple change lowers different risks for
 heart disease and the worsening of kidney disease. The investigators focus on a specific type
 of oxidant, advanced glycation endproducts (AGEs). A previous, smaller study, conducted by
 our group showed that a drug, already approved by the FDA, will lower AGEs in the
 investigators compared Renvela® to Tums®. Both of these drugs have few side effects and have
 been used for a long time in patients with diabetes and kidney disease. While our previous
 study was interesting, it was just too small to be able to be sure that it will help all
 people with diabetes, or if the good effects the investigators found were simply due to
 chance. The investigators are doing this new study to confirm or deny the possibility that
 Renvela® can really help people with diabetes and kidney disease.
Advanced glycation end products (AGEs) levels are elevated in diabetic patients and in
 patients with chronic kidney disease (CKD) and may contribute to the excessive cardiovascular
 disease in this population, by promoting oxidant stress and chronic vascular inflammation. It
 has recently been recognized that AGEs in the body originate not only endogenously, but also
 from the ingestion of preformed AGEs in the diet. We have shown that reduction of dietary AGE
 intake leads to significant reductions of circulating AGEs and insulin levels as well as
 levels of markers of oxidative stress and inflammation in both diabetic and CKD patients.
 Thus, the increased inflammation and oxidative stress (Infl/OS) in stable diabetes mellitus
 (DM) are largely due to advanced glycation end products (AGEs) from food, and restricting
 AGEs-intake reduces these risk factors in DM. High circulating AGEs and TNFR1/2 have been
 shown to be associated with progression in diabetic nephropathy. Ideally, a compound that
 binds food AGEs within the lumen of the intestine should have the same effect as dietary
 restriction of AGEs and could become an important therapeutic tool in the clinical care of
 these patients. We found that Sevelamer binds AGEs in vitro in a pH dependent manner. This
 led us to hypothesize that sevelamer carbonate, but not calcium carbonate, would sequester
 AGEs in the gut and reduce Infl/OS, including circulating AGEs and TNFα, in T2DM with Stage
 2-4 CKD. This hypothesis was tested in a Pilot Study (GCO-08-0976) we designed as a
 proof-of-concept trial to determine if a larger and longer trial is indicated. We conducted a
 randomized, open-label, intention-to-treat, two-month crossover study to compare stable
 diabetic patients with stage 2-4 CKD treated with either Sevelamer carbonate or calcium
 carbonate for 2 months, a 1 week wash-out, and then the opposite drug for 2 months. There
 were no changes in medications and food intake. We found that urinary phosphate excretion was
 decreased by both Sevelamer carbonate and calcium carbonate. Serum AGEs, lipids, HbA1c,
 FGF23, and 8-isoprostanes were reduced by Sevelamer carbonate compared to calcium carbonate.
 In addition, PMNC levels of AGER1, SIRT1 and TNFα were also decreased by Sevelamer carbonate,
 compared to calcium carbonate. We concluded that Sevelamer carbonate reduces HbA1c, FGF23,
 lipids, and TNFα via reduced inflammation and OS in stage 2-4 diabetic CKD. These changes
 were not seen with calcium carbonate. Since we found that sevelamer carbonate bound AGE-BSA
 (but not BSA) at pH 7.0, but not at pH 1.0 in vitro, we proposed that the mechanism action is
 sequestration of dietary AGEs and GI elimination. Based on these data, we concluded that a
 larger and longer trial is indicated to confirm these results.

 The current study proposes to confirm that Sevelamer Carbonate, an agent known to prevent the
 gastrointestinal absorption of phosphates, is also able to block the absorption of AGEs and
 improve certain aspects of diabetes and chronic renal disease in a larger group of patients
 who will be followed for a longer period of time.
Inclusion Criteria:

 -  Age > 18 years

 -  Evidence of CKD Stages II, III or IV

 -  Stage II CKD; eGFR 60-89 ml/min

 -  Stage III CKD: eGFR 30-59 ml/min

 -  Stage IV CKD: eGFR 15-29 ml/min

 -  Proteinuria (>200 mg/day or 300 mg/gm creatinine on a spot urine) on urinalysis on two
 occasions within 18 months of recruitment

 -  Diagnosis of diabetes and receiving at least one medication for diabetes mellitus

 -  HbA1c>6.5%

 Exclusion criteria:

 -  Age <18

 -  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.