Managing Chronic Inflammation in the Aging Diabetic Patient With CKD by Diet or Sevelamer Carbonate: A Modern Paradigm Shift

Division of Experimental Diabetes and Aging, Department of Geriatrics and Palliative Care, Mount Sinai School of Medicine, 1 Gustave Levy Place, NY 10029. .
The Journals of Gerontology Series A Biological Sciences and Medical Sciences (Impact Factor: 5.42). 10/2012; 67(12). DOI: 10.1093/gerona/gls195
Source: PubMed


The maintenance of normal metabolism and body defenses depends on the balance between cellular antioxidant and anti-inflammatory factors. This balance can be disrupted by agents/mechanisms in the extracellular milieu that induce excess reactive oxygen species (ROS) and inflammation. Cytopathic advanced glycation endproducts, present in ever increasing amounts in the modern diet, are one of the major environmental factors that cause excess ROS and/or inflammation at all ages and induce complications in aging, such as chronic kidney disease (CKD) and type 2 diabetes. Increased ROS and/or inflammation are present in both aging and CKD, and are associated with reduced cellular defenses against ROS and/or inflammation. Affected individuals have reduced defenses against further stress and are predisposed to organ failure, now a well-known phenomenon in aging. Thus, new methods are urgently needed to safely reduce ROS and/or inflammation in the aging type 2 diabetes patient with CKD. Studies of both normal aging and diabetic patients with kidney disease underline the fact that increased ROS and/or inflammation can be managed in these conditions by economical, safe, and effective interventions that reduce the uptake of advanced glycation endproducts by either modifying preparation of food or an oral drug. This communication reviews these data and adds new information on the efficacy of a drug, sevelamer carbonate, required to reduce ROS and/or inflammation in the aging type 2 diabetes patient complicated by CKD. If larger and longer studies confirm the hypothesis that one or both of these interventions reduce progression of CKD, it could represent a new paradigm in the management of complications in the type 2 diabetes patient with CKD.

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    • "Overall the positive results obtained with the two diets in our short-term study may be explained in part by the wellbeing (emotional and physical) state of our patients since they were located close to the sea, had a strict control on the caloric intake, perform regular (monitored) physical activity improving their overall quality of life. The greater effect of the Ma-Pi 2 diet compared to the control diet on a number of metabolic parameters may be due to several factors, from changes in inflammation and/or oxidative stress [37] to the composition of microbiota [22]. Ongoing studies should elucidate all these issues, hence a long-term sustainability of the Ma-Pi 2 diet, in particular the acceptance and adherence of the patient to the diet, the implying costs in the patient management remain to be proven. "
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    ABSTRACT: Diet is an important component of type 2 diabetes therapy. Low adherence to current therapeutic diets points out to the need for alternative dietary approaches. This study evaluated the effect of a different dietary approach, the macrobiotic Ma-Pi 2 diet, and compared it with standard diets recommended for patients with type 2 diabetes. A randomized, controlled, open-label, 21-day trial was undertaken in patients with type 2 diabetes comparing the Ma-Pi 2 diet with standard (control) diet recommended by professional societies for treatment of type 2 diabetes. Changes in fasting blood glucose (FBG) and post-prandial blood glucose (PPBG) were primary outcomes. HbA1c, insulin resistance (IR), lipid panel and anthropometrics were secondary outcomes. After correcting for age, gender, BMI at baseline, and physical activity, there was a significantly greater reduction in the primary outcomes FBG (95% CI: 1.79; 13.46) and PPBG (95% CI: 5.39; 31.44) in those patients receiving the Ma-Pi 2 diet compared with those receiving the control diet. Statistically significantly greater reductions in the secondary outcomes, HbA1c (95% CI: 1.28; 5.46), insulin resistance, total cholesterol, LDL cholesterol and LDL/HDL ratio, BMI, body weight, waist and hip circumference were also found in the Ma-Pi 2 diet group compared with the control diet group. The latter group had a significantly greater reduction of triglycerides compared with the Ma-Pi 2 diet group. Intervention with a short-term Ma-Pi 2 diet resulted in significantly greater improvements in metabolic control in patients with type 2 diabetes compared with intervention with standard diets recommended for these patients. Trial registration Current Controlled Trials ISRCTN10467793.
    Full-text · Article · Aug 2014 · Nutrition & Metabolism
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    • "In addition to lowering serum phosphate and reducing calcium burden, sevelamer hydrochloride or carbonate exerts diverse pleiotropic effects on parameters associated with cardiovascular risk in CKD/ESRD [Evenepoel, 2007; Nikolov et al. 2006] many of which may be mediated by their relationships to endothelial function. Specific effects and individual studies are summarized in Table 2. Broad categories of effects include direct improvements in endothelial and/or vascular function [Brandenburg et al. 2009, 2010; Caglar et al. 2008; Takenaka and Suzuki, 2005; Yilmaz et al. 2012]; reduced progression of vascular calcification in patients with dialysis-dependent ESRD [Asmus et al. 2005; Block et al. 2005; Braun et al. 2004; Chertow et al. 2002, 2003; Kakuta et al. 2011; Shantouf et al. 2010] or predialysis CKD [Caglar et al. 2008; Di Iorio et al. 2012; Russo et al. 2007]; reduced absorption of bile acids from the gut [Braunlin et al. 2002], leading to lower serum total and LDL cholesterol [Bleyer et al. 1999; Di Iorio et al. 2012; Evenepoel et al. 2009; Ferramosca et al. 2005; Gulati et al. 2010; Hervas et al. 2003; Lin et al. 2011], reduced absorption of endotoxin from gut bacteria [Stinghen et al. 2010; Sun et al. 2009], lower levels of inflammatory mediators and biomarkers [Caglar et al. 2008; Ferramosca et al. 2005; Shantouf et al. 2008, 2010; Stinghen et al. 2010; Sun et al. 2009; Yamada et al. 2005], reduced absorption of dietary AGEs [Vlassara et al. 2012a], and decreased carotid intima-media thickness (CIMT), a surrogate marker of atherosclerosis [Boaz et al. 2011]. CKD fosters pro-atherogenic conditions through multiple pathways, including oxidative stress, increased infection and inflammation, decreased clearance of inflammatory mediators, increased formation and decreased clearance of AGEs, LDL oxidation, and adverse changes in endothelial and vascular smooth muscle cells [Stenvinkel et al. 2003]. "
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    ABSTRACT: Endothelial dysfunction underlies multiple cardiovascular consequences of chronic kidney disease (CKD) and antecedent diabetes or hypertension. Endothelial insults in CKD or end-stage renal disease (ESRD) patients include uremic toxins, serum uric acid, hyperphosphatemia, reactive oxygen species, and advanced glycation endproducts (AGEs). Sevelamer carbonate, a calcium-free intestinally nonabsorbed polymer, is approved for hyperphosphatemic dialysis patients in the US and hyperphosphatemic stage 3-5 CKD patients in many other countries. Sevelamer has been observed investigationally to reduce absorption of AGEs, bacterial toxins, and bile acids, suggesting that it may reduce inflammatory, oxidative, and atherogenic stimuli in addition to its on-label action of lowering serum phosphate. Some studies also suggest that noncalcium binders may contribute less to vascular calcification than calcium-based binders. Exploratory sevelamer carbonate use in patients with stages 2-4 diabetic CKD significantly reduced HbA1c, AGEs, fibroblast growth factor (FGF)-23, and total and low-density lipoprotein (LDL) cholesterol versus calcium carbonate; inflammatory markers decreased and defenses against AGEs increased. Sevelamer has also been observed to reduce circulating FGF-23, potentially reducing risk of left ventricular hypertrophy. Sevelamer but not calcium-based binders in exploratory studies increases flow-mediated vasodilation, a marker of improved endothelial function, in patients with CKD. In contrast, lanthanum carbonate and calcium carbonate effects on FMV did not differ in hemodialysis recipients. The recent INDEPENDENT-CKD randomized trial compared sevelamer versus calcium carbonate in predialysis CKD patients (investigational in the US, on-label in European participants); sevelamer reduced 36-month mortality and the composite endpoint of mortality or dialysis inception. Similarly, INDEPENDENT-HD in incident dialysis patients showed improved survival with 24 months of sevelamer versus calcium-based binders. This review discusses recent exploratory evidence for pleiotropic effects of sevelamer on endothelial function in CKD or ESRD. Endothelial effects of sevelamer may contribute mechanistically to the improved survival observed in some studies of CKD and ESRD patients.
    Full-text · Article · Dec 2013 · Therapeutic Advances in Cardiovascular Disease

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