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      Metabolic Changes in Summer Active and Anuric Hibernating Free-Ranging Brown Bears ( Ursus arctos)

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          Abstract

          The brown bear ( Ursus arctos) hibernates for 5 to 6 months each winter and during this time ingests no food or water and remains anuric and inactive. Despite these extreme conditions, bears do not develop azotemia and preserve their muscle and bone strength. To date most renal studies have been limited to small numbers of bears, often in captive environments. Sixteen free-ranging bears were darted and had blood drawn both during hibernation in winter and summer. Samples were collected for measurement of creatinine and urea, markers of inflammation, the calcium-phosphate axis, and nutritional parameters including amino acids. In winter the bear serum creatinine increased 2.5 fold despite a 2-fold decrease in urea, indicating a remarkable ability to recycle urea nitrogen during hibernation. During hibernation serum calcium remained constant despite a decrease in serum phosphate and a rise in FGF23 levels. Despite prolonged inactivity and reduced renal function, inflammation does not ensue and bears seem to have enhanced antioxidant defense mechanisms during hibernation. Nutrition parameters showed high fat stores, preserved amino acids and mild hyperglycemia during hibernation. While total, essential, non-essential and branched chain amino acids concentrations do not change during hibernation anorexia, changes in individual amino acids ornithine, citrulline and arginine indicate an active, although reduced urea cycle and nitrogen recycling to proteins. Serum uric acid and serum fructose levels were elevated in summer and changes between seasons were positively correlated. Further studies to understand how bears can prevent the development of uremia despite minimal renal function during hibernation could provide new therapeutic avenues for the treatment of human kidney disease.

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          Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure.

          Atherosclerotic cardiovascular disease and malnutrition are widely recognized as leading causes of the increased morbidity and mortality observed in uremic patients. C-reactive protein (CRP), an acute-phase protein, is a predictor of cardiovascular mortality in nonrenal patient populations. In chronic renal failure (CRF), the prevalence of an acute-phase response has been associated with an increased mortality. One hundred and nine predialysis patients (age 52 +/- 1 years) with terminal CRF (glomerular filtration rate 7 +/- 1 ml/min) were studied. By using noninvasive B-mode ultrasonography, the cross-sectional carotid intima-media area was calculated, and the presence or absence of carotid plaques was determined. Nutritional status was assessed by subjective global assessment (SGA), dual-energy x-ray absorptiometry (DXA), serum albumin, serum creatinine, serum urea, and 24-hour urine urea excretion. The presence of an inflammatory reaction was assessed by CRP, fibrinogen (N = 46), and tumor necrosis factor-alpha (TNF-alpha; N = 87). Lipid parameters, including Lp(a) and apo(a)-isoforms, as well as markers of oxidative stress (autoantibodies against oxidized low-density lipoprotein and vitamin E), were also determined. Compared with healthy controls, CRF patients had an increased mean carotid intima-media area (18.3 +/- 0.6 vs. 13.2 +/- 0.7 mm2, P or = 10 mg/liter). Malnourished patients had higher CRP levels (23 +/- 3 vs. 13 +/- 2 mg/liter, P < 0.01), elevated calculated intima-media area (20.2 +/- 0.8 vs. 16.9 +/- 0.7 mm2, P < 0.01) and a higher prevalence of carotid plaques (90 vs. 60%, P < 0.0001) compared with well-nourished patients. During stepwise multivariate analysis adjusting for age and gender, vitamin E (P < 0.05) and CRP (P < 0.05) remained associated with an increased intima-media area. The presence of carotid plaques was significantly associated with age (P < 0.001), log oxidized low-density lipoprotein (oxLDL; P < 0.01), and small apo(a) isoform size (P < 0.05) in a multivariate logistic regression model. These results indicate that the rapidly developing atherosclerosis in advanced CRF appears to be caused by a synergism of different mechanisms, such as malnutrition, inflammation, oxidative stress, and genetic components. Apart from classic risk factors, low vitamin E levels and elevated CRP levels are associated with an increased intima-media area, whereas small molecular weight apo(a) isoforms and increased levels of oxLDL are associated with the presence of carotid plaques.
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            Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease.

            Currently, we are experiencing an epidemic of cardiorenal disease characterized by increasing rates of obesity, hypertension, the metabolic syndrome, type 2 diabetes, and kidney disease. Whereas excessive caloric intake and physical inactivity are likely important factors driving the obesity epidemic, it is important to consider additional mechanisms. We revisit an old hypothesis that sugar, particularly excessive fructose intake, has a critical role in the epidemic of cardiorenal disease. We also present evidence that the unique ability of fructose to induce an increase in uric acid may be a major mechanism by which fructose can cause cardiorenal disease. Finally, we suggest that high intakes of fructose in African Americans may explain their greater predisposition to develop cardiorenal disease, and we provide a list of testable predictions to evaluate this hypothesis.
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              Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers.

              Hyperphosphatemia is a risk factor for the development of several different complications of chronic kidney disease (CKD), including secondary hyperparathyroidism and cardiovascular complications, due to the formation of calcium-phosphate deposits. Fibroblast growth factor-23 (FGF-23) is a recently discovered protein that is mutated in autosomal-dominant hypophosphatemic rickets, an inherited phosphate wasting disorder, and it may represent a novel hormonal regulator of phosphate homeostasis. We therefore hypothesized that FGF-23 levels may be altered in hyperphosphatemia associated with renal failure and that its concentration changes in response to different levels of phosphate intake. Using a two-site enzyme-linked immunosorbent assay (ELISA) detecting the C-terminal portion of FGF-23, serum concentration was measured in 20 patients with different stages of renal failure (creatinine range 155 to 724 micromol/L), in 33 patients with end-stage renal disease (ESRD) on dialysis treatment, and in 30 patients with functioning renal grafts. Furthermore, six healthy males were given oral phosphate binders in combination with low dietary phosphate intake for 2 days followed by 3 days of repletion with inorganic phosphate. FGF-23 levels were determined at multiple time points. FGF-23 serum levels were significantly elevated in CKD with a strong correlation between serum creatinine and FGF-23 concentration. Independent correlations were also seen between FGF-23 and phosphate, calcium, parathyroid hormone (PTH), and 1,25(OH)2D3. No changes in serum FGF-23 levels were observed in volunteers following ingestion of oral phosphate binders/low dietary phosphate intake, which led to a decline in phosphate excretion or during the subsequent repletion with inorganic phosphate through oral phosphate and a normal diet. Circulating FGF-23 was significantly elevated in patients with CKD and its concentration correlated with renal creatinine clearance. In healthy volunteers, FGF-23 levels did not change after phosphate deprivation or phosphate loading.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                9 September 2013
                : 8
                : 9
                : e72934
                Affiliations
                [1 ]Division of Renal Medicine, Department of Clinical Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
                [2 ]Department of Cardiology, University Hospital of Örebro, Örebro, Sweden
                [3 ]Department of Medical & Health Sciences, Experimental Renal Medicine, Linköping University, Linköping, Sweden
                [4 ]Zoologisches Institut, Goethe-Universität, Frankfurt am Main, Germany
                [5 ]Faculty of Arts & Sciences, Department of Environmental & Health Studies, Telemark University College, Porsgrunn, Norway
                [6 ]Institute for Wildlife Biology & Game Management, University for Natural Research & Life Sciences, Vienna, Austria
                [7 ]Department of Nephrology, Aarhus University Hospital, Aarhus, Denmark
                [8 ]Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden
                [9 ]INSERM Unit 872-E2, Centre de Recherche des Cordeliers, Paris, France
                [10 ]Division of Renal Diseases and Hypertension, University of Colorado Denver, Denver, Colorado, United States of America
                University of Sao Paulo Medical School, Brazil
                Author notes

                Competing Interests: Dr. Johnson is listed as an inventor on two patents related to lowering uric acid as a means for treating hypertension (Treatment for Cardiovascular Disease US Patent No 7,799,794 B2, Issued Sep 21, 2010) or insulin resistance (Compositions and Methods for Treatment and Prevention of Insulin Resistance Serial No. 11/572,270; filed January 18, 2007 Serial No. 11/572,270; filed January 18, 2007, approved June 23, 2013). He also has patent applications related to blocking fructokinase in metabolic diseases. He has received funding from the NIH, State of Colorado, Danone, Questcor and Amway, and is on the Scientific Board of Amway. He has two lay books (The Sugar Fix, Rodale, 2008 and The Fat Switch, Mercola.com, 2012). None of these declarations are relevant to the current study. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: OF AF AZ JJ MS BS. Performed the experiments: BA ME ACB. Analyzed the data: PS BA LB RJ. Contributed reagents/materials/analysis tools: PS TL BA ARQ. Wrote the paper: PS OF FP TL AZ LB RJ.

                Article
                PONE-D-13-22044
                10.1371/journal.pone.0072934
                3767665
                24039826
                f001c079-ca7c-4705-9b5f-9fc640a6ebce
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 May 2013
                : 12 July 2013
                Page count
                Pages: 9
                Funding
                Peter Stenvinkel's research benefited from support by Swedish Medical Research Council (VR). The authors thank the field personnel of the Scandinavian Brown Bear Research Project (SBBRP). The SBBRP was funded by the Swedish Environmental Protection Agency, the Norwegian Directorate for Nature Management, the Swedish Association for Hunting and Wildlife Management, the Research Council of Norway, and the Austrian Science Foundation a Nordforsk research network grant (project no. 44042) and The Lundbeck Foundation (R126-2012-12408). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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