Inflammation and premature aging in advanced chronic kidney disease

Systemic inflammation in end-stage renal disease (ESRD) is an established risk factor for mortality and a catalyst for other complications which are related to a premature aging phenotype, including muscle wasting, vascular calcification and other forms of premature vascular disease, depression, osteoporosis and frailty. Uremic inflammation is also mechanistically related to mechanisms involved in the aging process, such as telomere shortening, mitochondrial dysfunction, and altered nutrient sensing, which can have direct effect on cellular and tissue function. In addition to uremia-specific causes such as abnormalities in the phosphate- Klotho axis, there are remarkable similarities between the pathophysiology of uremic inflammation and so-called "inflammaging" in the general population. Potentially relevant, but still somewhat unexplored in this respect are abnormal or misplaced protein structures as well as abnormalities in tissue homeostasis, which evoke danger signals through damage associated molecular patters (DAMPS) as well as the senescence associated secretory phenotype (SASP). Systemic inflammation, in combination with the loss of kidney function, can impair the resilience of the body to external and internal stressors by reduced functional and structural tissue reserve, and by impairing normal organ crosstalk, thus providing an explanation for the greatly increased risk of homeostatic breakdown in this population. In this review, the relation between uremic inflammation and a premature aging phenotype, as well as potential causes and consequences are discussed

Methylglyoxal and glyoxalase I in atherosclerosis

Abstract Cardiovascular disease, caused predominantly by atherosclerotic plaque rupture, remains one of the leading causes of death. However, the mechanism of plaque rupture remains largely unknown. Recent studies have linked high metabolic activity in inflamed atherosclerotic plaques to the development of plaque rupture. AGEs (advanced glycation end-products) are known to be formed as a result of high metabolic activity and are higher in rupture-prone than stable plaques. Furthermore, AGEs seem to be more than mere markers of metabolic activity, as recent studies have elucidated that AGEs and their major precursor, MG (methylglyoxal), may have an important role in the progression of atherosclerosis and plaque rupture. MG can be detoxified by Glo1 (glyoxalase I), thereby preventing the accumulation of MG and MG-derived AGEs. In the present review, data concerning MG, Glo1 and AGEs in the context of plaque phenotype are discussed

Endoplasmic reticulum stress-induced apoptosis in the development of diabetes: is there a role for adipose tissue and liver?

Diabetes mellitus (DM) is a multifactorial chronic metabolic disease characterized by hyperglycaemia. Several different mechanisms have been implicated in the development of the disease, including endoplasmic reticulum (ER) stress. ER stress is increasingly acknowledged as an important mechanism in the development of DM, not only for β-cell loss but also for insulin resistance. Accumulating evidence suggests that ER stress-induced apoptosis may be an important mode of β-cell loss and therefore important in the development of diabetes. Recent data also suggest a role of ER stress-induced apoptosis in liver and adipose tissue in relation to diabetes, but more extensive studies on human adipocyte and hepatocyte (patho)physiology and ER stress are needed to identify the exact interactions between environmental signals, ER stress and apoptosis in these organs

The renewable energy and energy efficiency potential of Waitakere City : a thesis presented in partial fulfilment of the requirements for the degree of Masters of Technology in Energy Management at Massey University

Electricity restrictions and blackouts have occurred in Waitakere City in the past and are likely to occur again in the future unless the city can become more self reliant by meeting, at least in part, the increasing energy requirements for what is one of the fastest growing cities in New Zealand. In this study the potentials for energy conservation, energy efficiency and renewable energy resources have been broadly quantified and assessed using desktop analysis of publicly available data for stationary final use energy systems (i.e. excluding transportation) within the geographical area of Waitakere City and adjoining waters. It was found that energy efficiency and energy conservation measures can consistently and predictably achieve overall energy savings and reduce daily and seasonal peak demand. The best renewable energy resource potential exists with solar and geothermal for heating applications and wave, offshore and inshore wind and tidal currents for electricity generation. There is very limited potential for hydro and bioenergy systems beyond what already exists. PV solar and land based wind power generation are currently only feasible for limited off-grid applications. This scoping study confirms the achievability of the vision expressed in Waitakere City Council's "Long Term Council Community Plan" (LTCCP) that by 2020 " Waitakere City will be an energy cell, not an energy sink. Air quality supports good health". A range of flagship projects have been identified to progress the achievement of this vision. Waitakere City Council can use this report as part of the development of a comprehensive energy management plan

Higher Plasma Soluble Receptor for Advanced Glycation End Products (sRAGE) Levels Are Associated With Incident Cardiovascular Disease and All-Cause Mortality in Type 1 Diabetes: A 12-Year Follow-Up Study

To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and allcause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, arterial stiffness, and advanced glycation end products (AGEs). RESEARCH DESIGN AND METHODS - We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of sRAGE and other biomarkers were measured at baseline. The median follow-up duration was 12.3 years (7.6 -12.5). RESULTS - The incidence of fatal and nonfatal CVD and allcause mortality increased with higher baseline levels of log-transformed sRAGE (Ln-sRAGE) independently of other CVD risk factors: hazard ratio (HR) 1.90 (95% CI 1.13-3.21) and 2.12 (1.26 -3.57) per 1-unit increase in Ln-sRAGE, respectively. Adjustments for estimated glomerular filtration rate (eGFRMDRD), but not or to a smaller extent for markers of endothelial dysfunction, low-grade inflammation, arterial stiffness, and AGEs, attenuated these associations to HR 1.59 (95% CI 0.91-2.77) for fatal and nonfatal CVD events and to 1.90 (1.09 -3.31) for all-cause mortality. In addition, in patients with nephropathy, the rate of decline of GFR was 1.38 ml/min/1.73 m2 per year greater per 1-unit increase of Ln-sRAGE at baseline (P = 0.036). CONCLUSIONS - Higher levels of sRAGE are associated with incident fatal and nonfatal CVD and all-cause mortality in individuals with type 1 diabetes. sRAGE-associated renal dysfunction may partially explain this association

L(+) and D(−) Lactate Are Increased in Plasma and Urine Samples of Type 2 Diabetes as Measured by a Simultaneous Quantification of L(+) and D(−) Lactate by Reversed-Phase Liquid Chromatography Tandem Mass Spectrometry

Background. Plasma and urinary levels of D-lactate have been linked to the presence of diabetes. Previously developed techniques have shown several limitations to further evaluate D-lactate as a biomarker for this condition. Methods. D- and L-lactate were quantified using ultraperformance liquid chromatography tandem mass spectrometry with labelled internal standard. Samples were derivatized with diacetyl-L-tartaric anhydride and separated on a C18-reversed phase column. D- and L-lactate were analysed in plasma and urine of controls, patients with inflammatory bowel disease (IBD), and patients with type 2 diabetes (T2DM). Results. Quantitative analysis of D- and L-lactate was achieved successfully. Calibration curves were linear (r2 > 0.99) over the physiological and pathophysiological ranges. Recoveries for urine and plasma were between 96% and 113%. Inter- and intra-assay variations were between 2% and 9%. The limits of detection of D-lactate and L-lactate in plasma were 0.7 μmol/L and 0.2 μmol/L, respectively. The limits of detection of D-lactate and L-lactate in urine were 8.1 nmol/mmol creatinine and 4.4 nmol/mmol creatinine, respectively. Plasma and urinary levels of D- and L-lactate were increased in patients with IBD and T2DM as compared with controls. Conclusion. The presented method proved to be suitable for the quantification of D- and L-lactate and opens the possibility to explore the use of D-lactate as a biomarker

An advanced glycation endproduct (AGE)-rich diet promotes accumulation of AGEs in Achilles tendon

Advanced Glycation Endproducts (AGEs) accumulate in long‐lived tissue proteins like collagen in bone and tendon causing modification of the biomechanical properties. This has been hypothesized to raise the risk of orthopedic injury such as bone fractures and tendon ruptures. We evaluated the relationship between AGE content in the diet and accumulation of AGEs in weight‐bearing animal Achilles tendon. Two groups of mice (C57BL/6Ntac) were fed with either high‐fat diet low in AGEs high‐fat diet (HFD) (n = 14) or normal diet high in AGEs (ND) (n = 11). AGE content in ND was six to 50‐fold higher than HFD. The mice were sacrificed at week 40 and Achilles and tail tendons were carefully excised to compare weight and nonweight‐bearing tendons. The amount of the AGEs carboxymethyllysine (CML), methylglyoxal‐derived hydroimidazolone (MG‐H1) and carboxyethyllysine (CEL) in Achilles and tail tendon was measured using ultraperformance liquid chromatography tandem mass spectrometry (UPLC‐MS/MS) and pentosidine with high‐pressure liquid chromatography (HPLC) with fluorescent detection. AGEs in Achilles tendon were higher than in tail tendon for CML (P < 0.0001), CEL (P < 0.0001), MG‐H1 and pentosidine (for both ND and HFD) (P < 0.0001). The AGE‐rich diet (ND) resulted in an increase in CML (P < 0.0001), MG‐H1 (P < 0.001) and pentosidine (P < 0.0001) but not CEL, in Achilles and tail tendon. This is the first study to provide evidence for AGE accumulation in injury‐prone, weight‐bearing Achilles tendon associated with intake of an AGE‐rich diet. This indicates that food‐derived AGEs may alter tendon properties and the development of tendon injuries

Impact of type 2 diabetes and the metabolic syndrome on myocardial structure and microvasculature of men with coronary artery disease

<p>Abstract</p> <p>Background</p> <p>Type 2 diabetes and the metabolic syndrome are associated with impaired diastolic function and increased heart failure risk. Animal models and autopsy studies of diabetic patients implicate myocardial fibrosis, cardiomyocyte hypertrophy, altered myocardial microvascular structure and advanced glycation end-products (AGEs) in the pathogenesis of diabetic cardiomyopathy. We investigated whether type 2 diabetes and the metabolic syndrome are associated with altered myocardial structure, microvasculature, and expression of AGEs and receptor for AGEs (RAGE) in men with coronary artery disease.</p> <p>Methods</p> <p>We performed histological analysis of left ventricular biopsies from 13 control, 10 diabetic and 23 metabolic syndrome men undergoing coronary artery bypass graft surgery who did not have heart failure or atrial fibrillation, had not received loop diuretic therapy, and did not have evidence of previous myocardial infarction.</p> <p>Results</p> <p>All three patient groups had similar extent of coronary artery disease and clinical characteristics, apart from differences in metabolic parameters. Diabetic and metabolic syndrome patients had higher pulmonary capillary wedge pressure than controls, and diabetic patients had reduced mitral diastolic peak velocity of the septal mitral annulus (E'), consistent with impaired diastolic function. Neither diabetic nor metabolic syndrome patients had increased myocardial interstitial fibrosis (picrosirius red), or increased immunostaining for collagen I and III, the AGE Nε-(carboxymethyl)lysine, or RAGE. Cardiomyocyte width, capillary length density, diffusion radius, and arteriolar dimensions did not differ between the three patient groups, whereas diabetic and metabolic syndrome patients had reduced perivascular fibrosis.</p> <p>Conclusions</p> <p>Impaired diastolic function of type 2 diabetic and metabolic syndrome patients was not dependent on increased myocardial fibrosis, cardiomyocyte hypertrophy, alteration of the myocardial microvascular structure, or increased myocardial expression of Nε-(carboxymethyl)lysine or RAGE. These findings suggest that the increased myocardial fibrosis and AGE expression, cardiomyocyte hypertrophy, and altered microvasculature structure described in diabetic heart disease were a consequence, rather than an initiating cause, of cardiac dysfunction.</p

Kidney and vascular function in adult patients with hereditary fructose intolerance

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium. Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups. Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study.</p