S. Arsov

Advanced glycation end-products and skin autofluorescence in end-stage renal disease: a review

Abstract Chronic kidney disease (CKD), especially in its end stage, is marked by extremely high cardiovascular rates of morbidity and mortality; hemodialysis patients have a five-fold shorter life expectancy than healthy subjects of the same age. In CKD the metabolic products that accumulate in the body are so-called uremic toxins. These include advanced glycation end-products (AGE). AGE levels are markedly increased in CKD patients not only because of impaired excretion but also because of increased production. AGE formation has initially been described as a non-enzymatic reaction between proteins and glucose in the so-called Maillard reaction, but they are also more rapidly formed during oxidative stress and subsequent formation of reactive carbonyl compounds like (methyl)glyoxal. AGE accumulate in tissue where they cross-link with proteins, e.g., collagen, inducing tissue stiffening of blood vessels and skin. They may also interact with receptor of AGE (RAGE) and other receptors, which lead to activation of intracellular transduction mechanisms resulting in cytokine release and further tissue damage in CKD. The accumulation of AGE in the skin can be measured non-invasively using autofluorescence. The skin autofluorescence is a strong marker of cardiovascular mortality in CKD. The focus of this review is on the role of tissue and plasma AGE, and of skin autofluorescence as a proxy of tissue AGE accumulation, in the increase in cardiovascular disease in end stage renal disease (ESRD). This review will also present the possibility of reducing the AGE accumulation in ESRD patients using the following five methods: 1) use of low AGE peritoneal dialysis solutions; 2) use of advanced hemodialysis techniques; 3) use of AGE reducing drugs; 4) optimizing the nutrition of hemodialysis patients; and 5) renal transplantation.

Increase in Skin Autofluorescence and Release of Heart-Type Fatty Acid Binding Protein in Plasma Predicts Mortality of Hemodialysis Patients

Advanced glycation end-products (AGEs) are uremic toxins that accumulate progressively in hemodialysis (HD) patients. The aim of this study was to assess the 1-year increase in skin autofluorescence (ΔAF), a measure of AGEs accumulation and plasma markers, as predictors of mortality in HD patients. One hundred sixty-nine HD patients were enrolled in this study. Skin autofluorescence was measured twice, 1 year apart using an AGE Reader (DiagnOptics Technologies BV, Groningen, The Netherlands). Besides routine blood chemistry, additional plasma markers including superoxide dismutase, myeloperoxydase, intercellular adhesion molecule 1 (ICAM-1), C-reactive protein (hs-CRP), heart-type fatty acid binding protein (H-FABP), and von Willebrand factor were measured at baseline. The mortality of HD patients was followed for 36 months. Skin autofluorescence values of the HD patients at the two time points were significantly higher (P < 0.001) than those of healthy subjects of the same age. Mean 1-year ΔAF of HD patients was 0.16 ± 0.06, which was around seven- to ninefold higher than 1-year ΔAF in healthy subjects. Multivariate Cox regression showed that age, hypertension, 1-year ΔAF, hs-CRP, ICAM-1, and H-FABP were independent predictors of overall mortality. Hypertension, 1-year ΔAF, hs-CRP, and H-FABP were also independent predictors of cardiovascular mortality. One-year ΔAF and plasma H-FABP, used separately and in combination, are strong predictors of overall and cardiovascular mortality in HD patients.

Skin and Plasma Autofluorescence During Hemodialysis: A Pilot Study

Skin autofluorescence (AF) is related to the accumulation of advanced glycation end products (AGEs) and is one of the strongest prognostic markers of mortality in hemodialysis (HD) patients. The aim of this pilot study was to investigate whether changes in skin AF appear after a single HD session and if they might be related to changes in plasma AF. Skin and plasma AF were measured before and after HD in 35 patients on maintenance HD therapy (nine women and 26 men, median age 68 years, range 33-83). Median dialysis time was 4 h (range 3-5.5). Skin AF was measured noninvasively with an AGE Reader, and plasma AF was measured before and after HD at 460 nm after excitation at 370 nm. The HD patients had on average a 65% higher skin AF value than age-matched healthy persons (P < 0.001). Plasma AF was reduced by 14% (P < 0.001), whereas skin AF was not changed after a single HD treatment. No significant influence of the reduced plasma AF on skin AF levels was found. This suggests that the measurement of skin AF can be performed during the whole dialysis period and is not directly influenced by the changes in plasma AF during HD.

Does hepatitis C increase the accumulation of advanced glycation end products in haemodialysis patients

BACKGROUND Hepatitis C may cause increased levels of oxidative stress that contribute to accumulation of advanced glycation end products (AGEs), which increase the risk of cardiovascular disease (CVD). The aim of this study was to determine the influence of hepatitis C on AGE accumulation in haemodialysis patients. METHODS AGE accumulation was measured by means of skin autofluorescence (AF) in 92 haemodialysis (HD) patients and 93 age-matched healthy controls. In the HD patients, CVD-related biochemical variables were also measured. The HD patients were tested for hepatitis C virus (HCV) antibodies and allocated to a HCV+ or HCV- group. RESULTS Skin AF of the healthy subjects was lower than skin AF in the HD patients (3.13 +/- 0.95 vs 2.2 +/- 0.47; P < 0.001). We calculated the average increase of skin AF in the healthy subjects to be 0.017 arbitrary units per year, being 14 times lower than in HD patients with CVD only and 20 times lower than in HD patients suffering from combined CVD and diabetes mellitus (DM). Multivariate regression analysis showed that AGE accumulation in HD patients can be described by the independent effects of age, DM, CVD and HD vintage. Although inter-cellular adhesion molecule 1 and liver enzymes were elevated in HCV+ HD patients, levels of oxidative stress markers and skin AF were not significantly different between HCV+ and HCV- HD patients. CONCLUSIONS AGE accumulation was higher in the HD patients than in the healthy controls. AGE accumulation did not differ in HCV+ and HCV- HD patients. This might be due to the fact that hepatitis C did not cause oxidative stress in our HD population. Independent markers of AGE accumulation were age, HD vintage, DM and CVD, but not hepatitis C.

The influence of body mass index on the accumulation of advanced glycation end products in hemodialysis patients.

Background/Objectives:The level of skin autofluorescence (AF) at a given moment is an independent predictor of mortality in hemodialysis (HD) patients. Skin AF is a measure of the accumulation of advanced glycation end products (AGEs). The aim of the study was to estimate the influence of nutrition on the 1-year increase of skin AF (ΔAF) in HD patients.Subjects/Methods:A total of 156 HD patients were enrolled in this study. Skin AF, body mass index (BMI), superoxide dismutase, myeloperoxidase, C-reactive protein, inter-cellular adhesion molecule-1, von Willebrand factor and heart-type fatty acid-binding protein were measured four times at intervals of approximately half a year. Data from the monthly routine blood analysis were also used. Daily calorie, protein and AGE intakes were assessed from food recordings over a period of 1 week.Results:A J-shaped relation was found between baseline BMI and ΔAF (P=0.01). The lowest point of the J-shaped curve is found for BMI=24.3 kg/m2. In the univariate analysis of the contributors to the 1-year ΔAF, we found that beside BMI=24.3 kg/m2, AGE and calorie intakes, as well as myeloperoxidase and HD vintage, had a P <0.10. The sole independent predictor of the 1-year ΔAF was BMI=24.3 kg/m2 (P=0.01).Conclusions:It appears that calorie, protein and AGE intakes hardly influence the 1-year ΔAF in HD patients. BMI of HD patients of around 24 kg/m2 resulted in a lower 1-year ΔAF.

Comparing changes in plasma and skin autofluorescence in low-flux versus high-flux hemodialysis

Background Tissue advanced glycation end products (AGE) are increased in hemodialysis (HD) patients, especially those with cardiovascular complications. Skin autofluorescence (skin-AF) can noninvasively estimate the accumulation of AGE in tissue. The aim was to clarify whether HD using a high-flux (HF) dialyzer favors plasma- or skin-AF removal compared to low-flux (LF) dialysis. Material and methods 28 patients were treated with either an HF-HD or LF-HD but otherwise unchanged conditions in a cross-over design. A glucose containing dialysate was used. Skin-AF was measured noninvasively with an AGE reader before and after HD. Fluorescence (370 nm/465 nm) of plasma (p-AF) was determined as total and nonprotein-bound fractions. Correction for hemoconcentrations were made using the change in serum albumin. Paired and nonpaired statistical analyses were used. Results Skin-AF was unchanged after LF- and HF-dialysis. Total, free, and protein- bound p-AF was reduced after a single LF-HD by 21%, 28%, and 17%, respectively (P<.001). After HF HD total and free p-AF was reduced by 5% and 15%, respectively (P<.001), while protein bound values were unchanged. The LF-HD resulted in a more pronounced reduction of p-AF than did HF HD (P<.001). Serum albumin correlated inversely with p-AF in HF-HD. Conclusions In the dialysis settings used there was no significant change in skin AF after dialysis, with LF or with HF dialysis. Although only limited reduction in plasma fluorescence was observed, this was more pronounced when performing LF dialysis. These data are not in overwhelming support of the use of HF dialysis in the setting used in this study.

HOW CAN WE OPTIMIZE HEMODIALYSIS TO PREVENT FROM AGES

Evaluation of air contamination incidences and in vitro settings and experiences of micro bubblesThe use of citrate-containing dialysate for anticoagulation in hemodialysis (hd). report of clinical experienceK1 (EI0154) AGES IN HEMODIALYSIS: TISSUEAND PLASMAAUTOFLUORESCENCE R. Graaff1, S. Arsov1, L. Trajceska4, P. Dzekova4, G.E. Engels1, M. Koetsier1, W. van Oeveren1, L Lundberg5, S. Assa2, C.F.M. Franssen2, A.J. Smit3, G. Rakhorst1, A. Sikole2, B. Stegmayr5 1Dept. of Biomedical Engineering, 2Internal Medicine, Div. Nephrology and 3Div. Vascular Medicine, University Medical Center Groningen, Groningen, The Netherlands; 4Department of Nephrology, University Clinic of Nephrology, Skopje, R. Macedonia; 5Department of Internal Medicine, University Hospital, Umea, SwedenObjectives: During HD previous studies have shown that especially micro bubbles of air may pass the air detector. These studies focused to analyse in vitro if the air trap of various producers may ...Artificial Kidney – Uremic Toxins – SYMPOSIUM, 606 Smart and Responsive Biomaterials – SYMPOSIUM, 607 Cardiovascular General 1: Devices – GENERAL SESSION, 608 Ambulatory Blood Processing – SYMPOSIUM, 610 Animal Models for Tissue Engineering – SYMPOSIUM, 610 Cardiovascular General 2: Devices Interaction – GENERAL SESSION, 612 Artificial Muscle for Internal Organ – SYMPOSIUM, 613 Functionalized Biomaterials – SYMPOSIUM, 614 Cardiovascular General 3: Physiology and Pump Control – GENERAL SESSION, 615 Vascular Access in Hemodialysis – SYMPOSIUM, 617 Polymeric Membranes/Blood Interfaces – SYMPOSIUM, 618 Nano and Micro Technology: Driving the Future of Organ Recovery & Development – SYMPOSIUM, 619 Roadbumps for Tissue-Engineering Artificial Organs – SYMPOSIUM, 621 Artificial Liver GENERAL SESSION, 621 Tissue Engineering Approaches – SYMPOSIUM, 622 Cardiovascular General 4: Cardiopulmonary – GENERAL SESSION, 624 Artificial Kidney Dialysis – SYMPOSIUM, 625 Tissue Engineering of Skin: Creating a New Bio-Artificial Organ for Clinical Application – SYMPOSIUM, 627 Cardiovascular General 5: Device & Biology – GENERAL SESSION, 628 Citrate Anticoagulation A Future Option for Extracorporeal Blood Purification – SYMPOSIUM, 629 Latest Advances in Preventive and Regenerative Medicine Technologies – SYMPOSIUM, 630 Intra-Aortic Balloon Pump as a Cardiac Assist Device – SYMPOSIUM, 631 Artificial Organ Transplantation – SYMPOSIUM, 632 New Biomaterials and Scaffolds – SYMPOSIUM, 633 Modelling of Cardiovascular and Pulmonary Function in Regard to Clinical Applications – SYMPOSIUM, 634 Artificial Kidney Dialysis Techniques – SYMPOSIUM, 635 Natural Based Polymeric Biomaterials and Composites for Regenerative Medicine – SYMPOSIUM, 637 Partial Cardiac Support in Shortand Long-Term Application – SYMPOSIUM, 638 Artificial Organs – Practical Applications – GENERAL SESSION, 639 Non-Destructive Techniques to Monitor 3D In Vitro Tissue Engineering Constructs – SYMPOSIUM, 640 Stent and Vascular Prosthesis – GENERAL SESSION, 641 Dialysis Techniques Access – GENERAL SESSION, 643 Scaffolds for TE Via Electrospinning-Structures and Biomaterials – SYMPOSIUM, 644 Drug Delivery Systems – GENERAL SESSION, 646 “Approval Procedures for Medical Devices: Facts, Figures and Basic Rules Seen from Different Continental Perspectives – Artificial Organs and Society: Recent Trends in Japan”, 647K1 (EI0154) AGES IN HEMODIALYSIS: TISSUEAND PLASMAAUTOFLUORESCENCE R. Graaff1, S. Arsov1, L. Trajceska4, P. Dzekova4, G.E. Engels1, M. Koetsier1, W. van Oeveren1, L Lundberg5, S. Assa2, C.F.M. Franssen2, A.J. Smit3, G. Rakhorst1, A. Sikole2, B. Stegmayr5 1Dept. of Biomedical Engineering, 2Internal Medicine, Div. Nephrology and 3Div. Vascular Medicine, University Medical Center Groningen, Groningen, The Netherlands; 4Department of Nephrology, University Clinic of Nephrology, Skopje, R. Macedonia; 5Department of Internal Medicine, University Hospital, Umeå, SwedenDoes the advanced glycation end-products (ages) food intake influence mortality in dialysis patients?

Corrigenda: The influence of body mass index on the accumulation of advanced glycation end products in hemodialysis patients (vol 69, pg 309, 2015)

Correction to: European Journal of Clinical Nutrition (2015) 69, 309–313; doi: 10.1038/ejcn.2014.261; published online 14 January 2015 Since the publication of this article, the authors have noticed that several of the author names were published incorrectly. The correct author names are listed above.

Skin Autofluorescence, a Measure of Cumulative Metabolic Stress and Advanced Glycation End Products, Decreases During the Summer in Dialysis Patients

Tissue advanced glycation end products (AGEs) are a measure of cumulative metabolic and oxidative stress and cytokine-driven inflammatory reactions. AGEs are thought to contribute to the cardiovascular complications of hemodialysis (HD) patients. Skin autofluorescence (SAF) is related to the tissue accumulation of AGEs and rises with age. SAF is one of the strongest prognostic markers of mortality in these patients. The content of AGEs is high in barbecue food. Due to the location in northern Sweden, there is a short intense barbecue season between June and August. The aim of this study was to investigate if seasonal variations in SAF exist in HD patients, especially during the barbecue season. SAF was measured noninvasively with an AGE Reader in 34 HD-patients (15 of those with diabetes mellitus, DM). Each time the median of three measures were used. Skin-AF was measured before and after each one HD at the end of February and May in 31 patients (22 men/9 women); the end of May and August in 28 (20 m/8 w); the end of August and March in 25 (19 m/6 w). Paired statistical analyses were performed during all four periods (n = 23, 17 m/6 w); as was HbA1c of those with DM. There was at a median 5.6% increase in skin-AF during the winter period (February-May, P = 0.004) and a 10.6% decrease in the skin-AF during the summer (May-August, P < 0.001). HbA1c in the DM rose during the summer (P = 0.013). In conclusion, skin-AF decreased significantly during the summer. Future studies should look for favorable factors that prevent skin-AF and subsequently cardiovascular diseases.

Skin and Plasma Autofluorescence During Hemodialysis: A Pilot Study: Thoughts and Progress

Skin autofluorescence (AF) is related to the accumulation of advanced glycation end products (AGEs) and is one of the strongest prognostic markers of mortality in hemodialysis (HD) patients. The aim of this pilot study was to investigate whether changes in skin AF appear after a single HD session and if they might be related to changes in plasma AF. Skin and plasma AF were measured before and after HD in 35 patients on maintenance HD therapy (nine women and 26 men, median age 68 years, range 33-83). Median dialysis time was 4 h (range 3-5.5). Skin AF was measured noninvasively with an AGE Reader, and plasma AF was measured before and after HD at 460 nm after excitation at 370 nm. The HD patients had on average a 65% higher skin AF value than age-matched healthy persons (P < 0.001). Plasma AF was reduced by 14% (P < 0.001), whereas skin AF was not changed after a single HD treatment. No significant influence of the reduced plasma AF on skin AF levels was found. This suggests that the measurement of skin AF can be performed during the whole dialysis period and is not directly influenced by the changes in plasma AF during HD.