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Glucose degradation products in patients on hemodialysis: interventional studies
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.ORCID iD: 0000-0002-5872-0583
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hemodialysis (HD) is the most frequently used treatment for end-stage renal disease. Despite all efforts to improve the outcomes, the mortality of patients on HD is still high, and this especially is related to cardiovascular diseases (CVD). Glucose degradation products accumulate in plasma and tissue as a result of oxidative stress in these patients. Such accumulation is strongly related to the risk of developing CVD. Tissue deposits of advanced glycation end products (AGE) can be easily assessed by a skin autofluorescence (SAF) technique. SAF is one of the strongest prognostic markers of mortality in HD patients. The aim of this thesis is to examine whether intervention on HD treatment can reduce the load of AGE of these patients.

The aim of the first study was to investigate whether changes in SAF appear after a single HD session and if they might be related to changes in plasma AF. Skin and plasma AF (PAF) were measured before and after HD in 35 patients on maintenance HD therapy. Median dialysis time was 4 h (range 3-5.5). SAF was measured noninvasively with an AGE Reader, and plasma AF was measured before and after HD. The HD patients had on average a 65% higher SAF value than age-matched healthy persons (P < 0.001). PAF was reduced by 14% (P < 0.001), whereas SAF was not changed after a single HD treatment. No significant influence of the reduced PAF on SAF levels was found. This suggests that the measurement of SAF can be performed during the whole dialysis period and is not directly influenced by the changes in plasma AF during HD.

In study 2 different dialysis filters were compared to clarify whether using a high-flux (HF) dialyzer favors plasma or SAF removal compared to low-flux (LF) dialyzer. Twenty-eight patients were treated with either an HF-HD or LF-HD but otherwise unchanged conditions in a cross-over design. SAF was measured non-invasively with an AGE reader before and after HD. PAF was determined as total and non-protein-bound fractions. Corrections for hemoconcentrations by volume changes were made using the change in serum albumin. Paired and non-paired statistical analyses were used. The different treatments did not change SAF after LF- and HF-dialysis. Total, free, and protein-bound PAF were reduced after a single LF-HD by 21%, 28%, and 17%, respectively (P<.001). After HF-HD total and free PAF 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 PAF than did HF-HD (P<.001). Serum albumin correlated inversely with PAF in HF-HD. There was no significant change in SAF after dialysis, either with LF or with HF dialysis. Although only limited reductions in PAF were observed, these were 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.

In the third study the effect on SAF was investigated using either glucose-containing or glucose-free dialysate. SAF and PAF were measured in patients on HD during standard treatment with a glucose-containing dialysate (n=24). After that, the patients were switched to a glucose-free dialysate for a 2 week period, and new measurements were performed on PAF and SAF.

There was an increase of pre-dialysis SAF measured at the beginning of the study compared with the values one month later (as in study 4). By comparing pre- and post-dialysis values there was a significant decrease of SAF only when using glucose-free dialysate. Free PAF decreased independently whether glucose-containing or glucose-free dialysate was used. The important finding was that increase in SAF seemed possible to slow down using glucose-free dialysate.

Study 4 was performed to investigate whether there are seasonal variations in SAF on a HD population. SAF was measured non-invasively with an AGE Reader in patients on HD at different seasonal periods during one year such as February-May (N=31), May–August (N=28), August–March (N=25). SAF was measured before HD. Paired statistical analyses were performed between each two periods.  Unexpectedly there was at a median 6% increase in SAF during the winter (p=0.004) and a 11% decrease from 4.0 to 3.5 arbitrary units of the SAF during the summer (p<0.001). The study concluded that SAF shows seasonal variation. The cause of these changes could not be clarified. A beneficial effect may be due to extended exposure to sunlight during the summer and/or to different dietary intakes during the seasons.

In conclusion, these interventional studies confirmed that PAF is lowered by dialysis. SAF was only decreased by HD when using glucose-free dialysate. SAF was not influenced by a single HD, with glucose-containing dialysate, independent of using HF or LF filters. These data favor glucose-free dialysate as a possible measure to slow down the progress of tissue AGE compared to glucose-containing dialysate. Longitudinal studies will help to clarify this issue further.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2016. , 92 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1828
Keyword [en]
Hemodialysis, advanced glycation end products, skin autofluorescence, plasma autofluorescence, glucose degradation products
National Category
Urology and Nephrology
Identifiers
URN: urn:nbn:se:umu:diva-125035ISBN: 978-91-7601-532-2OAI: oai:DiVA.org:umu-125035DiVA: diva2:957706
Public defence
2016-09-29, Sal E04, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-09-08 Created: 2016-09-04 Last updated: 2016-09-05Bibliographically approved
List of papers
1. Skin and Plasma Autofluorescence During Hemodialysis: A Pilot Study
Open this publication in new window or tab >>Skin and Plasma Autofluorescence During Hemodialysis: A Pilot Study
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2014 (English)In: Artificial Organs, ISSN 0160-564X, E-ISSN 1525-1594, Vol. 38, no 6, 515-518 p.Article in journal (Refereed) Published
Abstract [en]

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 4h (range 3-5.5). Skin AF was measured noninvasively with an AGE Reader, and plasma AF was measured before and after HD at 460nm after excitation at 370nm. 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.

Keyword
Hemodialysis, Skin autofluorescence, Plasma autofluorescence, Advanced glycation end products
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-91206 (URN)10.1111/aor.12205 (DOI)000337513600014 ()
External cooperation:
Available from: 2014-07-22 Created: 2014-07-21 Last updated: 2016-09-05Bibliographically approved
2. Comparing changes in plasma and skin autofluorescence in low-flux versus high-flux hemodialysis
Open this publication in new window or tab >>Comparing changes in plasma and skin autofluorescence in low-flux versus high-flux hemodialysis
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2015 (English)In: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040, Vol. 38, no 9, 488-493 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
Advanced glycation end products, AGE, Hemodialysis, Plasma fluorescence, Skin autofluorescence
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-112667 (URN)10.5301/ijao.5000434 (DOI)000365099400003 ()26481293 (PubMedID)
External cooperation:
Available from: 2015-12-11 Created: 2015-12-11 Last updated: 2016-09-05Bibliographically approved
3. Skin- and Plasma autofluorescence in hemodialysis with glucose-free or glucose-containing dialysate
Open this publication in new window or tab >>Skin- and Plasma autofluorescence in hemodialysis with glucose-free or glucose-containing dialysate
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Haemodialysis (HD) patients suffer from an increased risk of cardiovascular disease (CVD). Skin autofluorescence  (SAF) is a strong marker for CVD. SAF indirectly measures tissue advanced glycation end products (AGE) being cumulative metabolites of oxidative stress and cytokine-driven inflammatory reactions. The dialysates often contain glucose.

Methods: Autofluorescence of skin and plasma (PAF) were measured in patients on HD during standard treatment (ST) with a glucose-containing dialysate (n=24). After that the patients were switched to a glucose-free dialysate (GFD) for a 2-week period. New measurements were performed on PAF and SAF after 1 week (M1) and 2 weeks (M2) using GFD. Nonparametric paired statistical analyses were performed between each two periods.

Results: SAF after HD increased non-significantly by 1.2% while when a GFD was used during HD at M1, a decrease of SAF by 5.2% (p=0.002) was found. One week later (M2) the reduction of 1.6 % after the HD was not significant (p=0.33). PAF was significantly reduced during all HD sessions. Free and protein-bound PAF decreased similarly whether glucose containing or GFD was used. The HD resulted in a reduction of the total PAF of approximately 15%, the free compound of 20% and the protein bound of 10%. The protein bound part of PAF corresponded to approximately 56 % of the total reduction. The protein bound concentrations after each HD showed the lowest value after 2 weeks using glucose-free dialysate (p<0.05). The change in SAF could not be related to a change in PAF.

Conclusions: When changing to a GFD, SAF was reduced by HD indicating that such measure may hamper the accumulation and progression of deposits of AGEs to protein in tissue, and thereby also the development of CVD. Glucose-free dialysate needs further attention. Protein binding seems firm but not irreversible.

Keyword
Haemodialysis, Plasma autofluorescence, Skin autofluorescence, Glucose free dialysate
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-125034 (URN)
External cooperation:
Available from: 2016-09-04 Created: 2016-09-04 Last updated: 2016-09-05Bibliographically approved
4. Skin Autofluorescence, a Measure of Cumulative Metabolic stress and Advanced Glycation End Products, shows seasonal variations in dialysis patients
Open this publication in new window or tab >>Skin Autofluorescence, a Measure of Cumulative Metabolic stress and Advanced Glycation End Products, shows seasonal variations in dialysis patients
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Abstract

Tissue advanced glycation end products (AGE) 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 patients. Skin autofluorescence (AF) is related to the tissue accumulation of AGE, and is one of the strongest prognostic markers on mortality in these patients. The content of AGE is high in barbecue food. Since the barbecue season in northern Sweden is between June and August a longitudinal study was performed to investigate whether there are seasonal variations in skin-AF on a hemodialysis (HD) in this population. Skin-AF was measured non-invasively with an AGE Reader (Diagnoptics Technologies BV, Groningen, The Netherlands) in patients on HD at different seasonal periods during one year such as February-May (N=29, 21 men/8 women), May – August (N=26, 19 m/7 w), August  – March  (N=24, 18 m/6 w). Skin-AF was measured before and after dialyses. Paired statistical analyses were performed between each two periods. A second analysis was performed including only the patients with measurements at all 4 points of time (n=23, 17m/6w).

There was at a median 5.6% increase in skin-AF during the winter period (p=0.004) and a 10.6% decrease of the skin-AF during the summer (p<0.001). The study concluded that skin-AF shows seasonal variation. The cause of these changes could not be clarified. A beneficial effect may be due to extended exposure to sunlight during the summer and/or to different dietary intake during the seasons.

Keyword
Keywords: Skin autofluorescence - Haemodialysis – Seasonal Variations – Advanced glycation end products
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-125033 (URN)
External cooperation:
Available from: 2016-09-04 Created: 2016-09-04 Last updated: 2016-09-05Bibliographically approved

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