Skin autofluorescence as a risk marker in people receiving dialysis
Research type
Research Study
Full title
Association of advanced glycation end-product accumulation and adverse outcomes in peritoneal dialysis and haemodialysis patients and the impact of a dietetic intervention on skin autofluorescence
IRAS ID
200680
Contact name
Maarten Taal
Contact email
Sponsor organisation
The University of Nottingham
Clinicaltrials.gov Identifier
Duration of Study in the UK
5 years, 6 months, 1 days
Research summary
Summary of Research
The purpose of the present study is to investigate the association between the accumulation of advanced glycation end-products (AGE) and adverse outcomes (e.g. death) in people receiving haemodialysis and peritoneal dialysis based in Royal Derby Hospital, as well as the impact of a dietetic intervention on AGE accumulation. AGE will be measured non-invasively in the skin using a technique called skin autofluorescence (SAF).\n\nThe present study will be conducted in two parts: \n\nStudy 1: participants will be followed-up for five years. The research team will measure the accumulation of AGE in the skin using a quick (less than five minutes) and painless technique called SAF. This involves placing the forearm on a piece of equipment that shines a light on the skin and measures the amount of light that is reflected back. Participants will be asked to complete nutritional and quality of life questionnaires, measurements of weight, height, arm circumference and skinfold thickness (i.e. anthropometry), simple eyesight tests and blood tests.\n\nStudy 2: participants will be randomly assigned either to a low AGE diet (intervention group) or to a standard diet for people on dialysis (control group). Participants will be followed-up for 2 years and will receive precise oral and written instructions on how to comply with the diets. Blood and eyesight tests, SAF measurements, anthropometry and nutritional and quality of life assessments will be conducted. \n\nIn Studies 1 and 2, approximately two teaspoons of blood will be collected at each study visit and stored for future research use.Summary of Results
INTRODUCTION Advanced glycation end-products (AGEs) are toxins that are increased in people receiving dialysis due to increased production, impaired excretion, and inefficient removal. Sources of AGEs include high blood sugar levels (such as in diabetes), an imbalance between oxidants and antioxidants in the body (i.e., oxidative stress) and systemic inflammation, a common problem in people on dialysis caused by the body’s defence (immune) system communicating that something is wrong. Foods that are cooked under dry heat conditions and high temperatures (e.g., roasting, grilling, frying), cigarette smoke and glucose degradation products formed during the manufacturing of peritoneal dialysis (PD) solutions are also important sources of AGEs. Malnutrition, an important and frequent complication in people receiving dialysis that decreases quality of life and increases hospital admissions and the risk of death, may also contribute to AGE formation through its association with oxidative stress and systemic inflammation.Accumulation of AGEs in blood vessels and skin can be measured using a simple technique called skin autofluorescence (SAF). It has been reported that high SAF levels and malnutrition are each associated with an increased risk of death (i.e., mortality) in the dialysis population, but no studies have investigated these potentially related associations together. Moreover, an increase over time in SAF predicts higher risk of death on haemodialysis (HD); however, factors that contribute to changes in SAF over time in dialysis populations have not been sufficiently investigated.
On the other hand, malnutrition has been associated with some measures of poor quality of life in cross-sectional analyses in dialysis populations, but no studies have assessed the impact of malnutrition and dietary intake on change in multiple measures of quality of life over time.
OBJECTIVES
In Study 1, we aimed to investigate factors associated with high SAF levels in people receiving HD and performing PD at baseline, with a particular focus on nutritional factors including markers of malnutrition and dietary AGE intake. In addition, we analysed follow-up data to investigate the rate of change in SAF over one year and the factors associated with these changes. We also sought to determine the most important factors associated with poor quality of life on dialysis, as well as the predictors of change in quality of life over time, focusing on dietary intake and malnutrition. Finally, we simultaneously assessed SAF and malnutrition as risk factors for mortality in people receiving dialysis.In Study 2, we conducted a pilot study that aimed to investigate whether improvement of nutritional status by providing individualised dietetic advice would result in a decrease in SAF in malnourished people on dialysis.
METHODS
In Study 1, we included 120 HD and 31 PD participants. SAF was measured using a validated Autofluorescence Reader at baseline, 3, 6, 9 and 12 months. Detailed assessment of dietary intake and nutritional status was undertaken at baseline, 6 and 12 months by means of three 24-hour dietary recalls, a validated food frequency questionnaire to quantify AGE intake, anthropometric measurements (e.g., weight, mid-arm circumference and triceps skinfold thickness), handgrip strength (HGS) and the 7-point scale Subjective Global Assessment (SGA). Routine biochemical variables (e.g., serum albumin, potassium, cholesterol) and quality of life measures (Short Form-36 [SF-36] mental [MCS] and physical component scores [PCS] and European QoL-5 Dimensions [EQ5D] health state [HSS] and visual analogue scores [VAS]) were also measured at baseline, 6 and 12 months. Survival time was defined as the number of days between the baseline assessment and the date of death, with censoring for kidney transplantation or if still on dialysis on 30 September 2018.For Study 2, we followed up 1 PD and 27 HD participants with malnutrition for 6 months, who received individualised dietetic advice regarding food fortification (i.e., increase of calorie and protein content in foods without increasing portion sizes) and oral nutritional supplements according to estimated individual requirements for calories and protein. SAF was measured at baseline, 3 and 6 months. Detailed assessment of dietary intake and nutritional status (same assessments as in Study 1) was undertaken at baseline and 6 months. We compared the results with a control group of malnourished dialysis participants (n=41 HD and 8 PD) taken from Study 1, who did not receive the same individualised dietetic advice.
RESULTS
In baseline analysis, SAF was higher in malnourished people on HD compared with those who were well-nourished. Lower serum albumin, lower protein intake, lower HGS, presence of diabetes, history of smoking and longer time since dialysis initiation (i.e., dialysis vintage) were independent factors associated with higher SAF levels. Interestingly, higher dietary AGE intake was not associated with higher SAF(1). In people performing PD, baseline analysis reported that higher SAF was associated with lower dietary AGE intake, lower serum albumin, lower HGS and lower energy, protein, and fat intake. Higher SAF was also associated with longer dialysis vintage and higher total glucose exposure from PD solutions. Baseline data analysis also showed that malnutrition assessed by SGA was the only factor independently and negatively associated with all four measures of quality of life (i.e., lower SF-36 PCS, SF-36 MCS, EQ5D HSS and EQ5D VAS) in this dialysis population(2).In analysis of follow-up data, the rate of change in SAF observed was an increase of 0.30 ± 0.63 arbitrary units (AU) per year but this varied from a decrease of 0.43 ± 0.45 AU to an increase of 1.05 ± 0.42 AU per year in the 1st and 4th quartiles, respectively. Development and/or presence of malnutrition over one year, HD as first dialysis modality and current smoking were found to be independently associated with an increase in SAF over one year(3).
Follow-up data analysis also showed that no single factor was independently associated with a decrease in all measures of quality of life over one year. However, development and/or presence of malnutrition over one year was independently associated with the 1-year decrease in EQ5D HSS, and the decrease in fat intake over one year was independently associated with the 1-year decline in SF-36 MCS and PCS, and EQ5D VAS(2).
Finally, during a median follow-up time of 576 days, 33 (21.9%) participants died. Those who died had higher baseline SAF levels (3.8 ± 1.0 vs. 3.3 ± 0.8 AU; p=0.001) and were more likely to be malnourished (58% vs. 31%; p=0.006). Malnourished people who died had higher SAF values than those who died but were well-nourished (4.2 ± 1.1 vs. 3.3 ± 0.7 AU; p=0.007). We also found that although higher SAF and malnutrition are potentially inter-related, they were both independently associated with increased mortality in this dialysis population (SAF hazard ratio 1.44 [95% Confidence Interval 1.05-1.97]; p=0.02; malnutrition hazard ratio 2.35 [1.16-4.78]; p=0.02)(4).
In Study 2, in the intervention group all dietary intake components (i.e., calorie, protein and fat), including AGEs, as well as SGA and serum albumin improved significantly, while SAF levels remained stable over 6 months. In contrast, in the control group, SAF increased significantly during the observation period when there was no improvement in dietary intake and several other markers of malnutrition, though dietary AGE intake and SGA did increase(5).
CONCLUSIONS
Our findings suggest that malnutrition might be a more important risk factor for higher SAF than high dietary AGE intake in people receiving dialysis, and that correction of malnutrition may be an important strategy to decrease SAF. This hypothesis was supported in part by our interventional study (i.e., Study 2) in which improvement in nutritional status was associated with stable SAF levels despite an increase in dietary AGE intake. Our findings also strengthen the importance of undertaking nutritional screening and monitoring in all people on dialysis to identify malnutrition, and providing specialised, individualised dietetic advice in order to prevent malnutrition and/or improve nutritional status. We also observed that higher SAF and malnutrition were independently associated with a higher risk of death in this population, indicating that the association between higher SAF and mortality is not attributable to malnutrition alone. Further studies with larger sample sizes and longer follow-up are needed to evaluate the impact of dietetic interventions on quality of life and other clinical outcomes, including survival.REFERENCES
1. Viramontes Hörner D, Selby NM, Taal MW. The association of nutritional factors and skin autofluorescence in persons receiving hemodialysis. J Ren Nutr. 2019;29(2):149-55.
2. Viramontes-Horner D, Pittman Z, Selby NM, Taal MW. Impact of malnutrition on health-related quality of life in persons receiving dialysis: a prospective study. Br J Nutr. 2021:1-9.
3. Viramontes Hörner D, Selby NM, Taal MW. Factors associated with change in skin autofluorescence, a measure of advanced glycation end products, in persons receiving dialysis. Kidney Int Rep. 2020;5(5):654-62.
4. Viramontes Hörner D, Selby NM, Taal MW. Skin autofluorescence and malnutrition as predictors of mortality in persons receiving dialysis: a prospective cohort study. J Hum Nutr Diet. 2020;33(6):852-61.
5. Viramontes Hörner D, Willingham FC, Selby NM, Taal MW. Impact of dietetic intervention on skin autofluorescence and nutritional status in persons receiving dialysis: a proof of principle study. J Ren Nutr. 2020;30(6):540-7.REC name
East Midlands - Nottingham 1 Research Ethics Committee
REC reference
16/EM/0243
Date of REC Opinion
23 Jun 2016
REC opinion
Favourable Opinion