Associations of skin autofluorescence, a marker of tissue advanced glycation end-product accumulation, in persons receiving dialysis

Background: Advanced glycation end-products (AGEs) are uremic toxins that are markedly increased in persons receiving dialysis due to increased production, impaired excretion and inefficient removal. Endogenous sources of AGEs include hyperglycaemia, oxidative stress, and systemic inflammation. Foods that are cooked under dry heat conditions and high temperatures, cigarette smoke and glucose degradation products formed during the manufacturing of peritoneal dialysis (PD) solutions are also important sources of AGEs. Malnutrition, a major and frequent complication in persons receiving dialysis, may also contribute to AGE formation through its association with oxidative stress and inflammation. Tissue AGE accumulation can be assessed using skin autofluorescence (SAF). It has been reported that elevated SAF and malnutrition are each associated with increased mortality in the dialysis population, but no studies have investigated these potentially related associations together. Moreover, an increase over time in SAF predicts higher mortality on haemodialysis (HD); nevertheless, factors that contribute to changes in SAF over time in dialysis populations have not been adequately investigated. Objectives: In Study 1, we aimed to investigate in cross-sectional analysis the determinants of increased SAF in persons receiving HD and performing PD, with a particular focus on nutritional factors including markers of malnutrition and dietary AGE intake. We also investigated in a longitudinal prospective study the rate of change in SAF over 1 year, the factors associated with these changes and the prognostic value of SAF and malnutrition for predicting mortality in persons receiving dialysis. In Study 2, we conducted a non-randomised observational proof of principle study that aimed to investigate whether improvement of nutritional status by providing individualised dietetic advice would result in a decrease in SAF in malnourished persons on dialysis. Methods: In Study 1, we included 120 HD and 31 PD patients. 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, anthropometric measurements, handgrip strength (HGS) and the 7-point scale Subjective Global Assessment (SGA). Routine biochemical variables were also measured. Survival time was defined as the number of days between the baseline assessment and the date of death, censoring due to kidney transplantation or 30 September 2018. For Study 2, we followed-up 1 PD and 27 HD patients with malnutrition for 6 months, who received individualised nutritional advice regarding food fortification and oral nutritional supplements according to estimated nutritional requirements. 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 patients (n=41 HD and 8 PD) taken from Study 1. Results: In cross-sectional analysis, SAF was higher in malnourished persons receiving HD, dietary AGE intake was not positively associated with SAF, and lower serum albumin, lower protein intake, lower HGS, diabetes, smoking and dialysis vintage were independent predictors of increased SAF. In persons performing PD, cross-sectional analysis reported that higher SAF was negatively associated with dietary AGE intake, serum albumin, HGS and energy, protein and fat intake. SAF was also positively associated with dialysis vintage and total glucose exposure. In prospective analysis, the mean SAF trend 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/prevalence of malnutrition over 1 year, HD as first dialysis modality and current smoking were independent determinants of increasing in SAF in persons on dialysis. Multivariable Cox proportional hazards analysis identified SAF (HR 1.44 [95%CI 1.05-1.97]; p=0.02), malnutrition (2.35 [1.16-4.78]; p=0.02) and chronological age (1.60 [1.10-2.33]; p=0.01) as independent predictors of mortality. In Study 2, in the intervention group all nutritional intake components, 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 nutritional intake and several markers of malnutrition, though dietary AGE intake and SGA did increase. Conclusions: Our findings suggest that malnutrition might be a more important risk factor for increased SAF than high dietary AGE intake in persons receiving dialysis, and that correction of malnutrition may be an important strategy to decrease SAF. This hypothesis was supported in part by our prospective interventional study in which improvement in nutritional status was associated with stable SAF levels despite an increase in dietary AGE intake. We also observed that higher SAF and malnutrition were independently associated with increased mortality in this population, indicating that the association between increased SAF and mortality is not attributable to malnutrition alone. Further long-term studies of dietetic interventions with larger sample sizes are needed to test this hypothesis further and evaluate the impact on long-term outcomes, including survival.