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.

Dans un contexte de vieillissement de la population et d’accroissement des maladies chroniques liées à l’âge comme le diabète, de nouveaux biomarqueurs de l’état de santé à long terme doivent être étudiés. Les produits de glycation avancée (AGE) sont des molécules témoins de la charge métabolique accumulée au cours du temps, dénommée "mémoire métabolique". Les AGE jouent un rôle important dans les lésions à long terme dans le diabète et dans le déclin du métabolisme global lié au vieillissement. L’accumulation cutanée des AGE peut être mesurée par autofluorescence (AF) de manière instantanée et non invasive grâce à l’AGE-READER. Les objectifs de cette thèse étaient d’évaluer la valeur de l’AF cutanée des AGE en tant que marqueur de mémoire métabolique chez des personnes âgées de la cohorte des 3-Cités et parallèlement d’évaluer la valeur pronostique de l’AF pour les complications du diabète chez des patients porteurs de diabète de type 1. Chez les personnes âgées, nous avons montré que l’AF reflétait les statuts glycémique et rénal 10 ans avant la mesure. Chez les patients atteints de diabète de type 1, l’AF était associée à la présence d’une neuropathie 4 ans plus tard. De plus, dans cette même population, nous avons décrit l’évolution de l’AF sur 4 ans de suivi. Nous avons montré que les principaux déterminants de son évolution étaient la fonction rénale et le traitement par pompe à insuline. Enfin nous avons trouvé que l’augmentation de l’AF sur 4 ans de suivi était associée à la survenue de la maladie rénale. Ces travaux soulèvent de nouvelles perspectives de recherche quant à l’intérêt de l’AF à différents âges clés de la vie en tant que biomarqueur de pathologies qui évoluent sur des dizaines d’années. / In the context of the ageing of the population and the increase of age related diseases such as diabetes, new biomarquers of the long-term health status should be considered. Advanced glycation end products (AGE) are molecules indicators of the metabolic burden over time, called “metabolic memory”. AGE play an important role in long term diabetes injuries and in the global decline of the metabolism related to ageing. Skin accumulation of AGE can be measured by autofluorescence instantly and non-invasivly with a tool called AGE-READER. The objectives of my dissertation were to evaluate the value of the skin autofluorescence (sAF) of AGE as marker of metabolic memory in elderly people from the 3-City cohort and in parallel, in patients with type 1 diabetes, evaluate the prognostic value of sAF for diabetes complications. In the elderly population, we showed that sAF reflected glycemic and renal status of 10 years before. In patients with type 1 diabetes, sAF was associated to the presence of neuropathy 4 years later. Moreover, in this same population, we described the evolution of sAF in 4 years of follow-up and we showed that the principal determinants of the evolution of sAF were kidney function and insulin pump therapy. Finally, we also found that increase of sAF in 4 years was associated with the occurrence of kidney disease. This work rises new research opportunities about the interest of sAF at differents key ages as biomarker of pathologies which evolve in several decades.

Diabetes is a chronic disease with high prevalence and significant morbidity. Chronic changes in the wall of small and large vessels lead to main diabetes complications. Apart from long- term hyperglycemia, several factors are involved in the development of diabetes vasculopathy. The aim of this work was to describe new early biomarkers of these vascular changes, to identify risky patients. Alongside, gene polymorphisms involved in protective pathways of glucose metabolism were studied. In three human studies with Type 1 (T1D) and Type 2 (T2D) diabetes patients special biochemical parameters of receptor for advanced glycation endproducts (RAGE) and its ligands, deglycation enzyme glyoxalase 1 (GLO1) and fructosamine 3-kinase (FN3K) gene polymorphisms were analyzed. Non-invasive measurement of glycation by skin autofluorescence (SAF) was assessed in all subjects. Soluble RAGE, HMGB1 and endothelial dysfunction markers were increased in patients with diabetes as compared with controls, however the differences between T1D and T2D were not significant. For the first time, an association between FN3K (rs1056534) and (rs3848403) polymorphism and sRAGE concentration in diabetes was shown. GLO1 (rs4746) polymorphism was associated with changes in endothelial dysfunction. Patients with diabetes had higher...