This study shows acute AGE accumulation in ICU patients in a direct way by skin auto fluorescence. In this study the accumulation was not associated with disease severity, ICU length of stay or mortality.
Acute AGE accumulation is most likely mediated by oxidative stress, as the classical Maillard reaction is a slow non-enzymatic reaction. Oxidative stress causes formation of reactive carbonyl compounds, which react with protein to form AGEs [6
]. Also blocking nitric oxide activity causes the production of reactive oxygen species [13
]. Moreover binding of AGEs to RAGE generates intracellular reactive oxygen species [14
]. This results in diminished reduced glutathione, and ascorbic acid. Depletion of glutathione leads to reduced glyoxalase-1 recycling and decreased in situ activity. Glyoxalase-1, however, has an important role in reducing the cellular AGE load [16
]. Hence, an acute event could result in acute oxidative stress in the ICU patient, concomitant AGE accumulation, which itself could cause more oxidative stress, thus potentially causing a vicious cycle with progressive multiple organ failure.
The question is whether AGE accumulation is harmful? At least when evaluating chronic accumulation, AGE levels predict future microvascular and cardiovascular events in diabetic patients better than HbA1c [8
]. Moreover skin AGE accumulation predicts (cardiovascular) mortality in hemodialysis patients and in patients with type 2 diabetes [7
]. In addition, interventions aiming to modulate AGE accumulation have proved to alleviate end-organ damage in animal models [20
]. This may support the idea about AGEs playing a causal and potentially predictive role in end organ damage. In contrast to these chronic accumulation of AGEs, recent research is focussed on the less known acute AGE accumulation. One may hypothesize that this acute AGE accumulation, as seen in our study, may be harmful because of intracellular ROS formation as well as depletion of antioxidant mechanisms [15
]. In ICU patients, one study showed elevated levels of soluble AGE receptors (sRAGE) at admission in septic patients [21
]. Furthermore, application of an extracellular decoy for RAGE ligands, improves survival in mice after induction of sepsis, suggesting that RAGE is a central player in perpetuating the innate immune response [22
]. Also, AGEs content measured in pericardial fluids seemed to have a prognostic factor after cardiac surgery [23
] and plasma levels of sRAGE was associated with increased severity of lung injury and increased mortality in patients with acute lung injury [24
]. In addition, plasma sRAGE levels predicted length of stay in ICU in patients after lung transplantation [25
]. This is in concordance with our data finding elevated AGE levels already at admission in comparison to control subjects. However, we were not able to find an association with disease severity, ICU length of stay, nor with mortality. Besides differences in case mix and mortality rate, this difference might be explained by the fact that plasma sRAGE levels are not reflecting actual AGE accumulation, thus yielding different results. We did not measure plasma sRAGE in our patients. More research, with larger numbers of patients, and in defined subgroups, should be carried out to address these issues.
Several study limitations need to be addressed. First, this is a small, single center study. Hence, the results may be quite different in other case-mixes in other ICUs. Secondly, this is a small series of patients. Nevertheless, they are probably a reasonable reflection of admissions to our ICU, because the composition of the patient characteristics did not differ with those in a 1 year period preceding this study. Thirdly, the AGE reader itself has not been formally validated for use in an ICU setting since all previous studies have been done in outclinic patients. One might argue that factors like edema could have influenced the results. Indeed, because water is not autofluorescent, values could be mildly reduced in the presence of substantial edema in the arm that was measured. However, this should be structurally addressed in further studies. Fourth; patients with conditions, known to cause AGE accumulation were not included in this study. So AGE accumulation is therefore most likely caused by the ICU admission itself. But the design of this study was cross-sectional, so skin AF values before ICU admission of these particular patients are unknown. Further studies, should maybe focus on longitudinal skin AF measurements to show acute accumulation with ICU admission in the same patient.
In conclusion, acute AGE accumulation occurs in ICU patients, which probably reflects oxidative stress. The group was too small to allow any conclusions on the possible predictive value of skin AF for prognosis for patients on the ICU. Further studies should reveal whether measurement of AGE-accumulation will be a useful parameter in ICU patients.