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Prevention of glucose toxicity prevents renal damage during critical illness: mechanistic studies in a rabbit model.
The development of intensive care medicine allowed patients to survive life-threatening conditions thanks to sophisticated mechanical and/or pharmacological support. However, a considerable fraction of patients do not recover their acute critical illness within a few days, but enter astate of prolonged critical illness. Prolonged critically ill patients have a high risk of death, which is most often due to a sustained failure of multiple vital organs (multiple organ failure or MOF). The pathogenesis of MOF is complex. Both insufficient perfusion and oxygen delivery to vital organs and a decreased mitochondrial function appear involved.</>
Critically ill patients usually develop hyperglycemia, which is associated with a poor outcome. Three, large clinical studies performed in Leuven have demonstrated a potential causal link, as prevention of severe hyperglycemia by intensive insulin therapy clearly attenuated organfailure and decreased the mortality risk. However, the mechanisms involved in organ protection were poorly understood.</>
Hypercatabolism isanother characteristic metabolic alteration during critical illness, which contributes to muscle weakness and is associated with hampered recovery. Therefore, (artificial) feeding is initiated to counter-act catabolism. However, administration of nutrients often necessitates the use of the parenteral route due to a dysfunctional gastrointestinal tract , which has more inherent complications. Due to the lack of adequately designed studies on the optimal timing of (supplemental) parenteral nutrition, professional societies have recommended divergent feeding guidelines. The EPaNIC study, a large, randomized multi-center study performed by our clinical research team was the first study to address this importantgap of evidence and investigated the impact of early versus late initiation of (supplemental) parenteral feeding (gradual initiation of parenteral feeding soon after intensive care unit (ICU) admission if enteral nutrition does not meet the caloric requirement, versus initiation when the patient is still in ICU at day 8). The results were surprising: early administration was inferior to withholding parenteral nutrition for one week, as illustrated by a longer ICU stay and a longer duration of renalreplacement therapy.</>
The general objective of this PhD project was to gain more insight in metabolic mechanisms of organ failure during critical illness. More specifically, the effect of circulating glucose/insulin and nutrient administration on the pathogenesis of and recovery from organ failure was studied. In addition, the therapeutic potential of pharmacological stimulation of damage removal was investigated.</>
Ina first part, we investigated the impact of preventing hyperglycemia versus increasing insulinemia on renal damage in an animal model. Prevention of hyperglycemia protected the kidney, independent of insulin levels.The prevention of renal damage by maintenance of normoglycemia appearedexplained by a protection of the mitochondrial function, rather than byan improved perfusion or oxygen delivery to the kidney. An increased production of dicarbonyls, which are toxic byproducts of the glucose metabolism, emerged as potential link between hyperglycemia and mitochondrialdamage.</>
After identification of mitochondrial damage as a potentially important mediator of organ damage, we hypothesized that, apart from direct insults, also an inadequate activation of (mitochondrial) repair systems may contribute to the accumulation of mitochondrial damage, sustained organ failure and mortality risk of critical illness. Furthermore, we hypothesized that the mitochondrial protection brought about by prevention of hyperglycemia could also be mediated by an activation of mitochondrial repair, in addition to prevention of direct glucose toxicity to the mitochondria.</>
In a second study, we investigated the activation status of the mitochondrial repair pathways in liver biopsies of critically ill patients. These analyses suggested attempts for a compensatory activation of the three main mitochondrial repair pathways (mitochondrial fusion/fission, autophagy and biogenesis). However, this upstream activation appeared insufficient to cope with the damage, especially in patients with untreated hyperglycemia, as damaged mitochondria were abundantly present in these patients. In this regard, we observed clear signs that autophagy, the process that is responsible for clearance of damaged mitochondria, may be insufficiently activated. Prevention of hyperglycemia with insulin protected against mitochondrial damage, but had no orrather a negative impact on mitochondrial repair. Hence, these data suggested that insufficient autophagy may contribute to the accumulation ofcellular damage, in particular when hyperglycemia is not treated.</>
However, in this study, we could not investigate a potential association between insufficient autophagy and the degree of organ damage and ultimate outcome, as the observations were performed on biopsies from patients who died in the ICU. Therefore, we investigated in a third part the activation status of the mitochondrial repair mechanisms in an in vivo</>animal model of critical illness. This study confirmed the presence of insufficient autophagy in liver and extended the observation to kidney, where similar alterations were observed. Insufficient autophagy also appeared to have functional relevance. Indeed, the degree of insufficient autophagy correlated with more severe mitochondrial and organ damage. In addition, the phenotype of insufficient autophagy was more pronounced inorgans taken from non-surviving animals, compared to animals that had survived their study period. In contrast to autophagy, key mediators of mitochondrial fusion/fission and biogenesis were largely comparable for surviving and non-surviving animals, suggestive of a less determining impact on mitochondrial and organ function and ultimate outcome in the animal model. Prevention of hyperglycemia improved the efficiency of autophagy, which correlated with an improved mitochondrial and organ function.</>
In a fourth part, we performed an intervention study in the animalmodel, using two autophagy-activating compounds versus placebo in orderto demonstrate a potential causal link between insufficient autophagy and increased organ damage. Although spermidine initially appeared an ideal candidate autophagy inducer, it was unable to substantially stimulateautophagy in the animal model. In contrast, rapamycin, a well validatedautophagy inducer, stimulated autophagy in kidney, which correlated with an improved renal function. </>
As feeding is a powerful physiological suppressor of autophagy, an effect on autophagy may explain why the EPaNIC study found that early parenteral nutrition was inferior to withholding parenteral nutrition for one week. In a fifth part, the detailed impact of early versus late initiation of parenteral nutrition on the incidence and recovery of acute kidney injury (AKI) was studied. Surprisingly, however, the intervention had no major impact on the incidence and ultimate recovery of AKI. In the early initiation group, only a limited prolongation of the duration of AKI was observed in patients with stage 2 AKI. However, an important observation was the substantial elevation in markers of amino acid catabolism in the group receiving early parenteral nutrition, despite the increased amino acid supply. This finding is most likely explained by a considerable degradation of the extra amino acids. Indeed, over the first two weeks, about two third of the extra administered amino acids were degraded. These findings suggest that early parenteral nutrition only to a limited extent was able to counter-act catabolism. The increased production of urea by degradation of the supplementary administered amino acids may explain why the duration of dialysis was prolonged by early parenteral nutrition, despite a limited effect on the development of AKI and renal recovery.</>
In conclusion, we identified mitochondrial dysfunction and insufficient autophagy as potentially important mediators of MOF during critical illness. In an animal model, prevention of hyperglycemia and not insulin per se protected against renal damage, which may be explained both by prevention of direct (mitochondrial) damage and by stimulation of autophagy. Rapamycin stimulated autophagy in kidney in the animal model, which correlated with a protection of the renal function. Early initiation of parenteral feeding may suppress autophagy and may slightly prolong the duration of AKI. Extra aminoacid administration by early parenteral nutrition only to a limited extent appeared able to counter-act catabolism. These data open perspectives for therapies that activate autophagy in critical illness, in order tostimulate clearance of cellular damage, in particular in combination with therapies that can effectively suppress catabolism of healthy, lean tissue.</></>
Critically ill patients usually develop hyperglycemia, which is associated with a poor outcome. Three, large clinical studies performed in Leuven have demonstrated a potential causal link, as prevention of severe hyperglycemia by intensive insulin therapy clearly attenuated organfailure and decreased the mortality risk. However, the mechanisms involved in organ protection were poorly understood.</>
Hypercatabolism isanother characteristic metabolic alteration during critical illness, which contributes to muscle weakness and is associated with hampered recovery. Therefore, (artificial) feeding is initiated to counter-act catabolism. However, administration of nutrients often necessitates the use of the parenteral route due to a dysfunctional gastrointestinal tract , which has more inherent complications. Due to the lack of adequately designed studies on the optimal timing of (supplemental) parenteral nutrition, professional societies have recommended divergent feeding guidelines. The EPaNIC study, a large, randomized multi-center study performed by our clinical research team was the first study to address this importantgap of evidence and investigated the impact of early versus late initiation of (supplemental) parenteral feeding (gradual initiation of parenteral feeding soon after intensive care unit (ICU) admission if enteral nutrition does not meet the caloric requirement, versus initiation when the patient is still in ICU at day 8). The results were surprising: early administration was inferior to withholding parenteral nutrition for one week, as illustrated by a longer ICU stay and a longer duration of renalreplacement therapy.</>
The general objective of this PhD project was to gain more insight in metabolic mechanisms of organ failure during critical illness. More specifically, the effect of circulating glucose/insulin and nutrient administration on the pathogenesis of and recovery from organ failure was studied. In addition, the therapeutic potential of pharmacological stimulation of damage removal was investigated.</>
Ina first part, we investigated the impact of preventing hyperglycemia versus increasing insulinemia on renal damage in an animal model. Prevention of hyperglycemia protected the kidney, independent of insulin levels.The prevention of renal damage by maintenance of normoglycemia appearedexplained by a protection of the mitochondrial function, rather than byan improved perfusion or oxygen delivery to the kidney. An increased production of dicarbonyls, which are toxic byproducts of the glucose metabolism, emerged as potential link between hyperglycemia and mitochondrialdamage.</>
After identification of mitochondrial damage as a potentially important mediator of organ damage, we hypothesized that, apart from direct insults, also an inadequate activation of (mitochondrial) repair systems may contribute to the accumulation of mitochondrial damage, sustained organ failure and mortality risk of critical illness. Furthermore, we hypothesized that the mitochondrial protection brought about by prevention of hyperglycemia could also be mediated by an activation of mitochondrial repair, in addition to prevention of direct glucose toxicity to the mitochondria.</>
In a second study, we investigated the activation status of the mitochondrial repair pathways in liver biopsies of critically ill patients. These analyses suggested attempts for a compensatory activation of the three main mitochondrial repair pathways (mitochondrial fusion/fission, autophagy and biogenesis). However, this upstream activation appeared insufficient to cope with the damage, especially in patients with untreated hyperglycemia, as damaged mitochondria were abundantly present in these patients. In this regard, we observed clear signs that autophagy, the process that is responsible for clearance of damaged mitochondria, may be insufficiently activated. Prevention of hyperglycemia with insulin protected against mitochondrial damage, but had no orrather a negative impact on mitochondrial repair. Hence, these data suggested that insufficient autophagy may contribute to the accumulation ofcellular damage, in particular when hyperglycemia is not treated.</>
However, in this study, we could not investigate a potential association between insufficient autophagy and the degree of organ damage and ultimate outcome, as the observations were performed on biopsies from patients who died in the ICU. Therefore, we investigated in a third part the activation status of the mitochondrial repair mechanisms in an in vivo</>animal model of critical illness. This study confirmed the presence of insufficient autophagy in liver and extended the observation to kidney, where similar alterations were observed. Insufficient autophagy also appeared to have functional relevance. Indeed, the degree of insufficient autophagy correlated with more severe mitochondrial and organ damage. In addition, the phenotype of insufficient autophagy was more pronounced inorgans taken from non-surviving animals, compared to animals that had survived their study period. In contrast to autophagy, key mediators of mitochondrial fusion/fission and biogenesis were largely comparable for surviving and non-surviving animals, suggestive of a less determining impact on mitochondrial and organ function and ultimate outcome in the animal model. Prevention of hyperglycemia improved the efficiency of autophagy, which correlated with an improved mitochondrial and organ function.</>
In a fourth part, we performed an intervention study in the animalmodel, using two autophagy-activating compounds versus placebo in orderto demonstrate a potential causal link between insufficient autophagy and increased organ damage. Although spermidine initially appeared an ideal candidate autophagy inducer, it was unable to substantially stimulateautophagy in the animal model. In contrast, rapamycin, a well validatedautophagy inducer, stimulated autophagy in kidney, which correlated with an improved renal function. </>
As feeding is a powerful physiological suppressor of autophagy, an effect on autophagy may explain why the EPaNIC study found that early parenteral nutrition was inferior to withholding parenteral nutrition for one week. In a fifth part, the detailed impact of early versus late initiation of parenteral nutrition on the incidence and recovery of acute kidney injury (AKI) was studied. Surprisingly, however, the intervention had no major impact on the incidence and ultimate recovery of AKI. In the early initiation group, only a limited prolongation of the duration of AKI was observed in patients with stage 2 AKI. However, an important observation was the substantial elevation in markers of amino acid catabolism in the group receiving early parenteral nutrition, despite the increased amino acid supply. This finding is most likely explained by a considerable degradation of the extra amino acids. Indeed, over the first two weeks, about two third of the extra administered amino acids were degraded. These findings suggest that early parenteral nutrition only to a limited extent was able to counter-act catabolism. The increased production of urea by degradation of the supplementary administered amino acids may explain why the duration of dialysis was prolonged by early parenteral nutrition, despite a limited effect on the development of AKI and renal recovery.</>
In conclusion, we identified mitochondrial dysfunction and insufficient autophagy as potentially important mediators of MOF during critical illness. In an animal model, prevention of hyperglycemia and not insulin per se protected against renal damage, which may be explained both by prevention of direct (mitochondrial) damage and by stimulation of autophagy. Rapamycin stimulated autophagy in kidney in the animal model, which correlated with a protection of the renal function. Early initiation of parenteral feeding may suppress autophagy and may slightly prolong the duration of AKI. Extra aminoacid administration by early parenteral nutrition only to a limited extent appeared able to counter-act catabolism. These data open perspectives for therapies that activate autophagy in critical illness, in order tostimulate clearance of cellular damage, in particular in combination with therapies that can effectively suppress catabolism of healthy, lean tissue.</></>
Date:1 Oct 2008 → 2 Oct 2012
Keywords:Glucose toxicity, Kidney, Critical illness
Disciplines:Anaesthesiology, Intensive care and emergency medicine, Endocrinology and metabolic diseases, Urology and nephrology
Project type:PhD project