Hyperglycemic kidney damage in an animal model of prolonged critical illness

Abstract

Acute kidney injury frequently complicates critical illness and increases mortality; maintaining normoglycemia with insulin has been shown to reduce the incidence of intensive care unit (ICU)-acquired kidney injury. Here we tested the mechanisms by which this intervention might achieve its goal, using a rabbit model of burn-induced prolonged critical illness in which blood glucose and insulin were independently regulated at normal or elevated levels. Hyperglycemia caused elevated plasma creatinine and severe morphological kidney damage that correlated with elevated cortical glucose levels. Renal cortical perfusion and oxygen delivery were lower in hyperglycemic/hyperinsulinemic rabbits, compared to other groups, but this did not explain the elevated creatinine. Mitochondrial respiratory chain activities were severely reduced in the hyperglycemic groups (30-40% residual activity), and were inversely correlated with plasma creatinine and cortical glucose. These activities were much less affected by normoglycemia, and hyperinsulinemia was not directly protective. Mitochondrial damage, evident at day 3, preceded the structural injury evident at 7 days. Our study found that hyperglycemia evoked cellular glucose overload in the kidneys of critically ill rabbits, and this was associated with mitochondrial dysfunction and renal injury. Normoglycemia, independent of insulinemia, protected against this damage.

Hyperglycemia Exacerbates Burn-Induced Liver Inflammation via Noncanonical Nuclear Factor-κB Pathway Activation

“…In a rabbit model of critical illness, elevated blood glucose induced by alloxan administration evoked cellular glucose overload, inducing mitochondrial dysfunction (12). Maintenance of normoglycemia, but not hyperinsulinemia, protected against mitochondrial damage in the liver, myocardium and kidney (12). Zhang et al (13) reported that insulin administration increased wound protein and deoxyribonucleic acid (DNA) synthesis in a rabbit model of burn injury.…”

“…Heuer et al (11) reported that hyperglycemic and septic rodents had higher levels of cytokines/chemokines, serum organ damage markers and reduced survival. In a rabbit model of critical illness, elevated blood glucose induced by alloxan administration evoked cellular glucose overload, inducing mitochondrial dysfunction (12). Maintenance of normoglycemia, but not hyperinsulinemia, protected against mitochondrial damage in the liver, myocardium and kidney (12).…”

Hyperglycemia and acute kidney injury in critically ill children

“…9 It has been reported that oxidative stress plays an important role in the complications of diabetes, 11 and hyperglycemia causes oxidative stress in different ways. 12 Vanhorebeek et al 1 reported a rabbit mode of prolonged critical illness and found elevated plasma creatinine levels and severe morphological kidney damage that correlated with elevated cortical glucose levels. Renal cortical perfusion and oxygen delivery were lower in the rabbits with hyperglycemia.…”

“…[1][2][3] Srinivasan et al 4 found that blood glucose level >150 mg/dL was associated with a 3.5-fold increased risk of mortality. In critically ill adults, a large prospective randomized clinical study showed that strict control of blood glucose with insulin therapy reduced the incidence of acute kidney injury (AKI).…”

“…In critically ill adults, a large prospective randomized clinical study showed that strict control of blood glucose with insulin therapy reduced the incidence of acute kidney injury (AKI). 1 In children, the incidence of AKI is difficult to estimate because of the lack of a standard definition for AKI and lack of large prospective multicenter studies involving general intensive care population, making the AKI incidence prone to definition and center-specific bias. 5 Over 30 definitions of AKI have been published, 4 and pediatric AKI definition has been "extrapolated" from adult studies.…”