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.