Objective: To explain the paradigm of significant renal functional
impairment despite preserved hemodynamics and histology in
sepsis-induced acute kidney injury.
Design: Prospective observational animal study.
Setting: University research laboratory.
Subjects: Male Wistar rats.
Intervention: Using a fluid-resuscitated sublethal rat model of
fecal peritonitis, changes in renal function were characterized in
relation to global and renal hemodynamics, and histology at 6 and
24 hours (n = 6–10). Sham-operated animals were used as comparison
(n = 8). Tubular cell mitochondrial function was assessed
using multiphoton confocal imaging of live kidney slices incubated
in septic serum.
Measurements and Main Results: By 24 hours, serum creatinine
was significantly elevated with a concurrent decrease in renal lactate
clearance in septic animals compared with sham-operated
and 6-hour septic animals. Renal uncoupling protein-2 was elevated
in septic animals at 24 hours although tubular cell injury was
minimal and mitochondrial ultrastructure in renal proximal tubular
cells preserved. There was no significant change in global or renal
hemodynamics and oxygen delivery/consumption between shamoperated
and septic animals at both 6- and 24-hour timepoints. In
the live kidney slice model, mitochondrial dysfunction was seen in
proximal tubular epithelial cells incubated with septic serum with
increased production of reactive oxygen species, and decreases
in nicotinamide adenine dinucleotide and mitochondrial membrane
potential. These effects were prevented by coincubation with the
reactive oxygen species scavenger, 4-hydroxy-2,2,6,6-tetramethyl-piperidin-1-oxyl. Conclusions: Renal dysfunction in sepsis occurs independently
of hemodynamic instability or structural damage. Mitochondrial
dysfunction mediated by circulating mediators that induce local
oxidative stress may represent an important pathophysiologic
mechanism.