Effects of tempol on renal medullary tissue hypoxia in an ovine model of Gram-negative septic acute kidney injury.

Renal arterial infusion of tempol (RAT) at the onset of Gram-negative sepsis can prevent sepsis-induced medullary tissue hypoxia and acute kidney injury (AKI). However, it is not known whether treatment with tempol at a clinically relevant time point of sepsis is similarly effective. Thus, we examined whether tempol can reverse renal medullary tissue hypoxia after ovine Gram-negative septic AKI. Following right unilateral nephrectomy, the left kidney was instrumented with a renal arterial catheter and oxygen-sensing fibre-optic probes into the renal medulla. After 23 h of Escherichia coli infusion, conscious sheep were fluid resuscitated with Hartmann's solution (30 mL/kg over 0.5 h) and randomized to intravenous tempol (IVT; n = 7) at 30 mg/kg/h, RAT (3 mg/kg/h; n = 6) or vehicle (n = 5) from 24 to 31 h of sepsis. At 31 h, E. coli infusion ceased, and sheep received ceftriaxone (1 g) and were allowed a 48 h recovery period. At 23 h of E. coli infusion, septic sheep developed a 2.2 ± 0.8-fold increase in plasma creatinine and a 57% ± 6% decrease in urine output, and the renal medulla was ischaemic and hypoxic. Neither RAT nor IVT attenuated the sepsis-induced renal medullary tissue hypoxia during the 7 h intervention period. Renal medullary tissue partial pressure of O2 returned to the pre-morbid levels in all groups by 16 h after treatment cessation, and sepsis was resolved with antibiotics. In conclusion, in sheep with established septic AKI, treatment with RAT or IVT did not improve renal medullary oxygenation or kidney function, in contrast to the effectiveness we have shown in early sepsis. These findings emphasize the dramatically different response to a treatment in early compared with late stages of sepsis.