Intra‐renal and Urinary Oxygenation during Resuscitation with Norepinephrine and Angiotensin II in Ovine Acute Kidney Injury

Abstract

Background and AimsAcute kidney Injury (AKI) is a common phenotype of sepsis leading to high mortality rates. Norepinephrine (NE) is the first choice vasopressor used clinically to restore blood pressure and renal function, whilst there is emerging interest in angiotensin II (Ang II) as an effective adjunctive therapy in patients with septic shock. Increasing evidence suggests that hypoxia in the renal medulla may play a critical role in the pathogenesis of AKI. We therefore measured renal cortical and medullary tissue oxygen tension (PO2) in conscious sheep during development of septic AKI and following resuscitation with NE and Ang II. In addition, since the renal medullary vasa recta run close and parallel to the collecting ducts, we examined whether urinary PO2 and medullary tissue PO2 changed in a similar manner during development of septic AKI and treatment with NE and Ang II.MethodsSheep were surgically instrumented with a renal artery flow probe and fibre‐optic probes in the cortex and medulla to measure tissue perfusion and oxygenation. An oxygen probe was inserted into the tip of the bladder catheter for measurement of urinary oxygenation. Conscious sheep received a continuous infusion of live Escherichia coli (2.8 × 109 bolus + 1.26 × 109 colony forming units i.v) for 32 h. NE (0.4–0.8 μg/kg/h, n=8) or Ang II (0.5–33μg/kg/min, n=8) or saline‐vehicle (n=8) were infused from 24–30 h of sepsis.ResultsPrior to treatment, septic AKI was characterized by hypotension (~14 mmHg), renal hyperperfusion (~70%) and reduced glomerular filtration rate (~65%). Medullary perfusion (1289±95 to 628±113 blood perfusion units (BPU)), medullary oxygenation (32±3 to 16±4 mmHg) and urinary oxygenation (36±2 to 24±2 mmHg) were all significantly reduced. Restoring blood pressure with NE further reduced medullary perfusion (331±64 BPU), medullary PO2 (8±2 mmHg) and urinary PO2 (18±4 mmHg). In contrast, Ang II reversed the sepsis‐induced hypotension without further exacerbating medullary perfusion (553±58 BPU), medullary PO2 (26±2 mmHg) or urinary PO2 (24±1 mmHg). Cortical perfusion and oxygenation were preserved during development of septic AKI and resuscitation with NE and Ang II.ConclusionsRenal medullary hypoxia due to intra‐renal blood flow redistribution may contribute to the development of septic AKI. Resuscitation with NE reversed sepsis‐induced hypotension, but exacerbated the medullary hypoxia, which may have long‐term effects to worsen kidney injury. Interestingly, Ang II restored blood pressure without worsening medullary hypoxia, suggesting that Ang II has less adverse effects than NE on kidney oxygenation during treatment of septic AKI. The parallel changes in medullary tissue and urinary PO2 during development of sepsis and vasopressor treatment suggest that urinary PO2 may be a useful real‐time biomarker to monitor patients at risk of developing AKI.Support or Funding InformatioThis work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC, 454615, 1009280, 1050672), and by funding from the Victorian Government Operational Infrastructure Support Grant.