Acute kidney injury (AKI) affects 5 to 7% of all hospitalized patients 1 and independently increases mortality and the cost and complexity of care. Sepsis is the leading cause of ARF in the intensive care unit and septic ARF occurs most commonly in critically ill patients 2. The mortality of septic ARF remains high despite the application of renal replacement therapies and other supportive treatments 13.

The cardiovascular hallmark of severe sepsis is hypotension, which is widely held to cause reduced renal blood flow (RBF) leading to AKI 456. However, in recent animal studies reproducing the hyperdynamic sepsis typically seen in critically ill humans, RBF was found to be increased 78. In this setting, despite renal vasodilatation and a marked increase in RBF, animals still developed oliguria and decreased creatinine clearance 9. These findings concur with the limited studies of RBF in human sepsis 1011. They suggest that afferent and even greater efferent arteriolar vasodilatation may occur in early hyperdynamic sepsis. If this were true, selective vasoconstriction of the efferent arteriole with angiotensin II (Ang II) in this setting may be physiologically logical and safe and may attenuate renal dysfunction.

Ang II is a powerful vasoconstrictor hormone that causes a preferential increase in efferent arteriolar resistance 12. It has been rarely used in hyperdynamic sepsis 1314 due to concerns about its possible deleterious effects on regional blood flow and renal function. However, there are no studies of its effects on regional blood flows when administered by continuous infusion to restore blood pressure in hyperdynamic hypotensive sepsis. More relevant, there are no studies to confirm whether its potential adverse effects on renal blood flow are functionally important. To address these limitations in our knowledge and given the rationale that selective efferent arteriolar vasoconstriction may be desirable in this setting, we conducted a randomized controlled animal study and measured the systemic and regional hemodynamic effects and the renal functional effects of Ang II infusion compared with placebo in an animal model of hypotensive hyperdynamic sepsis.

In a model of hypotensive hyperdynamic sepsis, we examined the systemic and regional hemodynamic effects and renal functional effects of intravenous Ang II infusion. We found that Ang II at a dose titrated to restore MAP to baseline levels induced systemic vasoconstriction with limited vasoconstrictive effects on the mesenteric but not coronary or iliac vascular beds. We found, however, that Ang II decreased RBF and renal conductance to pre-sepsis levels, while increasing urine output, creatinine clearance and fractional natriuresis.

One of the characteristics of severe hypotensive hyperdynamic sepsis is peripheral vasodilatation 1819. However, it has been suggested that, in sepsis, such generalized vasodilatation might spare the kidney such that RBF decreases due to vasoconstriction, ischemia develops and renal function declines 456. In contrast, in our model of hyperdynamic sepsis, we found intense renal vasodilatation and increased RBF, as previously reported 89. Despite renal hyperemia, there was a significant decline in renal function, as shown by the decreased urine output and creatinine clearance. These changes suggest a marked reduction in glomerular filtration rate (GFR) and its major determinant, intra-glomerular capillary pressure. The effect of Ang II on urine output, creatinine clearance and natriuresis occurring in the setting of renal vasoconstriction and decreased RBF, as seen in our study, is consistent with the hypothesis that Ang II causes an increase in glomerular filtration pressure, possibly through selective efferent arteriolar vasoconstriction or changes in mesangial cell tone or both. To our knowledge, this is the first report of such effects in hyperdynamic sepsis. Previous animal studies in rats demonstrated a likely role for Ang II to oppose the hypotensive response to lipopolysaccharide-induced sepsis 20 and a reduced systemic pressor response to Ang II boluses at doses similar to ours, an effect which was associated with a variable renal vasoconstrictor response 21. None of these studies, however, measured the renal functional effect or systemic and renal hemodynamic effect of extended Ang II infusion.

The increase in urinary output, fractional natriuresis and creatinine clearance induced by infusion of Ang II in sepsis seems unlikely to be simply secondary to increases in arterial pressure. First, the MAP value during Ang II infusion was similar to baseline values and yet urine output and fractional natriuresis were much greater. Second, in previous identical studies, norepinephrine and epinephrine infusion caused similar increases in arterial pressure but produced much smaller and more transient improvements in renal function than Ang II 722.

The renal effect of Ang II may relate to its selective effects on intrarenal hemodynamics, where it controls tone in the afferent and efferent arterioles 14 and mesangial cells 23. Infusion of Ang II increases filtration fraction 242526, which has been proposed to result from a greater sensitivity of the efferent than the afferent arterioles to its vasoconstrictor action, a notion supported by several studies 272829303132. In contrast, the afferent and efferent arterioles have been shown to respond similarly to norepinephrine 27.

If Ang II is to be used in human sepsis, it is important to assess whether this treatment has harmful effects. We found that Ang II caused only limited reductions in blood flow to the heart, gut or skeletal muscle. Additionally, we found no evidence of adverse effects on electrolyte or lactate levels. Desensitization to the effects of vasoconstrictor agents, including Ang II, in sepsis is well established. In this study, the levels of Ang II required to increase MAP by 20 mmHg were up to five-fold more than the dose required in healthy animals 33. A similar desensitization to Ang II may occur in septic patients compared with healthy humans 1234. This phenomenon is not fully understood, but may result from high levels of nitric oxide counteracting the vasoconstrictor effect of Ang II or from down regulation of angiotensin AT-₁ receptors 35.

Our study has both strengths and limitations. It is randomized and placebo-controlled, conducted in conscious animals to remove the confounding effects of sedation or anaesthesia. Blood flows were measured by highly accurate probes inserted several weeks before the experiment. Furthermore, the renal effects of Ang II are clear, internally consistent and kidney specific. On the other hand, the indirect measurement of GFR by means of creatinine clearance is of limited accuracy in the absence of a steady state. The changes we observed, however, were marked and strongly suggestive of a true effect. Our model does not completely reproduce severe human sepsis. However, the systemic inflammatory syndrome developed and three major criteria for a hyperdynamic circulation were present throughout the study period. The decrease in arterial pressure and urine output and the increase in lactate meant that our animals fulfilled the ACCP/SCCM consensus criteria for severe sepsis 36. The mortality rate of 25% seen in our animals is similar to the 30% mortality rate seen in severe sepsis in humans. Nonetheless, the septic state in our animals was not sustained beyond 8 to 12 hours and our observations may not apply to prolonged or recurrent sepsis as seen in other large animal models of sepsis 37. In addition, our animals, unlike many septic humans, did not have old age, vascular disease, hypertension or diabetes. These differences between our model and human sepsis must be taken into account in the interpretation of our findings. We did not measure Ang II levels thus making it impossible to compare Ang II levels during the natural response to sepsis with those achieved duringAng II infusion. We did not administer fluid resuscitation, although such resuscitation is typically performed in human sepsis and might have modified our findings. The CO and total peripheral conductance during the untreated septic state in placebo animals showed small differences from animals allocated to Ang II. These differences may have affected our findings. Finally, we acknowledge that increases in blood pressure can, independent of the drug used, induce a diuresis 38. However, the effects fo Ang II or renal function during sepsis were more potent than those of doses of epinephrine and norepinephrine that caused similar increases in arterial pressure 722. It is also possible that the combination of lower dose vasopressor drugs (multimodal therapy) would achieve better renal protection with lower systemic side effects.

We found that, in a large animal model of experimental hypotensive hyperdynamic sepsis, infusion of Ang II at a dose that restores MAP to pre-sepsis levels, significantly reduced RBF and simultaneously increased urine output, fractional natriuresis and creatinine clearance. Ang II caused these renal changes without major adverse effects on blood flows to other vital organs, blood lactate or biochemical variables. These findings justify further investigations of Ang II in experimental and human sepsis.

• Experimental hyperdynamic hypotensive sepsis can be associated with renal vasodilatation and hyperemia while renal function becomes impaired

• The combination of renal vasodilatation with decreased GFR suggests combined afferent and efferent arteriolar vasodilatation with greater arteriolar dilatation

• Ang II infusion restores renal hemodynamic to normal

• Ang II-induced restoration of intra-renal hemodynamics to normal is associated with improved creatinine clearance and a marked increase in urine output.

AKI: acute kidney injury; Ang II: angiotensin II; CO: cardiac output; CVP: central venous pressure; FENa: fractional excretion of sodium; GFR: glomerular filtration rate; MAP: mean arterial pressure; RBF: renal blood flow.

As a result of this study, Drs. Clive May and Rinaldo Bellomo have applied for patent protection for the use of angiotensin II to treat septic acute kidney injury in man.

CNM, LW, CL and RB designed the study. LW and CNM performed the experiments and data analysis. All authors participated in the drafting of the final manuscript. All authors read and approved the final manuscript.