Renal blood flow in sepsis

We found only three studies conducted in septic ICU patients in which RBF was measured [17‐19]. The findings of these studies suggest an increase in RBF during sepsis (Table 1). In only one patient was renal plasma flow (RPF) determined in the setting of oliguric ARF [19]. Such RPF was markedly increased at 2000 ml/min (normal 650 ml/min).

We found 159 [20‐178] animal studies that measured RBF in sepsis. Of these, 99 (62%) reported a decrease, whereas the remaining 60 (38%) studies reported no change or an increase in RBF (Table 2, Fig. 1).

Currently, only invasive techniques for measuring RBF have a high degree of accuracy. They require renal vein sampling. Because of the risks associated with such invasive measurement of RBF, only a few such studies have been conducted in humans with sepsis. Noninvasive methods of measurement such as the PAH clearance method are also possible but they assume a constant PAH extraction ratio of 0.91, such that RPF can be calculated with measurement of PAH concentrations in blood and urine. Unfortunately, the 'constant' PAH extraction ratio is not at all constant, is markedly unstable and is influenced by many factors, all of which apply in sepsis and ARF [18, 19]. Therefore, in order to achieve improved accuracy, this method must be made invasive by inserting a renal vein catheter in order to calculate the true PAH extraction ratio. The RPF measured by this method is called the true RPF. Finally, a third method uses a thermodilution renal vein catheter. RPF and RBF determined by the thermodilution method were reported to correlate with corrected PAH clearances (r = 0.79) [17].

However, a recently reported study [179] demonstrated that both methods have a low reproducibility and a within group error of up to 40%. Therefore, these methods are not sufficiently accurate to detect potentially important changes in RBF. Nonetheless, within the boundaries of the technology, true RPF measurements from human studies (Table 1) consistently suggest that renal blood flow is increased during human sepsis. In only one study [19] was RBF estimated in a septic patient with ARF. The RPF was found to be 2000 ml/min in this patient, which contrasts with the normal RPF in humans of 600–700 ml/min [180].

We only interrogated two English language electronic reference libraries and might have missed original contributions reported in other languages. However, we believe that it is unlikely that enough such studies would exist to change our conclusions materially.

In order to make comparisons, we categorized experiments according to pre-set criteria (small versus large animals, methods of induction of sepsis, high versus low CO, etc.) that we hypothesized, on grounds of biological plausibility, were likely to affect experimental findings. We acknowledge that such criteria are by definition arbitrary and the subject of individual judgement. Furthermore, other criteria that we did not consider could be tested. Nonetheless, we found that many of these criteria appeared to have some effect in reality. We also found that such effects appeared to be mostly related to their association with the CO state, which overwhelmingly was the only independent predictor in MVLRA for the outcome of RBF. We consider it unlikely that the choice of other criteria for comparison would materially affect our conclusions.

The observation time in the reviewed articles varied widely as well. We compared articles with a shorter period after the insult (2 hours) versus studies with a longer period of observation. We acknowledge that this division is artificial and might not truly reflect what happened, because some groups waited until the animal reached defined criteria before starting their observation time and others begun the observation immediately after the septic insult, making this variable extremely heterogeneous. Nonetheless, once again, given the overwhelming effect of CO on RBF, we consider that refinements to this criterion are unlikely to influence our conclusions.

Our observations suggest that the widely held paradigm that RBF decreases in sepsis [12‐14] and that such a decrease is responsible for the development of ARF is indeed sustained by the majority of studies. However, the reality beyond such a simplistic observation is much more complex. The animal studies are extraordinarily heterogeneous in their design and monitoring of RBF. Furthermore, the support that the bulk of the data offer to the concept of decreased RBF in sepsis is conditional upon a particular model of sepsis being present (hypodynamic sepsis without an increase in CO). If the CO is increased and PVR is decreased, then the most common finding is actually one of increased or preserved RBF. In the light of this review, we suggest that measurement of CO is a vital component of all future experimental studies measuring RBF in sepsis.

We note that, in human sepsis, systemic vasodilatation with a high CO is the dominant clinical finding. Such vasodilatation might also affect the afferent and efferent arterioles of the kidney. If the efferent arteriole dilated proportionately more than the afferent arteriole, then there would be a decrease in glomerular filtration pressure. This change in filtration pressure would decrease glomerular filtration rate and lead to oliguria and loss of small solute clearance. Accordingly, loss of glomerular filtration rate can occur with either vasoconstriction or vasodilatation.

Our findings have important implications for clinicians and for future strategies directed at preserving renal function in sepsis. They highlight the absence of human data. They show the heterogeneity and model dependence of the animal data. They also emphasize the limitations of the indirect data upon which clinical strategies are based. Much research remains to be done if we are to establish what happens to renal blood flow in human sepsis, and techniques are needed that permit such measurements to be taken noninvasively.