The main finding of this study is that a high-MAP target of 80–85 mmHg compared to MAP of 65–70 mmHg in septic patients with AKI and prior hypertension is associated with increased UO, UNa and decreased sCr, resulting in increased glomerular function as assessed by the UV/P formula. Conversely, a high-MAP regimen does not affect the kidneys' ability to concentrate urine, with no variation in urinary osmolality, urine-to-plasma creatinine ratio and fractional excretion of sodium or urea, which may reflect no effect on tubular function.
The evaluation of renal function is complex in critically ill patients. Serum creatinine is traditionally used, because it is freely filtered into the glomerulus, with a small proportion being secreted along the tubule. The recommended formula for estimating GFR is UV/P, because it has the potential advantage that it can be used in the absence of a stable state . However, its main limitations are that many factors influence sCr, in particular the patient's volume of distribution  and the proportion of tubular creatinine secretion, which remains unpredictable and depends on the relative increase in sCr to the patient's baseline creatinine . However, the kidney has many other functions that are difficult to assess in AKI, including tubular transport. The ability of loop diuretics that are active on the renal tubule to induce natriuresis has, for example, been used to predict the development and severity of AKI and its prognosis . To our knowledge, no studies have estimated the impact of higher pressure regimen on tubular function in sepsis-associated AKI.
The effects of MAP level on AKI have been investigated in numerous studies, showing an improvement in UO with a MAP target between 65 and 75 mmHg . In the SEPSISPAM trial, 778 patients with septic shock were randomly treated with a low (65–70 mmHg) vs. high (80–85 mmHg) MAP target . The authors demonstrated less renal failure, as defined by the doubling of plasma creatinine (38.8% vs. 52.0%, respectively, P = 0.02) in patients with previous hypertension treated with a higher MAP target and a decrease number of patients requiring RRT. Conversely, the 65-trial comparing permissive hypotension to usual care in patients 65 years of age or older receiving vasopressors for vasodilatory hypotension did not demonstrate an increase in the use of RRT in patients with chronic hypertension randomized to a lower MAP target group . Legrand et al. also did not observe an association between most systemic hemodynamic parameters, including MAP and cardiac output, and sepsis-associated AKI . Our results confirm that in patients with sepsis-associated AKI and chronic hypertension, a higher MAP target is associated with a significant increase in UO and a decrease in sCr, resulting in better CrCl. The observed increase in CrCl may not be considered as the only result of the increase in UO (e.g., single doses of diuretics have no significant effect on CrCl ), but could rather be the consequence of a residual level of glomerular filtration function when capillary pressure increases during a high-MAP regimen [18, 19]. The stage of AKI interacted with variations in sCr in our study, possibly due to higher sCr values in patients with the most severe renal injury. More originally, we showed no variation in the ability to concentrate urine at a high-MAP regimen. Increased renal perfusion could, for instance, have curbed sodium reabsorption, but patients with low sodium excretion at inclusion showed no significant change in their ability to concentrate urine at high-MAP regimen compared to those with higher sodium excretion at inclusion. Furthermore, proximal tubular creatinine secretion accounts normally for 10–20% of the total creatinine clearance but increases to 50% in chronic kidney disease (CKD) when GFR falls . The high-MAP regimen in our study did not result in a significant increase in uCr, which may also reflect no effect on tubular secretion of creatinine.
This study has several limitations. First, this study should be considered exploratory and observational as the crossover was only performed at the individual level and not at the level of the grouping unit without randomisation. A carry-over effect remains, therefore, possible in this rapidly evolving disease without being able to assume that the patients had returned to their initial state before the application of the next MAP regimen. However, changes in creatinine clearance are described as rapid in AKI, with a period of approximately 7 h to reach a 100% increase when the baseline SCr is 88 µmol/L at a constant rate of creatinine production of 60 mg/h and a complete cessation of CrCl . A washout period was also possible on the urine sample, since it was collected on the last hour collection. The time to assess a change in renal tubular function is not known for this clinical setting either, but response to renal tubular function tests is often observed within hours in nephrology studies . Second, patients were included after the initial resuscitation of septic shock, i.e., after the crucial period for the onset and severity of AKI. The inclusions may then have been too delayed for the MAP-targeted norepinephrine regimen to have a significant impact on tubular function. Patient evolution prior to admission to the ICU may also have influenced our results and the time period for a potential impact of higher MAP regimen on renal function and its lasting effect is unknown. The haemodynamic stabilisation period defined by a stable or decreased dose of norepinephrine for 3-h fluid loading could also be debated. This delay was chosen to allow sufficient time to reach an optimised volume status before changing doses of norepinephrine, but without excessively delaying the possible effect of the change in pressure regimen on renal function. Estimation of GFR by calculation of a CrCl from a urine sample may be another limiting factor as it may not be representative of urine production over a longer period of time . However, our analysis at an intra-individual level in combination with an MAP regimen administered consecutively in two different orders may avoid other biases related to the normal evolution of sepsis-associated AKI, given the great diversity of septic patients, including the patient's creatinine generation rate, the volume of distribution of creatinine, and dynamic changes over time as well as “renal reserve” of patients.
The pathophysiological mechanisms underlying sepsis-associated AKI are still a matter of debate, but it has been demonstrated that AKI occurs during hyperdynamic sepsis with increased total renal blood flow [5, 23]. Several mechanisms have been proposed to play a role, including tissue hypoxia, changes in microcirculation, venous congestion and mechanisms independent of haemodynamic impairment, such as inflammation and oxidative stress. Beyond the filtration function of the kidney, tubular transport is a determining factor in its oxygen consumption and evidence is now accumulating that places the tubular system at the center of AKI pathophysiology and recovery in established sepsis . In addition, recent findings suggest that treatment with norepinephrine decreased medullary tissue oxygen tension by half and decreased medullary perfusion, region in which the renal tubules are inserted . The increase in GFR during norepinephrine infusion may also increase sodium delivery to tubular elements within the medulla, and thus utilization of oxygen for sodium reabsorption, which could contribute to the observed medullary hypoxia . Whether the risk of medullary hypoxia associated with high doses of norepinephrine combined to pressure induced glomerular injuries, which is the predominant pathway for nephron loss in CKD , have an impact on renal injury and its long-term prognosis is unknown. However, it is now well established that AKI survivors are at high risk of developing CKD, even if their AKI was not severe and their kidney function has recovered on discharge from the ICU . The impact of a high-MAP target on renal tubular function and on the longer term prognosis of sepsis-associated AKI in patients with prior hypertension should be further investigated in larger randomised trials.