Effects of angiotensin 2 infusion on the RAAS and alternative RAAS pathway

Dear editor,

With interest we read the article of Leisman et al. [1] describing the ‘AIMRITE’ blood pressure response to Angiotensin 2 infusion and its correlation with favorable outcome. In contrast to earlier data [2], baseline renin concentration did not predict the blood pressure response to Angiotensin II. To further forward our understanding of the physiological response to angiotensin II infusion in patients with septic shock we comprehensively assessed the Renin–Angiotensin–Aldosteron-System (RAAS) and the alternative RAAS [3]. The study was carried out in the Netherlands in accordance with the applicable rules concerning the review of research ethics committees and informed consent. All patients or legal representatives were informed about the study details and could decline to participate. Patients with a noradrenaline dose > 0.2 µg/kg/min were treated with angiotensin II between 6 and 48 h from the initiation of noradrenaline. A target mean arterial pressure (MAP) of ≥ 65 mmHg was maintained and patients were deemed a responder to angiotensin II if a reduction in noradrenalin infusion rate of > 25% was achieved. Blood samples were drawn at baseline, after 3 and 24 h. Renin, angiotensin I, angiotensin II, angiotensin 1–7 and angiotensin 1–5 were determined. We calculated angiotensin 1–7/1–5 ratio, as a proxy for Angiotensin-converting-enzyme (ACE) activity; and angiotensin II/1–7 ratio, as a proxy for ACE-2 activity. All data is presented as median [IQR].

Ten patients were included (Table 1), six patients responded to angiotensin II with a reduction of noradrenaline infusion rate of 72% [48–89%]. Kinetics of the RAAS pathway are shown in Fig. 1. Angiotensin II infusion rate was lower in responders than in non-responders at 3 h (23.8 [15.1–28.0] versus 35.0 [29.7–40.0] ng/kg/min) and 24 h (18.8 [4.7–19.8] versus 40.0 [40.0–40.0] ng/kg/min). Accordingly, the measured angiotensin II plasma concentrations were lower (612 [313–886] versus 1021 [593–1069] µU/ml) in the MAP-responders compared to non-responders. Plasma renin concentration decreased from 282 [95–368] to 71 [46–121] (3 h) and 34 [23–40] µU/ml (24 h) in patients responding to angiotensin II, while the decline in renin was much less pronounced in non-responders, from 446 [274–691] at baseline to 310 [272–581] and 300 [230–321] µU/ml, respectively. Angiotensin 1–7 plasma concentration was similar at baseline, but higher at 3 and 24 h in patients not responding to angiotensin II infusion. Also, baseline angiotensin 1–7/1–5 ratio was similar between responders and non-responders, and increased in patients not responding to angiotensin II infusion, illustrating attenuation of ACE activity. While ACE activity decreased, Angiotensin II infusion resulted in an increase in ACE-2 activity in non-responders, illustrated by a decrease in Angiotensin II/1–7 ratio.

Table 1.

Baseline characteristics, numbers are absolute values or median with interquartile range

	Responders (n = 6)	Non-responders (n = 4)
Age (years)	65 [50–74]	65 [55–70]
Sex M/F	5/1	3/1
BMI (kg/m2)	28.6 [23.1–29.4]	27.0 [22.8–33.3]
SOFA	9 [7–10]	13 [11–15]
Fluids administered 24 h before start ATII (ml/kg)	52 [38–62]	92 [67–97]
Baseline Norepinephrine dose (µg/kg/min)	0.23 [0.20–0.26]	0.51 [0.41–0.64]
Norepinephrine dose at 3 h (µg/kg/min)	0.08 [0.03–0.13]	0.45 [0.42–0.50]
Vasopressin (0.04 IE/min, number of patients/total)	2/6	3/4
Inotropics (number of patients/total)
Milrinone	1/6	2/4
Dobutamine	1/6	0/4
Pre-existent ACE-i use	1/6	0/4
Mechanical ventilation (h)	123 [80–511]	133 [79–431]
Albumin	20.5 [13.0–25.8]	17 [13.5–19.8]
Diuresis before start ATII (ml/h)	0.68 [0.42–0.85]	0.03 [0.03–0.03]
Plasma creatinine	113 [96–250]	248 [205–315]
AKI (number of patients/total)
No AKI	1/6	0/4
KDIGO stage 1	2/6	0/4
KDIGO stage 2	2/6	1/4
KDIGO stage 3	1/6	3/4
Renal replacement therapy	1/6	4/4
Diuresis 3 h after start ATII (ml/kg/h)	0.47 [0.38–0.54]	0.01 [0–0.01]
ICU mortality (number of patients/total)	2/6	3/4

Fig. 1.

Graphical representation of the RAAS pathway, each graph shows the plasma concentration of the different metabolites/calculated ratio’s (Y-axis) over time (X-axis). Straight light blue lines represent non-responders to angiotensin II, dashed dark blue lines represent responders to angiotensin II. Depicted values are medians with interquartile range. Patients that do not show a hemodynamic response to angiotensin II infusion received a higher infusion rate, resulting in higher circulating angiotensin II concentrations. Nevertheless, this did not result in a decrease in Renin concentrations in non-responders, while it did in responders. Over time, ACE-activity decreased, while ACE2-activity increased, in non-responders, illustrating impaired negative feedback and activation of the alternative RAAS pathway in non-responders

Our data shows that a decrease in plasma renin concentration better reflects the hemodynamic response to infusion of Angiotensin II than the absolute baseline concentration. This indicates an intact feedback mechanism of the RAAS-pathway in responding patients, while this not the case in non-responders despite higher angiotensin II infusion rates and subsequent circulating angiotensin II concentrations. In responders and non-responders both ACE and ACE 2 activity appear similar at baseline, however, ACE activity decreases over time in non-responders. Of interest, decreased ACE activity has been associated with increased mortality in patients vasodilatory shock [4]. Apart from the decrease in ACE activity in non-responders, Angiotensin II infusion increased their ACE-2 activity, illustrating activation of the alternative RAAS pathway over time. Again, this may be related to impaired clinical outcomes, as the secondary analysis of the VICTAS trial showed a significant association between a two-fold increase in plasma angiotensin 1–7 at day 3 and mortality [5]. These data suggest that not the absolute value of the plasma renin concentration, but the patients’ ability to decrease plasma renin concentrations (following Angiotensin II infusion), and thus activate an intact RAAS pathway, including its negative feedback mechanisms, relate to the more favorably survival following the initiation of angiotensin II treatment. Indeed declining plasma renin levels appear to translate to improved survival [5]. It is currently unclear whether or not this may explain the favorable survival data in the ‘high baseline renin-angiotensin II resistant’ patients as described by Leisman et al. [1].

In conclusion, in patients that do not show a hemodynamic response to angiotensin II infusion, there seems to be an inability to activate the angiotensin-2-receptor or its downstream pathway. The subsequent absence of a negative feedback mechanism on plasma renin concentration, even when a high plasma concentrations of angiotensin II are reached and activation of the alternative RAAS pathway occurs may be of prognostic importance.

Abbreviations

RAAS

Renin–angiotensin–aldosterone-system

MAP

Mean arterial pressure

ACE

Angiotensin-converting-enzyme

Author contributions

C-LS and DvL enrolled patients, collected samples, drafted the manuscript and prepared the figure. AEvH interpreted the data and reviewed the manuscript. TF reviewed the manuscript. PP designed and initiated the study and co-authored the manuscript. All authors reviewed the final version of the manuscript.

Funding

Determination of RAAS-metabolites were funded by PAION. PAION did not have a role in the design, enrolment, data acquisition, data analysis, and drafting of the manuscript. All coauthors reviewed, made adjustments, and approved the manuscript. The decision to submit the manuscript was made by the principal investigator and other coauthors.

Data availability

Data is available upon reasonable request.

Declarations

Competing interests

The authors declare no competing interests.