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. 2025 Mar 24;15(1):40.
doi: 10.1186/s13613-025-01463-x.

Alterations in the renin-angiotensin system during septic shock

Camille Benaroua  1   2 , Fabrizio Pucci  3 , Marianne Rooman  3 , Adrien Picod  4 , Raphaël Favory  2 , Matthieu Legrand  5 , Jean-Louis Vincent  1 , Jacques Creteur  1 , Fabio Silvio Taccone  1 , Filippo Annoni #  1 , Bruno Garcia #  6   7
Affiliations

Alterations in the renin-angiotensin system during septic shock

Camille Benaroua et al. Ann Intensive Care. .

Abstract

Background: Alterations in the classical Renin-Angiotensin Aldosterone System (RAAS) have been described during septic shock and are associated with patient outcomes. Since the alternative RAAS has also been reported to be altered in critically ill patients, and given that the RAAS can be modulated by specific therapeutics, such as angiotensin II, understanding its pathophysiology is of primary interest.

Objective: To describe the alterations in the classical and alternative RAAS during septic shock in comparison with healthy controls.

Methods: This prospective, monocentric, controlled study enrolled 20 patients fulfilling the septic shock diagnosis, as defined by the Sepsis-3 criteria, along with 30 controls. The main exclusion criteria were the use of any prior medication modifying the RAAS, prior liver failure (Child-Pugh score > 9), or chronic kidney disease (estimated glomerular filtration rate < 30 ml/min/1.73 m²). Equilibrium concentrations of RAAS peptides were analyzed using a liquid chromatography-mass spectrometry method from heparinized plasma. Circulating angiotensin-converting enzyme (cACE), cACE type 2 (cACE2) activities, and circulating dipeptidyl peptidase 3 (cDPP3) concentrations were assessed. Values were measured at diagnosis, 6 h after diagnosis and on days 1 and 3. The main timepoint of interest was 6 h after diagnosis. Values 6 h after diagnosis were compared to 30 controls.

Results: In septic shock patients, increased concentrations of the main peptides of the classical and alternative RAAS were observed compared to controls, particularly angiotensin I (Ang I) and angiotensin-(1-7) (Ang-(1-7)). Additionally, there was a significant increase in the Ang I/Ang II ratio (1.16 [0.74-3.31] vs. 0.34 [0.25-0.43], p < 0.05) and the Ang-(1-7)/Ang II ratio (0.15 [0.08-1.30] vs. 0.03 [0.02-0.04], p < 0.05). We also observed a significant reduction in cACE activity (3.38 [2.29-6.8] vs. 7.89 [6.39-9.05] nmol Ang II/L/h), an increase in cACE2 activity (814 [669-1987] vs. 214 [132-293] pmol Ang-(1-7)/L/h), and increased cDPP3 concentrations (54.6 [35-142.2] ng/mL vs. 13.7 [11.9-15.4] ng/mL, all p < 0.05).

Conclusions: Septic shock was associated with increased Ang I/Ang II and Ang-(1-7)/Ang II ratios, along with reduced cACE activity, increased cACE2 activity, and elevated cDPP3 concentrations compared to healthy controls.

Keywords: Angiotensin II; Angiotensin converting enzyme; Dipeptidyl peptidase 3; Distributive shock; Renin; Sepsis; Vasoplegia; Vasopressor.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was designed in accordance with legal and regulatory requirements (Belgian Law of 7 May 2004, Patient Rights (08/2002), Privacy (RD 2001), HBM (Human Body Material, Law of 19 December 2008)), as well as the Guidelines for Good Clinical Practice (International Conference on Harmonization, 1996), and the latest version of the Declaration of Helsinki (World Medical Association). The protocol was approved by the referring local ethics committee (Erasme University Hospital, Belgium) as minimal-risk research using data collected for routine clinical practice n°P2021/360/B4062021000188. Patients or their representatives provided written informed consent for inclusion in the trial and had the option to refuse participation. Consent for publication: Not applicable. Competing interests: C.B was supported by a grant from Université de Lille, France. F.P. & M.R. were supported by F.R.S.-FNRS Fund for Scientific Research. B.G. was supported by a grant from ISICEM asbl. F.A was supported by the Fonds Erasme. AP reports research grants from 4TEEN4 pharmaceuticals, the Société de Réanimation de Langue Française, Société Française d’Anesthésie-Réanimation, Zoll fondation and the Fonds pour la chirurgie cardiaque outside the scope of the submitted work. ML is supported by grant R01-GM151494-01 and R01DK139484-01 from the NIH and received consulting fees from Alexion, Radiometer, Viatris and La Jolla.

Figures

Fig. 1
Fig. 1
Angiotensin I/Angiotensin II ratio (A), Angiotensin-(1–7)/Angiotensin II ratio (B), Plasma Renin Activity-S (C), Aldosterone (D) and cDPP3 (E) concentrations at 6 h after diagnosis compared to controls. *p < 0.05 between septic shock and control groups
Fig. 2
Fig. 2
cACE and cACE2 activities 6 h after shock diagnosis. *p < 0.05 between septic shock and control groups
See this image and copyright information in PMC

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