Alterations in the renin-angiotensin system during septic shock

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.

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

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.

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).

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.