Renin–angiotensin system dysregulation in critically ill patients with acute respiratory distress syndrome due to COVID-19: a preliminary report

The renin–angiotensin system (RAS) may have an important role into the pathogenesis of the COVID-19. Indeed, SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) to gain entry to host cells. ACE2 is a peptidase that cleaves the potent vasoconstrictor angiotensin II (Ang II) to generate angiotensin 1–7 (Ang 1–7), a heptapeptide having vasodilator and anti-inflammatory function. Thus, ACE2 is a crucial counter-regulatory component of the RAS [1]. From March 9 to March 27, 2020, we analyzed plasma levels of renin, angiotensin I (Ang I), Ang II and Ang 1–7 in 32 consecutive patients with laboratory-confirmed SARS-Cov-2 infection and acute respiratory distress syndrome (ARDS) within 24 h of admission to ICU, approved by the Ethical Committee of Fondazione Policlinico Gemelli. All samples were drawn at morning. Before sample collection the hemodynamic parameters were optimized according to standard of care of our institution. RAS peptide concentrations were compared between survivors and non-survivors and correlated with clinical parameters. Compared to survivors, non-survivors had higher serum renin with lower Ang I, Ang II and Ang 1–7 (Table 1). The results were similar excluding from analysis 4 patients who were taking RAS inhibitors at inclusion (Table 2). Patients who required invasive mechanical ventilation (IMV) had lower Ang 1–7 than patients who never required IMV (214 pg/ml [IQR: 163–298] vs 335 [IQR: 259–499], p = 0.01). Our observations are consistent with a previous study on patients with vasodilatory shock, demonstrating that renin levels above the median of study population were associated with an increased risk of mortality. In these patients, treatment with synthetic Ang II reduced renin concentrations and the risk of mortality [2]. Therefore, the authors speculated that exogenous Ang II modulated the inflammatory response caused by excess renin. Furthermore, renin concentrations were positively correlated to Ang I/II ratios denoting an impaired conversion of Ang I to Ang II by angiotensin-converting enzyme (ACE). In our research, although not correlated to serum renin, Ang I/II ratios were markedly higher than those reported in healthy subjects (median Ang I/II ratio 1.8 vs 0.4, respectively) [3]. This relative Ang II deficiency is coherent with older studies on patients with ARDS unrelated to SARS-CoV-2 reporting a defect of endothelial–bound ACE activity due to endothelial injury [4]. Indeed, in patients with COVID-19 there is evidence of vascular involvement with diffuse inflammation which can result in widespread endothelial dysfunction [3, 5]. However, we did not measure all the angiotensin peptides, and hence, we cannot exclude an enhanced conversion of Ang I and Ang II to downstream products other than Ang 1–7, such as angiotensin 1–9 and angiotensin 1–5. Previous studies reported that some patients with COVID-19 and acute hypoxemic respiratory failure present near normal lung mechanics indicating that a loss of lung perfusion regulation may account for gas impairment [6]. In our series respiratory system compliance (Crs) was obtained in 18 out of 21 patients who received IMV. Median Crs was 39 ml/cm H2O [IQR: 38–52] and 6 out of 18 patients had a preserved Crs (52 ml/cm H2O [IQR: 52–55]). This subgroup of 6 patients had similar Ang II plasma levels despite renin concentrations significantly higher than the 12 patients with reduced Crs (median renin [IQR] 166.8 pg/ml [114.2–255.2] vs 13.6 [9–66.6], p = 0.02). Thus, the development of hypoxemia without marked loss of aerated lung could be explained by the worsening of ventilation perfusion mismatch induced by inadequate Ang II production. These preliminary data suggest that a more efficient RAS axis correlate with a better outcome in patients with ARDS due to SARS-Cov-2. Although the obvious limitations of our small, observational study preclude definitive conclusions, these findings could be considered hypothesis generating for future researches.