A dysregulation of the renin-angiotensin-system (RAS) has been involved in the genesis of lung injury and acute respiratory distress syndrome (ARDS) from different causes, including several viral infections. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection of pneumocytes, the hallmark of the pandemic coronavirus disease 2019 (COVID-19) involving both alveolar interstitium and capillaries, is linked to angiotensin-converting-enzyme 2 (ACE2) binding and its functional downregulation. ACE2 is a key enzyme for the balance between the two main arms of the RAS: the ACE/Angiotensin (Ang) II/Ang II type 1 receptor axis ("classic RAS"), and the ACE2/Ang 1-7/MasR axis ("anti-RAS"). The ACE2 downregulation, as a result of SARS-coronaviruses binding, enhances the "classic RAS", leading to lung damage and inflammation with leaky pulmonary blood vessels and fibrosis, when the attenuation mediated by the "anti-RAS" arm is reduced. ACE inhibitors (ACE-I) and Ang II type 1 receptor blockers (ARB), effective in cardiovascular diseases, were found to prevent and counteract acute lung injury in several experimental models, by restoring the balance between these two opposing arms. The evidence of RAS arms disequilibrium in COVID-19 and the hypothesis of a beneficial role of RAS modulation supported by preclinical and clinical studies are the focus of the present review. Preclinical and clinical studies on drugs balancing RAS arms might be the right way to counter COVID-19.

Real-life data confirming the favourable renal outcome in patients with heart failure (HF) treated with Sacubitril/Valsartan, previously found in several trials (RCTs), are still scant. We evaluated the renal effects of Sacubitril/Valsartan in a real-life sample of HF patients. Observational analysis of 54 consecutive outpatients affected by HF with reduced ejection fraction (HFrEF) and clinical indication for Sacubitril/Valsartan. Patients were evaluated at baseline (T0) and after six (T6) and twelve (T12) months after initiating Sacubitril/Valsartan and compared with a group of 30 historical controls. Mean age: 65.5 ± 11.7 years. Older patients: 29 (53.7%). Mean baseline estimated glomerular filtration rate (eGFR): 59.4 ± 19.2 ml/ min/1.73 m 2. Patients with chronic kidney disease (CKD), defined by an eGFR < 60 ml/min/1.73 m 2 , were 29 (53.7%). Sacubitril/Valsartan was less titrated in both older patients and patients with CKD. There were no changes in diuretics during follow-up. Systolic blood pressure (BP) decreased during follow-up (p = 0.014), while left ventricular ejection fraction (LVEF) slighly increased (p < 0.001). Renal function improved after 12 months compared to historical controls (p for interaction < 0.001) and a greater benefit was found in subjects aged < 65 years (p for interaction = 0.002) and patients with CKD (p for interaction = 0.009). A statistically (p = 0.009), but not clinically significant increase in serum potassium was also found, regardless of age and CKD. This is the first study focused on the renal effects of Sacubitril/Valsartan in HFrEF patients followed for 12 months in a real-life clinical context. The improved eGFR, despite lower BP, represents an important confirmation outside the peculiar world of RCTs.