key: cord-287786-zfe0el8i
authors: Dudoignon, Emmanuel; Moreno, Nabila; Deniau, Benjamin; Coutrot, Maxime; Longer, Romain; Amiot, Quentin; Mebazaa, Alexandre; Pirracchio, Romain; Depret, François; Legrand, Matthieu
title: Activation of the Renin-angiotensin-aldosterone system is associated with Acute Kidney injury in COVID-19
date: 2020-06-18
journal: Anaesth Crit Care Pain Med
DOI: 10.1016/j.accpm.2020.06.006
sha: 
doc_id: 287786
cord_uid: zfe0el8i

Abstract The pathophysiology of acute kidney injury (AKI) in COVID-19 patients is still poorly understood. SARS-CoV2 has been suggested to modulate the renin-angiotensin-aldosterone system (RAAS). In this series of COVID-19 critically ill patients, we report evidence of activation of the RAAS in COVID-19 patients with AKI.

The understanding of the pathophysiological characteristics of AKI in the setting of COVID-19 is limited. A direct renal tropism of the virus, systemic inflammation, and microvascular injury are potential contributors to the renal damaging mechanisms of SARS-CoV-2. The interaction of SARS-CoV-2 with the renin-angiotensin-aldosterone system (RAAS) has been intensely discussed, but its role in the pathophysiology of SARS-COV2 associated AKI remains unexplored. Such activation may have important therapeutic implications.

Characterisation and understanding of COVID-19 renal injury would improve the management of patients admitted to the intensive care unit (ICU). Here, we describe the renal response of patients with COVID-19 patients admitted to an intensive care unit (ICU), with a particular focus on the activation of the renin-angiotensin-aldosterone system.

Patients admitted to the ICU of St-Louis Hospital (Paris) between March 22 and April 15, 2020 for acute respiratory distress syndrome (Berlin Definition [7] ) with acute kidney injury (AKI, defined according to the Kidney Disease-Improving Global Outcome criteria [8] and using the admission serum creatinine as the baseline) were screened. COVID-19 diagnosis was performed with a positive result of reverse transcription-polymerase chain reaction assay of a nasal swab or bronchoalveolar lavage. COVID-19-associated ARDS management protocol included, lung-protective ventilation, with driving pressure optimisation, prone positioning in severe cases, control of fluid balance, haemodynamic optimisation, early recognition, and treatment of ventilator-associated pneumonia (VAP), and daily re-evaluation of sedation.

Patients under 18 years, with chronic kidney disease, and those who refused to participate were not included, whereas those who died within 72 hours of admission were excluded. All patients or their surrogate had information about the data collection and could refuse to participate (SFAR's ethical comity, IRB 00010254 -2019 -203).

As usually performed in our unit, plasma and urine chemistry and 24 hours proteinuria were collected every morning at 6 am. Plasma renin and aldosterone levels were measured by chemiluminescence immunoassay (CLIA) at ICU admission. To compare the two groups, Wilcoxon signed-rank test or Wilcoxon rank-sum test were used as appropriate. One-way ANOVA or Kruskal-Wallis test were performed for comparison over time as appropriate.

Fifty-one patients with laboratory-confirmed COVID-19 were included. Demographic, clinical characteristics, comorbidities, and urinary profile are summarised in Table 1 .

Twenty-six (51%) patients developed AKI, and most (80%) were severe AKI (stage 2 or 3, supplement), in a median of 4 [3] [4] [5] days after admission. Among them, ten (39%) patients required renal replacement therapy (RRT). The main indications were the need to control fluid balance in patients with anuria (50% of patients), hyperkalaemia in 3 patients (30%), and metabolic acidosis in 2 patients (20%). Seventy percent were treated with continuous RRT and 30% intermittent. On admission, patients with AKI had higher serum creatinine, but most other biomarkers, including proteinuria, D-dimers, and lactate deshydrogenase, were not significantly different from the non-AKI group. There was no difference between patients with and without AKI in terms of comorbidities or chronic treatment with Angiotensin-converting Enzyme inhibitors (ACEi) or Angiotensin-receptors blockers (ARBs) ( In line with the activation of the RAAS, patients with AKI showed lower urine Na + concentration during follow-up. Total proteinuria was not different between AKI and non-AKI J o u r n a l P r e -p r o o f patients. The patients with AKI had higher albuminuria (644 vs. 308 mg/L) at admission and during the following seven days (Figure 1 ).

In 51 patients with COVID-19 ARDS, half of the patients showed AKI and all proteinuria.

Patients with AKI showed direct (increased plasma renin and aldosterone concentration) and indirect (low urine sodium concentration) markers of activation of the RAAS [3] .

The interaction between SARS-CoV2 and the RAAS has long been debated. Binding of the virus to the ACE2 receptor is believed to increase the availability of angiotensin II to bind to the angiotensin II type 1 receptor. Activation of the RAAS is associated with kidney damage through the activation of inflammation and fibrosis [4] . The RAAS is also a key player in the development of remote cardiovascular injury after AKI [5] .

This study has a few limitations. First, the sample size is relatively small. However, we had enough power to detect significant differences between AKI and no AKI patients regarding the RAAS activation. Then, angiotensin II was not measured directly. Finally, no renal tissue histology was performed.

To conclude, we observed biological features compatible with an activation of the reninangiotensin-aldosterone system in COVID-19 patients with AKI [6] . Our findings call for a more extensive study exploring the role of RAAS among COVID-19-associated AKI and for a trial investigating the impact of inhibitors of the RAAS on outcomes. 

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