MO069SARS-COV-2 RECEPTOR ACE-2, TMPRSS2 AND SOLUBLE ACE-2 IN PATIENTS WITH END STAGE KIDNEY DISEASE
Authors: Arefin Samsul , Hernandez Leah , Ward Liam , Stenvinkel Peter , Kublickiene Karolina 
Published: May 2021

Abstract

Background and Aims
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to dramatic loss of lives due to COVID-19. Individuals with chronic conditions, including patients with kidney failure and/or kidney transplants, are affected more substantially due to multiple comorbidities and altered immune system. The first step of this infection process is the binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE-2) receptor, followed by its priming by transmembrane protease serine 2 (TMPRSS2). We hypothesized that the expressions of ACE-2 and TMPRSS2 are increased in microvasculature, in addition to increased circulating soluble ACE-2 levels in patients with end stage kidney disease (ESKD); i.e. prerequisites to explain to why ESKD patients are susceptible to SARS-CoV-2 infection. Therefore, we assessed if there is a difference in the expression of ACE-2 and TMPRSS2 receptors in the resistance artery and subcutaneous adipose tissue, alongside circulating soluble ACE-2 levels in ESKD patients versus controls.

Method
A total of 210 participants were enrolled, representing 80 ESKD and 73 healthy controls for soluble ACE-2 analysis, and 31 ESKD and 26 healthy controls for isolated subcutaneous vasculature bioassay. Immunofluorescence techniques were performed for the detection and evaluation of ACE-2 and TMPRSS2 in isolated subcutaneous resistance artery (200-300 µm of internal âCE€) and adipose tissue. Soluble ACE-2 protein concentration was detected using commercially available ELISA kits.

Results
Soluble ACE-2 levels were significantly higher in ESKD (3.8 ng/mL, IQR 2.4-5.5, n=80) vs control groups (2.7 ng/mL, IQR 2.1-3.7 ng/mL, n=73). There was no difference in soluble ACE-2 between females and males in either group. Soluble ACE-2 was positively correlated with IL-6 (rho=0.257, p=0.02, n=80), while it was negatively correlated with cholesterol (rho= -0.248, p=0.02, n=78) in ESKD patients. The expression of ACE-2 receptor was observed both on endothelium and vascular smooth muscle cells (VSMCs) in arteries from both groups. The expression was higher in ESKD patients (19.1%, n=23) vs controls (15.4%, n=15). Patients with ESKD on ACE-inhibitor/angiotensin receptor blocker treatment showed higher expression of ACE-2 vs. non-treatment group (treatment: 20.2%, n=12 vs non-treatment: 12.8%, n=11) in resistance artery. In subcutaneous adipose tissue the ACE-2 staining was not statistically different among the groups (ESKD: 2.9%, n=10 vs controls: 3.6%, n=10). In addition, TMPRSS2 was expressed both on endothelium and VSMCs in resistance artery, however there was no difference in the expression (ESKD: 8.4%, n=23 vs controls: 10.2%, n=15) between the groups.

Conclusion
Soluble ACE-2 levels and ACE-2 receptor expression in the vasculature were higher in patients with ESKD as compared to controls. The ACE-2 receptor is present both in the endothelium and VSMCs from arteries in peripheral microcirculation. This supports the suggestion that the uremic milieu induces an optimal environment for SARS-CoV-2 entrance in microcirculation with following consequence on the vasculature during the COVID-19. Similarly, TMPRSS2 expression was observed in vessels from both groups, while increased expression of ACE-2 receptor was observed in those ESKD patients receiving ACE-inhibitor/angiotensin receptor blocker treatment. Further studies are warranted to assess possible sex differences in the target receptor expressions with further elaboration on specific treatment regime(s) for different comorbidities present in patients with ESKD.