Angiotensin‐converting enzyme 2 and transmembrane protease serine 2 in female and male patients with end‐stage kidney disease

Abstract

Background Individuals with chronic kidney disease are affected by acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) due to multiple comorbidities and altered immune system. The first step of the infection process is the binding of SARS‐CoV‐2 with angiotensin‐converting enzyme 2 (ACE2) receptor, followed by its priming by transmembrane protease serine 2 (TMPRSS2). We hypothesized that circulating soluble ACE2 levels, as well as the expressions of ACE2 and TMPRSS2 in the microvasculature, are increased in patients with end‐stage kidney disease (ESKD). Methods A total of 210 participants were enrolled, representing 80 ESKD patients and 73 non‐CKD controls for soluble ACE2, and 31 ESKD and 26 non‐CKD controls for vasculature and fat tissue bioassays. We have assessed ACE2 expression in blood using ELISA and in tissue using immunofluorescence. Results Soluble ACE2 levels were higher in ESKD patients compared to controls; however, there is no sex difference observed. In ESKD and controls, soluble ACE2 positively correlated with Interleukin 6 (IL‐6) and C‐reactive protein (CRP), respectively. Similarly, ACE2 tissue expression in the vasculature was higher in ESKD patients; moreover, this higher ACE2 expression was observed only in male ESKD patients. In addition, TMPRSS2 expression was observed in vessels from males and females but showed no sex difference. The expression of ACE2 receptor was higher in ESKD patients on ACE‐inhibitor/angiotensin blocker treatment. Conclusion ESKD is associated with increased ACE2 levels in the circulation and pronounced in male vasculature; however, further studies are warranted to assess possible sex differences on specific treatment regime(s) for different comorbidities present in ESKD.

Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3)

“…This is also consistent with previous observations that soluble ACE2 levels are not affected by ACE-I or ARB. 31 Although previous studies have reported higher concentrations of soluble ACE2 in males than in females, 32 we found no difference in plasma ACE2 according to sex. The present results may be explained by the high average age of the study population.…”

“…with previous 19 There is a study which has reported higher serum ACE2 levels in patients with advanced CKD stage (eGFR <30 mL/min/1.73m 2 or ESKD), 31 but the present cohort includes few such patients with advanced CKD, requiring additional future study.…”

The authors reply

“…To link this with males, we note that males have higher risks of complications of acute COVID-19 such as shock and that may have contributed to their increased risk of AKI and better renal responses to ARBs. Angiotensin-converting enzyme 2 (ACE2) is on the X chromosome, expressed differentially (lower in males) in renal vasculature (6), rising plasma levels predict shock (7), and ACE2 genetic variants portend worse COVID-19 severity on males (8). Thus, ACE2 expression in males could explain more renal injury in males in acute COVID-19.…”