ACE-inhibitor/angiotensin receptor blockers (ACE-I/ARBs) therapy in COVID-19 infected dialysis patients

The novel severe acute respiratory syndrome-coronavirus2 (SARS-CoV-2) enters human cells by binding to the membrane bound angiotensin converting enzyme-2 (ACE-2) [1]. Angiotensin converting enzyme inhibitor/Angiotensin receptor blockers (ACE-I/ARBs) leads to upregulation of ACE-2 expression. This may hypothetically increase the risk of corona virus disease-19 (COVID-19) infection, severity and mortality [1]. Jarcho et al. demonstrated the results of retrospective studies favoring that ACE-I/ARBs therapy is not associated with higher mortality or worse outcomes in COVID-19 patients [2]. Other studies, have shown that the use of ACE-I/ARBs among hospitalized COVID-19 patients is associated with lower mortality [3]. In this meta-analysis, we summarize the results of large multicenter studies that assessed the safety of ACE-I/ARBs therapy in COVID-19 infected end stage renal disease (ESRD) dialysis patients. We involved the large multicenter studies published from the beginning of 2020 till May 2021. Hsu et al. performed a large multicenter study in the USA between February and June 2020. The study included 7948 dialysis patients; out of which 438 experienced COVID-19 infection. About 1=4 of the COVID-19 infected patients died (109/438) [4]. According to the results of Hsu et al., there was no statistically significant association between ACE-I/ARBs therapy and COVID-19 mortality (OR 0.78, 95% CI 0.45–1.33, p1⁄4 0.4) [4]. Sanchez-Alvarez et al in their multicenter study included around 580 COVID-19 infected dialysis patients in Spain in March and April 2020 [5]. The mortality rate was 26.3%. On multivariate analysis, ARBs therapy was also not associated with higher COVID-19 mortality (OR 0.66, 95% CI 0.38–1.12, p1⁄4 0.12) [5]. Lano et al conducted a multicenter observational cohort study in France between March and May 2020 [6]. A total of 2336 dialysis patients were enrolled. Out of 129 COVID-19 infected patients 34 died. Interestingly, this study showed a protective effect of ARBs therapy on mortality in COVID-19 infected dialysis patients (OR 0.093, 95% CI 0.005–0.54, p1⁄4 0.03). However, the authors outlined the limitation of the observational retrospective design of the study [6]. On pooling the data from the 3 aforementioned studies together, we found that ACE-I/ARBs therapy is associated with a protective effect among COVID-19 infected dialysis patients (OR 0.49, 95% CI 0.03–0.94, p1⁄4 0.007). These findings are demonstrated in Figure 1. A possible interpretation of our results is that patients not on ACE-I/ARBs might have a baseline hypotension with other multiple risk factors including frailty, all attributing to increased mortality. This may be confounded in favor of the use of ACE-I/ARBs in the hypertensive ESRD cohort. A clue to support this hypothesis, is the “apparent” protective effect of hypertension on mortality in COVID-19 infected dialysis patients found by Hsu et al. (OR 0.50, 95%


Dear Editor,
The novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) enters human cells by binding to the membrane bound angiotensin converting enzyme-2 (ACE-2) [1]. Angiotensin converting enzyme inhibitor/Angiotensin receptor blockers (ACE-I/ARBs) leads to upregulation of ACE-2 expression. This may hypothetically increase the risk of corona virus disease-19 (COVID-19) infection, severity and mortality [1]. Jarcho et al. demonstrated the results of retrospective studies favoring that ACE-I/ARBs therapy is not associated with higher mortality or worse outcomes in COVID-19 patients [2]. Other studies, have shown that the use of ACE-I/ARBs among hospitalized COVID-19 patients is associated with lower mortality [3].
In this meta-analysis, we summarize the results of large multicenter studies that assessed the safety of ACE-I/ARBs therapy in COVID-19 infected end stage renal disease (ESRD) dialysis patients. We involved the large multicenter studies published from the beginning of 2020 till May 2021. Hsu et al. performed a large multicenter study in the USA between February and June 2020. The study included 7948 dialysis patients; out of which 438 experienced COVID-19 infection. About 1 = 4 of the COVID-19 infected patients died (109/438) [4]. According to the results of Hsu et al., there was no statistically significant association between ACE-I/ARBs therapy and COVID-19 mortality (OR 0.78, 95% CI 0.45-1.33, p ¼ 0.4) [4].
Lano et al conducted a multicenter observational cohort study in France between March and May 2020 [6]. A total of 2336 dialysis patients were enrolled. Out of 129 COVID-19 infected patients 34 died. Interestingly, this study showed a protective effect of ARBs therapy on mortality in COVID-19 infected dialysis patients (OR 0.093, 95% CI 0.005-0.54, p ¼ 0.03). However, the authors outlined the limitation of the observational retrospective design of the study [6]. On pooling the data from the 3 aforementioned studies together, we found that ACE-I/ARBs therapy is associated with a protective effect among COVID-19 infected dialysis patients (OR 0.49, 95% CI 0.03-0.94, p ¼ 0.007). These findings are demonstrated in Figure 1. A possible interpretation of our results is that patients not on ACE-I/ARBs might have a baseline hypotension with other multiple risk factors including frailty, all attributing to increased mortality. This may be confounded in favor of the use of ACE-I/ARBs in the hypertensive ESRD cohort. A clue to support this hypothesis, is the "apparent" protective effect of hypertension on mortality in COVID-19 infected dialysis patients found by Hsu  CI 0.26-0.96, p ¼ 0.04) [3] and by the ERA CODA study (OR 0.61, 95% CI 042-0.88, p < 0.001) [7].

Conclusion
Our results are in favor of the safe use of ACE-I/ARBs in COVID-19 infected ESRD dialysis patients. A possible protective effect is yet to be determined by further randomized controlled trials assessing the effect of ACE-I/ARBs therapy in COVID-19 infected dialysis patients. It is hard to reach solid conclusions from our meta-analysis due to the small number of studies included due to paucity of literature available.

Disclosure statement
No potential conflict of interest was reported by the author(s). Drs. Rao and Soliman are members of the editorial board of Renal Failure.

Funding
The author(s) reported there is no funding associated with the work featured in this article.