Shining More Light on RAS Inhibition during the COVID-19 Pandemic

The coronavirus disease 2019 (COVID-19) pandemic has resulted in unprecedented challenges throughout the nephrology community. Notably, it was quickly realized that the virus responsible for COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), uses the angiotensin-converting enzyme 2 (ACE2) protein to gain entry into host cells. ACE2 is the same entry mechanism used by severe acute respiratory syndrome coronavirus-1, the virus responsible for the 2003 severe acute respiratory syndrome epidemic in Guangdong, China (1). ACE2 is a membrane-bound enzyme (also released into the circulation) that is produced in a variety of cell types, including lung, kidney, and small intestine, that serves as a pivotal counter-regulatory enzyme of the renin-angiotensin system (RAS). ACE2 is a carboxypeptidase that metabolizes the key proinflammatory, hypertensive eight–amino acid effector peptide of the RAS, angiotensin II, into the anti-inflammatory, hypotensive seven–amino acid peptide, angiotensin (1–7). Thus, the abundance of ACE2 is a key determinant of RAS activation. Early in the COVID-19 pandemic, concern arose about the possibility that commonly prescribed blockers of the RAS could lead to an increased abundance of ACE2 in the lungs or other organs, potentially leading to increased infectivity with SARS-CoV-2 (2). The concern of increased ACE2 expression after RAS blockade was primarily noted in preclinical studies in nonpulmonary organs and was amplified in journal correspondence and editorials as potentially leading to increased risk of infectivity with SARS-CoV-2 or worsening outcomes of COVID-19 in patients on chronic RAS blockade (ACE inhibitors or angiotensin receptor blockers [ARBs]) (3,4). However, during the initial few months of the COVID-19 pandemic, there was limited information about how RAS inhibitors directly affected ACE2 in the lung parenchyma or whether this portended worse or even better outcomes.

The last year and a half has led to an avalanche of studies aimed at understanding the relationship between SARS-CoV-2, ACE2, and RAS inhibitors. Many of these studies were observational in nature and thus had several important limitations, such as selection bias, collider bias, time-dependent biases, and confounders (5). For instance, the decision to stop, continue, or start RAS inhibitors in patients admitted to the hospital with COVID-19 is significantly confounded by the severity of illness. Nonetheless, a meta-analysis of 52 mostly observational studies representing 101,949 patients comparing COVID-19 outcomes in patients receiving versus not receiving RAS inhibitors during the hospitalization found no evidence for increased mortality or clinical severity (6). Surprising, adjusted data suggested a benefit in use of ACE inhibitors or ARBs, particularly in those with hypertension (6). However, it must be noted that each of the pooled studies have significant limitations. Most notably, many did not define criteria indicating if patients had been on these medications chronically (before admission for COVID-19). This is important because two well-conducted randomized clinical trials in which hospitalized patients with COVID-19 were randomized to either continue chronic RAS inhibitor therapy or discontinue therapy did not result in either harm or benefit (7,8). Although these clinical trials demonstrate that RAS blockade does not seem to affect outcomes in hospitalized patients, they do not answer the question about whether receipt of RAS inhibitors chronically leads to an increased risk of SARS-CoV-2 infection or a worsened clinical severity of COVID-19. Moreover, they do not address patients with kidney failure—either those on dialysis or those after kidney transplantation.

In this issue of CJASN, Soler et al. (9) describe the association between chronic RAS inhibitor use and the risk of COVID-19–related mortality in patients with kidney failure (both patients on dialysis and those with kidney transplants) by conducting an observational study using data from the European Renal Association COVID-19 database (ERACODA). This is a large, multicenter, observational cohort consisting of 128 centers in 28 European countries or countries bordering the Mediterranean Sea, with a total enrollment of 1511 patients with kidney failure (459 with a kidney transplant and 1052 on dialysis) who were diagnosed with COVID-19 and were SARS-CoV-2 positive. At the time of COVID-19 diagnosis, chronic RAS inhibitors were prescribed in 41% of the patients with a kidney transplant and 27% of the patients on dialysis. In concordance with prior publications (10,11), 28-day mortality rates were high in both groups; 19% of patients with a kidney transplant and 23% of patients on dialysis died within 28 days of COVID-19 diagnosis. No significant difference in the primary outcome, which was 28-day mortality, was seen between chronic RAS inhibitor users (17%) and nonusers (20%) in transplant recipients. Similarly, in patients on dialysis, there was no significant difference in 28-day mortality between chronic RAS inhibitor users (21%) and nonusers (28%). These results held after stratification for age, sex, frailty, BP, diabetes, heart failure, and antiviral and anti-inflammatory therapy. Additionally, there was no difference (both crude and adjusted) in the secondary outcome, which was hospitalization, intensive care unit admission, and ventilator support, between patients using chronic RAS inhibitors and those not using chronic RAS inhibitors in both the patients with kidney transplants and those on dialysis. Thus, from these data, it seems that the chronic use of RAS inhibitors does not affect the severity of COVID-19 in patients with kidney failure either on dialysis or with a kidney transplant. Of note, there is no stratification of ACE inhibitors versus ARBs in this cohort. It is possible that ACE inhibitors and ARBs might have discordant effects, especially given that ACE inhibitors additionally inhibit bradykinin formation, which could have deleterious effects in the lungs (5).

As mentioned, two randomized clinical trials have shown no difference in clinical severity or mortality in patients with COVID-19 who were chronically on RAS inhibitors and were randomized to either continuing or discontinuing therapy (7,8). However, these studies did not include patients with kidney transplants or those on dialysis. It must be noted that this clinical question (continuing or stopping RAS inhibitors) is particularly challenging to interpret in an observational cohort secondary to multiple confounders. Nonetheless, Soler et al. (9) analyzed 160 transplant recipients and 188 patients on dialysis who were hospitalized with COVID-19 and had information on ACE inhibitor or ARB usage before and during the hospitalization. In order to address the confounder of disease severity as the reason for discontinuation, additional factors were used to adjust for severity and included cough, shortness of breath, fever, heart rate, respiratory rate, lymphocyte count, C-reactive protein, and creatinine rise. They showed that patients with kidney transplants who discontinued RAS inhibitors had increased 28-day mortality compared with those who continued these in the hospital. However, this difference did not persist after adjustment with the disease severity covariates. No differences in 28-day mortality were seen in patients on dialysis in those who discontinued RAS inhibitors compared with those who continued. Thus, these findings corroborate the results of randomized clinical trials showing that RAS inhibition does not alter outcomes in hospitalized patients with COVID-19 (7,8).

This study continues to shed more light on the safety of RAS inhibition during the COVID-19 pandemic. It also provides valuable information on patients with kidney failure—both those on dialysis and those with kidney transplants. This is an extremely vulnerable group of patients, with an exceedingly high mortality rate with COVID-19. The unique attributes of the ERACODA database are the multinational collection of patients included and the careful discernment of home medications before COVID-19. The authors should be congratulated on the construction and execution of this important resource, and it is a model for how important questions in nephrology can be tackled when all stakeholders collaborate and coalesce. It should be noted that many questions remain to be answered in regard to RAS blockade, SARS-CoV-2, and COVID-19 (2). Notably, it is still unclear if the chronic use of RAS inhibitors modulates the risk of SARS-CoV-2 infection. We also do not know if the de novo use of RAS inhibitors in patients not already on them will affect outcomes in patients with COVID-19. Clinical trials are ongoing to answer these important questions (5). Soler et al. (9) and the ERACODA database provide important information demonstrating that RAS inhibition in patients on dialysis or with kidney transplants does not portend an increased severity of COVID-19 and does not alter mortality in hospitalized patients. However, it should be noted that the effect of COVID-19 is devastating in patients with kidney failure, with a 20% mortality rate, thus demonstrating the urgent need to immunize patients with kidney failure against SARS-CoV-2 to prevent infection altogether.

Disclosures

M.A. Sparks reports employment with Durham Veterans Affairs Health Care System; receiving research funding from the Renal Research Institute; receiving honoraria from Elsevier–Nephrology Secrets; serving as a scientific advisor or member of the American Board of Internal Medicine Nephrology Board, Board of Directors, NephJC; serving on the editorial boards of American Journal of Kidney Diseases, ASN Kidney News, Kidney360, and Kidney Medicine; and serving on KCVD Membership & Communications Committee of AHA, KCVD Scientific & Clinical Education Lifelong Learning Committee of AHA, and the National Kidney Foundation North Carolina Medical Advisory Board. The remaining author has nothing to disclose.

Funding

None.