Medications that inhibit the renin-angiotensin-aldosterone system (RAASi) do not appear to carry a unique acute kidney injury (AKI) risk in patients with COVID-19, according to a recent study.
The new study, which included 27,189 veterans hospitalized with either COVID-19 or influenza between October 1, 2019 and February 28, 2021, highlights the importance of carefully assessing a patient’s AKI risk factors when considering RAASi use in patients who are hospitalized for COVID-19.
“These findings suggest that the risk/benefit of RAASi use during COVID-19 infection needs to be weighed individually as in other acute illnesses, taking into consideration the illness severity, underlying comorbidities, and functional status,” said study investigator Edward D. Siew, MD, an associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee.
Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), the cause of COVID-19, enters the host cell via the angiotensin converting enzyme II protein. It had been hypothesized that RAASi may have a deleterious effect by upregulating expression of angiotensin-converting enzyme II and subsequently increase infectivity and lead to greater organ dysfunction.
The investigators previously examined AKI incidence in patients with COVID-19 compared to patients with influenza in a national veteran cohort and found that AKI was more common and severe in COVID-19. In this follow-up study, the researchers looked at prevalent RAASi use, which was defined as having pills on hand within 14 days before admission. Nonuse was defined as no RAASi pills within 365 days before admission. Dr Siew and colleagues used propensity score weighting to balance baseline demographics (4 variables), vitals (6 variables), conditions (20 variables), and medications (17 variables). The patients were divided into 4 exposure groups (RAASi users with COVID-19, nonusers with COVID-19, RAASi users with influenza, and nonusers with influenza).
The investigators identified 1,908 hospitalizations among RAASi nonusers for influenza and 15,028 hospitalizations for COVID-19. There were 1,276 hospitalizations among RAASi users for influenza and 8,977 hospitalizations for COVID-19. Among the entire cohort, AKI was significantly more common among patients with COVID-19 compared with influenza (30% vs 26%) and was significantly associated with 23% higher odds of AKI. In RAASi users compared with nonusers, the incidence of AKI was greater in both the influenza and COVID-19 groups, with a 26% higher odds of AKI among all-comers.
“There has been uncertainty regarding the potential for direct invasion of the kidney parenchyma by SARS-COV-2 and its role in AKI and whether this may be worsened in the presence of RAAS inhibition,” Dr Siew said. “While the rates of AKI were higher among those taking RAAS inhibitors in both groups of patients, the proportional increase in risk was similar.”
His team observed that AKI stage 2-3 was significantly more common in COVID-19 compared with influenza (11% vs 6%), and the incidence of AKI stage 2-3 was significantly higher in RAASi users (10% vs 7%).
“These findings do not support a major amplification in AKI risk among those taking RAASi inhibitors in COVID compared to patients hospitalized with influenza and are consistent with findings from other studies examining the risk for other poor outcomes in COVID-19 infection among patients taking RAAS inhibitors,” Dr Siew said.
This study is the first to examine the effect of RAASi use on AKI in COVID-19. The large number of patients is a study strength. Still, the study is limited by potential confounding factors due to illness severity or other in-hospital factors and a lack of histologic data and reduced generalizability to female patients and non-White patients.
“We were not surprised that RAASi use increased AKI risk, as prior work supported this,” said study investigator Michael E. Matheny, MD, MPH, an associate professor in the Department of Biomedical Informatics at Vanderbilt University Medical Center. “COVID has been a hard disease to pin down, and there was certainly concern RAASi would be associated with increased risk. I was relieved that it did not appear to have a disproportionate increased risk for AKI in this population.”
Eric Judd, MD, an associate professor in the University of Alabama at Birmingham Marnix E. Heersink School of Medicine Division of Nephrology, said the findings are clinically significant and argue against a separate kidney-specific mechanism for RAASi as a cause of AKI in patients with COVID-19. These findings align with existing observational studies demonstrating that background ACE inhibitor or angiotensin receptor block use was not associated with worsened severity of COVID-19, he noted.
Amy K. Mottl, MD, MPH, associate professor of medicine in the Division of Nephrology and Hypertension at the University of North Carolina in Chapel Hill, said the current study is well-designed and it includes a large, at-risk population for COVID-19, so the results are reassuring. “Kidney and heart failure patients are more often prescribed RAASi and are also at increased risk for COVID-19, so I think it’s fair to say this article can alleviate angst over use of this extremely important class of medications,” Dr Mottl said.
Birkelo BC, Parr SK, Perkins AM, et al. Renin-angiotensin-aldosterone system inhibitors and the risk of AKI in COVID-19 compared with influenza. Clin J Am Soc Nephrol. Published online February 2, 2022. doi:10.2215/CJN.11190821
Birkelo BC, Parr SK, Perkins AM, et al. Comparison of COVID-19 versus influenza on the incidence, features, and recovery from acute kidney injury in hospitalized United States Veterans. Kidney Int 100:2021:894-905. doi:10.1016/j.kint.2021.05.029