Hospitalized Patients With COVID-19 Have Higher Plasma Aldosterone-Renin Ratio and Lower ACE Activity Than Controls

Nisha I. Parikh; Folagbayi Arowolo; Matthew S. Durstenfeld; Gregory Nah; Joyce Njoroge; Eric Vittinghoff; Carlin S. Long; Peter Ganz; David Pearce; Priscilla Hsue; Alan H. S. Wu; Negin Hajizadeh; Kathleen D. Liu; Kara L. Lynch


J Endo Soc. 2022;6(12) 

In This Article

Abstract and Introduction


Context: SARS-CoV-2 infects cells via the angiotensin converting enzyme 2 (ACE2) receptor, whose downstream effects "counterbalance" the classical renin angiotensin aldosterone system (RAAS).

Objective: We aimed to determine to what extent circulating RAAS biomarker levels differ in persons with and without COVID-19 throughout the disease course.

Methods: We measured classical (renin, aldosterone, aldosterone/renin ratio [ARR], Ang2, ACE activity) and nonclassical (ACE2, Ang1,7) RAAS biomarkers in hospitalized COVID-19 patients vs SARS-CoV-2 negative controls. We compared biomarker levels in cases with contemporaneous samples from control patients with upper respiratory symptoms and a negative SARS-CoV-2 PCR test. To assess RAAS biomarker changes during the course of COVID-19 hospitalization, we studied cases at 2 different times points ~ 12 days apart. We employed age- and sex-adjusted generalized linear models and paired/unpaired t tests.

Results: Mean age was 51 years for both cases (31% women) and controls (50% women). ARR was higher in the first sample among hospitalized COVID-19 patients vs controls (P = 0.02). ACE activity was lower among cases at their first sample vs controls (P = <0.001). ACE2 activity, Ang 1,7, and Ang2 did not differ at the 2 COVID-19 case time points and they did not differ in COVID-19 cases vs controls. Additional adjustment for body mass index (BMI) did not change our findings.

Conclusions: High ARR, independent of BMI, may be a risk marker for COVID-19 hospitalization. Serum ACE activity was lower in patients with COVID-19 vs controls at the beginning of their hospitalization and then increased to similar levels as controls, possibly due to lung injury, which improved with inpatient disease management.


Several observations about the pathophysiology and epidemiology of the SARS-CoV-2 pandemic suggest a key role of the renin angiotensin aldosterone system (RAAS) in COVID-19 disease.[1] On the classical arm of the RAAS pathway, renin mediates conversion of angiotensinogen to angiotensin (Ang) (Figure 1). Angiotensin converting enzyme (ACE) mediates conversion of Ang to angiotensin 2 (Ang2). ACE is primarily localized in the lungs and to a lesser degree in the kidney. Ang2 has a number of cardiac and vascular effects including acting on the adrenal cortex to release aldosterone. Aldosterone acts on the kidneys to stimulate sodium and fluid retention, thereby elevating blood pressure. On the counterbalance RAAS pathway, angiotensin converting enzyme 2 (ACE2) converts Ang1 and Ang2 to Ang 1,9 and Ang 1,7 respectively (Figure 1). The latter acts vis the Mas receptor to downregulate aldosterone and exert other protective effects on the heart and blood vessels.[1]

Figure 1.

Renin-angiotensin aldosterone system and COVID-19.

SARS-CoV-2 virus leverages the membrane-bound RAAS counterregulatory protein, ACE2 cellular receptor, to infect its host.[2–4] ACE2 is a homolog of ACE and counteracts the adverse cardiovascular effects of RAAS activation.[5] Membrane-bound ACE2 negatively regulates RAAS by converting Ang2 to vasodilatory Ang1–7, diminishing and opposing the vasoconstrictor effect of Ang2.[2] There is differential tissue expression of ACE2 in heart, kidneys, and lungs of healthy patients, and its expression in the kidneys and lungs is positively correlated with age.[6] Circulating ACE2 levels were higher among patients with obesity and diabetes in 2 large cohorts of patients with atrial fibrillation.[7] In addition to older age and male sex, risk factors for COVID-19 hospitalization include obesity, diabetes, cardiovascular disease, and possibly hypertension.[8] A recent investigation demonstrated that higher ACE2 levels on hospital admission was associated with worse outcomes in COVID-19.[9] Other RAAS markers were not studied.[9]

Thus, the effects of SARS-CoV2 on circulating RAAS biomarkers in COVID-19 are not fully understood. Therefore, we undertook a study to compare levels of circulating RAAS biomarkers (renin, Ang2, ACE, aldosterone, aldosterone/renin ratio [ARR], ACE2, Ang 1,7) among persons not on RAAS blockers in: (1) Patients hospitalized with COVID-19 and (2) patients who received a respiratory viral panel for upper respiratory symptoms but who were negative for SARS-CoV-2 on PCR testing. We hypothesized that circulating RAAS markers may differ in patients with COVID-19 vs non-COVID-19-related respiratory infections and that there may be measurable differences in these RAAS markers at the start and end of a hospitalization for COVID-19.