High Renin Concentrations in Severe COVID-19 Are Indicative for a Hypo–Renin–Angiotensin-System State

To the Editor:

With great interest, we read the paper by Leisman and colleagues on injury marker dynamics in severe coronavirus disease (COVID-19) (1). These authors propose that endothelial injury markers rise later and associate with renin–angiotensin system (RAS) activation and 28-day outcome. The RAS activation consisted of rises in renin, the (pro)renin receptor, and ACE2 (angiotensin-converting enzyme 2). Given that these observations were made by Olink plasma proteomic assays, they indicate the soluble variants of both the (pro)renin receptor [s(P)RR] and ACE2 (sACE2). Leisman and colleagues speculate that the renin rise reflects the response to either a relative hypo-RAS state or prolonged sedation-induced vasodilatation or hypovolemia after diuresis in these patients.

We recently made the same observation with regard to renin and sACE2 in severe COVID-19, and by simultaneously measuring aldosterone, we were able to show that the aldosterone concentrations were actually lower in such patients (2). As a consequence, the aldosterone-to-renin ratio was remarkably decreased, and as such, this biomarker was correlated most strongly with COVID-19 severity. A decreased aldosterone-to-renin ratio is a well-known consequence of RAS blockade (e.g., by ACE inhibitors).

A unifying concept is that severe COVID-19 not only results in endothelial damage but simultaneously lowers the endothelial enzyme ACE (sometimes described as ACE1), responsible for angiotensin II generation. Given its endothelial origin, it seems logical that ACE concentrations might fall in severe COVID-19. Indeed, several recent studies also found low ACE concentrations in the plasma of patients with severe COVID-19 (3–5). In this respect, it may not be surprising that acute respiratory distress syndrome is associated with reduced pulmonary ACE activity (6).

ACE2 is one of many angiotensin II–degrading enzymes. Leisman and colleagues suggested that the upregulated sACE2 might have contributed to the rapid degradation of angiotensin II, thus creating a hypo-RAS state. However, if this mechanism is true, high sACE2 concentrations should correlate positively with high renin concentrations. We were unable to find such a correlation (2). Thus, we hypothesize that the most likely explanation for the rise in renin is a hypo-RAS state due to dropped ACE concentrations related to endothelial damage. This implies that even patients with severe COVID-19 who do not receive treatment with RAS blockers are in a state of relative RAS blockade. Finally, despite its name, the s(P)RR is unrelated to RAS activity, and thus its rise in COVID-19 warrants further research into its role in this disease.

In conclusion, we fully agree with Leisman and colleagues that renin’s utility as a marker of severe COVID-19 should be further explored. We suggest exploring the aldosterone-to-renin ratio in future studies as this might be an even stronger marker.