BackgroundAngiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is highly expressed in the kidneys. Beyond serving as a crucial endogenous regulator of the renin-angiotensin system, ACE2 also possess a unique function to facilitate amino acid absorption. Our observational study sought to explore the relationship between urine ACE2 (uACE2) and renal outcomes in COVID-19.MethodsIn a cohort of 104 patients with COVID-19 without acute kidney injury (AKI), 43 patients with COVID-19-mediated AKI, and 36 non-COVID-19 controls, we measured uACE2, urine tumor necrosis factor receptors I and II (uTNF-RI and uTNF-RII), neutrophil gelatinase-associated lipocalin (uNGAL). We also assessed ACE2 staining in autopsy kidney samples and generated a propensity-score matched subgroup of patients to perform a targeted urine metabolomic study to describe the characteristic signature of COVID-19.ResultsuACE2 is increased in patients with COVID-19, and further increased in those that developed AKI. After adjusting uACE2 levels for age, sex and previous comorbidities, increased uACE2 was independently associated with over 3-fold higher risk of developing AKI (OR 3.05, 95%CI:1.23‒7.58,p = 0.017). Increased uACE2 corresponded to a tubular loss of ACE2 in kidney sections and strongly correlated with uTNF-RI and uTNF-RII. Urine quantitative metabolome analysis revealed an increased excretion of essential amino acids in patients with COVID-19, including leucine, isoleucine, tryptophan and phenylalanine. Additionally, a strong correlation was observed between urine amino acids and uACE2.ConclusionsElevated uACE2 is related to AKI in patients with COVID-19. The loss of tubular ACE2 during SARS-CoV-2 infection demonstrates a potential link between aminoaciduria and proximal tubular injury.