Urinary angiotensin-converting enzyme 2 and metabolomics in COVID-19-mediated kidney injury

Lay Summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter host cells. Upon entry, the virus reduces membrane ACE2 expression through internalization or activation of a disintegrin and metalloproteinase 17 (ADAM17)-mediated shedding. We hypothesized that SARS-CoV-2-mediated loss of ACE2 drives kidney injury in coronavirus disease 2019 (COVID-19) patients. We demonstrated that urinary ACE2 (uACE2) is elevated in COVID-19 without acute kidney injury (AKI) and further increases in COVID-19 with AKI correlating with the loss of tubular ACE2 seen in autopsied kidney samples from COVID-19 patients. Moreover, higher uACE2 is independently associated with a greater incidence of AKI after accounting for other clinical risk factors, including age, sex or previous comorbidities. The uACE2 is of kidney origin and the urine metabolomic analysis revealed that loss of uACE2 is linked to increased urinary amino acid excretion. Therefore, increased uACE2 during SARS-CoV-2 infection represents a potential link between urine amino acid loss and kidney injury in patients with COVID-19. Background Angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (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 coronavirus disease 2019 (COVID-19). Methods In 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 tumour necrosis factor receptors I and II (uTNF-RI and uTNF-RII) and 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. Results uACE2 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 a >3-fold higher risk of developing AKI [odds ratio 3.05 (95% confidence interval 1.23-7.58), P = .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. Conclusions Elevated 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.

Automated summary

This study found that the urinary ACE2 levels are elevated in COVID-19 patients and are associated with the occurrence of acute kidney injury (AKI). The loss of tubular ACE2 during SARS-CoV-2 infection may be linked to aminoaciduria and proximal tubular injury.