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

Ander Vergara; Kaiming Wang; Daniele Colombo; Mahmoud Gheblawi; Jaslyn Rasmuson; Rupasri Mandal; Franca Del Nonno; Brian Chiu; James W Scholey; María José Soler; David S Wishart; Gavin Y Oudit

doi:10.1093/ckj/sfac215

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

Clin Kidney J. 2022 Sep 21;16(2):272-284. doi: 10.1093/ckj/sfac215. eCollection 2023 Feb.

Authors

Ander Vergara^{1

2}, Kaiming Wang^{1

2}, Daniele Colombo³, Mahmoud Gheblawi^{1

2}, Jaslyn Rasmuson^{1

2}, Rupasri Mandal⁴, Franca Del Nonno³, Brian Chiu⁵, James W Scholey⁶, María José Soler^{7

8}, David S Wishart⁴, Gavin Y Oudit^{1

2}

Affiliations

¹ Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
² Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
³ Department of Pathology, National Institute for Infectious Diseases "Lazzaro Spallanzani," IRCCS, Rome, Italy.
⁴ Metabolomics Innovation Center, University of Alberta, Edmonton, Alberta, Canada.
⁵ Department of Laboratory Medicine and Pathology, University of Alberta Hospital, Edmonton, Alberta, Canada.
⁶ Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada.
⁷ Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain.
⁸ Nephrology and Transplantation Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.

Abstract

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.

Keywords: COVID-19; acute kidney injury; angiotensin-converting enzyme 2; metabolomics; renin–angiotensin system.