Clin Kidney J . Urinary angiotensin-converting enzyme 2 and metabolomics in COVID-19-mediated kidney injury

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Clin Kidney J


. 2022 Sep 21;16(2):272-284.
doi: 10.1093/ckj/sfac215. eCollection 2023 Feb.
Urinary angiotensin-converting enzyme 2 and metabolomics in COVID-19-mediated kidney injury


Ander Vergara ^{1 2} , Kaiming Wang ^{1 2} , Daniele Colombo ³ , Mahmoud Gheblawi ^{1 2} , Jaslyn Rasmuson ^{1 2} , Rupasri Mandal ⁴ , Franca Del Nonno ³ , Brian Chiu ⁵ , James W Scholey ⁶ , María José Soler ^{7 8} , David S Wishart ⁴ , Gavin Y Oudit ^{1 2}



Affiliations

• PMID: 36751625
• PMCID: PMC9494506
• DOI: 10.1093/ckj/sfac215

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.