Vergara Ander, Wang Kaiming, Colombo Daniele, Gheblawi Mahmoud, Rasmuson Jaslyn, Mandal Rupasri, Del Nonno Franca, Chiu Brian, Scholey James W, Soler María José, Wishart David S, Oudit Gavin Y
Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
Clin Kidney J. 2022 Sep 21;16(2):272-284. doi: 10.1093/ckj/sfac215. eCollection 2023 Feb.
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).
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.
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), = .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.
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.
血管紧张素转换酶2（ACE2）是严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的受体，在肾脏中高度表达。ACE2除了作为肾素-血管紧张素系统的关键内源性调节因子外，还具有促进氨基酸吸收的独特功能。我们的观察性研究旨在探讨2019冠状病毒病（COVID-19）患者尿ACE2（uACE2）与肾脏结局之间的关系。
在一组104例无急性肾损伤（AKI）的COVID-19患者、43例COVID-19介导的AKI患者和36例非COVID-19对照中，我们测量了uACE2、尿肿瘤坏死因子受体I和II（uTNF-RI和uTNF-RII）以及中性粒细胞明胶酶相关脂质运载蛋白（uNGAL）。我们还评估了尸检肾脏样本中的ACE2染色，并生成了一个倾向评分匹配的患者亚组，以进行靶向尿代谢组学研究，以描述COVID-19的特征性特征。
COVID-19患者的uACE2升高，而发生AKI的患者uACE2进一步升高。在根据年龄、性别和既往合并症调整uACE2水平后，uACE2升高与发生AKI的风险高3倍以上独立相关[比值比3.05（95%置信区间1.23‒7.58），P = 0.017]。uACE2升高对应于肾切片中ACE2的肾小管丢失，并与uTNF-RI和uTNF-RII密切相关。尿定量代谢组分析显示，COVID-19患者必需氨基酸的排泄增加，包括亮氨酸、异亮氨酸、色氨酸和苯丙氨酸。此外，尿氨基酸与uACE2之间存在强相关性。
uACE2升高与COVID-19患者的AKI相关。SARS-CoV-2感染期间肾小管ACE2的丢失表明氨基酸尿与近端肾小管损伤之间存在潜在联系。
