Paranjpe Ishan, Jayaraman Pushkala, Su Chen-Yang, Zhou Sirui, Chen Steven, Thompson Ryan, Del Valle Diane Marie, Kenigsberg Ephraim, Zhao Shan, Jaladanki Suraj, Chaudhary Kumardeep, Ascolillo Steven, Vaid Akhil, Kumar Arvind, Kozlova Edgar, Paranjpe Manish, O'Hagan Ross, Kamat Samir, Gulamali Faris F, Kauffman Justin, Xie Hui, Harris Joceyln, Patel Manishkumar, Argueta Kimberly, Batchelor Craig, Nie Kai, Dellepiane Sergio, Scott Leisha, Levin Matthew A, He John Cijiang, Suarez-Farinas Mayte, Coca Steven G, Chan Lili, Azeloglu Evren U, Schadt Eric, Beckmann Noam, Gnjatic Sacha, Merad Miram, Kim-Schulze Seunghee, Richards Brent, Glicksberg Benjamin S, Charney Alexander W, Nadkarni Girish N
The Mount Sinai Clinical Intelligence Center (MSCIC), Icahn School of Medicine at Mount Sinai, New York, NY, USA.
The Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
medRxiv. 2022 Aug 29:2021.12.09.21267548. doi: 10.1101/2021.12.09.21267548.
Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Using measurements of ∼4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N= 437), we identified 413 higher plasma abundances of protein targets and 40 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p <0.05). Of these, 62 proteins were validated in an external cohort (p <0.05, N =261). We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p <0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury. Using clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.
急性肾损伤（AKI）是2019冠状病毒病（COVID-19）的一种已知并发症，与住院死亡率增加相关。使用生物样本进行的无偏蛋白质组学研究可改善风险分层并发现病理生理机制。通过测量两组COVID-19住院患者的约4000种血浆蛋白，我们发现并验证了COVID-19相关急性肾损伤（2期或3期）和长期肾功能障碍的标志物。在发现队列（N = 437）中，我们鉴定出413种与COVID-19相关急性肾损伤相关的血浆蛋白靶标丰度升高以及40种血浆蛋白靶标丰度降低（校正p<0.05）。其中，62种蛋白质在外部队列中得到验证（p<0.05，N = 261）。我们证明，COVID-19相关急性肾损伤与肾小管损伤（中性粒细胞明胶酶相关脂质运载蛋白）和心肌损伤的标志物增加有关。使用出院后测得的估计肾小球滤过率（eGFR），我们还发现62种与急性肾损伤相关的蛋白质中有25种与出院后eGFR降低显著相关（校正p<0.05）。与出院后eGFR降低最密切相关的蛋白质包括桥粒芯胶蛋白-2、三叶因子3、跨膜EMP24结构域包含蛋白10和胱抑素-C，表明肾小管功能障碍和损伤。利用临床和蛋白质组学数据，我们的结果表明，虽然急性和长期COVID-19相关肾功能障碍均与肾小管功能障碍标志物有关，但急性肾损伤主要由涉及血流动力学不稳定和心肌损伤的多因素过程驱动。
