Jayaraman Pushkala, Rajagopal Madhumitha, Paranjpe Ishan, Liharska Lora, Suarez-Farinas Mayte, Thompson Ryan, Del Valle Diane Marie, Beckmann Noam, Oh Wonsuk, Gulamali Faris F, Kauffman Justin, Gonzalez-Kozlova Edgar, Dellepiane Sergio, Vasquez-Rios George, Vaid Akhil, Jiang Joy, Chen Annie, Sakhuja Ankit, Chen Steven, Kenigsberg Ephraim, He John Cijiang, Coca Steven G, Chan Lili, Schadt Eric, Merad Miram, Kim-Schulze Seunghee, Gnjatic Sacha, Tsalik Ephraim, Langley Raymond, Charney Alexander W, Nadkarni Girish N
medRxiv. 2023 Oct 27:2023.10.25.23297469. doi: 10.1101/2023.10.25.23297469.
Acute kidney injury (AKI) is common in hospitalized patients with SARS-CoV2 infection despite vaccination and leads to long-term kidney dysfunction. However, peripheral blood molecular signatures in AKI from COVID-19 and their association with long-term kidney dysfunction are yet unexplored.
In patients hospitalized with SARS-CoV2, we performed bulk RNA sequencing using peripheral blood mononuclear cells(PBMCs). We applied linear models accounting for technical and biological variability on RNA-Seq data accounting for false discovery rate (FDR) and compared functional enrichment and pathway results to a historical sepsis-AKI cohort. Finally, we evaluated the association of these signatures with long-term trends in kidney function.
Of 283 patients, 106 had AKI. After adjustment for sex, age, mechanical ventilation, and chronic kidney disease (CKD), we identified 2635 significant differential gene expressions at FDR<0.05. Top canonical pathways were signaling, oxidative phosphorylation, mTOR signaling, and Th17 signaling, indicating mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Comparison with sepsis associated AKI showed considerable overlap of key pathways (48.14%). Using follow-up estimated glomerular filtration rate (eGFR) measurements from 115 patients, we identified 164/2635 (6.2%) of the significantly differentiated genes associated with overall decrease in long-term kidney function. The strongest associations were 'autophagy', 'renal impairment via fibrosis', and 'cardiac structure and function'.
We show that AKI in SARS-CoV2 is a multifactorial process with mitochondrial dysfunction driven by ER stress whereas long-term kidney function decline is associated with cardiac structure and function and immune dysregulation. Functional overlap with sepsis-AKI also highlights common signatures, indicating generalizability in therapeutic approaches.
Peripheral transcriptomic findings in acute and long-term kidney dysfunction after hospitalization for SARS-CoV2 infection are unclear. We evaluated peripheral blood molecular signatures in AKI from COVID-19 (COVID-AKI) and their association with long-term kidney dysfunction using the largest hospitalized cohort with transcriptomic data. Analysis of 283 hospitalized patients of whom 37% had AKI, highlighted the contribution of mitochondrial dysfunction driven by endoplasmic reticulum stress in the acute stages. Subsequently, long-term kidney function decline exhibits significant associations with markers of cardiac structure and function and immune mediated dysregulation. There were similar biomolecular signatures in other inflammatory states, such as sepsis. This enhances the potential for repurposing and generalizability in therapeutic approaches.
尽管接种了疫苗，但急性肾损伤（AKI）在感染SARS-CoV2的住院患者中仍很常见，并会导致长期肾功能障碍。然而，新冠病毒感染所致急性肾损伤的外周血分子特征及其与长期肾功能障碍的关联尚未得到探索。
在感染SARS-CoV2的住院患者中，我们使用外周血单个核细胞（PBMC）进行了批量RNA测序。我们对RNA测序数据应用了考虑技术和生物学变异性的线性模型，并计算了错误发现率（FDR），然后将功能富集和通路结果与一个历史脓毒症相关性急性肾损伤队列进行比较。最后，我们评估了这些特征与肾功能长期趋势的关联。
在283例患者中，106例发生了急性肾损伤。在对性别、年龄、机械通气和慢性肾脏病（CKD）进行校正后，我们在FDR<0.05时鉴定出2635个显著差异基因表达。排名靠前的典型通路包括信号传导、氧化磷酸化、mTOR信号传导和Th17信号传导，表明存在线粒体功能障碍和内质网（ER）应激。与脓毒症相关性急性肾损伤的比较显示关键通路有相当大的重叠（48.14%）。利用115例患者的随访估算肾小球滤过率（eGFR）测量值，我们鉴定出164/2635（6.2%）个与长期肾功能总体下降相关的显著差异基因。最强的关联是“自噬”、“通过纤维化导致的肾功能损害”以及“心脏结构和功能”。
我们表明，SARS-CoV2感染所致急性肾损伤是一个多因素过程，由内质网应激驱动线粒体功能障碍，而长期肾功能下降与心脏结构和功能以及免疫失调有关。与脓毒症相关性急性肾损伤的功能重叠也突出了共同特征，表明治疗方法具有通用性。
SARS-CoV2感染住院后急性和长期肾功能障碍的外周转录组学研究结果尚不清楚。我们使用拥有转录组数据的最大住院患者队列，评估了新冠病毒感染所致急性肾损伤（COVID-AKI）的外周血分子特征及其与长期肾功能障碍的关联。对283例住院患者（其中37%发生急性肾损伤）的分析突出了内质网应激在急性期驱动线粒体功能障碍的作用。随后，长期肾功能下降与心脏结构和功能标志物以及免疫介导的失调显著相关。在其他炎症状态如脓毒症中也有类似的生物分子特征。这增强了治疗方法重新利用和通用化的潜力。
